Brainstem Disorders
Peter P. Urban • Louis R. Caplan (Editors)
Brainstem Disorders
Editors Peter P. Urban Abteilung für Neurologie Asklepios Klinik Barmbek Rübenkamp 220 22291 Hamburg Germany
[email protected]
Louis R. Caplan Beth Israel Deaconess Medical Center 330 Brookline Ave Boston, MA 02215 USA
[email protected]
ISBN 978-3-642-04202-7 e-ISBN 978-3-642-04203-4 DOI 10.1007/978-3-642-04203-4 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011921399 Authorized translation of the 1st German language edition: Urban, Peter P. Erkrankungen des Hirnstamms, © 2009 by Schattauer GmbH, Stuttgart/Germany © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
Preface
Brainstem disorders may result in a broad spectrum of clinical signs and symptoms ranging from isolated signs, including vertigo, gait unsteadiness, and double vision, to complex clinical syndromes and life-threatening situations, such as basilar artery thrombosis. The complex topography of the brainstem represents a challenge even for experienced neurologists in localizing brainstem lesions and diagnosing brainstem disorders. Modern magnetic resonance imaging and electrophysiological techniques have significantly improved understanding of brainstem function. However, the clinical examination continues to be the cornerstone of topodiagnosis, and careful matching of clinical and technical findings is a prerequisite for the correct diagnosis. This comprehensive clinical handbook presents a review of all brainstem disorders and provides the relevant clinical knowledge required for the diagnosis. In addition to a detailed outline of the basic brainstem neuroanatomy the work discusses the state-of-the-art diagnostic imaging procedures for brainstem lesions. The topodiagnostic analysis of neurological findings is explained in detail and brainstem disorders are illustrated by a large number of magnetic resonance images and brief reports. Twenty-five contributors and two editors participated in the writing of this text. One of the most appealing features of this book is the vast experience of our authors evidenced by the many important contributions they made to the understanding of brainstem function in recent years. The editors want to thank and acknowledge all those who participated in the development of this text. We are profoundly aware of their genuine personal commitment and extensive time devoted to writing these chapters. It is our hope that this publication will be useful in clinical practice and enrich knowledge of brainstem disorders. Hamburg, Germany Boston, MA, USA
Peter P. Urban Louis R. Caplan
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Contents
1 Neuroanatomy of the Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anja K.E. Horn-Bochtler and Jean A. Büttner-Ennever
1
1.1 General Architecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.3 External Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
1.4 Internal Architecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
1.5 Pathways in the Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
1.6 Brain Stem Vascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
2 Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
2.1 Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peter Stoeter and Stephan Boor
38
2.2 Ultrasound diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Martin Eicke and Uwe Walter
54
2.3 Electrophysiologic diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jürgen Marx, Frank Thömke, Peter P. Urban, Sandra Bense, and Marianne Dieterich
61
Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
3 Diagnostic Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3.1 Disorders of ocular motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Frank Thömke
3.2 Horner’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Jürgen Marx
3.3 Central vestibular disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Marianne Dieterich and Sandra Bense
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3.4 Tinnitus and auditory disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Marianne Dieterich and Sandra Bense
3.5 Intra-axial Cranial Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 Frank Thömke and Peter P. Urban
3.6 Speech disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Peter P. Urban
3.7 Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Peter P. Urban
3.8 Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Peter P. Urban
3.9 Pareses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Peter P. Urban and Jürgen Marx
3.10 Sensory disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Peter P. Urban
3.11 Bladder disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Peter P. Urban
3.12 Drop attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Peter P. Urban
3.13 Respiratory disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Peter P. Urban
3.14 Disturbances of consciousness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Frank Thömke
3.15 Brain death diagnosis in primary brainstem injury . . . . . . . . . . . . . . . . 168 Frank Thömke
3.16 Clinical brainstem reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Peter P. Urban
3.17 Rare findings/symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Peter P. Urban Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
4 Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
4.1 Vascular brainstem diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Jürgen Marx, Peter P. Urban, Frank Thömke, Wibke Müller-Forell, Sandra Bense, and Marianne Dieterich
4.2 Inflammatory brainstem diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Uta Meyding-Lamadé and André Grabowski
4.3 Brainstem involvement in demyelinating diseases . . . . . . . . . . . . . . . . . . . 243 Oliver Kastrup
4.4 Paraneoplastic brainstem syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Heidrun Golla and Raymond Voltz
Contents
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4.5 Brainstem tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 Thomas Hundsberger and Dorothee Wiewrodt
4.6 Traumatic brainstem lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Raimund Firsching, Dieter-Heinrich Woischneck, and Stefan Schreiber
4.7 Degenerative Brainstem Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Andres Ceballos-Baumann
4.8 Abnormalities of brainstem development . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Wolfgang Wagner
4.9 Metabolic brainstem diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Joachim Wolf and Armin Grau
4.10 Vascular cranial nerve and brainstem compressions . . . . . . . . . . . . . . . 326 Frank Thömke and Peter P. Urban
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Contributors
PD Dr. Sandra Bense Neurologische Klinik, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany
[email protected] Dr. Stephan Boor Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Jean A. Büttner-Ennever Anatomische Anstalt, Lehrstuhl III, LMU München, Pettenkoferstrr. 11, 80336 München, Germany
[email protected] Prof. Dr. Andres Ceballos-Baumann Neurologisches Krankenhaus München, Tristanstr. 20, 80804 München, Germany
[email protected] Prof. Dr. Marianne Dieterich Neurologische Klinik, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany
[email protected] PD Dr. Martin Eicke Neurologische Abteilung, Klinikum Idar-Oberstein GmbH, Dr.-Ottmar-Kohler-Str. 2, 55743 Idar-Oberstein, Germany
[email protected] Prof. Dr. Raimund Firsching Klinik für Neurochirurgie, Universitätskliniken Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
[email protected] Dr. Heidrun Golla Klinik und Poliklinik für Palliativmedizin, Klinikum der Universität zu Köln, Kerpener Str. 62, 50924 Köln, Germany
[email protected] Dr. André Grabowski Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
[email protected] Prof. Dr. Armin Grau Neurologische Klinik, Städtisches Klinikum, Bremserstr. 79, 67073 Ludwigshafen, Germany
[email protected] PD Dr. Anja K.E. Horn-Bochtler Anatomische Anstalt, Lehrstuhl III, LMU München, Pettenkoferstr. 11, 80336 München, Germany
[email protected]
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Dr. Thomas Hundsberger Klinik für Neurologie, Kantonsspital St. Gallen, Rorschacher Str. 95, 9007 St. Gallen, Switzerland
[email protected] Dr. Oliver Kastrup Neurologische Klinik, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany
[email protected] PD Dr. Jürgen Marx Praxis für Neurologie, Holzhofstr. 5, 55116 Mainz, Germany
[email protected] Prof. Dr. Uta Meyding-Lamadé Neurologische Klinik, Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
[email protected] Prof. Dr. Wibke Müller-Forell Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Dr. Stefan Schreiber Klinik für Neurochirurgie, Universitätskliniken Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
[email protected] Prof. Dr. Peter Stoeter Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Frank Thömke Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Peter P. Urban Abteilung für Neurologie, Asklepios Klinik Barmbek, Rübenkamp 220, 22291 Hamburg, Germany
[email protected] Prof. Dr. Raymond Voltz Klinik und Poliklinik für Palliativmedizin, Klinikum der Universität zu Köln, Kerpener Str. 62, 50924 Köln, Germany
[email protected] Prof. Dr. Wolfgang Wagner Klinik und Poliklinik für Neurochirurgie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Uwe Walter Neurologische Universitätsklinik Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
[email protected] PD Dr. Dorothee Wiewrodt Neurochirurgie der Universitätsklinik Münster (UKM), Albert-Schweitzer-Str. 33, 49149 Münster, Germany
[email protected] Dr. Dieter-Heinrich Woischneck Klinik für Neurochirurgie, Universitätsklinikum Ulm, Steinhövelstr. 9, 89075 Ulm, Germany
[email protected] Dr. Joachim Wolf Neurologische Klinik, Städtisches Klinikum, Bremserstr. 79, 67073 Ludwigshafen, Germany
[email protected]
Contributors
1
Neuroanatomy of the Brainstem Anja K.E. Horn-Bochtler and Jean A. Büttner-Ennever
Contents 1.1 General Architecture . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.3 External Characteristics . . . . . . . . . . . . . . . . . . . . . . 1.3.1 Mesencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.2 Pons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.3 Medulla Oblongata . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.4 Retinal Inputs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.5 Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 3 4 4 4 4
1.4 Internal Architecture . . . . . . . . . . . . . . . . . . . . . . . . . 8 1.4.1 Cranial Nerve Nuclei of the Brainstem . . . . . . . . . . . . 8 1.4.1.1 Oculomotor Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Edinger-Westphal Nucleus . . . . . . . . . . . . . . . . . . . . . 9 Light Reaction and Near Response . . . . . . . . . . . . . . . 9 1.4.1.2 Trochlear Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1.4.1.3 Abducens Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1.4.1.4 Trigeminal Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Trigeminal Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.4.1.5 The Facial Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Facial Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.4.1.6 Vestibular Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.4.1.7 Cochlear Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1.4.1.8 Nuclear Groups of the Vagal System . . . . . . . . . . . . . . 14 Glossopharyngeal Nerve . . . . . . . . . . . . . . . . . . . . . . . 14 Solitary (Tract) Nucleus . . . . . . . . . . . . . . . . . . . . . . . 15 Vagus Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Dorsal Motor Vagal Nucleus (Dorsal Nucleus of the Vagal Nerve) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Nucleus Ambiguus . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 1.4.1.9 Nuclear Groups of the Accessory Nerve . . . . . . . . . . . 16 1.4.1.10 Nucleus Hypoglossus . . . . . . . . . . . . . . . . . . . . . . . . . 16 1.4.2 Reticular Formation: A Coordination Center for Complex Movement . . . . . . . . . . . . . . . . . . . . . . . . 16 1.4.3 Ascending Activating System: Attention, Wake–Sleep Rhythm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 1.4.4 Limbic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.4.5 Premotor Control of Eye Movements . . . . . . . . . . . . . 18 1.4.5.1 Saccades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.4.5.2 Vestibulo-ocular Reflex . . . . . . . . . . . . . . . . . . . . . . . . 19 1.4.5.3 Optokinetic Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 1.4.5.4 Smooth Pursuit Eye Movements . . . . . . . . . . . . . . . . . 20 1.4.5.5 Convergence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.4.5.6 Gaze Stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.4.6 Parasympathetic and Sympathetic Pathways . . . . . . . . 21 1.4.7 Nuclear Regions of the Mesencephalon . . . . . . . . . . . 23 1.4.7.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 1.4.7.2 Pretectum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.4.7.3 Superior and Inferior Colliculi . . . . . . . . . . . . . . . . . . 1.4.7.4 Red Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.7.5 Substantia Nigra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.7.6 Periaqueductal Gray . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8 Nuclear Regions of the Pons . . . . . . . . . . . . . . . . . . . . 1.4.8.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8.2 Pontine Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8.3 Parabrachial Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8.4 Pontine Micturition Center . . . . . . . . . . . . . . . . . . . . . 1.4.9 Nuclear Regions of the Medulla Oblongata . . . . . . . . 1.4.9.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.9.2 Inferior Olive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.9.3 Ventrolateral Cell Groups of the Medulla . . . . . . . . . . Cardiovascular Reflexes . . . . . . . . . . . . . . . . . . . . . . . Respiratory Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . Swallowing, Vomiting, and Sneeze Reflexes . . . . . . . . 1.4.9.4 Area Postrema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24 25 25 27 27 27 27 28 28 28 28 29 29 29 29 29 30
1.5 Pathways in the Brainstem . . . . . . . . . . . . . . . . . . . . 1.5.1 Descending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2 Ascending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.1 Lemniscal Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.2 Spinothalamic Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.3 Spinocerebellar Tracts . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.4 Auditory Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30 30 31 31 31 31 32
1.6 Brain Stem Vascularization . . . . . . . . . . . . . . . . . . . 1.6.1 Mesencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.2 Pons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.3 Medulla Oblongata . . . . . . . . . . . . . . . . . . . . . . . . . . .
32 32 34 34
Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
1.1 General Architecture The brainstem (truncus cerebri) comprises the medulla oblongata, the pons and the mesencephalon (midbrain) (Fig. 1.1). The brain develops from the neural tube and can be traced back to the primary blueprint in all its components. The brainstem contains. the fourth ventricle in the region of the medulla oblongata and the pons, as well as the aqueduct in the midbrain. These represent the cerebrospinal fluid reservoirs within the brainstem. A simplified description of the basic architecture of the brainstem divided into four longitudinal sections is presented in Fig. 1.1b, c (from dorsal to ventral).
P.P. Urban and L.R. Caplan (eds.), Brainstem Disorders, DOI: 10.1007/978-3-642-04203-4_1, © Springer-Verlag Berlin Heidelberg 2011
1
2 Fig. 1.1 Diagrammatic representation of the lateral aspect of the brain, showing all six parts including the intracerebral fluid containing spaces. The brain stem shown here includes the mesencephalon and the rhombencephalon (a). Depiction of the longitudinal zones (b) extending throughout the entire brainstem at varying degrees of expression (c)
1 Neuroanatomy of the Brainstem
a
Telencephalon
DiMesencephalon encephalon
Rhombencephalon
Pons
b
Medulla oblongata
Liquor spaces
Spinal cord
Brainstem Roof/roof plate lCSF spaces Tegmentum Floor
c Superior colliculus
Inferior colliculus Plexus choroideus Roof/roof plate
Aqueduct Liquor spaces Tegmentum
Cerebral peduncle
Pyramids
Base of pons Mesencephalon
1. Roof plate: A thick quadrigeminal plate (superior and inferior colliculus; tectum) in the mesencephalon, a thin velum (superior medullary velum) in the pons, and a singlelayer lamina (inferior medullary velum) with the choroid plexus in the medulla oblongata 2. Cerebrospinal fluid spaces: Fourth ventricle and mesencephalic aqueduct 3. Mesencephalic tegmentum: Contains all brainstem nuclei, including the reticular formation 4. Floor: Fibrous layer consisting of the cerebral peduncles, the base of the pons, and the pyramids The assignment of lesions to one of these four components can be readily achieved based on MRI-images, whereby the majority of clinical symptoms – with the exception of paralyses – can be attributed to injuries to the brain nuclei and to nerve tracts in the tegmentum.
Pons
Medulla oblongata
1.2 Development The neuroectoderm is induced in the epiblast by the mesodermal notochord and its head. The neuroectoderm forms the neural tube, neural crest, and placodes (congregation of specialized cells of ectodermal origin in the head region). The central nervous system develops from the neural tube, while the neural crest and the placodes give rise to the peripheral nervous system and parts of the large sense organs among other structures. The neural crest is divided into a cranial and a trunk part. While the cranial neural crest contributes to the development of the sensory and the parasympathetic nerve ganglia, it also forms the mesenchymal basis for the development of non-neuronal tissues, including the cranial bones (primarily skeletal bones of the face), cartilage, dentine, and the smooth musculature of vessels.
1.3 External Characteristics
3
1.3 External Characteristics
The complex morphogenic cell migrations during brain development are controlled by cell-intrinsic control genes and extrinsic signals (signal molecules) that mutually influence one another. Control genes, e.g. genes of the Hox family, transcription factors, e.g. Krox-20, and signal molecules like the Sonic Hedgehog (Shh) have a crucial role in brain stem and spinal cord development (Hofmann 2004). Around the 6th week of embryonic development eight transversal swellings, the rhombomeres (Fig. 1.2) become transiently visible at the floor of the fourth ventricle. This lends a segmented structure (rhombomere) to the brainstem, that is reflected in the organization of the cranial nerves and their nuclei. Each rhombomere is characterized by a specific gene expression pattern of the control gene, as well as by morphogenetic molecular factors. The absence of a control gene can lead to the loss of an entire rhombomere or prevent its merging with another rhombomere. The resulting damages would not only have an effect on the structures of the respective brain segments, but also on the tissue developing from the neural crest cells and placodes of the affected rhombomere (e.g. sensory cranial nerves and parasympathetic head ganglia, as well as parts of the cranial skeleton) (Kiernan et al. 2002).
1.3.1 Mesencephalon The dorsal surface of the mesencephalon is characterized by the quadrigeminal plate (Figs. 1.1c and 1.3b), which consists of the superior colliculi with visuomotor functions and the inferior colliculi as part of the auditory pathway (p. 32). The trochlear nerve (N. IV) exits the dorsal surface of the brain stem from behind the inferior colliculus. The dorsal view of the mesencephalon shows the broad exit pathway of the inferior colliculus, the brachium of the inferior colliculus, and its rostrolateral course towards the medial geniculate body. The posterior commissure forms the rostral border between the mesencephalon and the diencephalon and marks the opening of the mesencephalic aqueduct in the third ventricle. Located immediately dorsally to this is the epiphysis, or pineal body, a diencephalic structure with an important role in the regulation of circadian rhythms. The robust cerebral crura constitute the key feature of the basal aspect of the mesencephalon. They comprise fiber bundles of axons that descend from the cerebral cortex to
Pharyngeal arch 1–4
Cranial nerves III-XII Mesencephalon III IV Rhombencephalon R1
1 Trigeminal placodes Krox-20
Fig. 1.2 Diagram depicting the development of the brain stem and cranial nerves. Somatoefferent and visceroefferent neurons originate from the floor plate of the rhombomeres (R1-8) and the mesencephalon. They send their axons to the respective cranial nerves. Correspondingly, the peripheral and central axons are formed from ganglia of the somatoafferent and visceroafferent neurons. The vertical bars illustrate the expression of morphogenetic factors (Hox gene, transcription factor Krox-20, Kreisler) and demonstrate that each rhombomere is characterized by a specific gene expression pattern. (Modified from Neuhuber 2004)
Geniculate ganglion Ear placodes
V
R2
Hox b-1 2
R3 VII
R4
VIII R5 VI
Inferior ganglion N.IX Inferior ganglion N.X
3
Kreisler
R6
IX
R7
4
X, XI
R8
XII
Hox a,b,d-4
Hox a-2
Hox a,b,d-3
Hox b-2
4
the pons, where the majority of the axons terminate in the pontine nuclei. The cerebral crus with the adjacent tegmentum is also referred to as the cerebral peduncle. At the midline between the cerebral crura lies the interpeduncular fossa, from where the oculomotor nerves (N. III) emerge. On removal of the leptomeninx, the small arteries (interpeduncular perforating arteries) are avulsed and leave small holes in the brain substance, which lead this area to be described as the posterior perforated substance. The basis of the mesencephalon is bounded rostrally by the mammillary bodies.
1.3.2 Pons The ventral surface of the pons (“bridge”) is formed by a broad band of horizontally arranged fibers that run laterally by way of the medial cerebellar peduncle to the cerebellum (Fig. 1.3b). The corticopontine fibers from the ipsilateral cerebral peduncle synapse with a second neuron in the pons and form the large rounded eminence of the pontine nuclei. All efferents from the pontine nuclei form pontocerebellar fibers and decussate contralaterally. The chief cranial nerve, the trigeminal nerve (N. V), emerges laterally from the brainstem through the pontine fibers. On its dorsal surface the pons forms the floor of the fourth ventricle and the floor of the rhomboid fossa caudally. Two lateral recesses are viewed in the fourth ventricle at the level of the caudal pons. Through an aperture at the extremity of each lateral recess, the foramina of Luschka, cerebrospinal fluid from the fourth ventricle can drain into the subarachnoid space.
1.3.3 Medulla Oblongata The transition from the medulla to the spinal cord is located at approximately the level of the foramen magnum, superior to the ventral roots of the first cervical segment. The junction of the medulla and the spinal cord is formed ventrally by the decussation of the pyramids and dorsally by the tubercle of gracile, cuneate, and trigeminal (or cinereum) nuclei (Fig. 1.3). In the dorsal view the obex forms the caudal border of the medulla, the site at which the fourth ventricle continues the central canal. At this location an unpaired median aperture (the foramen of Magendie) is viewed in the inferior medullary velum, which connects the fourth ventricle with the subarachnoid space. The most prominent external landmark is the inferior olive, which forms a 14 mm long and 7 mm wide bulge on the ventral side of the medulla (Fig. 1.3a, b). The roots of the hypoglossal nerve (N. XII) leave the brainstem between the pyramids and the inferior olive; the roots of the glossopharyngeal (N. IX), the vagus (N. X) and
1 Neuroanatomy of the Brainstem
the accessory (N. XI) nerves emerge lateral to the inferior olive. More rostrally, at the junction of the medulla and the pons, the facial nerve emerges together with the intermediate nerve (N. VII), and the vestibulocochlear nerve (N. VIII) exits the brainstem at the cerebellopontine angle more laterally. The abducens nerve (N. VI) emerges from the brainstem at the upper border of the pyramid and the lower margin of the pons (Fig. 1.3).
1.3.4 Retinal Inputs Proceeding from the optic chiasm, the optic tract runs across the ventral surface of the cerebral peduncle and travels to the lateral geniculate nucleus in the diencephalon, the main projection area (Fig. 1.3b). Medially and parallel to the optic tract an additional small bundle of fibers exiting the retina follows a similar route across the cerebral peduncle. While they were originally described by Bernhard von Gudden (1881) as the transverse peduncular tract, today they are referred to as the inferior and superior fascicles of the accessory optic tract. Both the fibers of the optic tract and the accessory optic tract exit the retina, decussate in the optic chiasm and proceed as self-contained bundles to a number of small nuclei, the accessory optic nuclei in the mesencephalon: the dorsal terminal nucleus, the lateral terminal nucleus, the interstitial terminal nucleus and the various components of the medial terminal nucleus. The accessory optic system constitutes a phylogenetically old system and plays – together with the proximally located pretectal nucleus of the optic tract – an important role in evoking optokinetic reflexes (Büttner and Büttner-Ennever 2006; Gamlin 2006; Giolli et al. 2006). The accessory optic nuclei are located on the surface of the mesencephalon and are therefore vulnerable to potential external injury. Thus far no clinical picture has, however, been associated with damage to these structures.
1.3.5 Cranial Nerves Comparable to the spinal nerves with sensory dorsal and motor ventral roots connecting the spinal cord to the periphery, the brainstem is similarly connected to the periphery of the head by “cerebral,” or alternatively named, “cranial,” nerves. These serve to transmit information between the highly specialized head region (e.g. tongue, ears, eyes, facial muscles) and the brain. Among the 12 cranial nerves the first two, the olfactory and the optic nerve, do not constitute peripheral nerves in the true sense of the word, but form protuberances in the anterior portion of the brain that are ensheathed by the meninges and contain cells found exclusively in the CNS.
1.3 External Characteristics
5
a
b Geniculate body Pineal body – medial – lateral Pretectum
Cerebral crus
Roof of the third ventricle Colliculus – superior – inferior
N. III N. IV N. V
Mesencephalon
N. IV Superior medullary velum
Pons N. VI N. VII N. VIII N. IX
Pyramid N. XII
N. X
Inferior olive
Tubercle of cuneate Medulla nuclei Roots oblongata Tubercle of – cranial gracile accessory nerves nuclei – spinal Spinal accessory nerves cord N. XI
C1 ventral root Decussation of the pyramids
Cerebellar peduncle – medial – superior – inferior
Pons
Medullary striae Obex Median sulcus Trigeminal tubercle
c Superior colliculi Inferior colliculi
Cerebral crus
N. IV N. V N. VIII N. VII N. VI
N. IX N. XII
N. X
N. XI
C1 C2
Fig. 1.3 Brainstem and cranial nerves viewed from ventral (a), dorsal (b), and lateral (c)
The true cranial nerves may contain both efferent and afferent fibers of all modalities (Table 1.1). The pseudounipolar or bipolar nerve cell bodies of the sensory afferents are found outside the central nervous system within compact ganglia. In some instances they may, however, also be dispersed as cell groups within the nerve fascicle. The ganglia are components of the peripheral nervous system and constitute, with a view to embryonic development, a derivative of the neural crest (in contrast to the central nervous system which is a neural tube derivative). The peripheral
nervous system thus contains nerve and glial cells different from those of the central nervous system, and may therefore represent an entry zone for specific diseases (e.g. neuropathies) which are different from those of the central nervous system. In the region of the point of passage through the pia mater into the brainstem, the cranial nerves are characterized by a transition zone (up to 8 mm wide), the Obersteiner–Redlich line, where the peripheral Schwann cell myelination is replaced by central oligodendrocyte myelination (Carlstedt et al. 2004). Here the displacement
SVE SA SE SA? SVE VE SVA SSA SVE
Superior orbital fissure Round foramen Oval foramen Superior orbital fissure Internal acoustic meatus
Vestibulocochlear nerve (VIII) Internal acoustic meatus Jugular foramen Glossopharyngeal nerve (IX) Third pharyngeal arch nerve
Medulla oblongata
Abducens nerve (VI) Facial nerve (VII) (Intermediate nerve) Second pharyngeal arch nerve
Trigeminal nerve (V) First pharyngeal arch nerve - Ophthalmic branch (V1) - Maxillary branch (V2) - Mandibular branch (V3)
Pons
SA? SE
Superior orbital fissure
VE SA SVA VA
Cochlear nuclei Nucleus ambiguus Inferior salivary nucleus Spinal trigeminal nerve nucleus Solitary tract nucleus Solitary tract nucleus (caudal part)
Vestibular nuclei
Mesencephalic nucleus of trigeminal n. Chief sensory nucleus of trigeminal n. Spinal nucleus of trigeminal nerve Abducens nerve nucleus Facial nerve nucleus Superior salivary nucleus Solitary tract nucleus
Vestibular ganglion (Scarpa) Spiral ganglion Otic ganglion Superior ganglion Inferior (petrosal) ganglion
Geniculate ganglion
Pterygopalatine ganglion Submandibular ganglion
Trigeminal ganglion (Semilunar ganglion; Gasserion ganglion)
Motor nucleus of trigeminal nerve
Ciliary ganglion
Êdinger-Westphal nucleus Trochlear nerve nucleus
VE
Trochlear nerve (IV)
Sensitive and vegetative ganglia
Nucleus of the oculomotor nerve
Oculomotor nerve (III)
Mesencephalon
Optic canal
Area of nuclei of origin or termination
SE
Superior orbital fissure
Optic nerve (II)
Diencephalon
Lamina cribrosa, Ethmoidal orifice
Olfactory nerve (I) (olfactory filaments)
Quality
TelencePhalon
Point of passage in the cranium
Description
Brain segment
Tabl. 1.3 The Cranial Nerves
Sensory cells in semicircular canals, sacculus, utriculus Sensory cells in organ of Corti Pharyngeal constrictors (with N.X), stylopharyngeal muscle Parotid, buccal, labial gland Tongue (posterior 1/3; touch, temperature, pain) soft palate, pharynx, mucosa of the tympanic cavity Tongue (posterior 1/3; fibers of taste sensation) Chemoreceptors (Carotid glomus), pressoreceptors in the carotid sinus
Muscles of mastication (proprioceptive); facial skin, mucosa of the rhinopharyngeal space, tongue, anterior 2/3s, - mechanoreception) Lateral rectus muscle Proprioception? Muscles of facial expression, stylohyoid muscle, posterior belly of digastric muscle, stapedius muscle Lacrimal, nasal, palatine glands Submandibular, sublingual, anterior lingual glands Taste buds (anterior 2/3s of the tongue)
Muscles of mastication, floor of the mouth, tensor tympani muscle, tensor veli palatini muscle via V3
Superior, medial, inferior rectus muscles; inferior oblique muscle; levator palpebrae muscle Pupillary sphincter muscle, ciliary muscle Proprioception Superior oblique muscle
Retina
Olfactory mucosa
Area of distribution
6 1 Neuroanatomy of the Brainstem
Vagus nerve (X) Fourth pharyngeal arch nerve
Jugular foramen
Nucleus ambiguus Dorsal vagal nucleus Spinal trigeminal nerve nucleus
SVE VE SA
Pharyngeal muscles, soft palate (partially with N. IX), Laryngeal muscles Thoracic and abdominal organs to Cannon’s point Meninges (posterior cranial fossa, external auditory canal Taste buds on epiglottis
Prevertebral and intramural ganglia Superior ganglion (jugular) Solitary tract nucleus (rostral part) Inferior ganglion SVA (nodosal) Mucosa of pharynx and larynx, Solitary tract nucleus (caudal part) Inferior ganglion VA pressoreceptors in the aortic arch, chemoreceptors (aortic glomus), thoracic and abdominal organs Trapezius muscle, sternocleidomas Spinal nucleus of accessory nerve SE Jugular foramen Accessory nerve (XI) toid muscle Tongue muscles Nucleus of hypoglossal nerve SE Hypoglossal canal Hypoglossal nerve (XII) SA = somatic afferences, SE = somatic efferences, SSA = special somatic afferences, SVA = special visceral afferences, SVE = special visceral efferences, VA = visceral afferences, VE = visceral efferences
Medulla oblongata
1.3 External Characteristics 7
8
of a vascular loop can lead to the compression of a cranial nerve and thus be a cause of neuralgia (Fig. 1.17, p. 31) (Duus et al. 2003).
1.4 Internal Architecture
1 Neuroanatomy of the Brainstem
a posterior
Alar plate (sensory)
Sulcus limitans
Basal plate (motor)
1.4.1 Cranial Nerve Nuclei of the Brainstem Spinal nerves comprise four functionally different categories of nerve fibers: 1. Somatoefferent (SE) or somatomotor fibers which innervate the striated muscles 2. Visceroefferent (VE) or visceromotor fibers which supply the smooth muscles or glands 3. Visceroafferent (VA) or viscerosensory fibers and 4. Somatoafferent (SA) or somatosensory fibers The neurons of the SE-fibers are derivatives of the basal plate and form an anterior column ventrally in the spinal cord. SA-fibers from the periphery terminate posteriorly in the posterior horn, a derivative of the alar plate. Located between these are a general-visceroafferent and a generalvisceroefferent central column (Fig. 1.4). Three additional fiber components are found in the cranial nerves which innervate the sense organs and the striated pharyngeal arch musculature in the head and cervical region: 1. Special-somatoafferent (SSA-) fibers innervate the cochlea and the labyrinth via N. VIII. 2. Special-visceroafferent (SVA-) fibers of the taste buds course in nerves N. VII, N. IX and N. X. 3. Special-visceroefferent (SVE-) fibers innervate the striated muscles that derive from the pharyngeal arch mesoderm. These include motor fibers in N. V, which innervate the muscles of mastication as well as the tensor tympani, the tensor veli palatini, the mylohyoid and the anterior belly of the digastric muscles; motor fibers in N. VII for the pharyngeal levator muscles (the stylopharyngeus, palatopharyngeus, salpingopharyngeus muscles), as well as motor fibers in N. X (in part together with N. IX) to the pharynx constrictors, all inner larynx muscles, the cricothyroid muscle, the striated musculature of the upper twothirds of the esophagus and the muscles of the soft palate (excepting the tensor veli palatine muscle) (Neuhuber 2004). The organization of the functional nuclei of origin and termination of the cranial nerves in the brainstem follows in principle that of the spinal cord. As a result of the “bursting” of the cerebrospinal fluid containing spaces in the region of the medulla and the pons, the sensory (dorsal horn-) regions are shifted laterally, while the motor (anterior horn-) regions are moved to a near-midline location. The view of the dorsal
anterior
b
Sulcus limitans
Motor sensory
Vestibuloacoustic organ, SSA
Pharyngeal arch muscles SVE
Skin, SA Taste, blood pressure, SVA, VA
Viscera VE Brainstem
Muscles of myotomal origin, SE
Fig. 1.4 Schematic cross-section of the spinal cord and brain stem. In the early developmental stage of the spinal cord a sensory alar lamina (gray) can be differentiated from a motor basal lamina (red). (a). The “opened up” diagrammatic view of the brain (b) shows the sensory and motor cerebral nuclei. SSA special somatic afferents, SVA special visceral afferents, VA visceral afferents, SA somatic afferents, SVE special visceral efferences, VE visceral efferences, SE somatic efferences
brain stem showing the cranial nerve nuclei (Fig. 1.5) confirms that the described organization applies to the entire brainstem: the motor nuclei are located medially, sensory nuclei are found laterally, while the visceral nuclei are located between these. In the cross-section, the boundary between the afferent and efferent columns, both in the spinal cord and the brain stem, are marked by the sulcus limitans (Fig. 1.4). 1.4.1.1 Oculomotor Nucleus The oculomotor nerve nucleus is a compact paired nucleus situated in the tegmentum of the mesencephalon, inferior to the mesencephalic aqueduct and superior to the fibers of the medial longitudinal fascicle. It contains the motor neurons that supply the ipsilateral inferior rectus muscle, the inferior oblique muscle, the medial rectus muscle, and the contralateral superior rectus muscle. The motor neurons of the individual eye muscles are topographically arranged in the oculomotor nucleus. The central caudal nucleus is an unpaired nucleus located at the caudal end of the oculomotor nucleus and contains motor neurons of the levator palpebrae muscle which elevates the eyelid. The motor neurons of the levator palpebrae muscles of both sides are intermixed, while the premotor projections to the motor neurons most likely are present on separate sides, an assumption that is supported
1.4 Internal Architecture
9 Sensory nuclei
Motonuclei Edinger-Westphal nucleus
Mesencephalic trigeminal nucleus
III
Oculomotor nucleus
IV
Principal trigeminal nucleus
Trochlear nucleus
V
Motor trigeminal nucleus V
V
Abducens nucleus
Vestibular nuclei VIII
Cochlear nucleus
Facial nucleus VI
Superior and inferior salivary nucleus
VII N. VII
N. IX N. X
N. VII N. VI
XII IX X
N. VIII
N. XI V
Solitary nucleus Spinal trigeminal tract and nucleus XI
Nucleus ambiguus
N. IX N. X Cuneate nucleus Dorsal nucleus of the vagus nerve Gracile nucleus Hypoglossal nucleus Nucleus accessorius
Fig. 1.5 Dorsal view of cranial nerve nuclei. The sensory cranial nerves containing projections of sensitive fibers of cranial nerves are shown on the left side. Depicted on the right side are the somatomotor (dark red)
nuclei, motonuclei of the original pharyngeal arch musculature (pink), and the visceromotor or parasympathetic (red) nuclei
by the occurrence of unilateral supranuclear eye movement disorders. Three separate groups of motor neurons of the medial rectus muscle have been identified within the oculomotor nucleus and are referred to as the A-, B-, and C-group. The C-group contains motor neurons supplying multiple innervated muscle fibers of the medial rectus muscle. Two main categories of muscle fibers can be differentiated in the eye muscle:
Edinger-Westphal Nucleus
1. Twitch muscle fibers with a central endplate zone, similar to those in skeletal muscles, respond to activation with a twitch, according to the all-or-nothing principle and 2. Multiple innervated, or non-twitch muscle fibers that react with a gradual contraction to a stimulus The motor neurons of non-twitch muscle fibers are located in the periphery of the classic oculomotor nucleus (Fig. 1.6) and receive different premotor projections from the classic motoneurons within the oculomotor nucleus. It is assumed that the non-twitch motoneurons and non-twitch muscle fibers serve eye alignment during gaze fixation, while the larger twitch motoneurons within the nucleus together with the twitch muscle fibers promote the actual eye movement (phasic components) (Büttner-Ennever 2006b).
Today the Edinger-Westphal nucleus is usually described as the nucleus that contains the parasympathetic preganglionic cells, whose efferent axons in the oculomotor nerve travel to the ciliary ganglion in the orbits where they are relayed to postganglionic neurons, whose fibers innervate the pupillary sphincter in the anterior eye. The nucleus is located posterior to the oculomotor nucleus and is also known as the accessory oculomotor nucleus. More recent findings suggest that, in humans, parasympathetic preganglionic neurons are not located within the boundaries of the traditional EdingerWestphal nucleus, but dispersed dorsal to it (Olszewski and Baxter 1982; Horn et al., 2008).
Light Reaction and Near Response The pupils normally act as an aperture diaphragm and ensure sufficient depth of focus in near viewing. Luminance in the retina is also regulated by pupillary size, whereby adaptive circuits in the retina have a significantly greater influence on the retinal response than pupillary width. The light reflex, i.e. constriction of the pupil on exposure to light, is mediated via the following pathway: ganglionic cells of the retina, optic
10
1 Neuroanatomy of the Brainstem Oculomotor nerve (N. III)
Trochlear nerve (N. IV)
Abducens nerve (N. VI)
N. IV
Facial nucleus N. VII N. III
Nucleus ruber N. VI
Oculomotor nucleus
Abducens nucleus
Trochlear nucleus
C-Group
Salivary nucleus superior and inferior
N. VII
IV IR VI
IO III SR
MLF
MLF N. VI
MR
Fig. 1.6 Schematic representation of the eye muscle nuclei and nerves. The top row shows a schematic cross-sections of the brainstem to illustrate the location of the eye muscle nuclei (oculomotor, trochlear, abducens nuclei) in the tegmentum and the course of their nerves from the brain stem. See also the course of the facial nerve around the abducens nucleus (genu of facial nerve) and the neurons of origin of the superior and inferior salivary nucleus circling the facial nucleus.
The bottom row shows detailed schematic depictions of the eye muscle nuclei and illustrates the location of non-twitch motoneurons (black dots). The twitch motoneurons are located within the nuclei (red). The location of the individual motor neuron groups for each muscle is illustrated in the oculomotor nucleus. MLF medial longitudinal fasciculus, IO inferior oblique muscle, IR inferior rectus muscle, MR medial rectus muscle, SR superior rectus muscle
nerve and optic tract, pretectal region (see p. 24), (bilateral pretectal olivary nucleus), parasympathetic preganglionic cells of the Edinger-Westphal nucleus (bilaterally), synapse on postganglionic neurons in the ciliary ganglion whose fibres activate the pupillary sphincter muscle. The consensual light response of both pupils to ipsilateral illumination is ensured by the bilateral connections of retinal afferents to the pretectal area and its bilateral influence on the EdingerWestphal nucleus via the posterior commissure.
96–98%) motor neurons of the contralateral superior oblique muscle, whereas the motor neurons of the multiple innervated fibers are found immediately above (Fig. 1.6). The trochlear nerve is the only cranial nerve that exits from the dorsal aspect of the brainstem (Fig. 1.3b, c).
1.4.1.2 Trochlear Nucleus The trochlear nucleus forms a compact, somewhat rounded paired nucleus (divided into a rostral and a dorsal group, respectively) located just caudal to the oculomotor nucleus in the mesencephalic tegmentum. The neurons are partially embedded in the fibers of the medial longitudinal fasciculus. The trochlear nucleus contains almost exclusively (up to
1.4.1.3 Abducens Nucleus The abducens nucleus is located beneath the floor of the fourth ventricle inferior to the genu of the facial nerve (Fig. 1.6). It contains both the motor neurons that innervate the ipsilateral lateral rectus muscle and internuclear neurons (INT), whose axons cross at the level of the abducens nucleus, ascend in the contralateral medial longitudinal fasciculus, and end monosynaptically on motor neurons of the medial rectus muscle in the contralateral oculomotor nucleus (Fig. 1.12a, p. 20). Both groups of neurons receive the same premotor signals from the reticular formation for horizontal saccades, as well as
1.4 Internal Architecture
11
bilaterally from the vestibular nuclei for vestibuloocular reflexes, and so form the anatomical basis for conjugate horizontal eye movements (pp. 18–20). Although these two nerve groups are not separated from each other in the nucleus of the abducens nerve, internuclear neurons tend to be located more laterally and caudally. In contrast to cholinergic motor neurons, internuclear neurons use glutamate as a transmitter. In addition to motor neurons and internuclear neurons, a “rostral cap” of the abducens nucleus comprises neurons that project to the floccular region of the cerebellum; functionally these can be allocated to the so-called paramedian tract cell groups (PMT cells). These cells may have an important role in gaze stabilization (p. 20; Büttner-Ennever 2006).
and the mandibular nerve (jaw region V3) are important in the differentiation between peripheral and central trigeminal syndromes. The trigeminal nerve is a “mixed” nerve with primarily sensory and a smaller part of motor functions for the muscles of mastication and the tensor tympani muscle in the middle ear. As the spinal ganglia, the trigeminal ganglion contains pseudounipolar ganglion cells whose central projections transmit information, e.g. touch and pressure (thick axons) as well as pain and temperature (thin axons) to the sensory trigeminal nuclei (Figs. 1.5 and 1.7). The trigeminal nucleus is the largest of all cranial nerve nuclei and extends throughout the entire brainstem to the cervical region of the spinal cord. It is divided into three sensory and one motor part:
1.4.1.4 Trigeminal Nucleus
1. The mesencephalic trigeminal nucleus forms a slender cell column at the lateral border of the periaqueductal gray. It consists of pseudounipolar nerve cells (which are otherwise found only in spinal or cranial nerve ganglia), whose peripheral projections enter via the small motor root of the mandibular nerve and transmit proprioceptive signals from the muscles of mastication to the mesencephalic trigeminal nucleus. The central
The trigeminal nerve (N. V) is the principal somatosensory nerve for the head and serves as a sensor for pain, temperature, and strong touch as well as gentle touch and jaw proprioception. Knowledge of the distribution of the innervation patterns of the three trigeminal branches, the ophthalmic nerve (upper face, V1) maxillary nerve (middle face V2)
Mesencephalic trigeminal nucleus
Motor trigeminal nucleus
Trigeminal ganglion (Gasseri)
Principal trigeminal nucleus Ophthalmic nerve
Fig. 1.7 Depiction of the relationships between the trigeminal nerve and the trigeminal nuclear complex. The sensory nuclei (light gray) of the principal trigeminal nucleus and the spinal trigeminal spinal nucleus receive thick fibers for touch sensation and thin pain sensation fibers, respectively. Their pseudounipolar nerve cell bodies lie in the trigeminal ganglion. Descending, primarily thin fibers, form the spinal tract of the trigeminal nerve. The cell bodies of the proprioceptive afferents of the masseter muscle lie in the mesencephalic trigeminal nucleus (dark gray). They constitute the afferent limb of the masseter reflex; the motor fibers of the masseter muscle in the trigeminal nerve originating from the motor trigeminal nucleus (light red) form the efferent limb
Maxillary nerve Mandibular nerve
Spinal trigeminal tract Masseter reflex Spinal trigeminal nucleus
12
axons of the neurons of mesencephalic trigeminal nucleus terminate on the motor trigeminal nuclei in the pons and mediate the masseter reflex (Fig. 1.7). To elicit the masseter reflex, the chin of the patient is lightly tapped, which causes the masseter muscle to stretch, resulting in activation of the spindle afferents. Via direct synapses onto neurons of the motor trigeminal nucleus these then elicit a monosynaptic reflex, which can be observed on both sides. An abnormally pronounced masseter reflex serves as an indication of a central disturbance of muscle tone. 2. The Principal trigeminal nucleus lies in the pons rostral to the abducens nucleus and lateral to the motor trigeminal nucleus. It is the primary termination target for the thickly myelinated axons conveying touch and pressure (Fig. 1.7). In the older literature this nucleus is also described as the “relay nucleus of epicritic sensitivity.” The efferents decussate and ascend as the trigeminal lemniscus (Fig. 1.4a, b) dorsomedial to the medial lemniscus and so correspond to the tracts of the posterior white column in the spinal cord (Fig. 1.16b). 3. The spinal trigeminal nucleus and tract extend to the cervical spinal cord as a continuation of Lissauer’s tract and the substantia gelatinosa (Rexed layers I-III) of the dorsal horn. There the termination site of the afferents for pain and temperature in topographic order (mouth and nose are in a rostral location, concentric skin areas around mouth and nose are located more caudally). 4. The motor trigeminal nucleus is located in the lateral tegmentum of the pontine brainstem. It contains motor neurons of the mylohyoid muscle, the anterior belly of the digastric muscle, as well as the masseter, temporal, tensor veli palatini and tensor tympani muscles. A large number of thin axons of all three branches enter the caudal medulla where they form the “concentric-ring-topography” in the spinal trigeminal nucleus. The axons form the spinal trigeminal tract lateral to the nucleus region and represent a relay station of the “protopathic” pain system (Figs. 1.7 and 1.14). The ascending fibres of the spinal trigeminal nucleus cross in the medulla oblongata to the other side and join the spinothalamic tract to the contralateral ventroposterior thalamus (also termed the anterolateral tract). Based on the somatotopic organisation of the spinal trigeminal nucleus, caudal part, a small central lesion results in the selective loss of protopathic sensitivity (e.g. in the perioral region or the respective onion skin distribution of the side of the face). A lesion in the principal trigeminal nucleus leads to the selective loss of the epicritic sensitivity of the face, which would not occur in the presence of a peripheral lesion. The motor trigeminal nucleus and therefore the muscles of mastication and, the tensor tympani in the middle
1 Neuroanatomy of the Brainstem
ear receive bilateral central ipnuts via the corticonuclear tract, primarily from the contralateral side. Therefore a unilateral lesion of the supranuclear pathways does not result in a severe paralysis because of the presence of ipsilateral projections. The tensor tympani muscle modulates the mobility of the small bones in the middle ear to prevent sensory overload of the Corti organ as a result of loud noise. Supranuclear projections to the motor neurons of the tensor tympani provide protection from one’s own voice. Trigeminal Reflexes The sensory fibers of the trigeminal nerve are involved in several important reflex arcs: tactile stimulation of the cornea (ophthalmic nerve) activates neurons of the trigeminal nerve; these, in turn, have bilateral projections to the facial nucleus via intermediate neurons, whereby the blink reflex is elicited. For the sucking reflex, tactile stimulation of the lips (mandibular nerve) causes afferent signals to be transmitted to the principal trigeminal nucleus. The orbicularis oris muscle is activated via polysynaptic bilateral projections to the facial nucleus. Eliciting the sucking or nasal reflex the stimulation of trigeminal afferents results in the excitation of several muscle groups, and the reticular formation assumes an important role in coordinating activation of the different motor nuclei (pp. 16, 18 and 28). The masseter reflex has already been discussed above.
1.4.1.5 The Facial Nucleus The facial nucleus is located in the ventrolateral pontine tegmentum. Although the neurons are analogous to the motor anterior horn cells, they are developmentally derived from the second pharyngeal arch. During development the facial nerve is pushed dorsally by the abducens nucleus which grows in a posterior direction and loops around it, forming the internal genu of the facial nerve (Fig. 1.6). In its course from the anterolateral pons to the periphery, the facial nerve converges with fibers from the superior salivary nucleus as well as with fibers for taste sensation from the anterior third of the tongue (Fig. 1.5). In contrast to earlier assumptions, systematic investigation of the location of the salivary nuclei has not shown any differences between the distribution of the neurons of the superior and inferior salivary nucleus surrounding the facial nucleus (Blessing 2004). While the fibers of the intermediate and the facial nerve are intermingled in the pons, they leave the brainstem as two separate nerves – a thicker motor facial nerve and a thinner intermediate nerve, which contains visceroafferent and somatoafferent as well as visceroefferent fibers.
1.4 Internal Architecture
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The motor neurons of the facial nucleus innervate the facial mimetic muscles and are located in different subnuclei. The ventrolateral cell group supplies the perioral musculature, motor neurons in intermediate and dorsomedial locations innervate the orbicularis oculi and the forehead muscles. The stapedius muscle in the middle ear, the posterior belly of the digastric muscle and the stylohyoid muscle are innervated by cells outside the classic facial nucleus in the adjacent reticular formation. Corticonuclear (corticobulbar) connections for voluntary movement of facial muscles project bilaterally to facial motor neurons of the upper part of the face, but only contralaterally to those of the lower part of the face. These fibers cross in the caudal pons. Unilateral lesions of the corticonuclear pathway are associated with contralateral paresis of the facial muscles (sagging corners of the mouth), except the muscles of the forehead, which can be moved on both sides because of their bilateral innervation. The patient cannot produce a smile on the affected side on demand, whereas a spontaneous smile is possible. This phenomenon is accounted for by direct bilateral limbic influences on the facial nucleus. In contrast, the ipsilateral facial musculature is completely paralysed after a nuclear or peripheral injury (Holstege et al. 2004).
colliculus, whose efferents can also elicit a blink reflex via the facial motoneurons. Auditory projections via the cochlear nucleus activate the periolivary nucleus in the rostral pole of the superior olivary nucleus bilaterally and thereby also activating the motor neurons of the stapedius muscle, which increase the acoustic impedance of the auditory ossicles in the middle ear.
1.4.1.6 Vestibular Nuclei Primary afferents from the three semicircular canals and both otolith organs (utricle and saccule) are activated by angular or linear acceleration of the head, and effect compensatory movements of the eye, head, and cervical musculature via their connections in the brainstem (Fig. 1.8). Without these compensatory reflexes the visual perception of spontaneous movement would significantly be impaired. The primary afferents end in the vestibular nuclei as the first relay station (Figs. 1.5, 1.11 and 1.12). Four vestibular nuclei can be differentiated anatomically: • • • •
Facial Reflexes The facial nucleus is a component of different reflex arcs: corneal reflex, blink reflex and stapedius reflex. Sensory impulses from the conjunctiva reach the spinal trigeminal nucleus via the ophthalmic nerve, and are locally relayed via oligosynaptic and polysynaptic pathways of the reticular formation to motoneurons of the orbicularis oculi muscle in the facial nucleus. An intense light stimulus activates the superior
The superior vestibular nucleus (Bechterew) The lateral vestibular nucleus (Deiters) The medial vestibular nucleus (Schwalbe) The inferior vestibular nucleus (or descending vestibular nucleus)
At the border to the lateral vestibular nucleus a magnocellular part can be defined in the medial vestibular nucleus that represents a relay station for the vestibuloocular pathways (Fig. 1.12). The magnocellular part is also referred to as the ventral lateral vestibular nucleus and is differentiated from the dorsal part of the lateral vestibular nucleus which contains large “Deiters” cells projecting to the spinal cord. The inferior vestibular nucleus can cytoarchitectonically be Cerebral cortex Spatial orientation
Cerebellum Fine control of movements
Fig. 1.8 Block diagram showing the primary connections of the vestibular nuclei. The vestibular nuclei receive sensory input from the vestibular nerve and are connected to different regions of the brain where they are predominantly involved in the control of movements. PCI inferior cerebellar peduncle, MLF medial longitudinal fascicle, MVST medial vestibulospinal tract, LVST lateral vestibulospinal tract
Thalamus PCI
MLF
Ocular muscle nuclei Vestibuloocular reflexes
Vestibular nuclei Vestibular nerve Sensory input
MVST LVST
Spinal cord Control of body posture
Vegetative centers Cardiovascular, visceral and respiratory control
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differentiated from the other vestibular nuclei by their plaqueshaped pattern of the fiber bundles coursing through it. At the caudal end, superior to the inferior cerebellar peduncle (restiform body) lies the y-group, which forms a part of the bridge between the fourth ventricle and the lateral aspect of the brain stem. Upon entry of the vestibular nerve, each vestibular fiber divides as follows: one branch descends to the medial and the inferior vestibular nucleus, an ascending branch sends collaterals to the superior vestibular nucleus before continuing to the cerebellum, predominantly to the nodular lobe (lobule X) and the uvula (lobule IXd) (Voogd 2004). These pathways serve for fine control of movements (Fig. 1.8). Analogous to cerebellar nuclei, the vestibular nuclei receive direct projections from the Purkinje cell fibers of the cerebellar cortex. In this sense the vestibular nuclei may be regarded as externally located cerebellar nuclei. The lateral vestibular nucleus receives direct projections from the cerebellum but only very few from the periphery, predominantly from the saccule. Primary afferents from the saccule also terminate in the ventral part of the y-group, while those of the utricle terminate predominantly in the rostral part of the inferior vestibular nucleus and in the ventral aspect of the lateral vestibular nucleus. Descending pathways from these regions are important for compensatory body posture during head movements. Lesions in the vestibular system result in vestibular vertigo with nystagmus and disturbance of spatial orientation (Fig. 1.8). Acoustic neuromas do not arise – as the name suggests – from the acoustic, but from the vestibular nerves. The slow growing tumor can cause increased excitability of the vestibular system. Because this disturbance continues to be centrally compensated by the vestibular nuclei, the patient does usually not feel vertigo. The pathways of the vestibuloocular reflex are shown in Fig. 1.12a on page 20.
1 Neuroanatomy of the Brainstem
and whose axons cross in the medullary stria or in the reticular formation before projecting via the lateral lemniscus directly to the contralateral inferior colliculus (p. 31 and Fig. 1.16b, d).
1.4.1.8 Nuclear Groups of the Vagal System Due to various common functions of the glossopharyngeal, vagus, accessory (cranial part) and intermediate nerves and their nuclear regions, including the solitary tract nucleus, the ambiguus and trigeminal nuclei, the system is often described as the vagal system (Figs. 1.5, 1.9, 1.14, 1.15 and p. 29; Holstege 1991; Neuhuber 2004).
Glossopharyngeal Nerve In addition to motor fibers the glossopharyngeal nerve comprises predominantly sensory, visceral afferent fibers (Table 1.1, p. 6; Figs. 1.5, p. 9 and 1.9). Tactile stimulation of the somatosensory afferent fibers projecting to the principal trigeminal nucleus will elicit the gag reflex, a constriction of the pharyngeal musculature. The swallow reflex is a response to stimulation of the oropharynx, mediated by visceroafferent fibers of the glossopharyngeal nerve projecting to the caudal solitary tract nucleus – also named the commissural nucleus – which, in turn, has connections to the adjacent swallowing center in the reticular formation. Cerebral cortex, thalamus Parabrachial complex
1.4.1.7 Cochlear Nuclei Within the cochlear nerve (N. VIII) afferent nerve fibers of the bipolar cells of the spiral ganglion traverse the internal acoustic meatus and enter the brainstem at the cerebellopontine angle. The fibers divide in a t-shaped fashion and form short ascending and descending branches before terminating in the ipsilateral posterior and anterior cochlear nucleus, respectively (Fig. 1.5). The anterior cochlear nucleus comprises several parts that process various aspects of auditory signals, e.g. tonotopy, tone intensity, and the determination of the interaural time difference of a sound source, which are important for directional hearing. The axons leave the anterior cochlear nucleus via the dorsal intermediary or ventral acoustic stria and cross in the trapezoid body of the pons to the contralateral side. The posterior cochlear nucleus contains neurons (pyramid cells) that process complex acoustic processes,
N. VII Gustatory Respiratory Cardiovascular Visceral Respiratory Cardiovascular Visceral
N. X N. IX
Gustatory nucleus Cardiorespiratory part Commissural nucleus Solitary tract nucleus
Fig. 1.9 Subnuclei of the solitary tract nucleus and representation of the primary afferents. Based on afferent termination sites, the solitary tract nucleus (light gray) can be divided into different subnuclei: afferents carrying taste information reach the rostral gustatory nucleus via the intermediate nerve (N. VII), respiratory and cardiovascular afferents terminate predominantly in middle cardiorespiratory part, visceral afferents end in the posterior commissural nucleus. The information is conducted via the glossopharyngeal (N. IX) and the vagus nerve (N. X)
1.4 Internal Architecture
The functions of the glossopharyngeal nerve can be divided into a number of different categories: • Afferent somatosensory fibers from the mucosa of the oropharynx and nasopharynx, the soft palate, the pharyngopalatine arch, the tympanic cavity, as well as the Eustachian tube project to the principal trigeminal nucleus (touch), or to the spinal trigeminal nucleus (pain and temperature) (p. 11). • Special visceroafferent fibres from the taste buds of the posterior third of the tongue project to the solitary tract nucleus (also described as the gustatory nucleus). • Visceroafferent pathways from the carotid sinus (arterial pressure, baroreflex) and the carotid body (fall in pO2 or a rise in pCO2) project to the middle part of the solitary tract nucleus. • Visceroafferent fibers from the viscera terminate in the caudal solitary tract nucleus (commissural nucleus) (Fig. 1.9). • Visceroefferent fibers from the inferior salivary nucleus course within the glossopharyngeal nerve and innervate the parotid gland. • Somatosensory fibers with origin in the nucleus ambiguus supply the striated musculature of the pharynx and stylopharyngeal muscle. A detailed description of the reflex pathways in the medulla is found elsewhere in the literature (Blessing 2004). Solitary (Tract) Nucleus The solitary nucleus is a sensory nucleus and receives afferents via the facial (middle part), the glossopharyngeal, and the vagus nerves (Figs. 1.5, 1.9, 1.14a, e). It stands out anatomically because it is accompanied along its entire length by compact myelinated axons of the solitary tract. Functionally the solitary (tract) nucleus can be divided into four regions (Fig. 1.9): 1. The rostral part, as the gustatory nucleus, receives afferent taste information from the taste buds of the tongue and the pharynx. 2. The dorsal respiratory nucleus is situated in the middle and lateral part. 3. The baroreceptor nucleus, cardiorespiratory part, is located in the middle and medial part. 4. Caudally the solitary tracts of both sides converge to form the commissural nucleus. This part receives visceroafferent signals from the intestinal and the respiratory tract (p. 29).
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“vagus” is “wandering” and the name serves as an indication of its complicated peripheral course. The vagus nerve is an important visceromotor nerve for the heart, lung and viscera, although it also contains a fourfold greater share of sensory fibers. The visceromotor fibers originate in the dorsal nucleus of the vagus nerve, while the somatomotor fibers originate in the nucleus ambiguus. The viscerosensory afferents with ganglia cells in the superior or inferior ganglion (Table 1.1, p. 6) project to the spinal trigeminal nucleus. Somatomotor fibers from the nucleus ambiguus innervate the striated musculature of the pharyngeal arch derivatives, the pharynx, soft palate, larynx (vocal nerve), and the esophagus. Visceromotor fibers from the dorsal nucleus of the vagus nerve innervate the smooth musculature and the glands of the digestive and respiratory tract. The axons of these motor fibers are relayed to intramural ganglion cells in the periphery. Visceromotor fibers of the vagus nerve also regulate cardiac action. Visceral sensory afferents of the vagus nerve from the heart, lung and viscera located in the ganglion cells of the larger nodose ganglion (inferior) terminate in the caudal solitary tract nucleus, the commissural nucleus (Fig. 1.9) These visceral afferents mediate important reflexes, e.g. the Bainbridge reflex (increase in heart rate due to stretching of right atrium), the cough reflex (after stimulation of the tracheobronchial system) and the Hering-Breuer reflex (inhibition of the dorsal respiratory center after stimulation of the stretch receptors in the lung) (see Fig. 1.15 and p. 29) (Holstege 1991; Blessing 2004). Somatosensory afferents from the external auditory meatus as well as from the meninges of the posterior cranial fossa also course in the vagus nerve and terminate in the spinal trigeminal nucleus.
orsal Motor Vagal Nucleus (Dorsal Nucleus D of the Vagal Nerve) The dorsal motor vagal nucleus represents the largest collections of preganglionic parasympathetic neurons in the brainstem. The name of this nucleus emphasizes its primary function as a visceral motor nucleus. Together with the solitary tract nucleus it extends from the rostral medulla to the level of the decussation of the pyramids (Fig. 1.5). Because of the described close relationship between the solitary tract nucleus and the dorsal motor vagal nucleus the structure is frequently referred to as the “vagus-solitary complex.”
Nucleus Ambiguus Vagus Nerve The vagus nerve (N. X) is the largest nerve of the parasympathetic system. The literal translation of the Latin word
The nucleus ambiguus is a cytoarchitectonically inconspicuous nucleus insofar as it contains motor neurons, interneurons and preganglionic neurons in relatively widely scattered locations. The axons of the motor neurons travel
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together with the glossopharyngeal, vagus and accessory (cranial part) nerves to the musculature of the soft palate, the pharynx and the larynx, as well as to the striated musculature in the superior esophagus. The nucleus ambiguus lies within the reticular formation on the level of the middle part of the spinal trigeminal nucleus interpolaris part, (Figs. 1.5, 1.14d, e, 1.15). In this central location it receives afferents from structures in the immediate vicinity via reflexes elicited by, retching, coughing and swallowing. The nucleus retroambiguus forms the caudal extension of the nucleus ambiguus and plays a role in expiration via its projections to the respective motoneurons in the spinal cord (Holstege et al. 2004).
1.4.1.9 Nuclear Groups of the Accessory Nerve The accessory nerve (N. XI) comprises two roots: the spinal and the cranial root. The spinal portion is purely motor: the alpha and gamma motor neurons lie in the anterior horn of C2–C6 in the nucleus of the accessory nerve (Fig. 1.5). The roots pass laterally between the dorsal and ventral roots into the subarachnoidal space, before ascending and joining the roots of successive, higher segments (Fig. 1.3, not shown). The spinal root enters the skull via the foramen magnum (for this reason the accessory nerve is also described as a “false cranial nerve”) and joins the cranial root along a short path to the jugular foramen, the exit site of the accessory nerve. The spinal portion exits the accessory nerve as the external ramus and passes at the level of the neck to the pharyngeal arch derivatives, the sternocleidomastoid muscle and the trapezius (upper part) muscle. In the cervical plexus the accessory nerve is joined by additional motor (C2–C4) as well as sensory (proprioceptive) fibers. Activation of the trapezius muscle results in lifting of the shoulder, activation of the sternocleidomastoid muscle causes a head turn the contralateral side. The neurons of origin of the N.XI cranial root are located in the nucleus ambiguus (Fig. 1.5). The axons exit the spinal portion already in the jugular foramen, join the vagus nerve, and innervate the muscles of the larynx, except the cricothyroid muscle. Modern classifications of the cranial nerves have assigned the cranial root to the vagus nerve and not to the accessory nerve proper (Table 1.1).
1.4.1.10 Nucleus Hypoglossus The nucleus hypoglossus consists of several groups of motoneurons that innervate the extrinsic and intrinsic muscles of the tongue. The extrinsic muscles move the tongue as a whole, while the interior musculature alters the shape of the tongue. The majority of studies have shown that both muscle groups are innervated by motor neurons of the same
1 Neuroanatomy of the Brainstem
side. A lesion in the nuclear region is generally associated with a bilateral flaccid paresis that may be accounted for by the medial location of both hypoglossal nuclei. After exiting the cranium via the hypoglossal nerve canal, the hypoglossal nerve (N. XII) descends along the internal carotid artery. It forms anastomoses with the vagus nerve, the superior cervical ganglion and the lingual nerve. The hypoglossal nerve also carries fibers of proprioceptive afferents from C1 for innervation of the numerous muscle spindles in the tongue. The nucleus hypoglossus receives bilateral premotor afferents from the adjacent reticular formation as well as from the trigeminal nuclei and the solitary tract nucleus conveying sensory information from the oral cavity as well as from the masticatory and tongue musculature. These inputs are important for reflex movements of the tongue (swallowing, chewing, sucking, licking). Since the supranuclear control of the nucleus hypglossus is exerted predominantly, but not exclusively, by the contralateral cortex, unilateral cortical injury is not associated with major impairments of tongue mobility.
1.4.2 Reticular Formation: A Coordination Center for Complex Movement Fifty years ago an ascending system was identified in the brainstem that regulates attention processes in the forebrain. In animals, stimulation of large regions of the brainstem evokes an awakening reaction, causing the sleeping animal to wake up. Based on the diffuse cytoarchitecture of these attention pathways within the “core” of the brainstem (i.e. the reticular formation), this system was unfortunately described as the ascending reticular activating system (ARAS). Today the exact origin of the diffuse ascending and descending nerve tracts of the brainstem that regulate the wake-sleep rhythm is well known. These regions are not part of the unstructured reticular formation, but are embedded in compact nuclei as, e.g. the locus caeruleus or the raphe nuclei that are described below (see Figs. 1.10 and 1.14). The term ascending activating system is therefore a more appropriate scientific name to describe this system. There are a number of definitions for the reticular formation; some descriptions also include the raphe nuclei and the locus caeruleus in the term. In the light of more recent findings on the origin of the ascending activating system it is more appropriate to define the discrete reticular formation as “cell groups of the tegmentum with a characteristic cytoarchitecture” between well defined cranial nuclei as, e.g. the red nucleus and the cranial nerve nuclei. In the past century Forel was the first researcher to identify the reticular formation as a cytoarchitectonic unity that extends throughout the
1.4 Internal Architecture Fig. 1.10 Dorsal view of the reticular formation and neuromodulatory brainstem nuclei. Shown on the left side is a schematic representation of the cytoarchitecture of the reticular formation whereby a medial magnocellular part can be differentiated from a lateral parvocellular part. Shown against a gray background is the region of the paramedian pontine reticular formation (PPRF), which is important in the generation of horizontal saccades. The right side shows brainstem nuclear groups with neuromodulatory function. The asterisks mark the locus caeruleus. The parabrachial nuclei are found on both sides of superior cerebellar peduncle (S). M medial cerebellar peduncle, I inferior cerebellar peduncle
17 Reticular formation
Neuromodulatory brainstem nuclei Dorsal raphe nucleus
Mesencephalic cuneiform nucleus
Dorsal tegmental nucleus
Nucleus reticularis pontis oralis Nucleus reticularis pontis caudalis Gigantocellular nucleus Paramedian reticular nucleus
Pedunculopontine tegmental nucleus
S S
M I
Lateral parabrachial nucleus Medial parabrachial nucleus Locus caeruleus and subcaeruleus Superior central nucleus
Parvocellular reticular nucleus
Nucleus raphe magnus Nucleus raphe obscurus Nucleus raphe pallidus
entire brainstem (Fig. 1.10, left side). The reticular formation forms a long column of discrete multipolar neurons, while the medial longitudinal zone contains larger neurons from which bilateral reticulospinal tracts branch off; posture and orienting movements are modulated via these pathways (Nieuwenhuys et al. 1991; Büttner-Ennever and Horn 2004). The lateral parvocellular zone contains interneurons with short ipsilateral axons that coordinate the activity of motor neurons in the facial and ambiguus nuclei, as well as the hypoglossal and trigeminal nerves during activities such as breathing, vomiting, swallowing, chewing, licking and calling (Holstege 1991). The lateral parvocellular zone extends rostrally to the parabrachial nuclei (Fig. 1.10) as well as to the Kölliker-Fuse nucleus and continues in the spinal cord as the intermediate zone (Rexed layers V–VIII). In contrast to the ascending activating system (raphe nuclei and locus caeruleus), the reticular formation functions as a coordination center where information is very specifically conveyed (see pp. 18 and 27); small areas of the reticular formation in the pons relay signals, e.g. premotor signals for the motor neurons of the external eye muscles, and generate exact saccadic eye movements.
1.4.3 Ascending Activating System: Attention, Wake–Sleep Rhythm A number of brainstem nuclei have particularly long efferent axons, whose fine and diffuse terminal fields cover huge projection areas as, e.g. the entire cerebral cortex, the cerebellum, and the spinal cord, and transport transmitters to these areas.
Examples of these include the noradrenergic locus caeruleus, the serotoninergic raphe nuclei, the cholinergic cells in the pedunculopontine tegmental nucleus, the dorsolateral tegmental nucleus, and dopaminergic cell groups in the ventral tegmental area of the mesencephalon (Fig. 1.10), as well as the cholinergic basal nucleus of Meynert in the basal forebrain. These networks exert a modulating effect that intensifes specific signals (Saper et al. 2001; Halliday 2004). The neurons of the cholinergic pedunculopontine tegmental and the dorsolateral tegmental nucleus project topographically to the thalamus and are assumed to be indispensable for thalamocortical transmission. These neurons are particularly active during REM sleep. The monoaminergic cell groups (locus caeruleus, dopaminergic neurons of the ventral periaqueductal central gray substance, raphe nuclei) project to the nonspecific thalamus, but also extend via a fiber tract running through the basal forebrain into the entire cerebral cortex. The firing frequency of monoaminergic neurons is strongly correlated with wakefulness: the neurons are most active during the state of attention, less active in sleep, and completely inactive during REM sleep. The ascending activating system is accompanied by histaminergic axons of the tuberomammillary nucleus and orexincontaining neurons of the lateral hypothalamus (Sakurai 2005). Current hypotheses assume that the different activities of the cholinergic and monoaminergic ascending activating systems regulate the state of attention or sleep and REM sleep, and thus emphasize the close relationship between these states and eating behaviour, thermoregulation and circadian rhythms (Saper 2006). The locus caeruleus is characterized by descending axons that terminate throughout the entire spinal cord as well as in the
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nucleus raphe magnus and the nucleus raphe pallidus. From the nucleus raphe magnus these fibers descend bilaterally in Lissauer’s tract and terminate almost exclusively in the dorsal horn, primarily in the substantia gelatinosa (Rexed layer I). By way of their transmitter serotonin, these diffusely distributed terminals cause inhibition of the enkephalinergic interneurons of the dorsal horn. They are therefore able to control the sensory input to the spinal cord and effect stimulus- or stress-induced analgesia (Holstege 1991). Conversely, descending fibers of the nucleus raphe pallidus terminate primarily in the ventral horn and thus have a vital influence on the entire motor system. It is of importance that the control of the spinal cord by raphe nuclei or the locus caeruleus is not organized topographically and is therefore effective throughout the system. The raphe nuclei are subject to rigorous control by the periaqueductal gray matter. However, in a life-threatening situation endorphin influences from the hypothalamus can disinhibit the periaqueductal gray matter, and thus gain supraspinal control of pain afferents.
1.4.4 Limbic Control The anatomic organization of the brainstem provides evidence of an emotional or ‘limbic’ motor system (Holstege et al. 2004). The limbic premotor pathways which proceed separately from the somatomotor system terminate on motoneurons in the caudal brainstem, and are concerned with generating motor activity patterns during micturition, swallowing, vomiting, vocalization, sexual behavior, and with respiratory and cardiovascular reactions. The descending limbic pathways originate in the preoptic region of the lateral hypothalamus, the central nucleus of the amygdala, and the lateral aspect with the nucleus of the stria terminalis. Loosely packed projections pass from these telencephalic regions to the periaqueductal gray substance (p. 25) and to the lateral tegmentum of the caudal brain stem, which contains the respective premotor and preganglionic neurons (Figs. 1.10 and 1.13). The periaqueductal gray substance also provides important input to these limbic cell groups. The limbic pathways can be divided into medial and a lateral components. The medial part projects to the raphe nuclei and the pedunculopontine tegmental nucleus via diffuse pathways, modulates both motor and sensory activity, and thereby serves as a way to determine threshold values. The lateral part activates specific motor behavior patterns that have a role in emotional behavior.
1.4.5 Premotor Control of Eye Movements Five different eye movement types – saccades, vestibulo-ocular reflex, optokinetic reflex, smooth pursuit eye movements,
1 Neuroanatomy of the Brainstem
convergence – and gaze stabilization can be differentiated in humans. They are generated in different neuronal networks and their efferent premotor pathways converge on motor neurons of the eye muscles and continue to the orbit as a short common pathway before terminating (Fig. 1.11). Consequently, damage to one premotor pathway or to an individual premotor region of the brain can lead to a relatively selective loss of one eye movement type, while the others remain intact (Leigh and Zee 2006).
1.4.5.1 Saccades Information about a gaze target is transmitted via different rostral regions of the brain to the superior colliculus, and then these neurons in the deep layers of the colliculus project to premotor centers in the reticular formation, which in turn activate motor neurons of the eye muscles, thus generating a rapid eye movement (saccade) (Fig. 1.11). This results in the generation of horizontal saccades in the paramedian pontine reticular formation (PPRF), while vertical and torsional saccades are generated in the mesencephalic reticular formation. The paramedian pontine reticular formation comprises anatomically the nucleus reticularis pontis caudalis and contains the premotor neurons for horizontal saccades to both sides, as well as inhibiting glycinergic omnipause neurons located near the midline and control the triggering of saccades in all directions (Fig. 1.10; Büttner-Ennever and Horn 2004). Efferent connections from the PPRF exist to the abducens nerve nucleus, the prepositus hypoglossal nucleus, the medial vestibular nucleus, and to motor neurons of the cervical muscles that are activated on changes in gaze direction. Unilateral damage to the paramedian pontine reticular formation therefore leads to horizontal gaze paresis to one side, while a lesion located in proximity to the midline is associated with complete gaze paresis (Leigh and Zee 2006). Premotor neurons for vertical and torsional saccades are located in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and in the interstitial nucleus of Cajal (INC) (Fig. 1.4a and p. 19). The riMLF and adjacent INC are embedded in the fibers of the medial longitudinal fasciculus, inferior to the thalamus and dorsolateral to the rostral pole of the oculomotor nucleus (Büttner-Ennever and Horn 2004). In addition to projections to motoneurons of the vertically moving eye muscles in the oculomotor and trochlear nuclei, the riMLF and INC have efferent connections to cell groups of the paramedian tract in the pons and medulla, as well as to vestibular nuclei and the spinal cord via the medial longitudinal fasciculus. Bilateral lesions of the riMLF lead to vertical gaze paresis, mostly upward or downward and – in rare cases – to isolated down gaze paresis due to the presence of very small lesions (Leigh and Zee 2006).
1.4 Internal Architecture
19 PPRF riMLF
Frontal eye fields
SC
1 Saccades
Basal ganglia
Vestibular nuclei Motor neurons
2 Vestibulo-ocular reflex (VOR)
Accessory optic nuclei Nucleus of the optic tract
Eye muscle
3 Optokinetic reflex (OKN)
Retina
Visual cortex
Vestibular nuclei
Floccular region
Pretectum MRF
?
Interstitial nucleus of Cajal Prepositus hypoglossal nucleus
4 Smooth pursuit Eye movements
Pontine nuclei
5 Vergence
Vestibular nuclei
Floccular region
6 Gaze stabilization
Fig. 1.11 Block diagram illustrating the premotor pathways of eye movements. Five eye movement types and gaze stabilization can be differentiated. They are generated via separate premotor pathways that converge, on motoneurons in the eye muscle nuclei. Some of the same premotor
pathways are used by different eye movement types (vestibulo-ocular and optokinetic reflexes). riMLF rostral interstitial nucleus of the medial longitudinal fasciculus, PPRF paramedian pontine reticular formation, SC superior colliculus, MRF mesencephalic reticular formation
1.4.5.2 Vestibulo-ocular Reflex
the prepositus nucleus via collaterals, cell groups of the paramedian tracts, the interstitial nucleus of Cajal, and the rostral interstitial nucleus of the medial longitudinal fasciculus. Furthermore, a group of vestibulo-ocular secondary neurons in the medial and inferior vestibular nuclei send collaterals via the contralateral medial vestibulospinal tract to the spinal cord ending on motor neurons of the cervical muscles. Purely vestibulospinal pathways project from the lateral vestibular nucleus ipsilaterally in the lateral vestibulospinal tract and innervate the cervical musculature (Fig. 1.8 and p. 13) (Shinoda et al. 2006).
The vestibulo-ocular reflex occurs in the form of a slow compensatory eye movement in response to excitation of the semicircular canals (rotation of the head), interrupted by rapid return saccades of the eyes (Fig. 1.11). Repeatedly occurring compensatory and saccadic eye movements are described as “nystagmus”; the direction is defined by the direction of the fast (saccadic) phase of the nystagmus. While return saccades are generated via premotor pathways of the saccadic system, the compensatory movement is generated via a short and therefore very rapidly reacting three neuron arc: primary afferents from the semicircular canals activate secondary neurons in the rostral third of the vestibular nuclei monosynaptically, which then directly activate the motor neurons of one eye muscle pair (superior oblique muscle and inferior rectus muscle; superior rectus muscle and inferior oblique muscle; lateral rectus muscle and the internuclear neurons in the abducens nerve nucleus, the medial rectus muscle motoneurons). In this process excitatory vestibular pathways cross to contralateral, while inhibitory pathways remain ipsilateral (Fig. 1.12). Nearly all of these neuronal connections project via the medial longitudinal fasciculus. The inhibiting vestibuloocular connections of the horizontal system use glycine as transmitter, while GABA is used by the vertical systems (BüttnerEnnever and Gerrits 2004; Highstein and Holstein 2006). The vertical vestibulo-ocular pathways further innervate
1.4.5.3 Optokinetic Reflex The vestibulo-ocular reflex is complemented by the optokinetic system, which is activated by large-field visual stimuli moving across the retina, e.g. movement from the surrounding world (Fig. 1.11). Two anatomic systems play an important role in the generation of the resulting compensatory eye movement, the optokinetic reflex: the accessory optic system (see ‘Retinal Inputs’ p. 5) and the pretectum with the nucleus of the optic tract (see p. 24). Retinal signals are transmitted to the vestibular nuclei via the nucleus of the optic and the accessory optic nuclei via different parallel pathways and with involvement of the prepositus nucleus. From the vestibular nuclei the same premotor pathways as those for the vestibulo-ocular reflex are used for optokinetic responses (Fig. 1.11).
20
1 Neuroanatomy of the Brainstem
a
b
c
IO+ MR
LR
+SR
IO
SR
LR
–SO
–IR
SO +
IR +
III
MLF INT
III
III
IV
IV MLF
MLF
VI –
HC +
MLF
Vestibular nuclei
–
AC +
Vestibular nuclei
MLF
–
PC
+ Vestibular nuclei
Fig. 1.12 Representation of pathways for the vestibulo-ocular reflex. Primary afferents of the semicircular canals are relayed to excitatory (red) and inhibitory secondary neurons (black axons) in the vestibular nuclei; these in turn travel to the motor neurons of the respective eye muscles, which they activate (red, with red arrow) while inhibiting their antagonists (gray, dotted line arrow). Shown here is the pulling direction of eye muscle, not the muscles themselves. On excitation of the horizontal canal (a) internuclear neurons (INT) in addition to lateral rectus muscle (LR) motoneurons are activated in the abducens nucleus
(VI), which then excite the medial rectus muscle (MR) neurons in the contralateral oculomotor nucleus (III). The result of bilateral activation of the anterior semicircular canal (b) is an upward eye movement, while activation of the posterior canal (c) leads to a downward movement. IV trochlear nerve nucleus, VI abducens nerve nucleus, IO inferior oblique muscle, SO superior oblique muscle, IR inferior rectus muscle, SR superior rectus muscle, AC anterior canal, HC horizontal canal, MLF medial longitudinal fasciculus, PC posterior canal
1.4.5.4 Smooth Pursuit Eye Movements
1.4.5.5 Convergence
Signal processing for smooth pursuit eye movements, which permit the constant representation of a small moving gaze target on the fovea, is initiated via corticopontine-cerebellar pathways. In this process visual information is transmitted from the retina through the lateral geniculate nucleus to the primary visual cortex to be transformed into the respective smooth pursuit eye movements via activated parietotemporal visual cortex areas, the frontal eye fields, pontine nuclei, cerebellum and vestibular nuclei (other areas than those for the vestibulo-ocular reflex) (Fig. 1.11). In addition, parallel pathways project through the nucleus of the optic tract to the pontine nuclei and the nucleus reticularis tegmenti pontis (Fig. 1.14c), which corresponds in humans to the nucleus papilliformis together with the pontine gray supralemniscal process (Olszewski and Baxter 1982). Cell groups of the pons around the corticopontine and the descending fiber bundles of the corticospinal tract are described as pontine nuclei. Based on their anatomic location they are divided into different subnuclei, these subnuclei do not represent functional unities. The dorsolateral and adjacent dorsomedial pontine nuclei constitute the primary components of the pathways for smooth pursuit eye movements (Thier and Möck 2006).
In convergence, the only type of normally occurring disconjugate eye movements, motor neurons of the medial and inferior rectus muscles of both eyes are activated simultaneously. The premotor connections for convergence have not been extensively investigated thus far. Premotor neurons are assumed to be located in an area dorsomedial to the oculomotor nerve nucleus and in the pretectum (Fig. 1.11). Additional premotor pathways for convergence are found in the vestibular nuclei. Activation of the otoliths as a result of linear acceleration (e.g. on a toboggan) automatically produces compensatory convergence eye movements whose amplitude is dependent upon the distance from the point of visual fixation. In this connection an independent monosynaptic activation of medial rectus motor neurons also occurs from the ipsilateral ventrolateral vestibular nucleus via the ascending tract of Deiters.
1.4.5.6 Gaze Stabilization On completion of an eye movement, velocity signals in the motor neurons must be converted into a position signal to maintain the eyes in a stable position. An important role regarding this integrator function is assumed by the
1.4 Internal Architecture
21
Fig. 1.13 Overview of the vegetative nervous system. The central sympathetic pathway from the hypothalamus activates the neurons of origin of the visceral efferent pathways of the sympathetic nervous system in the lateral horn of the spinal cord segments T1-L2 (black). These are relayed in different ganglia of the sympathetic nerve trunk to postganglionic neurons with relatively long axons projecting to the effector organ, whereby the sympathetic pathway for the orbital region (broken black line) takes a particularly long and thus vulnerable course. The central parasympathetic pathway from the hypothalamus (red) activates the visceral efferent motor neurons in the parasympathetic brainstem nuclei and in the sacral region of the spinal cord
• Superior tarsal muscle • Dilatator of the pupil • Orbital muscle • Sweat glands vessels of the face
Hypothalamus
Central sympathetic pathway Central parasympathetic pathway
Internal carotid artery Brainstem Pupillary constrictor muscle ciliary muscle
Oculomotor nerve Facial nerve
Lacrimal and salivary glands
Vagus nerve Thoracoabdominal cavity Superior cervical ganglion
Proximal ganglia
T1
• Head region • Thoracoabdominal cavity • Extremities Sympathetic nerve trunk L2
Pelvic cavity Pelvic nerves
prepositus nucleus for horizontal (McCrea and Horn 2006), and by the interstitial nucleus of Cajal for vertical and torsional eye movements (Horn 2006). The prepositus nucleus is located medially on the floor of the fourth ventricle between the abducens nucleus and the hypoglossal nucleus, and the interstitial nucleus of Cajal lies dorsolateral to the oculomotor nerve nucleus. Both nuclei have reciprocal connections to the respective premotor neurons of the horizontal and vertical/torsional saccadic and vestibular system, as well as to the cerebellar flocculus (Fig. 1.11). The eye position signal is presumed to be transmitted via their projections to the respective motor neurons in the abducens nucleus or the oculomotor and trochlear nuclei. It is further assumed that the recently described paramedian tract neurons near the midline in close proximity to the raphe
nuclei in the pons and medulla, play a key role in the feedback control for maintaining gaze position, because they also receive input from all premotor areas and in turn project to the cerebellar flocculus. An injury to these neurons may serve in some cases to explain gaze stability disturbances (Büttner-Ennever and Horn 1996).
1.4.6 Parasympathetic and Sympathetic Pathways The function of internal organs of importance for respiration, circulation, metabolism, body temperature, water balance, digestion, secretion, procreation, etc. is dependent on the interaction of visceral efferents of the parasympathetic
22 Fig. 1.14 Schematic cross-sections at different levels of the brainstem. Shown are cross-sections at the level of the mesencephalon (a), the pons (b, c) and the medulla oblongata (d, e). The most important nuclear regions and fiber tracts are represented in all of the cross-sections
1 Neuroanatomy of the Brainstem
a
Aqueduct
III
Periaqueductal gray
Central sympathetic pathway Inferior brachium of the midbrain
Interstitial nucleus of Cajal Spinothalamic tract Lemniscus – trigeminal – medial
Mesencephalic tract of the trigeminal nerve
Corticopontine tract Red nucleus
Mesencephalic reticular formation
Corticospinal/nuclear tract
Medial longitudinal fasciculus Tegmental decussation
b
Medial longitudinal fasciculus
Ventral tegmental area
Substantia nigra
Fourth ventricle
Locus caeruleus Lateral lemniscus Reticular formation Superior central nucleus
Corticopontine tract
Central sympathetic pathway Mesencephalic tract of the trigeminal nerve Superior cerebellar peduncle Spinothalamic tract Rubrospinal tract
Tegmental decussation
Medial lemniscus Trigeminal lemniscus
Pontine nuclei
Corticospinal/nuclear tract Tectospinal tract
c
Superior cerebellar peduncle Locus caeruleus Nucleus reticularis pontis oralis Lateral lemniscus Central tegmental tract Medial lemniscus Nucleus reticularis tegmenti pontis
Anterior medullary velum
Medial longitudinal fasciculus Central sympathetic pathway Motor trigeminal nucleus Principal trigeminal nucleus Spinal trigeminal nucleus
Spinothalamic tract Rubrospinal tract Tectospinal tract Pyramidal tract
Pontine base
1.4 Internal Architecture Fig. 1.14 (continued)
23
d
Nucleus raphe obscurus Hypoglossal nucleus
Prepositus nucleus Vestibular nuclei
Solitary tract Dorsal motor vagal nucleus Inferior cerebellar peduncle
Spinal trigeminal nucleus Central sympathetic pathway Medial longitudinal fasciculus
Rubrospinal tract Spinothalamic tract Nucleus ambiguus Hypoglossal nerve
Tectospinal tract Inferior olivary nucleus Medial lemniscus Pyramidal tract
e
Commissural nucleus Spinal tract nucleus of the trigeminal nerve Medial longitudinal fasciculus Central sympathetic pathway Spinothalamic tract Tectospinal tract Medial lemniscus
and sympathetic nervous systems. In contrast to visceral efferents, visceral afferents cannot be subdivided into parasympathetic or sympathetic. The parasympathetic or sympathetic systems are controlled either by the hypothalamus as the higher control center for descending pathways through the brainstem, or via the hormonal path with use of the hypothalamic-hypophyseal system (Fig. 1.13). The most important efferent connections of the hypothalamus to the brainstem comprise the medial forebrain bundle (medial telencephalic fasciculus) and the mammillotegmental tract. The dorsal longitudinal fasciculus (bundle of Schütz) takes a periventricular position in its course, immediately dorsal to the medial longitudinal fasciculus (Figs. 1.13 and 1.14). Signals from the rostral hypothalamus are transmitted along the descending pathways and are relayed at several sites before reaching the parasympathetic preganglionic neurons in the brainstem tegmentum, the Edinger-Westphal nucleus, the superior and inferior salivary nuclei (Figs. 1.5 and 1.13), and the dorsal motor vagal nucleus. Further parasympathetic preganglionic neurons are located in the lateral horns of the sacral region of the spinal cord (pelvic parasympatheticus, S2, S3 and S4). On stimulation of the caudal hypothalamus the sympathetic pathways are more likely to be activated. Sympathetic fibers from the hypothalamus decussate in the mesencephalon and travel in the central tegmental tract of the reticular formation through the pons and medulla to the intermediolateral cell column of the upper thoracic region of the spinal cord (Fig. 1.13, central sympathetic pathway, Fig. 1.14). Similar to the descending pathways of the parasympathetic system, the path is discrete and does not form a compact fiber tract.
Gracile nucleus
Dorsal motor vagal nucleus Cuneate nucleus External cuneate nucleus Solitary tract Hypoglossal nerve nucleus Nucleus ambiguus Pyramidal tract
The parasympathetic innervation of the eye (pupil) is discussed in Sect. 1.4.1. Sympathetic innervation to the eye is controlled by the sympathetic tract through activation of preganglionic neurons in the lateral horn of the spinal cord (C8-T2), in the so-called ciliospinal center. The preganglionic sympathetic fibers in the cervical sympathetic trunk project from there and are relayed in the superior cervical ganglion onto postganglionic neurons. The postganglionic fibers travel along the internal carotid artery, continue without synapsing through the ciliary ganglion and innervate the pupil dilatator muscle (Fig. 1.13, black dotted line). Lesions in the course of central or peripheral sympathetic pathways on their way to the eye are associated with loss of pupil dilator muscle function and lead to ptosis (Horner’s syndrome). A particularly frequent example of damage to the descending sympathetic tract is found in the presence of a circulatory disturbance of the lateral medulla oblongata after an infarct in the region of the posterior inferior cerebellar artery (Wallenberg’s syndrome) (Figs. 1.13, 1.14d, e, 1.18c, and p. 33).
1.4.7 Nuclear Regions of the Mesencephalon 1.4.7.1 Overview The nucleus of the posterior commissure is closely associated with the fibers of the posterior commissure in the medial pole of the mesencephalon. It can be divided into at least five different subgroups. One subgroup, the subcommissural nucleus, contains virtually no neurons and comprises the
24
1 Neuroanatomy of the Brainstem
a
b XII
Parabrachial nuclei (“pneumotaxic center”)
Solitary nucleus Medial vestibular nucleus
Bötzinger complex
Dorsomedial respiratory complex
Pre-Bötzinger complex Dorsomedial respiratory complex
Nucleus ambiguus
Rostral respiratory complex Ventrolateral respiratory complex
Diaphragm motoneurons C3-C7
Ventrolateral respiratory complex Caudal respiratory complex
Fig. 1.15 Representation of premotor brainstem respiratory areas involved in the regulation of respiratory activity. (a) The crosses within the ventrolateral respiratory complex represent the excitatory premotor neurons of the sympathetic system in the rostral ventrolateral medulla for the baroreceptor-vasomotor reflex. The dotted line in the dorsal
view of b marks the plane of section for a. (b) The parabrachial nuclei form a pneumotaxic center and modulate the dorsomedial and ventrolateral premotor respiratory complex in the rostral medulla, which in turn activate the motoneurons of the respiratory muscles in the nucleus ambiguus. XII hypoglossal nerve nucleus
circumventricular subcommissural organ, a neurohumoral region (McKinley et al. 2004). In neurohumoral regions hormones are produced in the neurons and released into the bloodstream. Lesions in the posterior commissural nucleus or the posterior commissure are frequently caused by tumours of the nearby pineal body and can lead to vertical upward gaze paresis (Leigh and Zee 2006; Horn 2006). In primates premotor neurons for vertical and torsional saccades are located in the rostral interstitial nucleus of the medial longitudinal fasciculus as well as in the interstitial nucleus of Cajal (Fig. 1.14a and p. 18-22), and in the fibers of the medial longitudinal fasciculus at the anterior end of the mesencephalon. The nucleus of Darkschewitsch is situated immediately above the interstitial nucleus of Cajal (INC) in the periaqueductal gray. Both the INC and the red nucleus receive and project to the inferior olive. Contrary to various older descriptions, the nucleus of Darkschewitsch does not constitute part of the premotor pathways for eye movements (Büttner-Ennever 2006). The area medial to the substantia nigra is named the ventral tegmental area; like the adjacent pigmented parabrachial nucleus it contains dopaminergic neurons and possesses strong connections to the limbic structures (Fig. 1.14a; Holstege et al. 2004).
Baldauf and Herczeg 2002); a number of them have specialized visual motor functions, while others are involved, e.g. in the processing of pain stimuli (Gamlin 2006). • Pretectal olivary nucleus: this nucleus has an important role in the mediation of the pupillary light reflex. • Nucleus of the optic tract: it corresponds to the region which was formerly also described as the lentiform nucleus. In primates, the pretectal olivary nucleus is completely enveloped by cells of the nucleus of the optic tract, which suggests increasing cooperation between these nuclei. The nuclei of the optic tract on both sides are connected by commissural fibers via the posterior commissure. They have an important function in the generation of optokinetic nystagmus, smooth pursuit eye movements, and gain adaptation of the horizontal vestibuloocular reflex (Fig. 1.11 and p. 19). • Posterior pretectal nucleus: the nucleus has traditionally been described as the sublentiform nucleus. • Medial pretectal nucleus: this nucleus corresponds to the pretectal area involved in accommodation. • Anterior pretectal nucleus: the findings of recent studies provide evidence that this nucleus has an inhibitory influence on afferent pathways in the dorsal horn of the spinal cord.
1.4.7.2 Pretectum 1.4.7.3 Superior and Inferior Colliculi The pretectum is located just rostral to the superior colliculus below the brachium of the superior colliculus, where it forms the transition region between the brainstem and the diencephalon (Fig. 1.3). It contains several small nuclei (Borostyankoi-
The superior colliculus acts as a central relay station for fast orientation movements, which are also described as the ‘visual grasp reflex’. Histologically it consists of several layers
1.4 Internal Architecture
(I–VII). The superficial layers (I–III) receive exclusively sensory input from the retina and the visual cortex, while the intermediate (IV) and deep (V–VII) layers receive multimodal input from the trigeminal, auditory, somatosensory and vestibular systems (May 2006). The superior colliculus has an important function in the transformation of visual and auditory stimuli to motor signals. Electrical stimulation of the superior colliculus is followed by a saccade to the contralateral side, whose amplitude and direction depends upon the site of stimulation. The topographic representation of the visual field in the superficial layers correlates with motor map contained in the deeper layers. In the caudal superior colliculus larger saccades are induced by electrical stimulation and are frequently combined with movements of the head; small saccades are induced by electrical stimulation in the rostral aspect. Stimulation in the rostral area of foveal representation leads to fixation of the eyes (Fig. 1.11 and p. 18). The deeper layers also receive input from the cerebral cortex (frontal eye fields), the basal ganglia, including the substantia nigra (reticular part), cerebellar nuclei and the prepositus nucleus. The descending efferents of the deeper layers cross in the dorsal tegmental decussation (Meynert); at this level it gives rise to a bundle ascending to the thalamus, the basal ganglia, and the rostral interstitial nucleus of the medial longitudinal fasciculus, while another branch travels just below the medial longitudinal fasciculus in the tectoreticulospinal tract (predorsal bundle) and innervates via collaterals, among other structures, the paramedian pontine reticular formation, the abducens nucleus, and the inferior olive. The tectoreticulospinal tract terminates on motor neurons in the rostral spinal cord that supply the cervical musculature. The inferior colliculus is subdivided into the central nucleus, a laminar nucleus for ascending fibers of the auditory pathway (Fig. 1.16b, e and p. 31), the pericentral nucleus for descending fibers of the auditory pathway from the auditory cortex, and the external nucleus for descending fibers from the cortex and thalamus, as well as for afferents from the contralateral inferior colliculus, the trigeminal nucleus, and the solitary tract nucleus. The external nucleus forms a zone between the superior and the inferior nucleus. The multisensory afferents of this nucleus and its connection to the superior colliculus support the hypothesis that it has an important role in orienting responses to auditory stimuli. The afferent axons from the inferior colliculus converge in the lateral zone and form the brachium of the inferior colliculus. From here the fibers ascend to the medial geniculate body (Moore and Linthicum 2004).
1.4.7.4 Red Nucleus Like the pyramidal pathway, the red nucleus controls fine movements of the distal extremities (hand and finger), although
25
this applies mainly to automatically performed and not to newly learned movements. It represents the largest nucleus of the midbrain, is topographically organized (face dorsal, upper extremities medial, lower extremities ventrolateral), and interspersed with numerous bundles of medullated fibers of the brachium conjunctivum, some of which terminate in this nucleus. In addition, roots of the oculomotor nerve on their way to the interpeduncular fossa, as well as the tractus retroflexus, travel through the red nucleus without terminating there. Within the red nucleus a caudal magnocellular part can be differentiated from a rostral parvocellular one. The nucleus receives its main inputs from the cerebral cortex and the cerebellum, and sends efferent axons to the inferior olive and the spinal cord; the cells in the magnocellular part are the origin of the rubrospinal tract. Compared to the situation in monkeys and cats, the rubrospinal tract in humans is only rudimentary (Holstege 1991, Holstege et al., 2004). This topographically organized fiber pathway exits the nucleus medially, crosses in the ventral part of the important ventral tegmental decussation (tegmental decussation of Forel, Fig. 1.14a, b), descends initially in the ventrolateral pons and medulla and from there travels in the dorsolateral funiculus of the spinal cord (Fig. 1.16). Here the areas with representation of the hand and wrist receive the largest number of terminals. The magnocellular part of the red nucleus receives inputs from the motor cortex and is connected via reciprocal projections with the emboliform and globosus nuclei of the spinocerebellum. The size of the parvocellular part of the red nucleus is related to development of the cerebellar hemispheres (neocerebellum). It receives inputs primarily from the cerebral cortex that originate from larger areas than those to the magnocellular part. The corticorubral tract descends in the ipsilateral internal capsule to the parvocellular part of the red nucleus. The efferents from the parvocellular part also cross in the ventral tegmental decussation and project via several adjacent mesencephalic structures (nucleus of Darkschewitsch, medial accessory nucleus of Bechterew, interstitial nucleus of Cajal and mesencephalic reticular formation) to the inferior olive. From there crossed fibers pass as climbing fibers via the inferior cerebellar peduncle to the cerebellum. These pathways form important neural loops for motor learning.
1.4.7.5 Substantia Nigra The substantia nigra contains a mixed population of neurons located in the ventral mesencephalon and constitutes the major tissue between the cerebral crus and the red nucleus (Halliday 2004). At approximately the age from 15 to 18 years it becomes strongly pigmented due to the presence of neuromelanin, a metabolic product of dopamine. The dopaminergic part of the substantia nigra is described as
26
1 Neuroanatomy of the Brainstem
a
Internal capsule
b
Thalamus
III
IV
V
VI VII XII X
Lateral lemniscus Gracile nucleus
Red nucleus XII
Medial lemniscus
XI
Corticospinal tract Anterior corticospinal tract
Spinothalamic tract
Lateral corticospinal tract
Cuneate nucleus
c Parietopontine tract
Inferior colliculus
Medial longitudinal fasciculus
Red nucleus Corticonuclear tract Rubrospinal tract
To cerebral cortex
d Occipitopontine Superior tract cerebellar peduncle
Frontopontine tract
Corticonuclear tract Middle cerebellar peduncle Inferior cerebellar peduncle
Temporopontine tract Red nucleus
Cerebral crus Corticospinal tract
III Red nucleus IV
Rubrospinal tract Medial longitudinal fasciculus
Vestibulocerebellar tract
Corticopontine tract
V VI VII Lateral corticospinal tract (crossed)
Pontine nuclei
XII XI
Inferior olive Anterior corticospinal tract (uncrossed)
Anterior spinocerebellar tract Posterior spinocerebellar tract
e Red nucleus Central tegmental tract
Medial lemniscus Inferior colliculus Lateral lemniscus
f Red nucleus Decussation
Corticopontine tract
Superior cerebellar peduncle
Pontine nuclei
Medial cerebellar peduncle
Spinothalamic tract
Cuneate nucleus Gracile nucleus
Trapezoid body
Dentate nucleus Inferior olive
Inferior olive Anterior spinocerebellar tract
Fig. 1.16 Connections of pathways in the brainstem. (a–c) Lateral view of brainstem connections; (d–f) dorsal view with descending (red) and ascending pathways (dark gray). Pathways descending from the cortex are
Inferior cerebellar peduncle
Olivocerebellar tract Posterior spinocerebellar tract
shown in (a) and (d), pathways of the spinothalamic tract and the lemniscal system ascending to the cortex are shown in (b) and (e); and connections to the cerebellum in (c) and (f) (modified from Bähr and Frotscher, 2003)
1.4 Internal Architecture
the pars compacta and can be divided into a dorsal and a ventral layer. Located ventral to the pars compacta is a third layer, the pars reticulata, a group of unpigmented neurons. The three layers of the substantia nigra can be further divided into columnar cell groups that have a close topographic relationship to the basal ganglia, the thalamus and the brainstem. The cells of the pars reticulata contain GABA and are frequently described as the caudal extension of the internal part of the globus pallidus. The lateral part of the substantia nigra has a visual motor function (Harting and Updyke 2006). Functionally, the substantia nigra forms an integral part of the basal ganglia, which play a role in the modulation or generation of movement. The striatum (caudate nucleus and putamen) is a central part of the basal ganglia and has reciprocal connections to the dopaminergic pars compacta, and is controlled by striatal activity. The GABAergic cells of the pars reticulata form (via the superior colliculus) the second most important output of the basal ganglia. The substantia nigra is separated from the red nucleus by the nucleus parabrachialis pigmentosus, a loosely packed dopaminergic cell group, which is referred to as A10 or the dorsal part of the substantia nigra. All Parkinson disease types, not only the classical form, are characterized by progressive death of dopaminergic cells in the pars compacta of the substantia nigra. Three of the types, progressive supranuclear palsy, corticobasal degeneration, and postencephalitic Parkinson’s disease are also characterized by the loss of non-dopaminergic cells of the pars reticulata (Hardmann et al. 1997).
1.4.7.6 Periaqueductal Gray Owing to the fact that staining of cells or fibers does not enable the identification of individual cell groups within the periaqueductal gray, staining with neurochemical markers (NADPH diaphorase, NO synthetase, acetylcholine) and examination of their connections are used for this purpose. The functional mapping studies show that the periaqueductal gray can be divided into quadrants consisting of a dorsomedial, dorsolateral, lateral and ventrolateral column. From a neuroanatomical point of view, the subdivisions of the periaqueductal gray represent a relay station for ascending sensory pathways, responsible for the transmission of pain stimuli, as well as for the descending limbic pathways; both of these interact with the ventrolateral column, while the dorsomedial column transmits information to the thalamus and receives afferents from the limbic regions of the cerebral cortex. Conversely, the dorsolateral part is associated with the neighboring intermediate and deeper layers of the superior colliculus, and thereby serves to support the orientation of the body in response to alarm stimuli. Functionally, the periaqueductal gray is involved in a wide range of coordinated emotional behavior, including the modulation of pain, cardiovascular regulation,
27
vocalization, micturition, defence reactions and sexual behavior (Holstege et al. 2004).
1.4.8 Nuclear Regions of the Pons 1.4.8.1 Overview The term pontine nuclei refers to the clusters of neurons embedded among the fiber bundles of the pontine base, while all other cell groups of the pons are located in the dorsal tegmentum (Fig. 1.1). The mesencephalic trigeminal nucleus, the proprioceptive nucleus of the muscles of mastication (Fig. 1.7 and p. 11), is situated in the rostral part, in addition to the locus caeruleus which is located at the border of the central gray substance (Fig. 1.14c). Both nuclei extend further caudally through the entire pons. The reticular formation is penetrated by the caudal part of the decussation of the superior cerebellar peduncles (brachium conjunctivum). The parabrachial nuclei lateral to the brachium conjunctivum are particularly developed at this level (Fig. 1.10 and p. 16). The lateral lemniscus proceeds along the outer limit to the inferior colliculi. Several smaller nuclei are embedded in its course, which constitute relay nuclei of the auditory pathway. The raphe nuclei are found at the midline of the medial pons and both the motor nucleus and principal nucleus of the trigeminal nerve are situated laterally (Figs. 1.7, 1.14c and p. 11). Located in the caudal pons are the abducens nucleus, the facial nucleus, as well as the spinal trigeminal nucleus. Located ventrolaterally to these structures is the lateral lemniscus with the medially adjacent complex of the superior olivary nucleus, which is essential for directional hearing (p. 31). Figure 1.10 shows the location of the paramedian pontine reticular formation, comprising the nuclei reticularis pontis caudalis and oralis.
1.4.8.2 Pontine Nuclei Numerous neuronal islets, the pontine nuclei, are found in the pontine base; these can be divided into groups on the basis of their location, but not with regard to functional relationships. The corticopontine fibers, which run in the crura of the cerebrum lateral to the corticospinal and the corticonuclear tract terminate on these pontine nuclei. After synapsing in the pontine nuclei, and maintaining the same topography (Thier and Möck 2006), the majority of axons of the pontine nuclei (90% in monkeys) cross to the contralateral side and travel in the medial cerebellar peduncle before reaching the nuclei and the medial cerebellar cortex as mossy fibers. The nucleus reticularis tegmenti pontis (nucleus papilliformis and the pontine gray supralemniscal process – Olszewski and Baxter 1982) is situated just dorsal
28
1 Neuroanatomy of the Brainstem
1.4.8.4 Pontine Micturition Center
Internal carotid artery Middle cerebral artery
Anterior cerebral artery Anterior communicating artery
Posterior communicating artery Basilar artery N. V Anterior inferior cerebellar artery (AICA)
Posterior cerebral artery Superior cerebellar artery N. VI
N. VIII N. VII N. IX N. X
Vertebral artery Posterior inferior cerebellar artery (PICA)
Anterior spinal artery
Posterior spinal artery
Fig. 1.17 Ventral view of the brainstem arteries. The arterial system forms an anastomotic ring (“arterial circle of Willis” ventrally). The posterior communicating artery connects the middle cerebral artery with the posterior cerebral artery; the anterior communicating artery connects the anterior cerebral artery with the contralateral anterior cerebral artery. There is a close spatial relationship between some of the vessels and the cranial nerves, whose sensory transition zone (Redlich-Obersteiner zone) is marked in black here. The vascular loops of the superior cerebellar artery pose a particular threat to N. V; the loops of the anterior inferior cerebellar artery represent a threat to N. VIII
to the pontine nuclei and, like these, projects only to the cerebellum. Although the pontine nuclei and nucleus reticularis tegmenti pontis are similar with a view to afferents and function, they cannot be equated.
Micturition describes the sequence of coordinated muscle activations needed for urination. This action is mediated by contraction of the smooth muscle of the urinary bladder with simultaneous relaxation of the striated external urethral sphincter (Holstege et al. 2004). The muscle of the urinary bladder is innervated by parasympathetic motor neurons of the intermediolateral column of the sacral region of the spinal cord and by sympathetic motor neurons of the intermediolateral column of the thoracic and lumbar regions of the spinal cord (T11-L2); the external urethral sphincter receives innervation from the motor neurons of the nucleus of Onuf (anterior horn of the sacral region of the spinal cord, S1–S3; Fig. 1.13, p. 21). The parasympathetic motoneurons receive direct excitatory input from the pontine micturition center (M-region or Barrington’s nucleus). There is experimental evidence that activation of the M-center can be stimulated by the preoptic region, which terminates in the periaqueductal gray substance and projects to the parabrachial area. The M-region in turn projects to the inhibitory interneurons in the sacral region of the spinal cord that inhibit the motor neurons in Onuf’s nucleus locally and thereby induce relaxation of the sphincter, thus enabling urine flow simultaneously with contraction of the bladder. There are also indications of the presence of a lateral L-region in the lateral pontine tegmentum, which activates Onuf’s nucleus – and thus sphincter activity. The exact relationship between parabrachial nuclei and the M- and L-region is still unknown (Holstege et al. 2004).
1.4.9 Nuclear Regions of the Medulla Oblongata 1.4.9.1 Overview
1.4.8.3 Parabrachial Nuclei The medial and lateral parabrachial nuclei surround the superior cerebellar peduncle and consist of a number of subnuclei (Fig. 1.10). While this complex was previously classified as being part of the lateral zone of the reticular formation, today it is viewed as an independent nuclear complex. Due to reciprocal connections with the vagalsolitary-complex, the ventrolateral medulla (Fig. 1.15), the limbic system, the hypothalamus, the insular and prefrontal cortex, the thalamus and the spinal cord, the parabrachial nuclei can be regarded as an ‘integration center’ for brainstem reflexes, forebrain behavior and central-autonomous systems. Of importance is the transmission of visceral information, pain and taste sensation. Located in the same region as the parabrachial nuclei are the pneumotaxic and the micturition center.
Approximately 90% of the corticospinal tract fibers cross at the caudal border of the medulla oblongata and form the lateral corticospinal tract of the spinal cord. Both dorsal column nuclei lie at this level: the gracile nucleus (lower extremities) is located medially, and the cuneate nucleus (upper extremities) laterally. The sensory relay nuclei contain the second neuron of the lemniscal system for touch and proprioception. Their efferent axons cross via the internal arcuate fibers into the medial lemniscus and continue from there to the contralateral thalamus. Laterally, the cuneate nucleus is joined by the external cuneate nucleus, whose neurons carry information from the spinal afferents of the upper extremities to the cerebellum. Further rostral, the inferior cerebellar peduncle (restiform body) and the posterior or dorsal spinocerebellar tract (from the lower extremities) are joined by these ascending fibers. However, the reciprocal connections between the
1.4 Internal Architecture
nuclear complex of the inferior olive and the cerebellum constitute the main part of the inferior cerebellar peduncle. The spinal trigeminal nucleus extends throughout the entire length of the medulla oblongata; running more lateral is the spinal tract of the trigeminal nerve as well as the ascending fibers of the spinothalamic tract (also known as the anterolateral system), which are responsible for the conduction of pain and temperature in the contralateral part of the body, the rubrospinal tract, and the descending central sympathetic pathway (Figs. 1.14 and 1.16). The fourth ventricle opens at the level of the obex; the area postrema in the wall of the ventricle is also found at this site. The other medullary nuclei, including the hypoglossal nucleus and the prepositus nucleus, the nucleus ambiguus, the solitary tract nucleus and the dorsal nucleus of the vagus nerve have been discussed elsewhere in this chapter (see p. 14).
1.4.9.2 Inferior Olive The nuclear complex of the inferior olive consists of the principal olivary nucleus and its subnuclei, the dorsal and the medial accessory olivary nuclei. The olivocerebellar tract exists through the hilum, crosses the midline, travels in the inferior cerebellar peduncle to the cerebellum, and projects there as climbing fibers exclusively to the cerebellar nuclei and the cerebellar cortex. On its way topographically organized longitudinal zones are formed in the cerebellar cortex. The inferior olive is the only source of climbing fibers, and modulates the activity of the cerebellum in its function as coordinator of precise voluntary movements via these glutaminergic projections (Barmack 2006). The climbing fibers define spatial coordinates for Purkinje cells of the entire cerebellar cortex and determine the output from the cerebellum via their inhibitory GABAergic axons projecting onto the cerebellar and vestibular nuclei. The major afferents of the inferior olive emerge from the red nucleus, the nucleus of Darkschewitsch, the pretectum, and the superior colliculus.
1.4.9.3 Ventrolateral Cell Groups of the Medulla
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the ‘rostral ventrolateral cell complex’ in the rostral medulla, including the adrenergic group C1, then via descending sympathetic pathways, effect a reduction in peripheral vasoconstriction and bradycardia (Fig. 1.5). In a similar manner, an incipient fall in blood pressure would lead to reflexive vasoconstriction via the solitary tract nucleus. The parasympathetic control of blood pressure via the vagus nerve efferents may possibly be exerted via a direct projection from the solitary tract nucleus to the dorsal vagus nerve nucleus.
Respiratory Reflexes Inspiration and the final phase of expiration are active motor activities and are controlled by cervical and thoracic motor neurons (C3–C5; phrenic nerve, T6–T12; intercostal nerve). The respective relay circuit is located in the caudal brainstem. There the inspiratory premotor neurons are situated in the lateral solitary tract nucleus and form a dorsomedial respiratory group. Their axons project, among others, to the motoneurons of the diaphragm (C3–C7) in the spinal cord. Expiratory and inspiratory premotor neurons constitute a rostral respiratory group in the ventrolateral medullary reticular formation, dorsal to the nucleus ambiguus and project to the spinal cord (Fig. 1.15). Other neighboring structures to the ventrolateral and dorsomedial respiratory group are the premotor neurons of the sympathetic control of the baroreceptor-vasomotor reflex (crosses in Fig. 1.15a). The respiratory centers form a vertical column consisting of different cell groups, and extends from the level of the area postrema to the parabrachial nuclei of the pons, which function as a pneumotaxic center. A circumscribed area of this column constitutes the pre-Bötzinger complex, a center for respiratory rhythm generation (Blessing 2004). Sensory signals from the periphery of importance for respiratory activity are transmitted via the glossopharyngeal and vagus nerves from stretch receptors in the lung, chemoreceptors, or several glomera located in the cervical zone along the trunk and the branches of the two cranial nerves, the largest of which represents the carotid body.
Cardiovascular Reflexes Stretch receptors (baroreceptors) in the carotid sinus and the aortic arch are activated by a sudden rise in blood pressure. This information is transmitted via afferent nerve fibers in the glossopharyngeal and vagus nerves, whose cell bodies are located in the neighborhood of the jugular foramen in the petrosal or nodose ganglion, and activate neurons in the caudal part of the solitary tract nucleus (commissural nucleus) (Blessing 2004). It is currently hypothesized that efferents from the solitary tract nucleus activate a group of GABAergic neurons in the ‘caudal ventrolateral medulla’ which relays to
Swallowing, Vomiting, and Sneeze Reflexes Motor neurons of the tongue (hypoglossal nucleus), the floor of the mouth, the pharynx and larynx (nucleus ambiguus), as well as of the face (facial nucleus) are involved in a number of reflexes, e.g. swallowing, vomiting, or sneezing. Coordination of the correct sequence of activity in the individual muscle nuclei is the responsibility of the immediately adjacent reticular formation in the medulla. The reticular formation distributes from here the afferent sensory stimuli
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from the solitary tract nucleus, the spinal, or the principal trigeminal nucleus, as well as inputs from more rostral centers to the appropriate motoneurons to trigger the respective reflex. In parallel, the premotor neurons coordinate the respiratory network.
1.4.9.4 Area Postrema Immediately rostral to the obex, appearing as a paired bulge on each side of the floor of the fourth ventricle lies the area postrema, one of the circumventricular organs. These are characterized by a close contact to the blood and cerebrospinal fluid spaces. To perform this function, they possess a modified ependyma, a pronounced glial network, as well as a dense vascularisation with wide perivascular spaces and fenestrated blood capillaries, which cause the blood– brain barrier to be broken down at these sites. Neurons of the circumventricular organs are therefore able to gain access to the circulating humoral mediators in blood (McKinley et al. 2004). Neurons of the area postrema are very small and difficult to differentiate under a microscope from astroglia. Efferent nerve fibers emanating from the area postrema terminate in the nearby dorsal motor vagal nucleus and the solitary tract nucleus, in the noradrenergic neurons of the caudal ventrolateral medulla, the nucleus ambiguus, the parabrachial nuclei, as well as in the cerebellar nuclei (nucleus fastigii). The majority of these connections are reciprocal; additional afferents to the area postrema originate from the hypothalamus. The area postrema serves as a chemical trigger for the vomiting reflex.
1.5 Pathways in the Brainstem 1.5.1 Descending Pathways The corticospinal pathways cross in the pyramidal decussation to the contralateral side (Fig. 1.16d); damage to these pathways in the brainstem therefore leads to contralateral function disturbances. The corticospinal pathways arise from the pyramidal cells in the cortical lamina V of the frontal lobe (60%) and the parietal lobe (40%). The fibers course in the corona radiata to the posterior crus of the internal capsule in the following topographic order: the rostral half terminates on motor neurons of the highest levels of the spinal cord, the caudal half innervates increasingly lower spinal cord levels. The topographic order is sustained in the cerebral crus and the more caudal pyramidal
1 Neuroanatomy of the Brainstem
pathway, whereby the parts for the upper extremities are found in a medial and those for the lower extremities in a lateral location. Eighty-five to ninety percent of the corticospinal fibers decussate at the transition from the medulla to the spinal cord and form the also topographically ordered lateral corticospinal tract, while the uncrossed fibers course in the anterior corticospinal tract. Parallel to the corticospinal pathways, the corticonuclear connections travel in the corticonuclear tract, which has also been described as the corticobulbar tract (“bulbus” = former term of the medulla oblongata). The corticonuclear fibers run through the genu of the internal capsule and congregate in the medial cerebral crus, along with the corticospinal fibers. The mesencephalic, pontine and bulbar corticonuclear fibers exert an influence on the cranial nerve nuclei, which control the skeletal musculature (Neuhuber 2004). While some of these projections may be direct, the majority terminate initially near the respective motor brainstem nuclei on interneurons of the reticular formation. Nuclei of the ocular muscle nerves (N. III, N. IV, N. VI) are thus controlled indirectly by frontal and parietal eye fields of the cortex via gaze control centers in the midbrain (e.g. superior colliculus) and the pons (e.g. omnipause neurons). Both the motor trigeminal and the facial nuclei are innervated bilaterally, while the activation of motoneurons for the lower part of the face is initiated almost exclusively by the contralateral cerebral cortex. The medial longitudinal fasciculus (MLF) runs from the rostral end of the reticular formation to the spinal cord. It contains heavily myelinated fibers of the rostral interstitial nucleus of the medial longitudinal fasciculus, the interstitial nucleus of Cajal, as well as of the oculomotor and vestibular nuclei, which form important ascending and descending connections for the coordination of eye movements (Fig. 1.12 and p. 9). The dorsal longitudinal fasciculus (Schütz-bundle) is located dorsal to the medial longitudinal fascicle in the central gray substance and, in contrast to the MLF, can be seen only with difficulty, due to its fine, weakly myelinated fibers. The dorsal longitudinal fascicle carries information from the medial hypothalamus primarily to the periaqueductal gray substance and therefore has an indirect influence on the autonomic nuclei of the brain stem. The corticopontine component of the fiber systems descending from the cortex is strongly pronounced in humans (Fig. 1.16c, f). Corticopontine fibers originate in both motor and non motor areas and terminate in the pontine nuclei of the pontine base. The neurons of the pontine nuclei, in turn, send their fibers via the medial cerebellar peduncle (pontine brachium) to the contralateral side, but with collaterals also projecting to the ipsilateral side. The function of this pontocerebellar system consists of the control of motor processes. The cerebellum is connected on both sides to the brainstem via three cerebellar peduncles (Fig. 1.16c, f); the superior cerebellar peduncle (brachium conjunctivum) represents the
1.5 Pathways in the Brainstem
output pathway for information from the cerebellar nuclei to the thalamus and the red nucleus. Alone the anterior spinocerebellar tract uses the superior cerebellar peduncle as an entrance pathway to the cerebellum. The middle cerebellar peduncle (brachium pontis) projects fibers only from the pons to the cerebellum. The inferior cerebellar peduncle (restiform body) contains reciprocal vestibulocerebellar and spinocerebellar fibers, in addition to the fibers emanating from the inferior olive. The most important function of the cerebellum is the coordination of movements: structures near the midline (vermis and nucleus fastigii) participate in processing vestibular information, the adjacent intermediate regions receive input from the spinal cord, while the cerebellar hemispheres process information from the cerebral cortex. MRI images illustrate this impressively when they show that the contralateral cerebral cortex but the ipsilateral cerebellar hemisphere are activated during movements of the hand or finger. These images show that a decussation between the cerebellar efferents to the cortex is indispensable; decussation for afferents to the cerebellum occurs in the pontine nuclei and the crossing for efferents from the cerebellum ascending to the thalamus (dentate nucleus) takes place in the massive decussation of the superior cerebellar peduncle (Figs. 1.14b, 1.16f).
1.5.2 Ascending Pathways 1.5.2.1 Lemniscal Systems The ascending pathways coursing within the medial lemniscus of the brainstem are referred to using the term the lemniscal system (Fig. 1.16c, c). Central processes of the spinal ganglia cells transmit information regarding light touch, vibration and pressure ipsilaterally via the dorsal columns of the spinal cord to the dorsal column nuclei, the medially located gracile nucleus and the laterally situated cuneate nucleus (Kaas 2004). At this relay station, descending pathways like the corticospinal tract and the fiber systems of the reticular formation have an influence on information transmission. The topographic organization of the dorsal column is preserved after decussation in the dorsal column nuclei. In the caudal medulla oblongata the axons of the secondary neurons immediately decussate to the contralateral side and course from there as the medial lemniscus through the brainstem. At the level of the rostral medulla oblongata, the medial lemniscus is joined at its dorsolateral aspect by the decussated fibers of the trigeminal lemniscus, which forms the respective conduction pathway for mechanoreceptors from the head region. The spinothalamic tract approaches the lateral pole of the medial lemniscus in the mesencephalon. Both fiber bundles terminate together in the thalamus, primarily in the
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ventral posterolateral nucleus; the fibers of the trigeminal lemniscus reach the ventral posteromedial nucleus. 1.5.2.2 Spinothalamic Tract The pain fiber system is composed of primary afferent nociceptors, the ascending pain pathways in the spinal cord and trigeminal system, as well as of descending modulating pathways, and a number of different areas of the brain that process pain information. The lateral spinothalamic tract and the anterior spinothalamic tract transmit signals for pain, temperature and coarse pressure sensations, and are often termed the “anterolateral system” or “spinothalamic tract.” The cells of origin are located in lamina I and V of the spinal cord where the majority of fibers cross over in the spinal commissure and ascend in the contralateral half of the spinal cord to the thalamus. The spinothalamic tract is organized somatotopically. Recent studies have shown that a further visceral pain pathway courses in the dorsal columns and follows the lemniscal pathways to the ventral posterolateral nucleus of the thalamus. The cells of origin of this pain pathway are located near the central canal and form the dorsal funiculus in the midline. Unilateral injury to a spinal cord segment (unilateral lesion according to Brown-Séquard) is associated with a loss of pain and temperature sensation caudally and contralaterally to the lesion, due to the fact that the spinothalamic tract crosses over in the spinal cord to the other side. Conversely, the modalities subserving discrimination, vibration and depth sensitivity that are conducted via the lemniscal system, are disturbed on the side of the body affected by the lesion. This is described as dissociated sensory loss. 1.5.2.3 Spinocerebellar Tracts There are four major connections between the spinal cord and the cerebellum on each side (Fig. 1.16c, f). The dorsal horn cells transmit information from the lower extremities via the posterior spinocerebellar tact, and from the upper extremities via the cuneocerebellar tract. The somatotopically arranged pathways project to the ipsilateral spinocerebellum via the inferior cerebellar peduncle. The other two pathways originate in the cells of the intermediate zone and transmit information on the activity of interneurons in the spinal cord and on spinal reflex activity. Information from the lower half of the body, decussate and travel in the contralateral anterior spinocerebellar tract through the medulla oblongata to the pons, and from there back to the ipsilateral cerebellum via the decussation of the superior cerebellar peduncles. Proprioceptive information from muscles of the upper extremities is transmitted ipsilaterally directly into the inferior cerebellar peduncle and directly into the cerebellum.
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1.5.2.4 Auditory Pathway Acoustic signals are transmitted to the ventral and dorsal cochlear nuclei in the brainstem via the cochlear nerve, and from there in several ascending pathways to the thalamus and the cerebral cortex. During this process tonotopy, the spatial location of sound sources, as well as feature extraction of complete sound patterns (e.g. language) are preserved. The massive trapezoid body is only one of the commissural pathways which characterize the auditory system (Fig. 1.1b,e). Because information from both ears is represented on both sides of the brain, brainstem lesions rarely lead to severe neurologic disturbances. At the superior olive, a medial nucleus can be distinguished from a lateral nucleus and the periolivary region. The neuronal relay for directional hearing is accomplished via the medial and lateral nucleus of the superior olivary nucleus. The main projection from the superior olive extends from the lateral lemniscus to the inferior colliculus. The periolivary region further represents the only source of efferents projecting within the olivocochlear bundle to the ipsilateral and contralateral cochlea. These efferents course initially in the vestibular part of N. VIII and cross in the internal acoustic meatus to the cochlear nerve before reaching the outer (thick axons) and inner (thin axons) hair cells of the cochlea. The olivocochlear bundle controls otoacoustic emission and improves the signal-noise-relationship, i.e. selective auditory attention.
1.6 Brain Stem Vascularization Blood supply to the brain is carried by four large arteries: two internal carotid arteries supply the anterior brain segments and two vertebral arteries carry blood to the posterior segments of the brain, including the occipital lobes, parts of the temporal lobe, splenium of the corpus callosum, caudal parts of the thalamus, caudal parts of the internal capsule, cerebellum, and the brainstem (Nieuwenhuys et al. 1991). At the base of the brain these four arteries form an arterial ring, the arterial circle of Willis that interconnects the two supply territories (Fig. 1.17). The anterior, middle and posterior cerebral arteries are divided into four segments: segment A1, for the anterior cerebral artery, is located anterior to the anterior communicating artery, A2 lies posteriorly; segment M1, for the middle cerebral artery, forms the horizontal segment, and M2 is located on the insula. Segment P1, for the posterior cerebral artery, is situated between the bifurcation of the basilar artery and the posterior communicating artery, and P2 between the posterior communicating artery and the anterior temporal artery; located posteriorly are segments P3 and P4, which supply the lateral and medial occipital lobes. The spatial relationship of the cranial nerve roots to the arteries is shown in Fig. 1.17, including the vulnerable
1 Neuroanatomy of the Brainstem
‘transition zone’, the transition from the peripheral myelin of Schwann cells to the central myelin of oligodendrocytes. It becomes apparent that the vascular loops of the superior cerebellar artery can be a threat to the roots of the trigeminal nerve, vascular loops of the anterior inferior cerebellar artery (= AICA) can affect the facial, vestibulocochlear and abducens nerves, and loops of the posterior inferior cerebellar artery (= PICA) can represent a threat to the glossopharyngeal and vagus nerves. While the surface of the vascular network is characterized by considerable variability, the internal organization of the branches in the brainstem is relatively constant and similar at all levels. Three different vascular territories can be differentiated: • A ventral vascular territory • A lateral vascular territory and • A dorsal vascular territory (Fig. 1.18) The spinal cord veins represent an extension of the brainstem veins, which form a vascular net around the brainstem, consisting of interconnected longitudinal veins and horizontally branches, in addition to branches connecting them with the basal cerebral vessels.
1.6.1 Mesencephalon The mesencephalon is enveloped on both sides by several arterial arches that give rise to the radially arranged inner vessels. The short arterial arches emerge from the arcuate branches of the posterior cerebral artery, while the longer arterial arches emerge from the posterior cerebral, the quadrigeminal, superior cerebellar, and posterior choroidal arteries. The ventral vascular territory comprises the nuclei of the oculomotor and trochlear nerves, the medial longitudinal fasciculus, the Edinger-Westphal nucleus, and paramedian regions of the ventral tegmental area up to the mesencephalic aqueduct, as well as the red nucleus and medial parts of the substantia nigra and the cerebral peduncle. This territory is supplied by a number of paramedian branches, the interpeduncular perforating arteries (from the P1 segment of the posterior cerebral artery), the posterior communicating artery, as well as the short and long circumferential arteries. Some of the paramedian vessels emerge from the anterior choroidal artery branch of the internal carotid artery. The lateral vascular territory comprises lateral parts of the tegmentum (cerebral peduncle and medial lemniscus), the substantia nigra, as well as the medial and lateral geniculate body. It is supplied by the radial vessels from the long and short circumferential arteries.
1.6 Brain Stem Vascularization Fig. 1.18 The arterial blood supply to the brainstem in cross-sections. Three crosssections are shown at the level of the mesencephalon (a), the pons (b), and the medulla (c); the arteries are shown on the right and their supply territories are indicated on the left. P1 and P2 represent sections of the posterior cerebral artery
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a
Posterior cerebral artery
Superior cerebellar artery Quadrigeminal artery
Posterior cerebral artery
Superior cerebellar artery
Posterior choroidal artery
Posterior choroidal arteries
Interpeduncular perforating arteries (PI)
P2 posterior cerebellar artery
Superior cerebellar artery N. III Basilar artery
Posterior communicating P1 artery posterior cerebral artery
b Pontine branches
Pontine branches
Lateral branches
Lateral branches Medial branches
Medial branches
Basilar artery
c
Posterior spinal artery
Posterior inferior cerebellar artery (PICA)
Posterior inferior cerebellar artery (PICA)
Vertebral artery Anterior spinal artery Anterior spinal artery
Vertebral artery
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The dorsal vascular territory, the tectum or the superior colliculus, receives blood from the quadrigeminal artery (usually a branch from the P1 segment of the posterior cerebral artery) and – more caudal at the level of N. IV and the inferior colliculus – from the superior cerebellar artery (Fig. 1.18a).
1.6.2 Pons Blood supply to the pons is carried via three groups of arteries arising from the basilar artery. The ventral group of arteries arises from the medial branches, the lateral group from the lateral branches, and the dorsal group from pontine branches. The paramedian branches can extend to the floor of the ventricle where they supply the medial tegmentum, the pontine nuclei, including the corticospinal fibers passing through this structure, and the roots of the abducens nerve emerging from the brainstem. The short circumferential branches are found only in the lateral part of the pontine base, while the long circumferential branches supply the entire pontine tegmentum, including the facial nucleus, vestibulocochlear and trigeminal nerves, as well as a segment of the middle cerebellar peduncle. An additional blood supply is carried by the branches of the anterior inferior cerebellar artery (AICA) to the caudal pons, and by branches of the superior cerebellar artery to the rostral pons (Fig. 1.18b).
1.6.3 Medulla Oblongata The medulla oblongata is supplied via two to three branches of the vertebral artery: the anterior spinal artery, posterior inferior cerebellar artery (PICA), and the spinal artery (a branch of the PICA) (Fig. 1.18c). Similar to the pons and the mesencephalon, a lateral and a dorsal vascular group can be differentiated. The medial medulla is supplied by branches of the anterior spinal artery which ascends in the midline, (frequently to the left or right side), to the floor of the fourth ventricle. They supply the hypoglossal nerve and the nucleus of the hypoglossal nerve, the nucleus of the dorsal vagus nerve, the corticospinal tract, the medial lemniscus, the medial longitudinal fasciculus, and the medial accessory olivary nucleus. An occlusion occurring in the ventral vascular group leads to the medial medullary syndrome (Déjerine). Branches of the lateral vascular group can emerge from PICA or from the vertebral artery and enter the medulla oblongata lateral to the inferior olive. They supply parts of the tegmentum, including the solitary tract nucleus, dorsal motor vagal nucleus, spinal trigeminal nucleus and ambiguus nucleus, a part of the vestibular and dorsal column nuclei
1 Neuroanatomy of the Brainstem
with the ascending spinothalamic tract (anterolateral pathways for pain), spinal trigeminal tract, the central descending sympathetic pathway, and a part of the inferior cerebellar peduncle. Obstructions in this lateral vascular group result in lateral medullary syndromes (Wallenberg syndrome inclusive of Horner syndrome). The branches of the dorsal vascular group emerge at the level of the obex from the PICA and the ascending branch of the posterior spinal artery. They supply the dorsal column nuclei as well as the spinal trigeminal tract and nucleus. Lesions of these vessels are rare. In a more rostral location blood supply to the entire dorsal medulla is carried exclusively via the PICA; branches of the AICA are involved in blood supply at the rostral border with the pons only.
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35 Neuhuber W (2004) Hirnstamm. In: Drenckhahn D (Hrsg) Benninghoff/Drenckhahn. Anatomie – Makroskopische Anatomie, Histologie, Embryologie, Zellbiologie. Elsevier, Urban & Fischer, München, pp 326–383 Nieuwenhuys R, Voogd J, Van Huijzen C (1991) Das Zentralnervensystem des Menschen: ein Atlas mit Begleittext, 2 Aufl. Springer, Berlin, Heidelberg, New York Olszewski J, Baxter D (1982) Cytoarchitecture of the human brain stem. Karger, Basel/München/Paris/London/New York/Sydney Sakurai T (2005) Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 9: 231–241 Saper CB (2006) Staying awake for dinner: hypothalamic integration of sleep, feeding, and circadian rhythms. Prog Brain Res 14: 243–252 Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24: 726–731 Shinoda Y, Sugiuchi Y, Izawa Y, Hata Y (2006) Long descending motor tract axons and their control of neck and axial muscles. Prog Brain Res 151:527–563 Thier P, Möck M (2006) The oculomotor role of the pontine nuclei and the nucleus reticularis tegmenti pontis. Prog Brain Res 151: 293–320 Voogd J (1995) Nervous system – cerebellum. In: Berry MM, Standring SM, Bannister LH (eds) Gray’s anatomy. Churchhill Livingstone, London/New York, pp 1027–1065 Voogd J (2004) Cerebellum and precerebellar nuclei. In: Paxinos G, Mai JK (eds) The human nervous system. Elsevier Academic, San Diego, pp 321–392 Wilhelm H (1998) Störungen der Pupillomotorik. In: Huber A, Kömpf D (Hrsg) Klinische Neuroophthalmologie. Thieme, Stuttgart/New York, pp 622–630 Wilhelm H (2002) Pupillenstörungen. In: Lund O-E, Waubke TN (Hrsg) Neuroophthalmologie. Thieme, Stuttgart, pp 78–96
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Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics
Contents 2.1 Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1 Conventional Native Diagnostics . . . . . . . . . . . . . . . . . . 2.1.2 Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2.1 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . 2.1.2.2 CT in Investigations of the Brainstem . . . . . . . . . . . . . . 2.1.2.3 Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3 Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . 2.1.3.1 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . 2.1.3.2 MRI Investigations of the Brainstem . . . . . . . . . . . . . . . 2.1.3.3 Specialized Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3.4 Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4 Angiography and Endovascular Interventions . . . . . . . . 2.1.4.1 Diagnostic Angiography . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.2 Endovascular Interventions . . . . . . . . . . . . . . . . . . . . . . . Recanalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38 38 39 39 39 40 40 40 42 45 46 47 47 49 49 51
2.2 Ultrasound Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1 Vascular Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.1 Anatomic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.2 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . Continuous Wave (cw) Doppler . . . . . . . . . . . . . . . . . . . Pulsed Doppler Sonography (Pulsed Wave Doppler, pw Doppler) . . . . . . . . . . . . . . . Color Duplex Sonography . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.3 Ultrasound Signal Enhancers . . . . . . . . . . . . . . . . . . . . . 2.2.1.4 Reference Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.5 Stenosis Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.6 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Infarction/TIA . . . . . . . . . . . . . . . . . . . . . . . . Basilar Artery Thrombosis . . . . . . . . . . . . . . . . . . . . . . . Subclavian Steal Syndrome or Subclavian Steal Phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rotational Vertebral Artery Occlusion . . . . . . . . . . . . . . 2.2.2 B-Mode Sonography of the Brainstem . . . . . . . . . . . . . . 2.2.2.1 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . 2.2.2.2 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early Diagnosis of Idiopathic Parkinson’s Disease . . . . Differential Diagnosis of Parkinson Syndromes . . . . . . . Diagnosis of Affective Disturbances . . . . . . . . . . . . . . .
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2.3 Electrophysiologic Diagnostics . . . . . . . . . . . . . . . . . . 2.3.1 Blink Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.1.2 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1.3 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2 Masseter Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2.1 Anatomic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2.2 Clinical Application and Normal Values . . . . . . . . . . . .
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2.3.2.3 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3 Early Acoustic Evoked Potentials . . . . . . . . . . . . . . . . . . 2.3.3.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.3.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3.3 Physiologic Variability of EAEP and Abnormal Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3.4 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Central Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Ischemia/Bleeding . . . . . . . . . . . . . . . . . . . . . Brain Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4 Vestibulocollic Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.4.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4.3 Evaluation and Reference Values . . . . . . . . . . . . . . . . . . 2.3.4.4 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5 Exteroceptive Suppression of Masticatory Muscle Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . Afferences of Exteroceptive Suppression . . . . . . . . . . . . Interconnection of ES1 . . . . . . . . . . . . . . . . . . . . . . . . . . Interconnection of ES2 . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.2 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.4 Reference Values/Normal Variants and Pathologic ES Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.5 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6 Somatosensory Evoked Potentials . . . . . . . . . . . . . . . . . 2.3.6.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.6.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Generator Question and the Interconnection of SEPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Far-Field Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6.4 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6.5 Brainstem Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.7 Transcranial Magnetic Stimulation . . . . . . . . . . . . . . . . . 2.3.7.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.7.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corticofacial Projections . . . . . . . . . . . . . . . . . . . . . . . . . Corticolingual Projections . . . . . . . . . . . . . . . . . . . . . . . 2.3.7.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TMS of Corticofacial Projections . . . . . . . . . . . . . . . . . . TMS of Corticolingual Projections . . . . . . . . . . . . . . . . .
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2.3.7.4 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Ischemia Prognostic Significance of MEPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Topodiagnostic Significance of MEPs . . . . . . . . . . . . . . Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . Hereditary Spastic Spinal Paralysis . . . . . . . . . . . . . . . . 2.3.8 Laser Evoked Potentials . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.8.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8.4 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . .
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Central Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Ischemia/Hemorrhage . . . . . . . . . . . . . . . . . . 2.3.9 Recording of Eye Movements . . . . . . . . . . . . . . . . . . . . 2.3.9.1 Direct Current Recording . . . . . . . . . . . . . . . . . . . . . . . . 2.3.9.2 Infrared Reflective Oculography . . . . . . . . . . . . . . . . . . . 2.3.9.3 Videooculography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.9.4 Scleral Search Coil Technique . . . . . . . . . . . . . . . . . . . . 2.3.10 Other Electrophysiologic Methods for the Investigation of Brainstem Reflexes . . . . . . . . . . . . . . . . 2.3.10.1 Stapedius Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.10.2 Trigemino-Cervical Reflex . . . . . . . . . . . . . . . . . . . . . . . 2.3.10.3 Trigemino-Hypoglossal Silent Period . . . . . . . . . . . . . . .
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Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.1 Neuroradiology Peter Stoeter and Stephan Boor
2.1.1 Conventional Native Diagnostics Conventional native diagnostics of the skull no longer has an important role in disorders of the brainstem today, and conventional tomography has been completely abandoned for reasons of radiation protection. A similar situation exists with a view to special images of the skull base and the petrous bones (in projections according to Schüller and Stenvers), which have been replaced with thin section computed tomography (CT) scans that have a significantly higher detail resolution. Survey radiographs of the skull in two planes and a radiograph of the back of the head obtained in half-axial projection with the tube tilted toward the vertex are occasionally recommended after craniocerebral trauma and shotgun wounds, or for the detection of other metallic foreign bodies. The finding of fractures of the skull cap or skull base can serve as an indicator of violent assault. If not done at the time of the primary diagnosis, a CT scan is indicated at the latest on detection of a fracture on the plain radiograph, in particular in the presence of space-occupying bleeding. At the craniocervical junction, the search for a fracture of the upper cervical spine is important in trauma patients; in particular unstable fractures of the atlas or dens and luxations with ligament lesions after injury to the spinal cord and the caudal part of the medulla oblongata have to be identified, while a secondary lesion in these structures as a result of incautious manipulation must be prevented. This also applies to instabilities due to other causes, e.g. odontoid bone or rheumatoid arthritis. Radiographic functional studies in forward and backward tilt under fluoroscopy have to be carried out for the assessment of cervical spine stability (Fig. 2.1), whereby the differentiation from the physiologic mobility of the upper cervical vertebrae is not readily achieved, particularly in children.
Fig. 2.1 Craniocervical dysplasia. Plain radiograph in backward (a) and forward tilt (b) CT in sagittal reconstruction (c) T2-weighted MRI (d) shortening of the clivus, separate disposition of the dens process as odontoid bone with pseudoarthrosis and anterolisthesis (including atlas and occiput) vis-à-vis the dens, resulting in severe stenosis between the upwardly displaced posterior arch of the atlas and the posterior border of the second cervical vertebral body and dens with malacia (bright signal on T2-weighting) in the caudal part of the medulla oblongata. Only slight increase in forward slippage on forward tilt (comp. a and b). Synostosis C2–5
2.1 Neuroradiology
Further indications for plain radiographs are cranial anomalies (premature suture synostosis), general disorders of the skull cap and skull base as, e.g. Paget’s disease, or suspected metastases. Constrictions of the foramina of the skull base can lead to cranial nerve lesions. Constitutional or acquired constrictions at the craniocervical junction, like a basilar impression (upward displacement of the dens into the foramen magnum with resulting depression of the medulla oblongata), or achondroplasia (shortening of clivus with constriction of foramen magnum) can already be identified on the survey radiograph. Overall, however, the information provided by native diagnostics regarding brainstem involvement is limited compared to multislice diagnostic modalities.
2.1.2 Computed Tomography 2.1.2.1 Principles and Techniques In computed tomography (CT), which – like conventional native diagnostics – is based on x-ray absorption, the x-ray film is replaced by a detector system for the measurement of x-ray absorption. The patient is positioned on the examination table and moved longitudinally, i.e. in very precise small steps or nowadays continuously, through the measurement unit (gantry). The x-ray tube and detector ring are mounted opposite each other in the gantry. In units of the third and fourth generation they rotate continuously around the part of the body to be imaged at a speed of 0.3–3 revolutions per second. The emitted radiation beam is pulsed and collimated in a fanshaped fashion onto the slice of interest. Modern units enable the measurement of slice thicknesses from 0.5 to 10 mm. The individual detectors transform – as scintillation crystals or ionization chambers – the received radiation into electric signals, from which the image processor calculates the attenuation values of the x-rayed volume elements (voxels). In newer CT units with continuous rotation, the tube voltage is provided by slip rings, which obviates the need for repositioning of the cables. The examination table moves continuously through the gantry while a spiral scan of the object to be examined is conducted and a volume data set is acquired. The resulting data set can be used to reconstruct single slices of varying thickness. Multidetector systems enable the simultaneous acquisition of multiple (currently up to 640) slices of a specified width. By means of “folded rear projection” relative x-ray attenuation values of the individual voxels can be calculated from the measured detector voltage and correlated to the absorption values of water (0) and air (−1,000) as Hounsfield units (HU). The “density” of gray matter thus ranges at 45 HU, and that of white matter at 35 HU. Because the human eye can differentiate only approximately 20 grayscales, the width and
39
position of the viewing window have to be accurately adjusted to the contrast area to be differentiated. Conversely, all values above or below the window width are shown as “white” or “black” without further differentiation. Spatial resolution is also low in the presence of slight density differences, ranging only from about 2 to 3 mm, so that pathways and nuclei in the brainstem are poorly differentiated from each other, even when a narrow window width is used. However, in high contrast areas as, e.g. in the visualization of bony petrosal structures, spatial resolutions of up to 0.35 mm can be achieved with special reconstruction algorithms. Further section planes can be reconstructed from the data sets. With the commonly used 512 matrix the slice thickness is substantially greater than the edge length of the image elements (pixels), the resolution of secondary sections in the reconstruction direction has thus far been lower than for direct measurements. With the introduction collimation, units of the latest generation permit the measurement – or at least the calculation – of isotope voxels, which enables multiplanar reconstruction without quality loss. A further advantage of multiplanar systems, in addition to shorter measurement times, is reduction of partial volume effects and therefore an improved sharpness, resulting from the presence of structures with different densities in one voxel, and their visualization as one unit with proportional weighting. After intravenous bolus administration of iodized x-ray contrast medium, reconstruction of image elements with maximum intensities, e.g. of vessels using maximum intensity projection (MIP), as well as three-dimensional reconstructions with, e.g. shaded surface display (SSD) or volume rendering technique (VR), are also possible. In CT angiography it is important to ensure that the examination of the region of interest is carried out at exactly the moment when the injected contrast medium passes through the arteries or veins.
2.1.2.2 CT in Investigations of the Brainstem Due to the low spatial resolution in the low contrast area, the diagnostic value of CT in investigations of the brainstem is relatively limited. The primary indication – also in view of the short examination time – is emergency diagnostic imaging, particularly for the demonstration of skull base fractures after trauma, and bleeding in the brainstem or cisterns. Furthermore, calcifications of cavernomas (Fig. 2.2), other vascular malformations or various neoplasms, e.g. ependymomas, can be accurately identified. The majority of brainstem lesions like infarctions or patches of demyelinization are rare and can be conclusively shown primarily above the middle of the pons. In addition to low contrast resolution, this is due to the occurrence of streak artefacts (Hounsfield artefacts) that develop as the result of energetically different x-ray absorption in the bones of the skull base, primarily the petrous bones,
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• Vascular stenoses or vascular occlusions – particularly when a basilar artery occlusion is suspected • Arterial aneurysms (demonstration at 90% sensitivity as of a diameter of 5 mm) (Dammert et al. 2004) • Central cerebral veins or sinus thromboses The availability of modern units has rendered CT angiography coequal to MR angiography. As in MR angiography, the use of multislice CT scanners enables visualization of the entire supra-aortal vascular region.
Fig. 2.2 Cavernoma of the lamina quadrigemina. Axial CT at the time of diagnosis (a) and after 8 months (b). Calcifications in the right superior colliculus (a) and enlargement of the hyperdense region due to bleeding with compression of the aqueduct and CSF accumulation (b)
and mask the lower parts of the brainstem. The artifacts can be eliminated only partially with special programs using artefact filters and secondary slice reconstruction from consolidated thin sections. CT perfusion measurements for the differentiation between a nuclear infarct and an undersupplied penumbra do not yet play an important role in brainstem investigations. However, larger intracerebral and extracerebral tumors as well as other infratentorial space occupying masses like cysts and malformations at the craniocervical junction which may lead to CSF accumulation, can also be visualized on CT. The indication for the investigation may be valid in emergency patients with a suspected increase in intracranial pressure. When magnetic resonance imaging (MRI) can, for different reasons, not be done in patients with a suspected tumor, intravenous contrast medium has to be administered to visualize some intrinsic tumors, e.g. astrocytomas and medulloblastomas – blood–brain barrier disorders and conditions that have high vascular density (e.g. von Hippel-Lindau tumor/Hemangioblastoma or vascular malformations) can be better differentiated from the surrounding structures by contrast enhancement. This also applies to abscesses originating from the petrous bone, which may lead to clouding of pneumatisation cells and osteolytic destructions. Other destructions of the skull base, e.g. metastases, chordomas, chondromas or sarcomas, which may be a cause of brainstem compression are also well visualized on CT scans. Enlargements of the internal acoustic meatus (IAC) are indicators of schwannomas, although a negative CT finding alone is not sufficient for the exclusion of this lesion. In cases where MRI is contraindicated, CT cisternography after intrathecal contrast medium injection should be carried out, comparable to the application of this procedure for a suspected cyst, to clarify communication with the subarachnoidal space. CT angiography for brainstem imaging is further used to visualize
2.1.2.3 Risks In accordance with the X-Ray Ordinance for Radiation Protection, any x-ray application must be approved by specialists and is subject to strict regulations, in particular with regard to pregnant women. In the region of the head, the eye lens is especially sensitive to x-ray exposure and should, whenever possible, be protected from the beam path by tilting of the gantry. In spiral technique applications, an x-ray exposure of the eye lens to 70 mGy simulated petrousal bone investigation; (Giacomuzzi et al. 2001) may be assumed when multislice spiral CT is used; the required dose of 0.5–2 Gy (Maclennan and Hadley 1995) for cataract induction is therefore highly unlikely to be exceeded, even after repeated CT scans. The use of x-ray contrast media is also subject to specific requirements: special care has to be taken in the presence of known allergies (possible administration of H1 and H2 blockers), disturbance of kidney function with creatinine levels above 1.5 mg/dL (sufficient water intake and administration of acetylcysteine), increased thyroid hormone levels, or decreased basal TSH (poss. perchlorate blockade), and pathologic serum proteins, as in multiple myeloma. The occurrence of allergic reactions is expected in up to 3% of patients, even in those without a prior history of allergies. However, the allergic reactions only rarely (below 0.04%) lead to a severe circulatory shock if non-ionic contrast media are used. Where indicated, and in the absence of a kidney function disturbance, an iodine-containing contrast medium can be replaced with a gadolinium- containing contrast medium. Patients with cardiac insufficiency have to be monitored for a short-term increase in intravascular blood volume after contrast medium injection.
2.1.3 Magnetic Resonance Imaging 2.1.3.1 Principles and Techniques Magnetic resonance imaging (MRI) is based on electromagnetic waves generated by rotation of the positive proton load (spins). The MRI scanner uses a powerful magnetic field
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(0.2–3 T in clinical applications) to align the spins parallel and antiparallel to the main magnetic field. The rotation speed or Larmor frequency is dependent upon the strength of the magnetic field and ranges at 42.5 MHz for 1 T. There is a slight surplus of parallel aligned spins due to ambient heat, which leads to the generation of a magnetic moment in the direction of the main magnetic field, although this can not yet be measured in itself. The additionally applied energy in the form of a high frequency pulse, which has to be in resonance with the Larmor frequency, causes additional spins to be tilted in the antiparallel direction, while the rotation (precession) of the spins about the direction of the main field is synchronized or brought “in sync.” This leads to the brief generation of a magnetic moment, which rotates in a plane perpendicular to the main field and generates the initially mentioned electromagnetic waves. These are received by a coil, which functions like an antenna and can be used for image calculation (Lauterbur 1973). The energy exchange with the surrounding protons and minute local differences in magnetic field strength lead to rapid dephasing of precession of the individual spins and therefore to signal loss. This spin–spin relaxation is characterized by T2-time and occurs at a significantly slower rate in pure water than in the presence of macromolecules. The image signal from tissues with a high water content is therefore maintained also after a longer latency of above 100 ms, while tissues with a low water content do not emit a signal at this time point due to spin dephasing (T2-weighting: CSF bright, cortex gray, spinal cord dark gray). However, dephasing caused by inhomogeneous magnetic field effects can be reverted with the application of an additional high frequency pulse, which effects a reversal in the rotational direction of the spin, and an “echo” of the initial signal is formed. The described pulse consisting of an excitation and inversion (180°-) pulse sequence is described as spin echo- (SE-) sequence. The energy release to the surrounding protons, the “lattice,” causes the direction of additional spins generated by the high frequency pulse to be switched into the antiparallel direction, and the magnetic moment rotating in the perpendicular plane will decay with time. Concurrently, the original moment is restored parallel to the main field. This spin-lattice rela xation is described by the T1-time and is markedly (up to tenfold) slower than the spin-spin relaxation. If a second excitation pulse is applied at an earlier time point, the more slowly relaxing tissues with a high water content will not yet have recovered full “longitudinal magnetization” oriented toward the field, and only a small surplus of foldable parallel aligned spins is available. As a result, the signal received from these tissues is weaker than that from tissues with shorter T1 time (T1 weighting: CSF dark, cortex gray, spinal cord light grey). If the influence of both T1- and T2-times on the image signal (short echo and long repetition times) is suppressed by means of the selection of respective sequence parameters,
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the number of available protons is the decisive factor regarding the image signal (proton weighting: cortex brighter than spinal cord, CSF dark). Spatial encoding is achieved with MRI by superimposing three gradient fields above the main field. This enables the modification of the local magnetic fields in all three spatial dimensions, so that each voxel receives a specific field and therefore also a specific resonance condition. Special, time limited connections between these fields further permits variation of the rotation frequency of the spins at the time of the echo, to change their phase, and to enable their application for spatial encoding. Due to the small size of the brainstem, the images should have the highest spatial resolution possible, i.e. maximal matrix and thin slice thicknesses. Since the image signal of a voxel depends upon its size, imaging of the brainstem requires either a greater number of measurements (repetitions) or greater field strengths. With the application of several parallel-connected coils the measurement times are shortened and the threat of motion artifacts can be significantly reduced. Spatial resolution can be enhanced with the use of threedimensional techniques. Particularly suitable for T2 weighting is the constructive interference in steady state (CISS) sequence, which allows measurement of slice thicknesses below 1 mm. As a result of the especially long echo times virtually all structures outside the CSF-containing cisterns are visualized as dark areas. The vessels and cranial nerves coursing in the cisterns can be viewed in high resolution images, as can virtual endoscopy procedures (Boor et al. 2000; Fig. 2.3) and the labyrinth in the petrous bone, while intensity differences in the brainstem as, e.g. patches of demyelinization or fresh infarcts versus normal structures are almost impossible to differentiate. The CISS sequence is therefore used mostly to differentiate between a neurovascular compression or a cisternal space-occupying or for petrous bone diagnostic imaging. Epidermoids, which are also almost impossible to differentiate from the CSF-signal, can be shown as mildly (in comparison with CSF) hypointensive space-occupying masses with this modality. T1 weighted sequences are also capable of further enhancing spatial resolution with the measurement of a three-dimensional volume data set, which provides a high signal-to-noise ratio. For reasons of time, the refocusing pulse is not applied here and a (weaker) echo is generated with the application of gradient fields, although this reacts with considerably higher sensitivity to magnetic field inhomogeneities (gradient echo sequence). At the concurrent prolongation of echo time (T2* weighting), the demonstration of fresh bleedings and paramagnetic blood degradation products (ferritin), e.g. older bleedings and cavernomas, becomes possible (Fig. 2.4). The described effect of signal attenuation due to magnetic field disturbances can be used advantageously in imaging perfusion measurements, where
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Fig. 2.3 Acoustic neurinoma. Highresolution MRI (CISS) in T2-weighting (a) and respective calculation of virtual endoscopy (b). Mass at the entrance to the internal acoustic meatus right, and normal course of the statoacoustic nerve left in cerebellopontine angle cistern. View of the lower surface of the tumor and the AICA, viewed as if through an endoscope located more caudally in the parapontine cistern
Fig. 2.4 Pontine cavernoma. MRI in T2 weighting (a) and T2* weighting (b). Signal reduction due to iron deposit (old bleeding) is markedly greater in the T2* weighted sequence, which is substantially more sensitive to susceptibility disturbances
signal degradation as a result of repeated measurements can be observed during the passage of the contrast agent bolus. However, this technique, which has an important role in the diagnosis of supratentorial infarcts and tumors, is not as frequently used in brainstem imaging. The T1 weighted signal of stationary spins can be suppressed by reducing the time interval between two excitations (repetition time), so that in particular successive spins flowing into the excited slice produce a signal (time-of-flight [TOF] angiography for imaging of vessels). Venous overlay can be reduced by presaturation of the sinus above the convexity. Contrast agent infusion enables both suppression of artifacts due to turbulent flow and contrasting of veins (contrast enhanced MRA [CE-MRA]). Comparable to CT-angiography (CTA), the reconstruction of the course of the vessels can be accomplished with postprocessing programs in MRA. Both methods of MR angiography are used to show vascular stenoses and malformations (angiomas, aneurysms; Fig. 2.5), in addition to imaging of neurovascular compressions. For special questions regarding the venous system, the use of TOF-MRA has proven to be of advantage, primarily for intracranial segments, due to the higher spatial resolution, while the examination of a large area is enabled by CE-MRA, making this the more suitable method for the extracranial segments.
A further method for MR tomographic flow measurement – used in particular in investigating CSF-flow at the craniocervical junction, in the cisterns and in the aqueduct – consists of imaging with phase contrast images by means of a two-dimensional steady state free precession sequence at velocity encoding of 7–10 cm/s in the direction of the z axis. The CSF flow leads to a phase shift that is proportional to the flow velocity and therefore quantifiable (Fig. 2.6). However, these investigations are time consuming due to required synchronization with cardiac movements (ECG triggering). Diffusion imaging employs brief applications of strong gradients before and after a 180° pulse, causing only signals of stationary spins to be completely rephased, while spins of diffusing protons produce a weaker signal due to their exposure to gradients of varying strengths as a result of a change in their spatial orientation before and after reversal of the rotational direction. Areas with diffusion disturbances like infarcts and occasionally also fresh patches of demyelinization are therefore viewed with high signal in these images (Fig. 2.7). These lesions are characterized by high signal in both diffusion weighting and T2 weighting sequences, therefore the T2 effect has to be calculated as well as the apparent diffusion coefficient (ADC). Diffusion disturbances are viewed as dark areas on these ADC maps. 2.1.3.2 MRI Investigations of the Brainstem MRI is superior to other imaging modalities in imaging the form and tissue structure of the brainstem, and thus makes a major contribution to differential diagnosis. To be discussed in this chapter are primarily the technique used for the investigation and the brainstem anatomy, while examples of pathologic findings are presented in the respective specialized chapters. All cranial nerves in the cisterns can be shown and differentiated from adjacent vessels on both T1 and T2 weighted sequences. While the robust trigeminal nerve can also be
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Fig. 2.5 Aneurysm of the basilar artery tip. MR angiography (TOF sequence) (a) with MIP reconstruction (b) conventional vertebral DSA left (c) and 3D rotational angiography (d). The aneurysmal sack exits from the basilar artery tip and both P1 segments of the posterior cerebral arteries. The branches supplying the thalamus are visualized on DSA only
Fig. 2.6 Chiari-II (Arnold–Chiari) malformation. MRI in T1 weighting (a), phase contrast image of CSF flow during systole (b), and diastole (c). Descent of the entire brainstem and cerebellar vermis, which extends together with the cerebellar tonsils through the foramen magnum into the spinal canal, with compression of the medulla oblongata and blockade of retromedullary CSF flow. Premedullary CSF flow is still demonstrable, systolic in caudal (dark), and diastolic in cranial (bright) direction
Fig. 2.7 Fresh midbrain infarction. MRI in T2 weighting (a) diffusion weighting (b) and CE MRA (c). While the paramedian infarction (arrows) is visualized primarily as a bright diffusion barrier in DWI, the T2 image shows only slight signal enhancement. CE MRA of the supratentorial vessels does not demonstrate any relevant stenosis
identified on survey scans, this is the case for more delicate nerves like the trochlear or abducens nerve only when a sufficiently high spatial resolution is achieved with CISS or gradient echo sequences. Regarding the vestibulocochlear nerve and the facial nerve, the four bundles of the superior and inferior vestibular nerves, the auditory nerve and the facial nerve in the internal auditory meatus can be differentiated in sagittal sections, while conclusive differentiation between the glossopharyngeal nerve and the vagus is generally not possible. Form, location and size of the individual brainstem segments can be assessed without difficulty. This also applies to the fourth ventricle, and here in particular to the rhomboid fossa, the aqueduct, and the cerebellar peduncles. The internal structure of the brainstem is characterized by close interweavement of pathways and nuclei, which can be very well differentiated with the use of proton weighted sequences and diffusion tensor imaging (see Specialized methods) (Fig. 2.8). In proton weighted images the pathways and nuclei display varying degrees of brightness, depending on their proton content. Diffusion weighting visualizes the different courses of pathways by giving preference to the diffusion parallel to the pathway (signal reduction) or by reducing the diffusion perpendicular to it (signal enhancement).
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Fig. 2.8 Normal MRI anatomy of brainstem pathways. T2 weighting (a, b), proton density weighting (b, e, f) color coded DTI maps (c, f). Axial sections through the lower part of the pons (a, c, e) and the midbrain (b, d, f). 1 Pontine base with corticospinal tract (pyramidal pathway) and 2 pontocerebellar tract (middle cerebellar peduncle), 3 pontine tegmentum with tegmental tract, 4 medial longitudinal fascicle, 5 spinocerebellar tract (lower cerebellar peduncle), asterisk: lateral part of the reticular formation with vestibular nuclei, 6 substantia nigra, 7 crossing of cerebellar efferents (cerebellorubrothalamic tract), 8 medial lemniscus, color coding on DTI color maps, red: trajectories in right-left direction, green: trajectories in AP direction, blue: ascending and descending trajectories
Sections through the upper part of the medulla oblongata permit identification of the long pathways, e.g. the pyramidal pathway ventrally, the medial lemniscus in the center, and the olive and the ascending pain and cerebellar pathways laterally. Located in the dorsal part of the medulla, i.e. in the floor or exit of the fourth ventricle, is the medial longitudinal fascicle, as well as the primary nuclei of the cranial nerves IX–XII. The corticospinal tracts and the cerebellar afferents coursing in a lateral direction are visualized in the base of the pons and can be differentiated from the more dorsally located pontine tegmentum with the medial and lateral lemnisci, the central tegmental tract, and the medial longitudinal fascicle. Visualized in the sections through the midbrain are the descending pathways in the cerebral crus, as well as the substantia nigra with several markedly enlarged Virchow–Robin spaces in the T2 image, where the relatively bright crossing of the cerebellar efferents, and the more rostrally located red nucleus, the lamina quadrigemina and the periaqueductal gray can also be identified. Pathologic processes of the
brainstem associated with severe morphological changes as, e.g. complex malformations (Chiari malformation, Dandy– Walker complex, Joubert syndrome), tumors of the brainstem and adjacent structures, as well as obstructions of the CSF passage with resulting hydrocephalus can be identified without difficulty. Pronounced stenoses or occlusions of the aqueduct, e.g. after inflammations, typically appear as a trumpet-shaped enlargement of the rostral segment of the aqueduct, which is located anterior to the occlusion. These can often already be identified in T2 weighted images due to the absence of a flow signal (no flow-related signal decay). Under these conditions the phase-weighted sequences described above are particularly suitable for flow imaging. Furthermore, atrophies due to system degeneration, i.e. olivopontocerebellar atrophy (OPCA) or pseudobulbar paralysis can be identified based on apparent loss of substance in the medulla, pons and/or midbrain (mesencephalic sagittal diameter below 14 mm). Intracerebral lesions of the brain substance like infarcts and patches of demyelinization require the use of at least T2 weighted sequences with high resolution (512 MB matrix or a narrow field of view) and thin slicing (slice thickness 2–3 mm). Wallerian degeneration of brainstem pathways can also be shown with this procedure, as well as toxic or metabolic damage to pathways, as in pontine myelinolysis, or the rare occurrence of olivary pseudohypertrophy following central tegmental tract lesions. The evaluation of proton weighted images is not readily accomplished in the brainstem, due to the close anatomic relationship of the gray matter to the white matter; this is in contrast to the cerebrum where edemas and gliomas can be well identified using this weighting. As mentioned above, exact anatomic knowledge of brainstem structures is a prerequisite for the differentiation of circumscribed lesions of pathways and nuclei in proton weighted images. Furthermore, fluid attenuated inversion recovery (FLAIR) sequence, which provides valuable supratentorial information, also does not yield a contrast-rich image of small brainstem lesions. In the presence of acute vascular processes, in particular of ischemic infarctions, diffusion weighted sequences should be taken to ensure that small lesions are not missed, and can be differentiated from possibly existing older ones (Fitzek et al. 1998). Infarcts lead to the breakdown of cell metabolism and ion pumps. This results in development of intracellular edema with compression of the extracellular space, the location with the most prolonged and therefore MRI-relevant water diffusion. A diffusion obstacle is created as a result of cellular swelling and the interruption of the active proton transport through the membrane. As diffusion leads to signal loss in MRI images, the nuclear infarcts with diminished diffusion appear early and are characterized by high signal intensity, while signal enhancement in the T2 weighted image, which is dependent on the water content, occurs after several hours or days. MRI is therefore superior by far to CT,
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particularly for the early diagnosis of brainstem infarcts. Although brainstem bleedings are also visualized on MRI in the acute stage as space-occupying masses – and with signal inhomogeneities in the diffusion image – they can be better shown with a latency of several days, due to the pronounced increase in signal intensity on T1 and T2 weighting over time. Ferritin deposits can be identified even later but particularly well in T2* weighted images, whereby cavernomas exhibit a typical “mulberry-shaped” arrangement of dark borders and a bright center. These deposits are absent in teleangiectasies and in developmental venous anomalies (DVA). For the investigation of space-occupying masses, a gadolinium-containing MR contrast medium is generally administered to display disturbances of the blood brain barrier as, e.g. gliomas or abscesses. A contrast material should also be injected for lesions whose origin can not be conclusively identified (ischemic, traumatic, or degenerative) in order to detect the presence of a blood–brain-barrier disturbance and thus to enable the diagnosis of an acute occurrence and/or spread of a process. This is of particular importance in multiple sclerosis when a acute episode of the disease is suspected, as well in the also well localized acute disseminated encephalomyelitis (ADEM), where all lesions are at a similar stage of development and therefore capable of uniform contrast medium uptake in the acute stage. Other inflammatory processes – sarcoidosis, borreliosis, tuberculomas and other encephalitides (e.g. listeriosis) – as well as neoplastic infiltrations in the cisterns and the substance of the brainstem are further visualized as circumscribed areas with enhancement (Fig. 2.9). Acute Wernicke’s encephalopathy due to vitamin B1 deficiency is also characterized by blood–brain-barrier disturbances, typically in the central gray matter of the midbrain and the hypothalamus. Contrast medium is also given to detect the above- mentioned vascular malformations, although primarily for the
Fig. 2.9 Infiltration of basal cisterns and brainstem in lymphatic leukaemia. Sagittal section in T2 weighting (a) and T1 weighting following contrast medium application (b). Marked signal (T2) enhancement (edema) in the medulla oblongata with circumscribed barrier disturbance (contrast agent leakage), extra- and intracerebral
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performance of MR angiography. While the contrast medium free TOF method provides better spatial resolution, it occasionally is rendered less diagnostic by turbulence caused by artifacts and is dependent upon flow velocity. Contrast medium is given in patients with arteriovenous malformations mostly to image venous drainage, while the arterial feeders are better captured on TOF angiography. This also applies to showing neurovascular compressions like trigeminal neuralgia, as well as to other cranial nerve disturbances, e.g. vascular compression of the vestibulocochlear nerve with concomitant attacks of vertigo. In addition to the abovementioned CISS sequences, TOF angiographies before and after contrast medium application are used here, to enable the differentiation between arterial and venous vessels in close proximity to the nerves. Contrast enhanced MR angiography (CE-MRA) is used to show the entire supraaortal region. Compared with contrast medium free angiography, which provides a higher resolution, CE MRA offers the advantage, that turbulence artifacts can be reliably differentiated from genuine constrictions. The demonstration of therapy relevant stenoses and occlusions on CE-MRA can be accomplished with a high degree of certainty, so that conventional digital subtracted angiography in the vertebrobasilar region is used in exceptional circumstances and exclusively for diagnostic reasons. This also applies to TOF-MR angiography for the detection of aneurysms. A high reliability rate can be achieved with this modality for aneurysms of 3 mm in diameter and above (Hirai et al. 2005).
2.1.3.3 Specialized Methods The following specialized methods are used for investigations by MRI imaging: • Cerebral activation • Diffusion tensor imaging (DTI) • Spectroscopy During cerebral activation the linkage of neuronal activity and brain perfusion leads to vasodilation with a latency of a few seconds. This produces both an increase in perfusion and oxygenated and therefore diamagnetic hemoglobin content. Both effects lead to a small increase in signal intensity, although this is only slightly higher than the basic noise of the image signals. The statistic significance therefore has to be demonstrated based on the correlation between repeated activations and signal development. Brainstem activations can thus be demonstrated with horizontal and vertical gaze direction nystagmus at different levels (pons or mesencephalon). In patients, this method has so far been applied for the preoperative diagnosis of cerebral processes (motor and speech activation). Diffusion tensor imaging (DTI) represents a further development of diffusion weighting. Since the diffusion of
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water molecules is always isotropic in water, but restricted in tissue by cell borders, and particularly by axon sheaths (anisotropic diffusion), the degree of anisotropy and the principal diffusion direction can be determined with gradient applications in different directions, and the measurement of a nine component diffusion tensor. The degree of the averaged diffusion direction and anisotropy serves as a parameter for intact nerve tract function. The courses of the main nerve tracts can be reconstructed from the principal characteristic vector of the tensors in the form of direction-coded color maps (Fig. 2.10). In clinical practice this method is used primarily for preoperative imaging of cerebral tumors and vascular malformations. The purpose of
the depiction of pyramidal pathways or optic radiation, and transfer of the trajectories to neuronavigation systems is to avoid injury of these pathways in the course of surgical interventions. This method can also show the corticospinal projections that traverse the pontine base. The signal of protons from water molecules used for imaging is suppressed during spectroscopy, which causes signals of protons from other substances to be visualized. Depending on their molecular environment, these show a slight substance-specific shift in Larmor frequency compared to water. The described frequency shift permits differentiation of three major peaks (choline [CHO] as a marker for membrane reconstruction, creatinin [Cr] as an indicator of energy metabolism, and N-acetyl aspartate [NAA] as an osmolyte). In the presence of tumors and depending on the tumor grade, there is an increase in the choline level compared with the creatinin level, and a decrease in the level of N-acetyl aspartate (Fig. 2.11). A lactate peak might be observed in acute inflammations and demyelinizations. Other products of metabolism as, e.g. amino acids or acetates in abscesses may, in some instances, be shown on spectroscopy. This method is nevertheless rarely used in clinical brainstem diagnostic tests, because the small measurement volume required here necessitates a long examination time.
2.1.3.4 Risks
Fig. 2.10 Trajectories of the right medial longitudinal fasciculus calculated from DTI data sets in axial (a, b) and sagittal cross-section (c)
Apart from slight tissue warming and the occurrence of photopsias at high magnetic field strengths (3 T), no MR- specific side effects have been shown in tissue, on condition that specific absorption rates (SAR) are given consideration. The indication for MRI examinations should, however, be particularly strict in pregnant women – especially in the second part of pregnancy – because the fetus reacts with increased movement to the acoustic noise due to the rapid switching on and off of the magnetic field gradients. 1 12 10
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Fig. 2.11 Thalamus and brainstem glioma: T2 weighted section through the lamina quadrigemina (a) and proton spectroscopy (b). Right-paramedian, in T2 signal-intensive space-occupying lesion in medial part of the thalamus and the superior quadrigeminal bodies, with pronounced increase in the choline peak (1), a slightly decreased creatinin (2) and markedly decreased N-acetyl-aspartate (NAA) peak (3)
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4 2 0 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
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While MRI does not generally represent a health hazard, the situation is completely reversed in the presence of ferromagnetic foreign material in the body, e.g. iron or steel remnants (shell fragments, splinters after accidents, old implants), that may heat up and cause injury to the vessels or nerves as a result of displacement. This applies in particular to old aneurysm clips and intraorbital metal fragments. Metallic paints used in tattoos can also cause burns. Damage may further result from the antenna effect of metal wires inside and outside the body that are used as electrophysiologic leads (e.g. ECG cables and electrodes). Whenever possible, these should be replaced with light guides. Especially patients with pacemakers are at a high risk for burns and subsequent scarring, as well as for arrhythmias. In this context MRI is rarely indicated only in patients with specially designed pacemaker devices or with a vital indication, and under adherence to appropriate safety precautions (among others the presence of a reanimation team with cardiologic competence) (Loewy et al.2004). Although other metals, including platinum or tantalum are not paramagnetic, artifacts frequently appear. Substantial signal loss and major image distortions are also caused by dental braces. To a lesser degree these events may also result from body piercing and make-up, especially from eye shadow containing active magnetic substances. Another, not insignificant risk is posed by the presence of ferromagnetic objects (gurneys, wheelchairs, surgical instruments, gas bottles) in the examination unit, if these are pulled into the scanner with a great expenditure of energy and transported while being exposed to increasing magnetic field strength in the vicinity of the magnet. Monitoring of the patient in the scanner is also difficult. A MR compatible device for the measurement of vital parameters is not always available, so that particular attention must be paid to the occurrence of epileptic episodes, or cardiovascular and respiratory disturbances as well as sudden emesis, which may develop in brainstem processes. A similar problem may arise during chemical sedation which may be indicated in agitated patients, e.g. small children. Gadoliniumcontaining contrast agents are better tolerated than the contrast media used in x-ray radiography, since the volumes are smaller and no iodine is injected. Although allergic reactions are also rarer, they may nevertheless be life-threatening. The use of unbound gadolinium may lead to nephrogenic systemic fibrosis in patients with severe renal impairment, and an accurate diagnosis is imperative in these cases.
2.1.4 Angiography and Endovascular Interventions 2.1.4.1 Diagnostic Angiography Conventional angiography requires technical skill as well as experience and is, as an invasive procedure, associated with
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a complication rate. In the presence of an exclusively diagnostic indication it is therefore increasingly replaced by Doppler sonography and CT or MR angiography. Conven tional angiography provides a high spatial resolution and enables the depiction of blood flow phases in chronological order, therefore this “gold standard” cannot be completely abolished. Selective vertebral angiography is required for visualization of the vertebrobasilar vascular system and can, especially in younger patients, be performed without technical difficulties. The Seldinger technique with insertion of the catheter via the femoral artery is employed for this procedure. The use of the subtraction technique permits the elimination of bone densities and leads to a significant improvement in image quality, especially in the posterior cranial fossa where the overlying petrous bones can be dispersed. It is carried out in form of digital subtracted angiography (DSA), if possible with a biplane x-ray unit. By the use of selective catheter placement in a vertebral artery, this procedure enables reduction of the contrast medium volume to a few milliliters, at an iodine content of 250 mg/mL compared to injection into the subclavian artery. A 3D-technique for angiography has become available, equipped with a C-arm unit that rotates around the head of the patient placed in the isocenter. With this procedure, complete angiograms at intervals of only few angular degrees are possible. The obtained data sets are used for three-dimensional reconstructions of the cervical and intracranial vessels which provide details of particular value in the diagnosis and therapy of aneurysms (free projections of the aneurysm head, exact measurement). Indirect techniques like countercurrent angiography of the brachial artery with the injection of 30 mL of contrast medium using high pressure, and contrast medium injection via a central venous catheter have been largely abandoned, as they do not offer any advantages over sectional image angiography with regard to image quality. Direct puncture of the vertebral artery is contraindicated due to the high risk of complications associated with intramural contrast medium injection. In the arterial phase of angiography, the origin of the vertebral artery from the subclavian artery is slightly constricted, also under normal conditions. Visualized in the further path of the vessel are the V1-segment up to its entry into the transverse foramen of the sixth cervical vertebra, the V2-segment in the homonymous “canal,” the arch of the atlas (V3-segment) between the second cervical vertebra and the foramen magnum, and finally the V4-segment until it unites with the contralateral vessel. From its cervical part, the vertebral artery sends muscle branches which anastomose with the other cervical arteries, principally with the external occipital artery. In the presence of embolizations in this region, these anastomoses have to be regarded as possibly “dangerous.” From the V4 section two meningeal branches supplying the dura mater originate extracranially, while the posterior inferior cerebellar artery (PICA) originates at a different level from an intradural location and divides, after a variable, loop-shaped course along the
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medulla oblongata, into two branches which supply blood to the basal parts of the vermis of the cerebellum and the cerebellar hemispheres. Small branches originating from the intracranial vertebral artery cross the lateral medullary fossa to supply the lateral medullary tegmentum and dorsal lateral base. The anterior spinal artery also originates from the V4 segment in a mostly asymmetrical fashion. Conversely, the anterior inferior cerebellar artery (AICA) branches off the proximal section of the basilar artery in the prepontine cistern and supplies the medial portions of the cerebellum; it also characterized by a vicarious relationship with the PICA and the more distally arising middle cerebellar artery. Angiographic depiction of the latter, as well as of the pontine branches, is possible only if the vessels are dilated due to the abnormally rapid rate of blood flow associated with arteriovenous malformations or fistulae, otherwise the vessels are too small to demonstrate. The superior cerebellar artery (SCA) arises in the distal segment of the basilar artery, frequently divided into two branches on one side. The cisternal segment of the artery winds around the midbrain and supplies the surface of the cerebellum, sending one branch to the superior vermis, one marginal hemispheric branch to the lateral fissure, and additional branches to the cerebellar convexity. At its tip, the basilar artery divides into the posterior cerebral arteries which proceed parallel to the superior cerebellar artery in the ambient cistern, i.e. rostral to the oculomotor nerve that travels in an anterior direction between these two arteries. The cisternal posterior segments (P1 and P2) are individually variably connected with the carotid siphon via the posterior communicating arteries and are therefore of critical importance for the basal collateral circulation (cerebral arterial circle [circle of Willis]). The thalamic perforating branches, as well as the medial posterior choroidal artery which proceeds to the plexus of the third ventricle, arise from the cisternal segment and require particular attention in the presence of basilar tip aneurysms. Increased vascular filling in the posterior cranial fossa occurs after an arterial phase of approximately 3 s and a long capillary phase of 2 s, a period during which vascular staining is observed only in pathological cases. The anterior and posterior veins of the cerebellar surface draining into the great cerebral vein (vein of Galen) and the tentorial sinus can be differentiated, as well as, in some instances, the veins draining into the transverse and sigmoid sinuses. Perimesencephalic and prepontine veins are further visualized, and parapontine imaging of the vein of Dandy draining into the superior petrosal sinus is accomplished. In addition to the blood flowing through the jugular foramen into the bulb of the internal jugular vein, which also receives blood from the inferior petrosal sinuses and occasionally from the occipital sinus, the occipital emissaries participate, as a variation, in the drainage of the intracranial space. Vascular drainage is further achieved via
the basilar plexus located intradurally on the clivus, and via veins in the neighborhood of the foramen magnum travelling to the internal vertebral venous plexus. The basilar venous plexus may also be responsible for prognostically benign perimesencephalic subarachnoid hemorrhage (SAH), in this case an aneurysm is generally not detected. The indication for diagnostic angiography of the vessels of the posterior cranial fossa is currently made in compliance with strict guidelines. While patients with malformations and tumors of the posterior cranial fossa previously also underwent angiography for the visualization of tumor vessels, or to at least enable the identification of the tumor location on the basis of the demonstrated arterial or venous displacement, today these examinations are carried out primarily in preparation for endovascular interventions. They become possible under certain prerequisites in the presence of vascular processes with stenoses and occlusions of the vertebral or basilar arteries. An investigation of the subclavian artery is further indicated when subclavian steal syndrome is suspected, as well as in cases of vascular malformations, primarily aneurysms, arteriovenous angiomas and dural AV fistulas. On occasion, conventional angiography is required for the preoperative identification of venous anomalies in the neighborhood of brainstem cavernomas, or of venous or sinus occlusions if CT angiography does not provide conclusive findings. Further indications include the confirmation of vasculitis, a disease which, comparable to degenerative vascular processes, is associated with arterial stenoses, although these may appear to be less punched out and can be accompanied by vascular dilatation. Angiography is also performed when intra-arterial treatment (thrombolysis or mechanical extraction of thrombi is considered as is discussed further below). Safety measures to be considered regarding the application of contrast media, especially in patients with a history of allergic reactions, have already been discussed in the section on computed tomography. The specific risk for neurologic complications associated with diagnostic cranial vessel angiography remains unchanged and ranges from 0.5% to 1%, despite the use of modern non-ionic contrast media with reduced osmolality and the technological improvements of catheters and guide wires (Willinsky et al. 2003). In addition to pareses, ataxias and eye movement disturbances represent the most severe complications in the vertebrobasilar system. The causes of these events may be small infarctions induced by embolic mechanisms that can be shown with diffusion weighted MRI in up to 20% of purely diagnostic angiographies, but remain in most cases clinically silent. The incidence of these lesions can be markedly reduced by using air bubble filters and heparinization of the contrast medium, as well as flush solution (Bendszus et al. 2004). Transient amnesia and cortical blindness may develop following infusion of larger contrast agent volumes in patients with the respective disposition, although these events
2.1 Neuroradiology
usually occur only after one or two successive injections. These complications have been interpreted as posterior encephalopathy on the basis of typical MR findings (Saigal et al. 2004). Radiation exposure is dependent upon the duration of angiography, and particularly on the screening time during cerebral interventions. The effective dose value for single interventions varies from 1.5 to 16 mSv, and may be in excess of 40 mSv for multiple procedures (Livingstone et al. 2003).
2.1.4.2 Endovascular Interventions Recanalization Recanalization is performed for vertebrobasilar stenoses and occlusions. These usually develop either as the result of a vascular wall lesion of atheromatous or inflammatory origin with localized thrombosis, or can be of atrial origin emboli due to dysrhythmia, septum defect, or generalized clotting disorders. The most common sites include the already relatively narrow origin of the vertebral artery from the subclavian artery, the intracranial V4 segment, as well as the entire course of the artery. The cervical vertebral segment may also very rarely be constricted from outside by osteophytes of the cervical vertebral joints. The symptoms, e.g. vertigo, can be provoked by certain neck or head positions. Vascular compression may also be caused by tumors like meningeomas or tumors of the base of the skull at the craniocervical junction. Further causes involving both the vertebral and carotid arteries include dissections with bleeding within the vascular wall, e.g. following whiplash injury or chiropractic maneuvers; they may also occur spontaneously in vascular wall disorders, e.g. fibromuscular dysplasia. A distinctive feature of this distribution area is the subclavian steal syndrome. It develops as a result of retrograde vertebral artery blood flow in response to high-grade proximal subclavian artery stenosis or occlusion. For the detection of vascular stenoses or occlusions, including those in the vertebrobasilar region, Doppler sonography represents the method of choice, followed by CTA or MRA techniques. Only when these do not provide a satisfactory confirmation of the tentative diagnosis, or if conflicting clinical findings are reported, can invasive conventional angiography be applied for diagnostic purposes. In the presence of proximal vascular processes, the origins of the vertebral arteries on both sides may be so severely narrowed that even short-term occlusions resulting from catheter insertion on one side are not tolerated. With a view to the possible development of brainstem ischemia, selective catheterization should be dispensed with for safety reasons, and the depiction of the vertebral artery should be attempted by means of a survey angiography of the subclavian artery, a
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possibility to improve the quality in these cases is the simultaneous compression of the respective brachial artery manually or during blood pressure reading. Although this does not provide a high-contrast image, it is generally satisfactory to permit a conclusive diagnosis. In the setting of proximal vertebral artery occlusion, the depiction of the collateral supply via cervical branches of the subclavian artery – the ascending or the deep cervical artery – as well as of superior cervical anastomoses with the occipital artery may be required. Endovascular therapy for stenoses of the vessels responsible for blood supply to the brain was introduced in the 1980s. While this initially involved widening of stenoses at the carotid bifurcation and in the proximal section of the subclavian artery in the presence of a steal syndrome (Kachel et al. 1991), these interventions were later also successfully performed at the origin of the vertebral arteries and, more recently, also along the extracranial and intracranial course of the vertebral and basilar arteries. The therapeutic intervention is initiated by introducing a guide catheter over which a micro guidewire and a microcatheter can be advanced through the stenosis. After a exchange-maneuver, a balloon catheter is then passed over the microwire and inflated to dilate the stenosis. Subclavian artery occlusions can also be recanalized in this manner, provided a guidewire is successfully advanced through the occluded passage from the proximal or distal lumen of the vessel (after puncture of the brachial artery). The inflated balloon does, however, not only push atheromatous plaque into the vascular wall, but may also cause dissections and thus the risk of distal emboli affecting the entire vertebrobasilar system if they develop in the subclavian artery. Acute thrombosis of the dilated vascular segments represents a further, albeit rare complication. The administration of platelet aggregation inhibitors (acetylsalicylic acid, clopidogrel) before and after the intervention is therefore indispensable. With the use of these agents, subclavian artery interventions, also without additional stent applications, were reportedly associated with the recurrence of vascular occlusions in only 10% of cases over a 5-year postinterventional period. The prognosis for vertebral artery origin stenoses and intracranial artery stenoses after dilatation alone was less favorable, so that stenting was increasingly required to provide vascular wall support. In contrast to coil closure of aneurysms, where the stent serves to prevent coil loop prolapse into the parent vessel and wall stress in the artery is lower, stenoses have to be widened and patency of the lumen must be maintained. For this reason, primarily balloon-tipped models are mainly used for stenosis dilatation (Fig. 2.12). Vascular dilatation can be carried out after predilatation or concurrently with stent placement. Stents with a great radial force have to be employed in vertebral artery origin stenoses, similar to those used for renal artery origin stenoses, in order to ensure sustainable success. In the further course of the vertebral artery, specifically in the intracranial segment,
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Fig. 2.12 Dilatation/stenting for intracranial vertebral artery stenosis persisting under anticoagulation therapy. Vertebral artery angiography (a) before and (b) after stent application in the subtracted image, native image (c) with stent (arrows)
high-flexibility stents have to be used to avoid injury to the vascular wall during placement. Self-expanding stents for use in the intracranial territory are available today, although in some instances redilatation may be required. The risk for occlusion of the small arteries arising from intracranial segments of the vertebral and basilar arteries is apparently less high than initially assumed, due to the rare occurrence of ischemic complications in the area adjacent to the stent. This also applies to “overstenting” at the origin of larger vessels like the cerebellar arteries, which remain patent in the vast majority. The risk for complications associated with the intervention itself (ischemia, stent thromboses, bleeding) has been shown to range 9–15% (Weber et al. 2005; Kurre et al. 2010). Recurrences observed for coronary arteries unfortunately also occur in the cerebrovascular system. Six months after dilatation and stent therapy the incidence rate of intracranial residual stenoses ranged at 30%, while a rate of more than 40% was reported for extracranial residual stenoses, which were most frequently observed at the origin of the vertebral artery. These lesions were resymptomatic in more than a third of cases (SSYLVIA Study Investigators 2004). The therapy of vertebral artery origin stenoses may therefore be started by dilatation without stent placement and the intervention can be repeated should restenosis occur. A staged procedure has recently been proposed for therapy of intracranial stenoses where dilatation and stenting is performed at intervals of several weeks. Overall, stent-assisted dilatation for arteries supplying blood to the brain is an area undergoing continuing development of materials and application techniques, and therefore does not enable a concluding statement at this time. An evidence-based advantage of invasive therapy over conservative treatment has not been demonstrated in the available literature. The indication for stent-assisted dilatation of stenoses must thus be carefully considered. With respect to subclavian artery interventions it should be limited to patients with symptomatic steal syndrome, and in the presence of vertebral artery origin stenoses to patients with bilateral constrictions and ischemic symptoms persisting under anticoagulation therapy. The latter also applies to intracranial vertebral and basilar artery stenoses where collateralization via the posterior communicating artery does not infrequently occur.
Regarding the performance of acute dissections, reserve is also essential in judging the indication for interventional vessel dilatation, to prevent vascular wall bleeding from being pressed out with the subsequent danger of embolizations into distal regions. The thorough pre- and postinterventional therapy with thrombocyte aggregation inhibitors is indispensable for any stent application. A different situation is encountered in patients with acute occlusion of both vertebral arteries, or of the basilar artery due to the very poor prognosis for the spontaneous course, where the omission of lysis is known to result in a mortality rate of 40%, as well as in the need for constant care in two thirds of survivors (Schonewille et al. 2005, 2009). While embolism represents the most common cause in the distal basilar segment, in the proximal segment pre-existing stenosis with subsequent thrombosis may be the causative factor. The occlusion should be removed as early as possible due to the otherwise poor prognosis, whereby the local procedure has been the preferred measure for over 20 years compared with systemic lysis. Similar to supratentorial acute infarction, basilar or vertebral artery occlusions always represent a medical emergency. In the absence of a conclusive Doppler sonography finding, the diagnosis of vascular occlusion can be confirmed by CT or MR angiography. In contrast to middle cerebral artery trunk occlusion, the time limit to fibrinolysis has not been definitely defined and depends on the clinical condition: a rapid, invasive procedure in the presence of progressing symptoms, but reserve in patients with symptoms of several hours or prolonged infarctions. All other contraindications to lysis therapy, comprising bleedings, injuries, or prior surgical interventions, must self-evidently be observed. The optimal therapeutic procedure for this entity is still under intense discussion (Schonewille et al. 2009; SchulteAltedorneburg et al. 2009), the BASICS registry opened that field again. The intravenous versus the intraarterial use (with or without a bridging concept) of thrombolytic drugs is recommendable, the superiority of one of the concepts has not been thoroughly investigated. Intra-arterial lysis is performed via microcatheter with the infusion of urokinase (upto 1,000,000 IU) or recombinant tissue plasminogen activator (rT-PA upto 100 mg). Alternatively,
2.1 Neuroradiology
glycoprotein IIb–IIIa inhibitors can be used. In thrombolytic therapy, the tip of a microcatheter is either advanced to the proximal end of the thrombus or the embolus, or moved past this within the vascular lumen with the help of a guiding catheter; lysis is then achieved on slow catheter withdrawal. Despite the application of high doses, recanalization of the arteries can be expected in only 44–80% of cases, depending upon the volume of the thrombus and the time interval to onset of lysis. In addition, there is the danger of embolizations into the superior cerebellar and the posterior cerebral arteries. Mechanical thrombus removal is therefore frequently attempted, although with unpredictable success. Applied are wire loops, wire spirals and wire baskets for the retraction of an embolus, mechanical destruction using ultrasound or negative pressure (water jet pump effect), as well as “simple” aspiration via microcatheter, which is considered to be relatively effective, in particular in combination with preceding partial lysis (Fig. 2.13). The effectiveness of recent developments like mechanical thrombus fragmentation, brush-type microwires, and temporary stent insertion for acute therapy remains to be shown. Because proximal occlusions frequently occur in combination with stenoses, additional dilatation with stent application is recommended in these patients. A similar procedure is also possible for distal occlusions if lysis or mechanical thrombectomy is unsuccessful after a period of time. However, the paucity of currently available data does not permit a definitive statement on the success of this procedure. Critical prognostic factors include the patient’s clinical condition, and the latency to vascular recanalization (Eckert et al. 2002). For each intervention, additional bridging to the onset of therapy is possible with systemic administration of r-TPA or eventually glycoprotein IIb–IIIa inhibitors, and additional postinterventional heparinization over a minimum period of 24 h is requisite. Since platelet aggregation inhibitors further have to be given when stents are used, the anticoagulation regimen needs to be tailored to individual needs, to avoid provocation of intracranial bleeding. The reported survival rates for these invasive procedures currently range from 30% to 60%, while comparative independence was found in more than 50% of survivors (Pfefferkorn et al. 2005). The results of additional studies have to become available to ascertain if the results obtained
Fig. 2.13 Recanalization of an acute distal basilar artery occlusion. CTA (a) and DSA before (b) and after (c) recanalization. After only partially successful lysis with 10 mg rTPA, the residual (suspected embolic) material was aspirated via vertebral artery catheter. Residual posterior cerebral artery stenosis, right, and occlusion due to floated off emboli, left
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with this procedure are also improved according to evidencebased criteria over those obtained in patients undergoing conservative therapy or systemic lysis.
Embolization Embolization is a therapeutic option for the treatment of vertebrobasilar aneurysms, arteriovenous angiomas and dural arteriovenous fistulas comparable to conditions in the “anterior” circulation. two different types of aneurysms are observed in the posterior cranial fossa: berryshaped aneurysms that classically develop at the junction of vessels where they form a saccular pouch, and fusiform aneurysms formed along the wall of the vessel as the result of a vascular wall disorder (degenerative, inflammatory, or after dissection). In the majority of cases, the first type leads to typical subarachnoid hemorrhage (SAH), or may be an incidental finding, while the second type is more frequently associated with symptoms of brain stem or cranial nerve compression and potential SAH. Berry aneurysms of the vertebrobasilar system occur primarily at the tip of the basilar artery, with the aneurysm neck being located between the two posterior cerebral arteries, or between the posterior cerebral artery and the superior cerebellar artery, but less frequently at the origin of the PICA. They are rarely found at the origin of the AICA, or along the course of the basilar artery, the posterior cerebral artery, or the cerebellar arteries. Although they may occur in conjunction with arteriovenous angiomas. The incidence of vertebrobasilar aneurysm bleeding is markedly higher (1.8% p.a.) than in the anterior circulation, so that their therapy, including that of incidentally found aneurysms, is indicated for all sizes (Vindlacheruvu et al. 2005). After the occurrence of bleeding, emergency treatment should be commenced, due to the possibility of rebleeding, which places the patient at increased risk. Out of two competing therapeutic options, i.e. neurosurgical clipping of the aneurysm neck and endovascular coiling of the aneurysm sack, endovascular intervention in the posterior circulation has gained a certain advantage over clipping, because of the difficult surgical access to the principal
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locations. In the absence of very pronounced atherosclerotic changes in the vertebral artery, an aneurysm at the origin of the PICA, or at the tip of the basilar artery can be accessed via the endoscvascular route without major difficulties by experienced hands. Provided the aneurysm neck is small, a microcatheter is advanced to the site of the aneurysm and the aneurysm sack is occluded with detachable spiral coils (Fig. 2.14). Differently shaped coils consisting of platinum wires formed in the shape of a double helix are available for this procedure. The coils may be made of untreated metal, be coated with a hydrogel matrix, Dacron threads, or vasoactive substances. Separation of the coil from the delivery wire, which is retrieved later, can be achieved by electrolytic, thermic, or mechanical means. Coil occlusion is, however, more difficult to accomplish in wide-necked aneurysms, where the aneurysm neck can be occluded with a temporary balloon during coiling to avoid coil protrusion into the parent vessel (remodeling technique). An assistive stent can also be used for this purpose, and is a suitable device with great flexibility but relatively low thrust force that has been available for a number of years. The disadvantage of this method in an acute patient is the need for anticoagulation, which is mandatory after stent application but requires complete aneurysmal occlusion and leads to difficulties in
Fig. 2.14 Coil occlusion of a distal posterior inferior cerebellar artery aneurysm following acute subarachnoidal bleeding. DSA and 3D angiography (a, b) prior to and after (c) coiling of the aneurysm with visualization of the coil packet in the unsubtracted image (d)
the performance of subsequent procedures, e.g. the insertion of intraventricular drainage. The choice of the appropriate treatment option therefore needs to be agreed on in each individual patient by the neurosurgeon and the neuroradiologist. Reliable data on the benefit of one of these approaches over the other in the posterior fossa, in contast to the vessels in the anterior circulation, was not shown by the results of the ISAT study (Molyneux et al. 2002), due to the small number of patients with vertebrobasilar aneurysms included in the study. The decisive factor for the success of aneurysm coiling is the size, shape of the aneurysm sack and the configuration of the aneurysm neck. On average, therapeutic effective (sub) total occlusion can be expected in 80% of cases. The periprocedural complication rate of incidental aneurysms, without consideration of sequelae after bleeding, ranges below 5%. Coil compaction or widening of the aneurysm neck may lead to recurrence (~15%). Angiographic follow-up studies are therefore recommended after 6 months and 2 years; at these time points a re-coiling (Fig. 2.15) may be performed (Berkefeld et al. 2004). Recurrent bleeding occurred in 1% of
Fig. 2.15 Coil occlusion of a fusiform vertebral artery aneurysm left with brainstem compression. MRI with partially thrombosed aneurysm before intervention (a), vertebral DSA left before coil occlusion (b) and vertebral DSA right before a second intervention with recanalization and widening of aneurysm (c). After stent application via the vertebral artery right, and repeat coil occlusion of the distal aneurysmal segment (d)
2.1 Neuroradiology
cases during the first 12 months after coil occlusion, but developed less often after clipping. The findings of the ISAT study (Molyneux et al. 2002) showed a significant and durable better clinical result – at least in the anterior circulation – after the endovascular procedure than after neurosurgical clipping. Fusiform aneurysms of the vertebral or basilar arteries can lead to life-threatening brainstem compressions. The prognosis is also very poor in patients with vasodilatation developing after a dissection with intracranial bleeding. If an additional circumscribed saccular dilatation is present in the fusiform dilated segment, this can be treated with a neurosurgical or endovascular approach (using stenting and coils as in saccular aneurysms). Although coiling does not remove the space-occupying mass, it can reduce pulsations and thus lead to an improvement of symptoms. Occlusion of the entire dilated segment with clipping or coiling (trapping) represents a therapeutic alternative. In this setting, a balloon occlusion test has to be carried out prior to clipping/ coiling to ensure that the described occlusion will be tolerated. Another alternative is occlusion of one or even both vertebral arteries in the V4 segment to achieve a change in flow dynamics (although its form can not be accurately predicted) in an attempt to effect (partial) embolization of the aneurysmal lumen. The prerequisite for this procedure is, once again, adequate collateralization of the basilar artery via the cerebral arterial circle. Closed-wall stents (covered stents), very fine-meshed stents (flow-remodelling stents) and multiple telescoped intracranial stents are capable of blood flow modelling that enables extensive reconstruction of the original vascular lumen and thus offers further therapeutic options. Techniques like that were previously limited by the unsatisfactory flexibility of previously available stents (Saatci et al. 2004). Only 5–20% of cerebral arteriovenous angiomas or malformations (AVM) are found at an infratentorial location, with only 25% of these being situated in the brainstem. They may occur as part of a general “angiomatosis,” e.g. Osler’s disease, or Wyburn-Mason syndrome. They can become manifest most frequently in the form of bleedings and less often with neurologic deficits. Whether the tendency to hemorrhages is increased compared to the supratentorial location is controversially discussed. The precarious location renders both neurosurgical and endovascular interventions difficult, because not only misembolization into non-target arteries, but also perinidal edema and hemorrhages may occur after successful embolization. If an occlusion of the respective segment is nevertheless indicated in patients with rebleeding or progression of symptoms, and in view of the fact that the size of brainstem AVMs is generally in the favorable range of below 10 mm,
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stereotactic radiation represents the therapy of choice. However, the finding that post-therapeutic perinidal gliosis and rebleeding may occur until the time of definitive obliteration of the vessel after a period of up to 3 years has to be accepted. Successful embolization of brainstem AVMs has been reported in a small series of patients, in whom the usual procedure (injection of a N-butyl-cyanoacrylate [NBCA]lipiodol mixture into the nidus via microcatheter) was performed without significant complications, although complete obliteration was achieved in only one out of six patients (Liu et al. 2003). On principle, embolization is a factor which requires consideration in the decision on the therapeutic concept for brainstem AVMs. Comparable to pial AVMs, dural arteriovenous fistulae (DAVF) can cause bleeding and neurologic deficits, the latter developing as a result of venous reflux leading to edema and subsequent gliosis. DAVFs of the posterior cranial fossa are supplied by branches of the external occipital artery, the ascending pharyngeal artery, the medial and posterior meningeal arteries, as well as by the internal carotid artery (tentorial artery), that drain primarily into the sigmoid and transverse sinuses. In uncomplicated cases they may cause pulse-synchronous bruits in the ear. In cases of orthograde drainage (Borden Type I) there is no absolute need for therapy. In the presence of additional sinus stenoses, retrograde drainage into the cranial veins may develop (Borden Type II); this may further be observed in lesions located on the border of the tentorium. There may also be direct shunt drainage into the leptomeningeal veins (Borden Type III), which are then frequently characterized by circumscribed stenoses and widening (Szikora 2004). As space-occupying masses, the latter can cause brainstem and cranial nerve compression. Involvement of the cranial nerves is often associated with subarachnoidal or intracerebral bleedings, so that shunt occlusion must always be attempted when cranial nerves are involved. While a short-term improvement may be observed following transarterial embolization with particles, NBCA or OnyxR, the ramified vascular network can only less often be completely occluded with this therapeutic measure. Because the actual fistula points are mostly confined to a circumscribed region of the drainage vein, this region can be coil occluded via a transvenous approach, which enables complete obliteration of the fistula. Prior to this intervention it has to be angiographically confirmed that no other cranial veins drain into the segment designated for occlusion. This is of particular importance for fistula drainage into the transverse or sigmoid sinuses, whose occlusion could otherwise lead to bleeding due to passive hyperemia. Available alternatives to the endovascular approach in the therapy of DAVFs or incomplete fistula obliteration include neurosurgical interventions, e.g. “skeletization” of a sinus, or stereotactic radiation.
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2.2 Ultrasound Diagnostics Martin Eicke and Uwe Walter Ultrasonic diagnostic procedures of the brainstem have undergone continuous development over the past 20 years. The possibility of non-invasive identification of intracranial vertebrobasilar stenoses was first opened with the introduction of transcranial Doppler sonography in the mid-1980s. The advent of color duplex systems in the early 1990s saw the beginning of the age of accurate anatomic localization of intracranial vessels. The further development of duplex systems finally enabled transcending the boundaries of “classical” vascular ultrasound and placing image-morphologic aspects in the foreground of scientific research. The potential of this method has not yet been exhausted, in particular with regard to the therapeutic possibilities for extrapyramidal system diseases. The following chapter therefore discusses both the aspects of vascular ultrasound as the currently well established standard procedure and the possibilities of intracranial morphologic B-mode image diagnostics.
2.2.1 Vascular Ultrasound 2.2.1.1 Anatomic Principles Extracranial course: The origin of the vertebral artery (V0) is the preferred site of atherosclerotic plaque formation in this vessel and the entire posterior circulation. Endothelial rupture due to the physiologic presence of shearing forces and turbulences develops particularly frequently in this region and may lead to emboligenic stenoses in the further course. The hemodynamic risk of proximal stenosis or occlusion is relatively low, as extensive anastomoses usually provide sufficient distal vessel refilling via the contralateral vertebral artery or branches of the external carotid artery. The vertebral artery then travels craniad, anterior to the scalene muscle (prevertebral segment, V1) and enters the costotransverse foramen at the level of the sixth vertebra (transverse segment, V2). Distal to the foramen of the axis it initially curves at a 90° angle lateralward and runs again upward; after issuing from the foramen in the transverse process of the atlas the vessel bends backward at a right angle (V3). It finally curves medially and crosses the atlas via the vertebral artery sulcus (atlas segment, atlas loop); in this region the vessel is also predisposed to atherosclerotic changes and trauma, due to its pronounced tortuosity. The vertebral artery then pierces the posterior atlantooccipital membrane as well as the dura mater and continues in a rostral direction in the intracranial subarachnoidal space (intracranial segment, V4).
Intracranial course: The intracranial location of the vertebral arteries varies considerably, as significant side shifting may develop. The basilar artery arises at the confluence of the vertebral arteries and is approximately 30 mm long and 3 mm in diameter. In the majority of individuals the vessel courses rostrally in the midline, but in 10–20% of individuals extensive deviations to the right or left may be observed.
2.2.1.2 Principles and Techniques Three different system types are used in vertebrobasilar diagnostics: • Continuous wave (cw) doppler • Pulsed doppler sonography • Color duplex sonography
Continuous Wave (cw) Doppler This instrument evaluates the so-called Doppler shift, the frequency differences between the emitted and the reflected signal. According to the Doppler equation, this frequency difference is dependent on the relative speed of the reflector in relation to the probe on the one hand, and the emitted output frequency on the other hand. Frequency shifts resulting at the usual output frequency of 4 MHz and physiologic flow velocities of 10–200 cm/s, extend from 0.2 to 16 kHz, and are therefore within the audible frequency range of the human ear. The advantages offered by these instruments are that they are easy to handle, reasonably priced, and offer excellent sensitivity. Depth localization is not possible. Conversion of the frequency shift (kHz) to velocity values is not admissible in the presence of an unknown insonation angle. Examination technique: In particular segments V0 and V3 are amenable to examination with cw Doppler sonography. With the transducer held medial and caudal, V0 is imaged approximately 3 cm above the clavicle. The vertebral artery can be differentiated from other vessels in this region (particularly the common carotid artery, thyrocervical trunk) by the strong reverse Doppler effect on intermittent compression in the region of the atlas loop. Optimal visualization of V3 below the mastoid can be achieved with the patient’s head turned slightly to the contralateral side. In contrast to the internal carotid artery, the vertebral artery can typically be depicted with the flow towards the transducer as well as, with slight tilting of the transducer, away from it. While extracranial vessels like the occipital artery can be compressed by applying pressure to the vessel with the transducer tip, which leads to the loss of the Doppler signal, this is generally not possible (except in very slim patients) on insonation of the vertebral artery.
2.2 Ultrasound Diagnostics
Pulsed Wave Doppler Sonography (pw Doppler) Pw Doppler devices offer the additional option of depth allocation. Selective presetting of a time window of interest between transmission and reception enables analysis of the reflected signal from a specified depth window. One advantage among others is that a vessel can be followed along its course deep into the tissue. In vertebrobasilar ultrasound this procedure is particularly appropriate for V4/basilar artery examinations with the use of a low frequency 2 MHz transducer capable of deep penetration. Examination technique: The patient should be in a sitting (or supine) position and lower the chin as far as possible to the chest. The transducer is placed in the midline, approximately 3 cm below the occipital tubercle. On slight turning of the transducer, the right and left vertebral arteries can generally be differentiated at a depth of 60–70 mm, due to the availability of different spectral frequencies and pulsatilities. The vessels can frequently be imaged with bidirectional flow to a depth of 65 mm (atlas loop), and at greater depths only with flow away from the transducer. The vertebral arteries can serve as guide vessels to the basilar artery. In the evaluation, consideration must be given to the fact that the identification of the exact transition zone of the vertebral arteries and the basilar artery by means of pw Doppler can be made only with great reservations. Findings reported in the literature vary, depending on the application pressure, from 70 to 110 mm (!) (von Büdingen and Staudachet 1987; Ringelstein et al. 1990). It is therefore indispensable that a minimum depth of 100 mm is reached for secure identification of the proximal basilar artery. Complete visualization of the basilar artery to its division into the posterior cerebral arteries (tip of basilar artery) is possible in maximally 70% of cases, owing to deterioration of the signal-to-noise ratio. (von Büdingen and Staudachet 1987). A conversion of the frequency shift (Hz) into flow velocity is usually preferred by most sonographers on insonation of V4/basilar artery. The basis for this is the assumption that the insonation angle may be <30° and can therefore be disregarded. Color Duplex Sonography In the performance of color duplex sonography color coded sonographic flow velocity information is superimposed onto the morphologic information provided by the B-mode image. Furthermore, a spectral Doppler image (pw mode) can be derived from the vessel segment of interest using the B-mode image. Because the vascular band can be identified along its course and at its location in the tissue by means of the B-mode image, it is possible to perform an angle correction, which enables conversion of the measured frequency shift (Hz) into physiologic flow velocity data (cm/s). In section V3, the differentiation between an
55
atherosclerotic lesion and a dissection can be made in individual patients. However, the vertebral artery is located deeper in the tissue along its entire course than the carotid artery, so that the image quality is poorer due to signal attenuation and can not compete with the resolution obtained for the carotid arteries. Duplex sonography can, on principle, be used for all of the described vessel segments. It further enables examination of the V1 and V2 segments. Examination technique: In a first step, the distal common carotid artery is visualized inclusive of its bifurcation. The transducer head is then tilted so that the ultrasound beam is directed laterally, in order to image the dorsolaterally located vertebral artery. It is normally readily identifiable between the vertebrae (acoustic shadow), by means of color coding and is located directly below the vertebral vein. From here it is possible to advance segment by segment to caudal or cranial. While optimal visualization of segments V0–V3 is accomplished at a frequency of 5 MHz, a 2–2.5 MHz transducer must be used for imaging of V4/basilar artery due to its location at a greater depth. Scanning with this transducer does not provide information on plaque morphology. A disadvantage of color duplex sonography is the frequently inadequate visualization of deeper basilar artery segments due to its moderate color sensitivity. To compensate this effect, the additional application of an ultrasound signal enhancer is frequently required. 2.2.1.3 Ultrasound Signal Enhancers The relatively great depth and small diameters of the vessels to be examined are factors that diminish the diagnostic power of ultrasound in a large number of patients. Ultrasound enhancers are particles capable of enhancing the signal by 10–30 dB after entering the circulation. Currently available substances for signal enhancement consist of two components: gas and an encapsulating outer shell. The presence of the gas is crucial for signal enhancement, while the shell “only” serves to stabilize the bubble. When the sound beam reaches the interface between the liquid and the gas, the different high impedance triggers a strong reflection, which leads to signal enhancement at the receiver. The substances for signal enhancement are able to pass through the capillary bed and, as a rule, enable better visualization of the vascular system over a period of 3–5 min. The substances with current regulatory approval are shown in Table 2.1. Levovist® (legally approved in Germany, Italy, France and Spain) is contraindicated in patients with galactose (not lactose!) intolerance. Due to three reported deaths of patients with cardiopathies, SonoVue® (EMA approved; FDA approval applied) is contraindicated in patients with acute coronary syndrome and clinical instability.
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Table 2.1 Ultrasound contrast agents with current regulatory approval for use in (transcranial) signal enhancement Signal enhancer Gas Outer shell Approval (Trade name) Levovist® 4 mg
Galactose-air microparticles
Palmitic acid
D, E, F, I
SonoVue®
Sulphur hexafluoride
Phospholipids
EUR, Asia FDA approval (12/2010)
The application of signal enhancing substances in the vertebrobasilar system is expedient in the absence of visualization of the V4 segments and the basilar artery. Visualization of the V4 segments is achieved in most patients with these substances; an average improvement in the penetration depth of about 1 cm to a maximum of 10 cm has been reported for the basilar artery. The tip of the basilar artery is, however, usually not reached (Brunner-Beeg and von Reutern 1999; Iglseder et al.2000).
2.2.1.4 Reference Values “Reference values” are overall less reliable than in the anterior circulation, because the vertebrobasilar system is characterized by a wide inter- and intraindividual range of flow velocities. Furthermore, pronounced caliber differences are often found when making a bilateral comparison, so that the direct bilateral comparison is of lesser importance here than, e.g. in assessing the carotid arteries. Pulsatility is lower, the more cranial the examination of the vessels is performed: a typical finding for vessels with pronounced downstream parenchymal perfusion. The presence of vertebral artery hypoplasia (2–4%) represents a physiologic variation from the norm. The average diameter of this vessel is 3.81 ± 0.46 mm (Bartels et al. 1991) in the V2 segment, so that hypoplasia is defined as a vessel with diameter of <2.5 mm. Typical in hypoplasia is a change in the Doppler spectrum in terms of a resistance profile, due to the fact that the hypoplastic vessel does not connect to the basilar artery which supplies the brain. This finding should not be confused with a pathologic resistance profile in vascular occlusion. In these cases the vessel diameter is not reduced.
2.2.1.5 Stenosis Criteria One of the primary (direct) stenosis criteria is an increase in flow velocity in the region of the stenosis, where the highest values are measured immediately poststenotically, in the socalled jet. The presence of a stenosis >95% and subsequent decreased flow volume, lead to a reduction in flow velocity, which may be characterized by pseudonormal values. A
Table 2.2 Stenosis criteria in the V4/basilar artery territory (according to Widder et al. 1999) Finding Criteria Flow velocity (cm/s) Definitive finding of stenosis
High suspicion of stenosis
Maximum systolic value and/or Mean value
³120
Maximum systolic value and/or Mean value and/or Significant flow disturbance
³100
³70
³60
serviceable categorization was proposed by Widder for the region of the V4 segment and the basilar artery (see Table 2.2). A more differentiated allocation of stenoses to appropriate grades on the basis of primary stenosis criteria, analogous to the procedure for the internal carotid artery, is difficult; it is not essential in clinical practice. No results of studies demonstrating the need for making the choice of the therapeutic procedure contingent upon the allocation to a precise stenosis grade have been published thus far. Secondary stenosis criteria comprise changes in the flow profile, which are verifiable as indirect results of a major flow obstacle: • Prestenotically, reduced diastolic flow velocities in terms of a resistance profile serve as indicators of a distally located high-grade stenosis. In particular the detection of diastolic zero flow provides objective evidence of a downstream severe, high-grade stenosis or vascular occlusion. Hypoplasia must, however, be excludable in the B mode image. Differentiation between a distal occlusion and severe highgrade stenosis is frequently not possible (Fig. 2.16a). • Poststenotically, reduced pulsatility with a relatively high diastolic flow velocity at a markedly reduced systolic flow velocity is an indicator of a major flow obstacle (Fig. 2.16b). Tertiary stenosis criteria provide evidence of collateral vessels which are demonstrable only in the presence of high-grade stenoses. It has to be taken into consideration that in the presence of a unilateral vertebral artery occlusion/high grade stenosis, the contralateral vessel functions as the collateral vessel and may be physiologically characterized by a corresponding long-segment (slight to moderate) increase in flow velocity. Proximal vertebral artery occlusions are generally well collateralized by external vertebral artery anastomoses in segments V2–V4, which usually enable the demonstration of a return to normal flow conditions as early as in the V4 segment. In highgrade proximal basilar artery stenosis/occlusion or bilateral vertebral artery occlusion, retrograde filling of the basilar artery via the posterior communicating artery may occur in particular cases (thereby enhancing survival of the patient).
2.2 Ultrasound Diagnostics
57
a
b Col 86% Scale 5 WF low PRF 2000 Hz Flow–opt: mid. V
Col 86% Scale 5 WF low PTG 2000 Hz Flow–opt: mid. V
Fig. 2.16 (a) Vertebral artery dissection (V2). The dissection membrane is represented in the B mode image, the remaining lumen is narrowed. Diastolic flow (resistance signal) is absent prestenotically.
(b) Transnuchal insonation of the same patient: color duplex shows poststenotic flow in the left V4 segment normal right V4 segment. Confluence of the vertebral arteries and the proximal basilar artery are visualized
2.2.1.6 Clinical Application
segments on cw Doppler investigations. The examination of both these segments enables an initial assessment of the presence of a severe proximal or distal flow obstacle. When indicated, the finding has to be supplemented by an examination of the V0/V1 segments. In TCD, independent of the intracranial transtemporal finding, an additional transnuchal assessment of the V4/basilar artery segment should be carried out. Results of large randomized studies on the therapeutic consequences of a diagnostically conclusive stenosis are not
Brainstem Infarction/TIA The documentation guidelines issued by the German Society of Ultrasound in Medicine (DEGUM) and the American Institute of Ultrasound in Medicine (AIUM) call for mandatory visualization and documentation of the V2 segments at each color duplex examination, and respectively of the V3
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available at this time, although interventional therapies may certainly be expected to open up new options for the therapy of recurrent refractory brainstem ischemias. Currently reported data showing a high re-stenosis rate of 47% do, however, not justify routine stent application, or surgical intervention with transposition of the proximal vertebral artery to the common carotid artery.
Basilar Artery Thrombosis The diagnosis of basilar artery thrombosis is a controversially discussed topic. Due to its non-invasiveness sonography is, on principle, a valuable tool for establishing this diagnosis. Nevertheless, the basilar artery can frequently, at least in the distal segment (basilar tip thrombosis), not be conclusively diagnosed, owing to its location deep in the tissue. Furthermore, flow profiles in the proximal basilar artery without abnormal findings do not permit exclusion of a distal occlusion. Although ultrasound signal enhancers are able to improve the sensitivity of this method significantly, their use does not permit the definite exclusion of a thrombosis. Only in case of bilateral preocclusive flow signals in the vertebral arteries and missing signal of the basilar artery the diagnosis of proximal basilar artery thrombosis can be established with relatively great diagnostic certainty.
in the contralateral vertebral artery is characterized by orthograde relatively high flow velocities. In the ipsilateral vertebral artery of a patient with the full clinical picture of subclavian steal syndrome, complete flow reversal can be identified already during rest. Because the flow profile can bear a striking resemblance to a normal flow profile (but: absence of early diastolic aortic valve reversion phenomenon!), attention needs to be paid to the flow direction in performing any routine imaging procedure of the vertebral artery. An initial finding in “incomplete” steal effect consists of systolic deceleration at unchanged diastole. At later stages, pendulous flow with retrograde flow during systole and orthograde flow during diastole are observed. Subclavian steal syndrome can further be provoked with the brachial artery ischemia test (Fig. 2.17): the brachial artery is first compressed – by means of inflation of the pressure cuff to suprasystolic values over 1 min – to cause ischemia in the lower arm. The peripheral arterioles in the arm are thus maximally dilated and compensatory hyperemia is triggered on sudden decompression. This leads to an immediate effect in the ipsilateral vertebral artery in the form of instantaneous retrograde flow in the vessel, or to enhancement of the retrograde flow component. This test can be performed additionally in the basilar artery to assess the effect on this vessel (carotidobasilar overflow). The possibility of dynamic and continuous recording offered by Doppler sonography makes it the method of choice for the diagnosis of steal effect.
S ubclavian Steal Syndrome or Subclavian Steal Phenomenon Rotational Vertebral Artery Occlusion The patient with subclavian steal syndrome typically complains of non-specific dizziness, in some cases also of loss of consciousness after muscular stress in one arm. Subclavian artery syndrome is a consequence of an occlusion or high-grade stenosis of the subclavian artery or the brachiocephalic trunk. To meet the oxygen requirements in the lower arm, collateralization occurs via the contralateral vertebral artery or, in some instances additionally, via the basilar artery, leading to retrograde flow in the ipsilateral vertebral artery. the identical hemodynamic finding, occuring in an asymptomatic form, is described as a subclavian steal phenomenon. Examination technique: In addition to occlusion or a stenosis signal of the subclavian artery, the steal syndrome
A differential diagnosis is proposed in patients complaining of head rotation related vertigo and syncope (Hunter’s stroke) to confirm the suspected presence of rotational vertebral artery occlusion. In particular patients with known unilateral vertebral artery occlusion report that the symptoms are regularly provoked on extreme rotation of their head. Principal causative factors comprise processes in the region of C II/III; degenerative bony structures, ligaments, as well as muscles may compress the vertebral artery on head rotation (Netuka et al. 2005). Examination technique: Alternatively, cw Doppler may be used to visualize the V3 segment, and the V2 segment may be examined with duplex sonography. During
–20
Fig. 2.17 Subclavian steal effect. Pendulous flow (V2) with systolic deceleration (retrograde flow) and orthograde diastolic flow at ipsilateral subclavian artery stenosis. Complete flow reversal after decompression of the brachial artery
–20 cm/s
cm/s 20
20
40
40 Decompression
60
ConVis
2.2 Ultrasound Diagnostics
59
rest the vertebral artery is usually represented without abnormal findings. The patient is then asked to move the head in such a way that the symptoms are elicited. The diagnosis is confirmed in the presence of a change from an unremarkable Doppler signal into a high resistance Doppler signal with disappearing diastole at the concurrent development of clinical symptoms.
2.2.2 B-Mode Sonography of the Brainstem The use of transcranial B-mode sonography of the brainstem is expedient for particular neurologic and psychiatric disorders, as it is capable – superiorly to conventional MRI – of showing specific changes in the substantia nigra and midbrain raphe. Ground-breaking was the discovery of characteristic findings in Parkinson’s disease and depression (Becker et al. 1995a, 1995b). These findings have since been replicated and clinical applications have been defined.
2.2.2.1 Principles and Techniques Imaging is performed using an optimized ultrasound system with a phased array sector transducer (1.6–2.5 MHz). On principle, the same transducer as that applied for color duplex sonography can be used; a number of different equipment manufacturers have, however, developed special transducers providing higher resolutions for B-mode imaging. Generally selected device parameters include an image depth of 14–16 cm, and a dynamic range of 45–50 dB. The examination is carried out using the temporal bone window in axial section, with the transducer being placed preauricularly, parallel to the orbitomeatal line. Despite optimization of the image parameters (image brightness, time gain compensation, among others), brainstem assessment is not possible, or possible to a limited extent only, in 5–10% of a
patients. During the examination consideration has to be given to the fact that axial image resolution is superior to lateral image resolution. Tissue harmonic imaging (THI mode) is capable of improving resolution, although it is even more strongly dependent on the insonation window; it has, not yet been sufficiently investigated by relevant studies. In the sectional image the mesencephalon is viewed as a butterfly-shaped hypoechogenic structure surrounded by the strongly echogenic cisterns (Fig. 2.18). The echogenicity of the following structures is assessed in this plane: the ipsilateral substantia nigra – appearing as a patchy area or as a delicate band, the ipsilateral red nucleus, and the median brainstem raphe. Hyperechogenicity denotes an abnormally increased intensity or area of the ultrasound echo compared with a normal finding. The gradation of echogenicity can be done semiquantitatively according to the visual impression or – in particular for the substantia nigra – quantitatively by planimetric measurement of echogenic areas (Fig. 2.19). Because planimetric measurements are device- and transducer-dependent, reference values have to be established in larger normal populations separately for each ultrasound system. A marked increase in substantia nigra hyperechogenicity exists at values above the 90% percentile measured in the normal population, moderate substantia nigra hyperechogenicity is present at values above the 75% percentile (Berg et al. 2001a). On measurement with the Siemens Sonoline Elegra system, substantia nigra areas smaller than 0.20 cm2 are classified as normally hyperechogenic, areas ranging from 0.20 to 0.25 cm2 are classified as moderately, and areas as of 0.25 cm2 as significantly hyperechogenic. Echogenicity of the median raphe is assessed semiquantitatively (Becker et al. 1995b). In normal conditions the raphe nucleus is viewed as a continuous linear structure (Fig. 2.20). Echogenicity is regarded as being moderately reduced when the raphe nucleus is still identifiable, but viewed as a low-echogenic or interrupted band; echogenicity is considered to be significantly reduced when the raphe nucleus – despite good visualization of the nucleus ruber – is not differentiable from the surrounding midbrain parenchyma. b
Left
Fig. 2.18 Sonogram of the brain. (a) Axial section at midbrain level. The contralateral cranial bone is readily identified as a bright structure at the lower edge of the image. At the center, the mesencephalon is viewed as a butterfly-shaped hypoechogenic structure surrounded by the strongly echogenic basal cisterns. Visualized at increased echogenicity in the midbrain cross section is the substantia nigra bilaterally
Dorsal
Ventral
Dorsal
Right
Left
(ipsilateral: arrow 1), the nucleus ruber bilaterally (ipsilateral: arrow 2), the median brainstem raphe (arrow 3), as well as the aqueduct (arrow 4). (b) Schematic representation of (a); 1 ipsilateral substantia nigra, 2 ipsilateral red nucleus, 3 brainstem raphe, 4 aqueduct. The image inserted at the top right shows a corresponding MRI image for easier orientation
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2 Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics
a
b
c
Dorsal
Ventral
Right
Left
Fig. 2.19 Substantia nigra in axial sonogram of the midbrain. (a) Unremarkable finding: the substantia nigra is viewed as a delicate echogenic band- or patch-shaped structure (arrows). Also readily identifiable is the border echo of the red nucleus bilaterally (arrow heads). (b) Pathologic finding: the substantia nigra is markedly hyperechogenic
a
b
bilaterally (arrows). The assessment and planimetric measurement of the surface area is always done ipsilaterally. For this measurement the substantia nigra was traced with the curser. The red nucleus can be differentiated bilaterally (arrow heads). (c) Schematic representation of (b): SN substantia nigra, NR nucleus ruber, R raphe A aqueduct
c
Dorsal
Ventral
Right
Left
Fig. 2.20 Brainstem raphe in an axial sonogram of the midbrain. (a) Abnormal finding: despite good visualization of the nucleus ruber bilaterally (arrows), the brainstem raphe (arrowhead) is not represented; a significantly reduced echogenicity is noted. (b) Unremarkable finding:
the midbrain raphe (arrowhead) is viewed as a distinctly echogenic, linear, continuous structure (arrow: nucleus ruber). (c) Schematic representation of (b): NR nucleus ruber, R – raphe
2.2.2.2 Clinical Application
abnormal protein binding. The high frequency of this finding in relatives of Parkinson patients speaks in favor of a genetic influence. Marked substantia nigra hyperechogenicity is also found in 10% of healthy adults, and at a similar incidence for successive decades of life up to age 80 years (Berg et al. 1999b). This finding correlates with results of PET studies in adults of approximately 30 years of age with a pathologic reduction in 18F-dopamine uptake in the caudate nucleus and putamen, with an accumulated incidence of parkinsonism following the administration of high-potency neuroleptics, and in patients older than 60 years without pre-existing extrapyramidal motor disorders, with motor slowing compared to individuals with normal substantia nigra echogenicity (Berg et al. 2001a). These findings suggest that substantia nigra hyperechogenicity reflects nigrostriatal dopamine system dysfunction already years or decades
Early Diagnosis of Idiopathic Parkinson’s Disease Approximately 95% of patients with idiopathic Parkinson’s disease show substantia nigra hyperechogenicity that is pronounced in 73–79%, and moderate in about 20% of cases (Berg et al. 2001b ; Walter et al. 2006a). No significant differences in substantia nigra echogenicity were found for the clinical subtypes (akinetic-rigid subtype, equivalent subtype, tremor-dominant subtype). Higher substantia nigra echogenicity is observed primarily contralaterally to the clinically affected side. It remains stable during the clinical course; a more pronounced manifestation correlates with an early onset and slow progression of Parkinson’s disease (Schweitzer et al. 2006). The cause of substantia nigra hyperechogenicity may be an (genetically conditioned?) increased iron deposition in
2.3 Electrophysiologic Diagnostics
61
before manifestation of a Parkinsonian disorder. The value of brainstem sonography for the prediction of later development of a Parkinsonian disorder is currently undergoing investigation by number of prospective studies.
2.3 Electrophysiologic Diagnostics Jürgen Marx, Frank Thömke, Peter P. Urban, Sandra Bense, and Marianne Dieterich
2.3.1 Blink Reflex
Differential Diagnosis of Parkinson Syndromes Brainstem sonography supports discrimination between idiopathic Parkinson’s disorder and atypical Parkinson syndromes (Walter et al. 2003, 2004a). Normal substantia nigra echogenicity differentiates multiple system atrophy from Parkinson’s disease at a specificity greater than 90%. The presence of bilateral marked hyperechogenicity enables differentiation of corticobasilar degeneration from progressive supranuclear palsy. Diagnostic certainty is enhanced by sonography of other structures (lentiform nucleus, third ventricle). The characteristic constellations of findings are shown in Table 2.3.
Diagnosis of Affective Disturbances Reduced echogenicity of the midbrain raphe was a frequent finding in unipolar depression, and in Parkinson’s disorder-related depression (Becker et al. 1995b; Berg et al. 1999a). Correlation was established between reduced raphe echogenicity and signal alteration on MRI in the region of the posterior raphe nucleus, and has been discussed as the expression of a central serotonergic system disturbance. Depressed patients with reduced raphe echogenicity showed a more favorable response to selective serotonin reuptake inhibitor therapy than patients with normal raphe echogenicity (Walter et al. 2006b). Studies are currently underway to determine whether sonography of brainstem raphe represents a useful instrument in the decision on the therapeutic strategy for depressive disorders.
The blink reflex has become the most widely used electrophysiologic test of brainstem function since its first electromyographic recording by Kugelberg (1952). It enables the quantitative assessment of the different components of the human blink response. Following unilateral stimulation of the trigeminal afferents, two successive reflex responses can usually be evoked in surface EMG of the orbicularis oculi muscle: an early component (R1), which is typically observed only ipsilaterally, and a late component, which can be induced ipsilaterally (R2) and contralaterally (R2c) to the site of stimulation (Fig. 2.21). While the R1 component does not have a clinical correlate, the R2 component corresponds to visible eye closure resulting from contraction of the orbicularis oculi muscle. In addition, inconstant recording of a third reflex response can be achieved ipsilaterally and contralaterally with stronger stimulation magnitudes fivefold to sixfold of the sensory threshold (Rossi et al. 1989). However, owing to the poor reproducibility of this response, it has not become an integral part of routine clinical diagnostics.
2.3.1.1 Anatomic and Physiologic Principles Sensory nociceptive parts of the supraorbital nerve, the first branch of the trigeminal nerve, constitute the peripheral afferents of the blink reflex. The facial nerve is the common efferent of all response components. Different topographic mapping studies have shown the central course of the early R1 component after entry of the trigeminal afferents to extend from the lateral aspect of the mid-pons to the
Table 2.3 Typical sonographic findings for the substantia nigra (SN), the lentiform nucleus, and the third ventricle in healthy persons older than 60 years, and in patients with different clinical pictures Syndrome SN hyperechogenic SN hyperechogenic Lentiform nucleus Third ventricle dilated at least unilaterally bilaterally hyperechogenic (>10 mm) Normal situation
+
(+)
+
(+)
Idiopathic Parkinson’s disease
+++
+
+
(+)
Multiple system atrophy
(+)
–
+++
–
Progressive supranuclear gaze paresis
+
–
+++
+++
Corticobasilar degeneration
+++
+++
+++
–
Lewy body dementia
+++
+++
+
(+)
Frequency of abnormal findings in previous studies: – not found in any patient; (+) very rare; + low incidence; ++ frequent finding; +++ demonstrated in the majority of cases
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Fig. 2.21 Electromyographic recording of a normal blink reflex obtained separately on either side after the respective supraorbital stimulation R1
0
R2
50 (ms) 100 Stimulation left, recording left
R2c
0
R1
R2c
0
(ms) 100 50 Stimulation right, recording left
ipsilateral region of the facial nucleus, in particular to the intermediate subnucleus (Marx et al. 2001). The exact course of the R1 reflex arc in the brainstem has been investigated by only a small number of experimental studies (Cruccu et al. 2005). The findings of clinical correlations and electrocoagulation studies in an animal model suggest a strictly ipsilateral dorsomedial pontine course with a close relationship to the principal trigeminal nerve nucleus (Ongerboer de Visser 1983). In humans, the frequent conjoint occurrence of R1-abnormalities and internuclear ophthalmoplegia is in favor of an anatomic proximity of the reflex arc to the medial longitudinal fasciculus. The bilaterally occurring late R2 response follows a polysynaptic reflex arc. After entry of the trigeminal afferents into the pons, the central fibers are assumed to descend together with the spinal tract of V from the dorsolateral pons to the level of the caudal pole of the hypoglossal nucleus in the medulla oblongata. After partial crossing at
50 (ms) 100 Stimulation left, recording right
0
R2
50 (ms) 100 Stimulation right, recording right
this level, they reascend through the propriobulbar segment of the reticular formation, medial to the spinal nucleus of the trigeminal nerve, bilaterally to the facial nucleus region (Cruccu et al. 2005. The fibers ascending to the ipsilateral facial nucleus may be located more laterally than those coursing to the contralateral nucleus (Tackmann et al. 1982). The central R2 reflex arc is subject to suprasegmental hemispheric and mesencephalic control. Both a supratentorial lesion and a disturbance of consciousness can influence the occurrence of the R2 response. The R2 response further habituates after multiple stimulations.
2.3.1.2 Clinical Application The supraorbital nerve is usually stimulated separately on both sides by means of surface electrodes placed on the
2.3 Electrophysiologic Diagnostics
63 Table 2.4 Upper limits of normal of blink reflex components published for different patient collectives Investigator Component Absolute Side differences latencies (ms) (ms)
Fig. 2.22 Technique for eliciting the blink reflex on supraorbital stimulation
supraorbital foramen (Fig. 2.22). The stimulation cathode should be positioned above the foramen, with the stimulation anode approximately 2 cm above it and rotated slightly laterally, to avoid transfer of the stimulation current to the contralateral side. If the infraorbital segment of the trigeminal nerve is to be examined, the stimulation cathode is placed on the infraorbital foramen above the exit point of the nerve, and the stimulation anode is positioned about 2 cm below. Stimulation is applied with supramaximal rectangular impulses of 0.1 ms, at an intensity of 3–20 mA. The stimulation strength can be increased until a stable maximal electromyographic response is obtained. The patient’s eyes should be closed lightly. The stimuli are applied at interstimulus intervals of at least 10–20 s to avoid habituation of the R2 response (Kimura 1989). The stimulus responses of each orbicular muscle are recorded separately on either side using surface electrodes. The different lead electrode is positioned directly below the lower eyelid, at an approximate mid-position between the inner and outer orbital border, the indifferent electrode is placed in the temporal region at the lateral orbital border. An additional ground electrode can be affixed submentally or to one forearm. Filter limits are usually set at 20 and 3,000 Hz. Measured are latencies from the trigger signal to initiation of the evoked reflex response. A minimum of five successive reflexes are recorded and evaluated for this purpose. Applying this technique, supraorbital stimulation evokes an ipsilateral R1 response and bilateral R2 responses in all healthy subjects. Defined as pathologic are • The absence of individual reflex components • Absolute latency prolongations above the upper limits of normal • Side to side latency differences above the upper limits of normal Pronounced intra- and interindividual amplitude fluctuations are usually not considered in the evaluation.
Kimura (1975)
R1 R2 R2c
<13.0 <40.0 <40.0
<1.2 <5.0 <7.0
Hopf et al. (1991)
R1 R2 R2c
<12.1 <42.5 <44.5
<1.2 <5.0 <7.0
While an R2 response can always be evoked on infraorbital stimulation, this is not consistently possible for the R1 component. Paired double stimulation with a short interval (<10 ms) exerts facilitating effects on the R1 component, in particular when the R1 component can not be evoked or appears unstable on single stimulation in the presence of a demonstrable R2 component (Kimura. 1975). The upper limits of normal are summarized in Table 2.4.
2.3.1.3 Interpretation of Findings A delay in all reflex components after simultaneous stimulation indicates an afferent defect and is observed after a peripheral ophthalmic or trigeminal nerve lesion. A lesion of the afferent type has also been described for intra-axial lateral pons lesions when these also involve the trigeminal entry zone (Hopf et al. 1992). An efferent defect can be shown as unilateral absence or delayed latencies of the orbicularis oculi muscle reflex response, and is typically detected in patients with Bell’s palsy (Kimura 1989). In this case the typical pattern develops mostly within 1 week after onset of the paresis. In defect healing with aberrant regeneration, an R1 or R2 response can also be obtained in the mentalis or frontalis muscles, in addition to an orbicularis oculi muscle response. In patients with Guillain-Barré syndrome, Fisher’s syndrome or congenital motor, and especially sensory neuropathy, markedly prolonged R1-latencies can be found bilaterally, while this is not the case for the R2 component, a finding that may be accounted for by the wider normal range (Valls-Solé et al. 1990). The blink reflex primarily represents a highly sensitive method for the demonstration of vascular or inflammatory brainstem lesions affecting the mid- and lower pons, as well as the medulla oblongata (Fig. 2.23). In a study that included 180 patients with brainstem infarctions undergoing diagnostic testing with a variety of electrophysiologic brainstem reflexes and evoked potentials, the blink reflex had a 30% rate of abnormal findings and emerged as the method with the highest sensitivity for verification of clinically suspected brainstem lesions (Cruccu et al. 2005). In patients with transient symptoms or the lack of a confirmed lesion on magnetic resonance imaging, the blink
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2 Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics
a Normal R* L R L*
R: Right orbicularis oculi muscls L: Left orbicularis oculi muscls *: Supraorbital stimulation
Afferent defect R* L R L*
R* L R L*
Pontine lesion R* L R L*
R* L R L*
Efferent defect R* L R L*
R* L R L*
Lateral R* medullary L lesion R L*
R* L R L*
Medial R* medullary L lesion R L*
R* L R L*
Paramedian R* medullary lesion L R L*
R* L R L*
Bilateral medial R* medullary lesion L R L*
R* L R L* Absence Delay of reflex component
b NMT V afferent defect
NPT
pontine lesion VII efferent defect
medial medullary lesion
lateral medullary lesion
paramedian medullary lesion
bilateral medial medullary lesion
NST
Fig. 2.23 Classical pathologic patterns of the blink (a) reflex and their assignment to the respective brainstem lesions (b). NMT trigeminal motor nucleus, NPT trigeminal principal nucleus, NST trigeminal sensory nucleus, V trigeminal nerve, VI facial nerve
reflex identified a central pathology in a relevant number of cases, which is of crucial importance for the decision on the subsequent therapeutic regimen as, e.g. the initiation of secondary stroke prevention (Marx et al. 2002). In addition, the blink reflex is a valuable tool in the economic follow-up of functional recovery after brainstem lesions. Topodiagnostic findings of imaging-based correlation studies have suggested a relationship between delays in the R1 component and ipsilateral pontine pathology (Cruccu et al. 2005; Fig. 2.24). An isolated R1 pathology – without involvement of the R2 component – is an indication of a lateral mid-pontine lesion, although an association with internuclear ophthalmoplegia is frequently found on clinical examination (Hopf et al. 1991). Different R2 abnormality patterns may develop in the presence of medullary lesions. In the majority of patients with a typical lateral or dorsolateral medulla oblongata infarction a loss or delay in the ipsilateral R2 and R2c response is often observed. Following extension of the
lesion medially beyond the spinal tract of V, an ipsilateral R2 and a bilateral R2c loss may develop, which is usually associated with extended or only incompletely remitting clinical symptoms. (Aramideh et al. 1997). A delay in the R2c alone is much more rarely noted and is suggestive of a contralateral paramedian medullary lesion. In contrast, a bilateral medial medullary injury most often only involves the crossed fibers for the R2c of both sides (Hopf 1994) However, the described constellations of findings often also occur in mixed forms. Suprasegmental lesions occurring primarily in the postcentral region are more likely to lead to a delay in the R2 than in the R1 component. In patients in coma due to supratentorial injury, the R2 component may initially be lost, while the R1 component is generally maintained until the development of a secondary brainstem lesion. As a rule, both components can be demonstrated in patients with apallic syndrome, although they are absent in the brain dead patient (Metha and Seshia 1976).
2.3 Electrophysiologic Diagnostics
65
a
0
b
50 (ms) 100 Stimulation left, recording left
0
50 (ms) 100 Stimulation left, recording right
*
0
50 (ms) 100 Stimulation right, recording left
0
50 (ms) 100 Stimulation right, recording right
Fig. 2.24 Example of an ipsilaterally absent R1-component (a) in a patient with acute right-pontine brainstem ischemia in the respective T2-weighted MRI (b)
2.3.2 Masseter Reflex Frank Thömke 2.3.2.1 Anatomic Principles The masseter reflex is a monosynaptically transmitted monophasic (myotatic) stretch reflex of the masseter muscle. In contrast to all other stretch reflexes, the cell bodies of the afferent neurons are located in the central nervous system, in the mesencephalic nucleus of the trigeminal nerve. Afferents are Ia fibers from the masseter muscle spindles, which run in the masticatory nerve possibly crossing to the sensory root via anastomoses in the Gasserian ganglion, before entering the brainstem at the
level of the mid-pons, and ascend in the mesencephalic tract of the trigeminal nerve to the mesencephalic nucleus of the trigeminal nerve. This nucleus contains the cell bodies of the first-order sensory neurons, which send collaterals down to the motor nucleus of the trigeminal nerve in the lower pons, where monosynaptic transmission to masseter muscle motoneurons takes place. The efferents of the masseter motor neurons in turn course in the motor root of the trigeminal nerve to the mandibular nerve, and finally travel in the masseter nerve before entering the masseter muscle (Fig. 2.25; Hopf 1994; Thömke 2003). According to current knowledge, masseter reflex abnormalities indicate ipsilateral brainstem lesions between the levels of the fifth nerve motor and the third nerve nucleus, provided that trigeminal nerve functions are intact (i.e.,
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Mesencephalic nucleus and tract of the trigeminal nerve
III IV
MLF Vm Vs
N. V VI
N. VIII
VII N. VI
VIII vest
Fig. 2.25 Representation of the central masseter reflex arc and adjacent structures (According to Nieuwenhuys et al. 1989). MLF medial longitudinal fascicle; III oculomotor nucleus; IV trochlear nucleus; Vs main sensory trigeminal nucleus; Vm motor trigeminal nucleus; VI abducens nucleus; VII facial nucleus; VIII vest: vestibular nucleus; N. V trigeminal nerve; N. VI abducens nerve; N VIII vestibulocochlear nerve
normal corneal reflex, trigeminal sensory function, and masseter function). The masseter central reflex arc has a close topographic relationships to numerous brainstem structures. In the pons it is closely related to the vestibular nerve segment adjacent to the vestibular nucleus (and to the medial vestibular nucleus), to the inner knee of the facial nerve, as well as to the proximal segment of the abducens nerve. In the midbrain, the intramesencephalic segments of the trochlear and oculomotor nerves lie in close proximity (Nieuwenhuys et al. 1989; Hopf 1994; Thömke 1999). Between the mid-pons and the third nerve nucleus level there are also close anatomical relationships to the medial longitudinal fasciculus, to descending excitatory projections to the paramedian pontine reticular formation, and to the widely ramified neuronal network involved in the generation of smooth pursuit eye movements.
2.3.2.2 Clinical Application and Normal Values The masseter reflex is elicited by a brisk tap with a reflex hammer on the patient’s jaw, which stretches the masseter muscles on both sides. The examiner places the index finger on the tip of the patient’s chin, whose mouth is slightly open, and taps his index finger with the reflex hammer. The
recording is triggered at the moment of the mechanical tap by a signal from a piezo-electric element mounted in the hammer. The reflex is recorded simultaneously on both sides. Recording of the reflex response is primarily performed noninvasively with the use of surface electrodes, that are placed above the muscle belly 25 mm above the margin of the mandible (recording electrode), and over the zygoma at the lateral edge of the orbit (reference electrode) with a bandwidth of 20–2,000 Hz (overview see Thömke 2003). With a more invasive technique signals are recorded by concentric needle electrodes, although this method is not widely used and has thus far been investigated by a very small number of studies only (Yates and Brown 1981; Cruccu et al. 1987). The reflex responses recorded by surface electrodes are biphasic compound muscle action potentials of the masseter muscle. The latency is the time interval between the impact of the reflex hammer on the tip of the chin and the negative deviation of the compound muscle action potential from baseline, and the amplitude represents the maximal negative deflection of the compound muscle action potential from baseline (Fig. 2.26). All published studies reported relatively large interindividual differences of latency and amplitude, whereas intraindividual fluctuations on repeated stimulations were only small. There was a wide difference in the number of the recorded reflex responses, which ranged from 3 to 35, and the calculation of latencies has not always been well-defined.
Amplitude
Latency
1 mV 10 ms
Fig. 2.26 Original registration of a simultaneous masseter reflex recording in a healthy person. The two upper graphs depict the recording of ten successive individual reflex responses; the two lower graphs show the cumulative average curve derived from the individual recordings
2.3 Electrophysiologic Diagnostics
67
Some authors based the evaluation on the shortest among three reflex responses as proposed by (Goodwill 1968). The criterion established by (Ferguson 1978) is an abnormal side difference of more than 0.5 ms based on more than ten reflex responses. In our experience, the mean value calculated from ten successive reflex responses has proven of value. With a good reproducibility of the individual responses, the mean latency of the ten responses is identical to the latency of the cumulative average curve (Fitzek et al. 2001). In a variety of normative collectives investigated with different registration techniques, a certain amount of variability of absolute latencies was observed. However, a side difference in latencies of below 0.5 ms, as well as increasing latencies at increasing age were well reproducible with all registration systems (Table 2.5; Hopf and Gutmann 1990; Krämer et al. 1992; Bremer 1993; Ben Ghezala et al. 1996; Fitzek et al. 2001).
In contrast to the latencies, masseter reflex amplitudes are substantially codetermined by muscular tension, in addition to being characterized by a significantly higher interindividual variability. Furthermore, the amplitudes have not been investigated as extensively as the latencies. Reductions in amplitude from one third up to one half of the higher amplitude have been described as abnormal by different studies (Table 2.6). In one study (Cruccu et al. 1987) even a reduction of one fourth with reference to the higher amplitude was considered to be outside the normal range, i.e. of the mean value plus a 2.5-fold standard deviation. In this study the reflex responses were obtained with concentric needle electrodes, but with surface electrodes in all other studies. In addition to the delay in the absolute latency, an abnormal side difference has been identified as the most sensitive parameter of pathologic change.
Table 2.5 Normal values of masseter reflex latencies reported by different studies Latencies (mean value ±SDa)
Side differences (mean value ±SDa)
Goodwill (1968) n = 86
8.4 ± 1ms
£1 ms
Kimura et al. (1970) n = 20
7.1 ± 0.62 ms
0.27 ± 0.15 ms
Ongerboer de Visser and Goor (1974)
7 ms (20–30 years) ( n = 9) 7 ms (31–40 years) (n = 7) 7.4 ms (41–50 years) (n = 10) 7.8 ms (51–60 years) (n = 10) 8.4 ms (61–70 years) (n = 6) 7.8 ms (71–80 years) (n = 4) In another 5 patients aged 71–80 years no reflex response was evoked bilaterally
0.07 ± 0.15 ms for the entire group
Yates and Brown (1981) n = 21
8.7 ± 1s
0.1 ± 0.2 ms
Görömbey et al. (1986) n = 20
6.4 ± 0.9 ms
0.1 ± 0.2 ms
Lowitzsch and Marzi (1986) n = 24
7.6 ± 0.7 ms
0.23 ms
Cruccu et al. (1987a) n = 25
7.2 ± 0.8 ms
0.11 ± 0.15 ms
Hopf and Gutmann (1990) n = 58
6.9 ± 0.4 ms (£40 years) (n = 27) 7.6 ± 0.5 ms (>40 years) (n = 31)
0.15 ± 0.12 ms for the entire group
Bremer (1993) n = 112
6.4 ± 0.7 ms (£42 years) (n = 29 women) 6.9 ± 0.5 ms (£42 years) (n = 29 men) 7.3 ± 0.6 ms (>42 years) (n = 26 women) 7.5 ± 0.6 ms (>42 years) (n = 28 men)
0.17 ± 0.14 ms for the entire group
Fitzek et al. (2001) n = 105
7.7 ± 0.6 ms (£50 years) (n = 40 women) 8.1 ± 0.7 ms (£50 years) (n = 30 men) 8.8 ± 1 ms (>50 years) (n = 20 women) 8.8 ± 0.5 ms (>50 years) (n = 15 men)
£0.4 msb for the entire group £50 years £0.54 msb for the entire group >50 years
As far as indicated Upper limit of 95% confidence interval (as the normative collective of Fitzek et al. did not exactly fulfil the normal distribution criteria, the 95% confidence interval was used to determine the upper limit of normal reflex latencies) a
b
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2 Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics
Table 2.6 Normative values of masseter reflex amplitudes reported by different studies Amplitudes (mean value ±SDa) Side differences (mean value ±SDa) Cruccu et al. (1987) n = 25
0.8 ± 0.6 mV
7% ± 10%
Hopf and Gutmann (1990) n = 58
2.2 mV (£40 years) (n = 27) 1.9 mV (>40 years) (n = 31)
17.2% ± 8.6%b 18% ± 8.8%b
Bremer (1993) n = 112
3.2 ± 1.6 mV (£42 years) (n = 29 women) 2.8 ± 1.6 mV (£42 years) (n = 29 men) 2.7 ± 1.9 mV (>42 years) (n = 26 women) 2.4 ± 1.3 mV (>42 years) (n = 28 men)
£48.5%b,c for all women and men
Fitzek et al. (2001) n = 105
2.0 ± 0.9 mV (£50 years) (n = 40 women) 1.7 ± 0.8 mV (£50 years) (n = 30 men) 1.0 ± 0.5 mV (>50 years) (n = 20 women) 1.1 ± 0.6 mV (>50 years) (n = 15 men)
£33%b,c (or £0.8 mV) for the entire group £50 years £33%b,c (or £0.4 mV) for the entire group >50 years
As far as indicated Relating to the side with the higher amplitude c Indicated in all cases is the upper limit of the 95% confidence interval a
b
The following are regarded as pathologic findings:
Ferguson 1978; Cruccu et al. 1987). In the presence of clinically intact functions of the trigeminal nerve, i.e., normal • Side differences in latencies from ³0.5 ms (Fig. 2.27) corneal reflex, normal trigeminal sensory function, normal • Unilateral or bilateral latencies outside the age-related masseter function, an abnormal masseter reflex indicates normal range, i.e. higher than the respective mean value ipsilateral brainstem dysfunction between the caudal pons plus a 2.5-fold standard deviation and the rostral midbrain. Overall, the examination of the • Unilateral or bilateral reflex loss (Fig. 2.28); no reflex masseter reflex represents one of the most sensitive electroresponses may occasionally be recorded in healthy physiologic tests for the demonstration of a functionally patients older than 70 years relevant brainstem dysfunction, which may be attributed to • Partial reflex loss, i.e. the absence of four or more reflex the extensive rostrocaudal course of the central reflex arc. responses over ten examinations An abnormal masseter reflex is the most frequently iden• A difference in amplitude of more than 50% with regard tified abnormal electrophysiologic finding in patients with to the respective higher amplitude vertebrobasilar ischemia (Mika-Grüttner et al. 2001; Marx The single recording of an abnormal masseter reflex can on et al. 2002). In addition to the rostrocaudal extension of the principle be the expression of an acute or an older, pre- central reflex arc, the vascular architecture of the pontomesexisting lesion. The presence of an acute lesion is regarded encephalic brainstem is of crucial importance here. The as confirmed if one of the following findings is documented region of the central masseter reflex arc comprises not only in subsequent examinations: the terminal circulation territory of the long penetrating branches from the basilar artery but also vessels exiting from • A unilateral or bilateral reduction (or increase) in latency the lateral and dorsolateral segments of the circumferential of 0.8 ms or higher branches of the basilar artery (Hassler 1967). • A unilateral or bilateral return of a previously absent Abnormal masseter reflex findings have been reported in reflex response (Fig. 2.28) 30–60% of patients with multiple sclerosis, and their incidence may be higher than abnormal findings for the blink reflex or acoustic evoked potentials. Patients with internu2.3.2.3 Interpretation of Findings clear ophthalmoplegia also frequently show ipsilateral masseter reflex abnormalities (overview Thömke 2003). This Suprasegmental, i.e. supratentorial or cerebellar lesions do may be attributed to the close proximity of the medial longinot have an influence on the masseter reflex (Hopf et al. tudinal fascicle to the central reflex arc between the mid-pons 2000). However, damage to the peripheral segments of the and the rostral midbrain, which are at mutual risk for injury reflex arc outside the brainstem, i.e. lesions of the third from possible primarily ischemic or demyelinizing lesions branch of the trigeminal nerve, the mandibular nerve, or located in this region. masseter muscle pareses are possible causes of an abnorThe occurrence of masseter reflex abnormalities in patients mal masseter reflex (Kimura et al. 1970; Ongerboer de with isolated cranial nerve dysfunctions can also be explained Visser and Goor 1974; Ongerboer de Visser and Goor 1974; by anatomic conditions. The central reflex arc is located in
2.3 Electrophysiologic Diagnostics
69
Fig. 2.27 Patient with dorsolateral infarction of the rostral pons right. MRI (image at center); ipsilateral latencydelayed and amplitude-reduced masseter reflex right (left graph); at normal elicitation left (right graph)
Masseter reflex right
Masseter reflex left
1 mV
1 mV 9.5 ms
a
8.3 ms
c
Initial examination
8.4 Follow-up examination
b 8.4
Fig. 2.28 MRI: Patient with circumscribed dorsal mid-brain infarction right. Absence of ipsilateral masseter reflex at normal elicitation left (upper curves). Normalization at follow-up (lower curves) confirms presence of a current lesion
close proximity to the oculomotor, trochlear, abducens and facial (inner knee of facial nerve) nerves, as well as to the vestibular nerve proximal to the nucleus (and to the medial vestibular nucleus), so that mutual damage to these structures is possible (Thömke and Hopf 1999). In patients with Arnold–Chiari malformations, the masseter reflex has further proven highly useful for the identification of disturbed pontomesencephalic brainstem functions; the sensitivity is here again attributable primarily to the rostrocaudal extension of the central masseter reflex arc (Koehler et al. 2001).
2.3.2.4 Conclusion The electrophysiologic examination of the masseter reflex is a highly sensitive test for the demonstration of a functionally relevant pontomesencephalic brainstem dysfunction, which continues to be a valuable diagnostic tool. Electrophysiologic diagnostic methods (masseter reflex, blink reflex, electrooculography) are superior to magnetic resonance imaging (MRI)
R
8.6
L
0.5 mV 5 ms
when only T1 and T2 weighted sequences with slice thicknesses of ³4 mm are prepared (Mika-Grüttner et al. 2002; Thömke et al. 2002). As a result of the markedly improved visualization of the brainstem by means of more recent MRI techniques (e.g. diffusion weighted and fluid attenuated inversion recovery [FLAIR] sequences) and thinner, 2–3 mm thick slices, an increasing number, although not all, functionally relevant brainstem lesions are depicted (Mika-Grüttner et al. 2001, 2002; Marx et al. 2002). MRI identifies morphologic damage, which is frequently, although not always, associated with disturbed function of morphologically damaged structures. In contrast, electrophysiologic examinations detect disturbances of function, that are often due to morphologic damage, but which may also occur in the presence of normal (or only slightly damaged) morphology, i.e. in the absence of MRI-documented lesions. The electrophysiologic examination of the masseter reflex is a widely available, cost-effective, and readily reproducible test that can provide important information on the presence of a relevant brainstem dysfunction and the dynamics of its clinical course.
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2.3.3 Early Acoustic Evoked Potentials
sides. There are currently a number of indications that these waves in particular do not originate in a neuronal structure, but have multiple generators (Kaga et al. 1997).
Peter P. Urban 2.3.3.1 Anatomic and Physiologic Principles
2.3.3.2 Application Early acoustic evoked potentials (EAEP) are viewed as electrical potential fields in response to an auditory stimulus recorded from the scalp or the auditory canal, using electrodes with a latency of up to 10 ms. The anatomic course of the auditory path renders EAEP’s suitable for the detection of tegmental brainstem lesions. EAEP’s consist of five successive positive (in contrast to conventional upwards plotted) peak potentials (Fig. 2.29). Wave I originates in the cochlear segment of cranial nerve VIII, presumably near the exit site from its foramen. Wave II is generated in the most proximal part of the cochlear nerve in the region of the cochlear nucleus. Intraoperative tests on the exposed cochlear nerve lend support to the assumption that Wave II is generated by an abrupt change in the conductivity of cerebrospinal fluid compared to the cerebral parenchyma at the entrance site to the brainstem at the pontomedullary junction (Martin et al. 1995). The accurate topographic allocation of subsequent waves is, however, less well-defined. The possible origin of wave III may be in the horizontal connections between the cochlear nucleus, the nuclei of the medial and lateral superior olives, and the trapezoid body at the pontine level. The conjectured origin of waves IV and V is in the mesencephalic lateral lemniscus ascending to the inferior colliculus (Markland 1994). A reliable topographic allocation of the lesion to the right or left side is possible alone for wave I, and can be made with reservations only for wave II. In view of the bilateral projections in the brainstem, changes in waves III, IV and V do not permit a dependable allocation of the lesion to one of the
Stimulation Stimulation is achieved by clicks, i.e. sounds with a frequency spectrum ranging from 500 to 7,000 Hz, that are generated by a rectangle-shaped electric pulse of 100 ms transmitted through earphones. Depending on pulse polarity at the earphone membrane, the clicks generate a pressure (condensation click) or suction (rarefaction click) stimulus to the tympanic membrane. Rarefication clicks frequently lead to larger amplitudes of wave I, and more often produces readily distinguishable waves IV and V. In some settings, rarefication clicks are therefore used exclusively. The application of condensation clicks lead to larger wave V amplitudes. The alternating application of rarefication and condensation clicks, or subsequent averaging of the curves reduces the stimulus artefact. The use of alternating clicks alone is advised against because artefacts will also sum up and can thus simulate potentials. In addition, latency differences in individual waves between condensation and rarefication clicks may cause elimination of the waves due to summation. Furthermore, in some patients a pathologic finding is detected only with the use of one stimulation polarity, while it would have been missed with the application of alternating stimulation, or on stimulation with the other polarity only. The clicks are applied using a frequency of 10 Hz. The stimulus strength ranges 70 dB HL above the individual auditory threshold, which needs to be determined first; 95 dB HL should not be exceeded. The stimulus is applied monaurally and the contralateral ear is masked with white noise at a stimulus strength 40 dB HL below that of the click.
III I I
II
III
IV
V
Condensation click right Recording right 0.5 µV/U
V
IV
II
Condensation click right Recording right 0.5 µV/U III
I
IV
V
IV
V
Rarefication click right Recording right 0.5 µV/U
II
Rarefication click right Recording right 0.5 µV/U
III
I II
I I
Fig. 2.29 Normal EAEP finding
II
III
IV
III
IV
Summation of Condensation/Rarefication Recording right 0.5 µV/U Summation of Condensation/Rarefication Recording right 0.5 µV/U
V V
II 1.0 ms/Div
2.3 Electrophysiologic Diagnostics
This prevents stimulus conduction across the cranial bone to the non-stimulated ear. When the waves are not readily definable, stimulation strength should either be increased or decreased. While decreasing stimulus strength leads to reduced amplitudes at increased latencies, inter-peak latencies remain unaffected.
71
In some cases a normal click-auditory threshold may be identified, despite the absence of wave I. This may be an indication of high tone deafness, since wave I is generated by the high-frequency components of the click. Findings reported in the literature demonstrate that in these cases wave I can be shown in approximately 75% of patients with the application of needle electrodes in the outer auditory canal (Chiappa 1997).
Recording The potentials are mostly recorded bilaterally. The electrodes are placed on the mastoids or earlobes and are interconnected at Cz. The Cz electrode is the “different” electrode in EAEP applications and the electrode placed on the mastoid or earlobe represents the “indifferent” electrode, because as farfield potentials, EAEPs have their largest amplitude above the vertex. Employed are needle and surface electrodes, as there are no differences between these regarding latency and amplitude. The transition impedance must not be greater than 5,000 W. A filter setting of 100–3,000 Hz is recommended. Measured are the first 10 ms after stimulation. 1,000–2,000 stimulation trains are usually averaged. A second measurement is requisite to ensure reproducibility.
2.3.3.3 Physiologic Variability of EAEP and Abnormal Findings With increasing age, latencies of waves I and V are found to be increased in men only. Conversely, interpeak latencies (IPL) remain largely unchanged (Lopez-Escamez et al. 1999). Body temperature has a pronounced influence on EAEP latencies: latencies are decreased at lower temperatures. Women show slightly shorter waves III and V, as well as shorter IPLs I–III and I–V (Lopez-Escamez et al. 1999), which may be attributable to a higher mean body temperature in women. With increasing (senile) hearing loss – even when it is not yet of clinical significance – a decrease in amplitudes is observed, principally for wave I, but also for all subsequent waves. When wave I is so low that its latency can not be determined with certainty, determination of the IPL should also be dispensed with. Wave I is included in the stimulation-ipsilateral recording only. Wave II may also be absent in healthy subjects or be lost in the descending arm of wave I or in the ascending arm of wave III. Wave II is frequently better identifiable on stimulation-contralateral recording. A further variation is the merger of waves IV and V to a common entity. In certain conditions waves IV and V may be better differentiated on suction than on pressure stimulation. A decisive factor in the neurologic applicability of EAEPs is the differentiability of wave I.
2.3.3.4 Evaluation Evaluation parameters comprise latencies of waves I, III and V. From these, the more informative IPLs I–III, III–V, and I–V are calculated, because they are not as substantially influenced by biologic factors (sex, age, auditory disturbances, etc.) (Markand 1994). In addition to the absolute latencies of the individual waves and IPLs, side differences can be used in establishing a diagnosis. In view of the fact that amplitudes of the EAEPs are subject to a relatively wide fluctuation range, the absolute values are not suitable for diagnostic purposes. Only the quotient of wave V and I amplitudes is of diagnostic value. The amplitudes from the peak of the wave to the following negative minimum are measured for this purpose. In some instances abnormal findings are detected only on pressure or suction stimulation (Maurer 1985; Hammond et al. 1986). The separate evaluation of both stimulation types is therefore recommended. The mean value plus 2.5-fold standard deviation is usually defined as the maximum permissible value. Normative values have been described in the literature (e.g. Chiappa 1997), and should be tested for transferability in an own patient collective. IPL I–V represents the pathway from the distal vestibulocochlear nerve through the pons to the mid-brain, which can be pathologically prolonged due to a lesion along the entire peripheral and central segment. Isolated high tone deafness may lead to a paradoxical shortening of IPL I–V. Because only the low frequency components of the cochlea are present in these circumstances, the latency of wave I is delayed, although this does not apply to the latencies of the following waves. IPL I–III represents the pathway from the distal vestibulocochlear nerve to the lower pons. A delayed IPL I–III may therefore be generated by a lesion in the cerebellopontine angle (e.g. acoustic neurinoma), meningitis, neoplastic meningitis, Guillain-Barré syndrome, HMSN I, III, and pontomedullary lesions. IPL III–V represents the pathway from the lower pons to the tegmental pontomesencephalic region. The V/I amplitude quotient should be within a range from 0.5 to 3 (Pratt et al. 1999). This signifies that, as a rule, the amplitude of wave V is larger than that of wave I. At a V/I quotient <0.5, wave V is thus too low, which lends support to the presence of a central lesion.
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• P athologically prolonged IPL I–III with an V/I amplitude quotient <0.5 and normal waves I and II. This constellation may, however, also be observed in the presence of proximal lesions of the cochlear nerve. Indicative of a central lesion is a simultaneously prolonged IPL III–V, while IPL III–V is normal for peripheral lesions.
At a V/I quotient >3, wave I is too low; this finding serves as an indication of a peripheral lesion or hearing disturbance.
Central Lesions The following constellations serve as an indication of a central lesion in the brainstem: • N ormal waves I, II and III with absence or delayed and/or amplitude reduced waves IV and V, or wave V alone. The probability of a central lesion is increased if not only the V/I amplitude quotient is <0.5, but wave V is simultaneously also delayed (Figs. 2.30–2.33). • Pathologically prolonged IPL III–V, on condition that the V/I amplitude quotient is <0.5 and waves I and II are within the normal range. In clinical practice an extension of IPL III–V is only rarely observed. A prolonged latency of wave V at a still normal IPL III–V is detected more frequently.
Fig. 2.30 Arnold–Chiari-II-malformation. Loss of waves III–V. Upper two traces: condensation clicks; middle two traces: rarefication clicks; lower two traces: summation of condensation and rarefication clicks
Multiple Sclerosis Conflicting results have been reported regarding the incidence of pathologic EAEP findings in multiple sclerosis (MS). This is due to the different examination techniques, the size of the patient collectives, duration of the disease, and assessment criteria used. The more parameters as, e.g. absolute latency of individual waves as well as their right–left differences (and not only the IPL and V/I amplitude quotient), are used in the evaluation, and the narrower the limits of the upper norm are b
a
I II I
II
I II II I I
a
b
6.4
5.4
II I II
I
III
II
V
IV
II III
IV
V
I
II
5.4
6.4
III
IV
V
III
IV
V
I I II
III IV III
V V
I
IV
III
I
IV
II
V
IV V
III
II I I
II
III IV III
IV
V V
II I
II
Fig. 2.31 Pons infarction right. Delayed latencies of waves IV and V bilateral. Description of curves see Fig. 2.30
III
IV
V
III
IV
V
2.3 Electrophysiologic Diagnostics
a
b
73
c III
II
I
6.7
IV IV
V
III I
V
II
I
III
II I II
I
IV
III
IV
III
IV
II
V V
V
IV
V
III
I
II
Fig. 2.32 Cavernoma left pontine. Delay of wave V. Description of curves see Fig. 2.30
a
b
c I
III
II
IV
I II
I
IV
III III
II
IV
V
V
IV V
III
I II
IV
II I I
III II
V IV
III
V
Fig. 2.33 Cavernoma right pontine. Amplitude-ratio wave V/I < 0.5. Delay of wave V. Description of curves see Fig. 2.30
determined, the higher is the proportion of pathologic findings. The cumulative incidence rate of pathologic EAEP findings ranges from 30% to 60% for clinically confirmed (Friedli and Fuhr 1990; Chiappa 1997), and from 20% to 40% (Chiappa 1997; Buchner 2000) for clinically possible or probable MS. Although the incidence rate of pathologic EAEP findings is substantially lower than that for other evoked potentials (VEP, SEP and MEP), a pathologic EAEP finding
may, in individual cases, indicate the presence of a clinically silent lesion and increase the probability of the diagnosis. The EAEP patterns in MS correspond to the findings of a central lesion. Although patients with a central lesion do not have a hearing disorder in spite of distinct EAEP changes, MS patients with sudden unilateral hearing disturbance have been described, who showed demyelinating lesions in the pontomedullary junction, or in the dorsolateral caudal pons
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on MRI. These patients had an ipsilateral loss of waves II–V or IV and V on EAEP (Drulovic et al. 1993). In approximately 50% of all MS patients with pathologic EAEPs, this is abnormal on unilateral stimulation alone (Chiappa 1997). IPL III–V is generally only rarely pathologically prolonged, while this is very often observed for waves IV and V in the presence of normal waves I–III.
Brainstem Ischemia/Bleeding Unilateral brainstem lesions in the region of the lateral lemniscus and the inferior colliculus ordinarily do not lead to clinically observable hearing disturbances, despite the fact that differentiated investigations on interaural time discrimination have identified abnormalities (Levine et al. 1993). Bilateral lesions of the trapezoid body, the lateral lemniscus, and the inferior colliculus may, however, be causal factors of central bilateral hearing loss (Hoistad and Hain 2003). The correlation between the occurrence of hearing disturbances and EAEPs is, nevertheless, very limited with brainstem lesions. Pathologic EAEPs are most often detected in patients with clinically normal auditory function. On the other hand, normal EAEPs have been described for brainstem lesions on different levels, even in the presence of central hearing loss (Egan et al. 1996; Vitte et al. 2002; Lee et al. 2004). EAEP patterns in ischemia or bleeding in the brainstem correspond to the findings of a central lesion. EAEPs with monaural stimulation in patients with rostral brainstem lesions with involvement of the lateral lemniscus and the inferior colliculus have until now detected pathologic findings only on contralateral, but not on respective stimulation-ipsilateral recordings (Fischer et al. 1995; Cho et al. 2005). More caudally located unilateral lesions in the region of the superior olivary complex, the a
region of the cochlear nucleus, or the entrance site of the vestibulocochlear nerve can, however, represent the cause of ipsilateral hearing disturbances and pathologic EAEPs (Häusler and Levine 2000; Fig. 2.34). Infarctions of the dorsolateral medulla oblongata (Wallenberg’s syndrome) seldom cause changes in EAEPs (Chia and Shen 1993). In cases with maintained tegmental function, ventral infarctions of the base of the pons, ranging in severity to the clinical picture of locked-in syndrome are associated with normal EAEPs (Bassetti et al. 1994). An analysis of pontine hemorrhages did not show a correlation between clinical and EAEP findings, while a bilateral loss of waves III, IV and V was associated with a poor prognosis (Ferbert et al. 1990). EAEPs further provide prognostic information on the presence of brainstem compression in patients with space-occupying cerebellar infarctions (Krieger et al. 1993).
Brain Death The following EAEP patterns show the irreversibility of clinical defunctionalization symptoms in primary supratentorial and in secondary brain damage: • Progressive consecutive loss of waves with eventual bilateral loss of all components • Progressive consecutive loss of waves III–V at unilateral or bilateral preservation of waves I or I and II • Isolated preservation of waves I or I and II According to guidelines for brain death diagnosis issued by the Federal German Chamber of Physicians (BÄK) (Scientific Committee BÄK 1997) can “in primary supratentorial and in secondary brain damage under specified conditions the silence of EAEP confirm the irreversibility of clinical defunctionalization and substitute the observation period.” b
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Fig. 2.34 Acute decrease in hearing on the right. Infarction in the territory of the anterior inferior cerebellar artery (AICA). Delayed latencies of waves I–V. Description of curves see Fig. 2.30
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2.3.4 Vestibulocollic Reflex Sandra Bense and Marianne Dieterich
2.3.4.1 Anatomic and Physiologic Principles In recording the vestibulocollic reflex, also named “vestibularevoked myogenic potentials” (VEMP), the vibration sensitivity of the sacculus is used to test the reflex arc from the otoliths to the neck musculature (Colebatch and Halmagyi 2000). The reflex arc of the vestibulocollic reflex (VCR) courses from the sacculus via the inferior segment of the vestibular nerve, the vestibular nucleus region in the brainstem, interneurons, and a-motorneurons of the vestibulospinal tract to the sternocleidomastoid muscle. 2.3.4.2 Application In clinical diagnostics the VCR represents a readily performed screening test for side-related otolith function of the sacculus. It is usually evoked by a loud click sound markedly above the auditory threshold (in healthy subjects approximately 95–105 dB SPL [sound pressure level]), and is applied via earphones monoaurally with a repetition frequency between 3 and 5 Hz. The stimulation elicits brief inhibition and subsequent excitation of a small number of motoneurons in the neck musculature. The reflex potential is recorded by surface EMG from the neck musculature, preferably from the sternocleidomastoid muscle. For registration, electrodes are affixed bilaterally above the middle of the muscle belly and the sternal line. An additional electrode placed on the forehead serves as the ground electrode. From 50 to 100 stimulations per side are averaged for the recording. The study subject is placed in a supine position. pretensing of the sternocleidomastoid muscles should be ensured, as the resulting reflex muscle movement can be better recorded (Lim et al. 1995). This is achieved by slight lifting of the subject’s head (Fig. 2.35). Middle ear function of the study subject must be intact, although this does not apply to the auditory function.
Fig. 2.35 Experimental recording procedure of the click-evoked myogenic potential or vestibulocollic reflex (VCR) from the sternocleidomastoid muscle
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2.3.4.3 Evaluation and Reference Values
Fig. 2.36 Vestibulocollic reflex (VCR) in a healthy volunteer. A biphasic potential with a positive wave can be recorded ipsilateral to stimulation after approximately 14 ms (P14), and a negative wave after approximately 21 ms (N21)
In a healthy subject, a biphasic potential with a positive wave is recorded ipsilateral to stimulation after approximately 14 ms (P14), and a negative wave after about 21 ms (N21) (Fig. 2.36). The absence of these waves, or a decrease in amplitude are useful diagnostic criteria. Later components are not of vestibular, but of possible cochlear origin. Contralateral reflex responses are usually not recorded. The VCR can be obtained
in all persons under 60 years, although the amplitudes are lower with increasing age. Amplitudes further vary significantly interindividually, so that side differences greater than 35% or 50% have been shown to be more sensitive than absolute values (Welgampola and Colebatch 2001). Alternatively, the peak-to-peak amplitudes of the two recordable components
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(p14 – n24) can be used as a measure for the response; an amplitude of 100 µv should be reached in individuals younger than 60 years. The assessment of latencies is possible only on the basis of normative values under the respective stimulation and recording conditions (Basta et al. 2005), and is therefore primarily subject to the scientific objectives.
with caution in individuals older than 60 years, or under difficult recording conditions with inconstant muscle preinnervation.
2.3.5 Exteroceptive Suppression of Masticatory Muscle Activity
2.3.4.4 Interpretation Peter P. Urban In the past few years pathologic changes in the VCR have been described for a number of different central and peripheral vestibular disturbances (vestibular neuritis, otic zoster, Ménière’s disease or vestibular schwannoma) (Welgampola and Colebatch 2005). In approximately 35–54% of patients with advanced Ménière’s disease (De Waele et al. 1999), and in up to 80% of patients with vestibular schwannoma, pathologically changed or absent VCRs have been identified (Patko et al. 2003). The proportion of cases ranging from 12% to 39% in vestibular neuritis is substantially lower, and may be explained by the fact that vestibular neuritis affects primarily the superior segments of the vestibular nerve and spares the sacculus projections of the inferior segment (Murofushi et al. 1996; Chen et al. 2000; Ochi et al. 2003). In the rare Tullio’s phenomenon caused by an inner perilymph fistula (superior canal dehiscence syndrome), reduced stimulation thresholds and increased amplitudes may be found on the affected side (Watson et al. 2000; Minor et al. 2001). The VCR can be used as a rapid screening test in bilateral vestibulopathy, the bilateral loss of peripheral vestibular organ function of different etiology. However, in these patients sacculus function appears to be less frequently impaired than semicircular canal function on caloric testing (Zingler et al. 2008). Comparable to findings in patients with Ménière’s disease, in patients with vestibular migraine the amplitude is often found to be reduced bilaterally (in 68%) while latencies are normal (Baier and Dieterich 2009; Baier et al. 2009). As may be expected, the VCR in pontomesencephalic lesions above the vestibular nuclear region remains unaffected (Heide et al. 1999; Itoh et al. 2001). Abnormal VCRs, in particular latency delays have been described for pontomedullary lesions of different etiology (e.g. ischemic infarction, bleeding, compression) (Chen and Young 2003; Murofushi et al. 2001), and in lesions involving the vestibulospinal pathways (e.g. in disseminated encephalomyelitis) (Murofushi et al. 2001; Sartucci and Logi 2002; Versino et al. 2002; Bandini et al. 2004). Overall, the VCR is of secondary importance in the diagnosis of central-vestibular disturbances. Pathologic findings should be interpreted
Inhibition of masticatory muscle activity through the application of painful stimuli to the trigeminus-innervated buccal mucous membrane or the periglottis is an antinociceptive defense reflex that synapses in the brainstem and is not clinically verifiable. The electromyographically demonstrated inhibition of masticatory muscle activity by electrical stimulation of the trigeminal-innervated periglottis or other trigeminal-innervated areas has been described in the literature as the jaw-tongue reflex, the jaw-opening reflex, the masseter inhibiting reflex, or the masseter silent period. Electric stimulation of facial areas innervated by the sensory trigeminal nerve represents a readily standardized and widely available stimulation modality that has become an accepted technique for diagnostic purposes. The finding that in contrast to mechanical excitation, electrical stimulation activates only cutaneous afferences, lead (Godeaux and Desmedt 1975) to introduce the term “exteroceptive suppression” (ES) of masticatory muscle activity, which will be used in the following discussion. The diagnostic field of application for exteroceptive suppression of masticatory muscle activity comprises the functional assessment of sensory trigeminal afferents, of the reflex arc in the pontomedullary brainstem, and of motor trigeminal efferents to the masticatory musculature.
2.3.5.1 Anatomic and Physiologic Principles Afferences of Exteroceptive Suppression In an experimental setting one or two phases of suppression (ES1 and ES1) of the voluntarily preinnervated masticatory musculature can be evoked mechanically with reflex hammer tap, electric stimulation (e.g. of the mental nerve), or with selective stimulation of nociceptive or non-nociceptive fibers of skin areas innervated by the trigeminal nerve (Ellrich et al. 1997; Fig. 2.37). While inhibition of masticatory muscle activity can also be achieved with the application of acoustic (Meier-Ewert et al. 1974) and electric stimulation to the upper extremities (Erb’s point, median nerve) (Urban and
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Fig. 2.37 ES1 and ES2 of a healthy subject. EMG recording bilateral, electrical stimulation at the mental foramen right
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The findings obtained by experimental animal studies provide conclusive evidence of a disynaptic interconnection of ES1. Impulses from the primary afferents (pseudounipolar trigeminal neurons in the trigeminal ganglion Gasseri) are initially transferred to an inhibitory interneuron in the supratrigeminal nucleus, which is located immediately dorsomedial to the midpontine motor nucleus of the trigeminal nerve (Mizuno and Konishi 1975). The inhibitory interneurons are directly interconnected with the ipsilateral and contralateral motor neurons of the motor nucleus of the trigeminal nerve. Experimental or clinical tegmental midpontine lesions therefore lead to changes in the ES1 only (Goldberg 1972; Ongerboer de Visser et al. 1989; Ongerboer de Visser and Cruccu 1993; Fig. 2.38).
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Hopf 1992), this is not possible for the lower extremities. The multimodal and multitopic elicitation confirms a convergence of different afferent influences on the motor neuron pool of the masticatory musculature located in the midpontine segment.
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Fig. 2.38 Schematic drawing of the central pathways of the exteroceptive suppression of masticatory muscle activity (Modified according to Ongerboer de Visser 1983)
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Interconnection of ES2
Recording
The reflex path of the ES2 is significantly less well documented. The ES2 latency of 30–60 ms lends support to the assumption of a polysynaptic interconnection. The selective loss of ES2 in the presence of experimental lesions near the midline at the level of the obex confirmed a course of the reflex path extending to the medulla oblongata (Nakamura et al. 1973). Correlative with this finding, lesions of the upper and middle dorsolateral medulla oblongata showed changes in the ES2 alone (Ongerboer de Visser et al. 1989; Valls-Solé et al. 1996). Changes in the ES2 after acute supratentorial lesions speak in favor of an influence exerted on the ES2 by structures located in the rostral brainstem (Cruccu et al. 1988; Liepert et al. 1993).
Electromyographic recording of the reflex response is carried out with Ag/AgCl surface electrodes bilaterally from the masseter muscle (stimulation electrode: above the muscle belly; indifferent electrode: above the cheekbone), or from the temporal muscle (stimulation electrode: in the middle of the temporal muscle directly below the hairline; indifferent electrode before the tragus). Registration is done at an amplitude of 200–1,000 mV/cm and a sweep of 20 ms/div, at a lower/upper threshold frequency of 20/2,500 Hz. Recorded are a minimum of five applications.
2.3.5.2 Clinical Application
2.3.5.3 Evaluation
Stimulation
Included in the evaluation are latencies to the onset of EMG suppression and the duration of suppression. As suppression neither begins nor ends abruptly, it is essential to define the reduction degree of the initial activity, which determines the presence of suppression as well as its onset and end. Because the mean amplitude of the inference pattern over a period from 20 to 40 ms prior to the stimulus is frequently determined as the reference value, a delay circuit should be applied. The degree of the required reduction in initial activity has not yet been standardized and varies from 50% to 95% (Schoenen et al. 1987; Göbel et al. 1992, 1994; Bendtsen et al. 1996; Connemann et al. 1997). The raw or the rectified EMG signal can be used in the evaluation. A number of studies have evaluated every individual recording, and calculated the mean value and standard deviation. Other authors have averaged or superimposed the curves and based the determination of the presence of suppression on the resulting “sum-curve.” In view of the fact that the established values vary in dependence on the respective evaluation method, individual researchers need to determine their own reference ranges.
Proven and tested stimulation sites include, in dependence on the clinical problem (e.g. peripheral nerve lesions) the exit sites of the mental and infraorbital nerves (Cruccu et al. 1987). Two suppression periods can generally be distinguished on stimulation of the mental nerve. Suppression on stimulation of the supraorbital nerve is not observed in all healthy study subjects. Electric stimulation is applied using a bipolar stimulation electrode, with the cathode being placed above the nerve exit site. Stimulation time is 0.2 ms (rectangular stimulation). The stimulation frequency should not exceed 0.1 Hz in order to avoid habituation (Göbel and Schoenen 1993). The stimulation strength has an influence on the duration and degree of EMG suppression. The increase in stimulation strength mediates shortening of ES1 latency, an increase in ES1 duration, fusion of ES1 and ES2 latency into a long suppression phase, and a higher degree of suppression. The application of a constant stimulation strength of 20 mA is proposed for all individuals, with the aim of standardizing the elicitation of exteroceptive suppression. In order to account for differences in the perception of stimulation strength, it has alternatively been recommended to initially determine the perception threshold (= lowest stimulation strength, at which the study subject perceives the stimulation), before setting the definitive stimulation strength at a previously determined multiple (Kimura et al. 1994). Suppression is further influenced by the degree of preactivation of the masticatory musculature. A specified minimum of preactivation is required to enable suppression of EMG activity. At increasing strength of preactivation, the duration of suppression is shortened, and the occurrence of ES1 and ES2 fusion is reduced. A standardized preactivation (e.g. maximum masticatory force) is therefore indispensable (Connemann et al. 1997).
2.3.5.4 Reference Values/Normal Variants and Pathologic ES Criteria Reference values have been established for the latency and duration of ES1 and ES2, as well as for the duration of voluntary activity occurring between ES1 and ES2 (Keidel et al. 1994; Göbel and Dworschak 1996). A number of additional factors with an influence on the obtained measurements should be considered (recording site, stimulation site, duration and frequency of recording, recording electrode and strength, degree of
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preactivation, definition of ES, evaluation technique). The ES1 latency ranges from 10 to 15 ms, and from 35 to 60 ms for ES2. As a rule, ES1 and ES2 are separated by a voluntary activity phase. The interposed activation phase is described as “breakthrough voluntary activity” or “interposed EMG activity.” In particular in the presence of higher stimulation strengths and/or lower preactivation the facilitation period is absent, which leads to the merger of ES1 and ES2. Further variants observed in healthy subjects include, at decreasing frequency: absence of ES2, absence of ES1, absence of ES1 and ES2, or the occurrence of an ES3 (Göbel 1996). These variants can be confirmed with certainty as variants when they are found to be bilaterally symmetric. Unilateral changes in suppression may be an indication of the presence of a brainstem lesion (Ongerboer de Visser and Cruccu 1993). In addition to the absence of an ES, the finding of reduced suppression intensity can be assessed as pathologic. Prerequisites for the described evaluation include well standardized stimulation and recording techniques, as well as the quantitative assessment of the degree of suppression (Connemann et al. 1997). Further criteria for the presence of a pathologically changed ES are increased (onset of suppression) ES1 and ES2 latencies, as well as a shorter duration of ES2 (at normal latency). a
2.3.5.5 Interpretation of Findings Circumscribed brainstem lesions in the pontine and medullary tegmentum can induce changes in the ES pattern (Ongerboer de Visser et al. 1989; Ongerboer de Visser and Cruccu 1993; Valls-Solé et al. 1996) and thus contribute to the topodiagnosis. Afferent disturbances lead to a loss of ipsilateral and contralateral responses after stimulation of the affected side. Efferent disturbances are the cause of diminished or absent masseter activity on the affected side with ES1 and ES2 loss on both left and right stimulation. Pontine lesions: Isolated changes in ES1 can develop in the presence of a small ipsilateral lesion in the mid- to lower pons (Urban et al. 1999a; Figs. 2.39 and 2.40). Medullary lesions: Isolated changes in ES2 can be observed in the presence of medullary lesions (Urban et. al. 1999). However, ES2 may also be delayed or absent in the presence of supramedullary lesions. Changes in ES2 after acute supratentorial lesions may be evidence of an influence on ES2 by structures located rostral to the brainstem. A shortened duration of ES2 has been reported for acute supratentorial lesions with hemiparesis (Figs. 2.41 and 2.42).
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Fig. 2.39 Multiple sclerosis. (a) Demyelinating lesion in the tegmentum of the left pons. (b) ES1 latency delay on stimulation left (ES1 – stimulation left, recording masseter right: 19.0 ms, masseter left:
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20.0 ms. ES1 – stimulation right, recording masseter right: 15.8 ms, masseter left: 15.2 ms) at normal ES2 bilaterally
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Fig. 2.40 Multiple sclerosis. (a) Demyelinating lesion in the tegmentum of the right pons. (b) ES1 latency delay on stimulation right (ES1 – stimulation right, recording masseter right: 20.8 ms, masseter
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left: 20.2 ms. ES1 – stimulation left, recording masseter right: 16.2 ms, masseter left: 13.8 ms) at normal ES2 bilaterally
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Fig. 2.41 Mediolateral medulla oblongata infarction left. (a) MRI. (b) Absence of ES2 on stimulation left at normal contralateral ES2 and normal ES1 bilaterally
2.3 Electrophysiologic Diagnostics
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Fig. 2.42 Dorsolateral medulla oblongata infarction right. (a) MRI; (b) absence of ES2 on stimulation right at normal contralateral ES2 and normal ES1 bilaterally
2.3.6 Somatosensory Evoked Potentials Peter P. Urban Somatosensory evoked potentials (SEP) are changes in potentials resulting from electric stimulation of sensory peripheral nerves, and can be recorded with electrodes from the scalp, the cervical region or, in dependence on the stimulation site, from the extremities. Due to the anatomic course of the central somatosensory projections, median SEPs (stimulation of the median nerve) are suitable for the detection of circumscribed brainstem lesions, affecting the rostral segments of the dorsal columns and the medial lemniscus. In addition to median SEPs, stimulation of the trigeminal nerve is used in some instances to assess the integrity of the sensory afferents in this innervated region (Stöhr et al. 1981). The validity of trigeminal SEPs has, however, been questioned and is used by only a small number of laboratories in view of a pronounced stimulation artefact and inconstant reproducibility (Tackmann 2000). The median SEPs will therefore be discussed in this chapter.
somatosensory evoked potentials consist of changes in amplitudes generated along the peripheral pathways (peripheral nerve, plexus and posterior root) and the central projections (dorsal columns, dorsal column nuclei, medial lemniscus, thalamus and sensory cortex) by repeated stimulation of sensory peripheral nerves. Activation of the Ab fibers of the peripheral nerves that are capable of fast impulse conduction is chiefly responsible for the generation of the primary cortical SEP complex. Normal SEP consists of a complex wave formation, whose components are named in relation to polarity and peak latency. The polarity and latency of individual components is dependent upon • Individual variables: gender, height and age • Stimulation conditions: stimulation strength and stimulation frequency • Recording conditions: filter settings, electrode placement and interconnection
2.3.6.2 Application Stimulation
2.3.6.1 Anatomic and Physiologic Principles The SEP examination represents an objective function test of the somatosensory system. The early components of
Electrical stimulation of the median nerve is applied at the volar surface of the wrist above the nerve. Stimulation strength is set at 4 mA above the motor threshold (for mixed nerves),
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or at the threefold to fourfold sensory threshold (for purely sensory nerves) with a proximally positioned cathode. The duration of stimulation ranges from 0.1 to 0.2 ms at stimulation strengths from 3–5 Hz. Between 500 and 2,000 stimulation trains are averaged for an analysis time of 50 ms. The filter should be set at 10 Hz–2 kHz; recommended amplification is 50 mV per unit, and electrode impedance should be below 5 kW. Recording
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The potentials are recorded using thin subcutaneously placed steel needle electrodes or adhesive electrodes affixed above Erb’s point (N10), spinal process C7 (N13a), spinal process C2 (N13b) and sensory cortex C3’/C4’ (N20), against a reference electrode placed over Fz (10/20 system) (Fig. 2.43). An additional recording from C3’/C4’ and Fz (stimulation electrode) against a non-cephalic reference is required for assessment of brainstem potentials P14 and N18a, as well as for the peripherally generated P9 potential (Fig. 2.44).
2.3.6.3 Evaluation Latencies, amplitudes, as well as the waveform of the respective potentials are evaluated and compared with the reference values established by the individual laboratory. Latencies outside the 2.5-fold standard deviation of the age- and size-corrected mean value, and amplitude asymmetries ³60% on bilateral comparison are rated as pathologic (Maugière et al. 1999). The Generator Question and the Interconnection of SEPs
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Fig. 2.44 Median nerve far-field potentials – normal finding
stimulation of the median nerve and recording against Fz as reference. A negative potential can be recorded after 13 ms over C7. This so-called N13a potential originates from a horizontal dipole in the dorsal horn at the level of segment C6 and represents the first centrally generated potential. An N13b potential can also be recorded above C2, although its exact site of origin has not been conclusively identified. In addition to a postsynaptic response in the region of the cuneate nucleus, a presynaptic impulse in the region of the dorsal columns in the vicinity of the cuneate nucleus has been discussed as a possible generator. Results obtained by investigations in brain dead patients suggest, however, that the negative potentials recorded after 13 ms above C2 and C7 represent two different generator potentials (Besser et al. 1988). The principal cortical potential (N20) originates from gyrus 3b in the postcentral region. The latency difference between the N20 and the N13a potential constitutes the central conduction time.
The N10 potential of the brachial plexus in the region adjacent to the root is recorded above Erb’s point, following Far-Field Potentials N20
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Far-field potentials are generated on stimulation of the median nerve and recording against a non-cephalic reference (e.g. the contralateral shoulder). The initially recorded potential is P9 in the brachial plexus of the axillary region. Several authors have described a location in the region of the medial lemniscus for the subsequent P14 potential (Jacobson and Tew 1988; Dillmann et al. 1990), namely in the region between the cervicomedullary junction and the lower pons (Claß and Buettner 1993). P14 has, however, also been recorded in patients after brain death (Wagner 1996; Sonoo et al. 1999), which lends support to the hypothesis of a more caudal origin (Lueders et al. 1983). The N18a potential is a further brainstem potential whose precise point of origin has not yet been definitely defined; it can be determined on recording from Fz against a non-cephalic reference. The N18a potential represents a subcomponent of a broad-based N18 complex that can be
2.3 Electrophysiologic Diagnostics
optimally recorded above C3’ or C4’. A mesencephalic origin has nevertheless been suggested by findings obtained by brainstem and intraarterial recordings (Koehler et al. 2000). The N18 potential is generated in the medulla at the level of the cuneate nucleus and should not be confused with the N18a potential (Sonoo et al. 1992; Noel et al. 1996; Maugière et al. 1999).
2.3.6.4 Interpretation of Findings Brainstem lesions that include the medial lemniscus induce changes in the N20 potential and/or a prolongation of the central conduction time at a normal N13b potential above C2. Even though a diagnostic assessment of the lesion level in the longitudinal axis is not possible on the basis of this finding, it nonetheless permits assignment of the lesion to the transverse level. Further conclusions may be drawn following consideration of the far-field potentials.
2.3.6.5 Brainstem Lesions Only a small number of studies have reported reliable findings regarding a correlation between singular brainstem
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Fig. 2.45 Brainstem compression in Arnold–Chiarimalformation Type II. (a) MRI. (b) SEP: Absence of far-field potential N18 on median nerve stimulation right and normal finding on stimulation left. (c) SEP: Absence of N20 on stimulation of the right median nerve at a normal finding on the left side. Labelling of the potentials see Figs. 2.43 and 2.44
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lesions and SEPs. The most promising approach appears to be the inclusion of far field potentials. Although the exact diagnosis on the height of the lesion based on SEPs alone is generally not possible. in the presence of certain constellations SEPs can nevertheless provide topodiagnostic information. The cervical potentials N13a and N13b are preserved in all brainstem lesions with involvement of the medial lemniscus, while N20 is pathologically changed. This finding does, however, not permit any conclusions as to the topography of the lesion, which may be located between the cervical region of the spinal cord and the postcentral gyrus. Pontine lesions: The far field potentials P14 (Claß and Buettner 1993) and N18 (Sonoo et al. 1991; Raroque et al. 1994) are preserved in the presence of pontine lesions, while pathologic changes are manifested in N20. Medullary lesions: Lesions in the rostral aspect of the medulla are characterized by a preserved N18 at an absent P14 potential, which lends support to the assumption of an origin of P14 in the caudal medulla oblongata (Sonoo et al. 1996; Manzano et al. 1999). N18 may also be absent in cases with a high medullary lesion (Fig. 2.45). SEPs provide prognostic information on brainstem hemorrhage, basilar artery thrombosis and traumatic brainstem lesions: the bilateral absence of N20 potentials is always
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associated with a poor prognosis, although not with a unilateral extinction of the potentials (Ferbert et al. 1988, 1990; Christophis 2004).
Brain Death A typical initial finding in brain death on recording against a Fz reference is the absence of a cortical response at the concurrent demonstration of an N13b potential above C2 (Besser et al. 1988). The N13b potential is subsequently also lost (Stöhr et al. 1987). According to guidelines for brain death determination (Third update 1997, Scientific Committee, Federal German Chamber of Physicians) the extinction of N13b represents a criterion in the diagnosis of brain death, as it correlates with intact posterior column nuclei and is thus associated with the brainstem. In the further course, the N13a potential generated at the level of C6 may also be lost due to ischemic spinal cord injury with spinal vessel supply via the vertebral arteries. Primary supratentorial or secondary brain damage is a further precondition of SEP assisted brain death diagnosis. Additional diagnostic investigations (EEG, cerebral circulation) must be carried out in patients with primary infratentorial lesions. SEP diagnosis as the only diagnostic procedure is not permissible for suspected lesions in the cervical part of the medulla. Four channel recording is obligatory to identify peripheral lesions (e.g. polytrauma with brachial plexus injury) and to provide evidence of the preservation of peripheral potentials (N10).
2.3.7 Transcranial Magnetic Stimulation Peter P. Urban 2.3.7.1 Anatomic and Physiologic Principles Evaluation of motor evoked potentials (MEP) with the use of transcranial magnetic stimulation (TMS) permits the functional, non-invasive assessment of pyramidal pathway function. A capacitor discharges a very brief pulse of current which flows through a copper coil and initially induces a pulse-shaped magnetic field that passes through the skull cap without significant discomfort to the subject. The magnetic field in turn induces an electric field in the brain, which synchronously activates primarily presynaptic neurons of the motor cortex, thus triggering a series of descending action potentials, while the peripheral nerves are directly polarized. Individual segments of the corticobulbar and corticospinal tract can be examined by recording the compound muscle action potentials (CMAPs) from different target muscles. In the cranial nerve region these comprise mainly the facial nerve innervated mimic musculature and the tongue. In addition to the corticomuscular latency, the peripheral motor
latency is determined with stimulation of the proximal nerve segments or roots; the difference between these latencies corresponds to the so-called central motor conduction time (CMCT). The central motor conduction time reflects the function of the pyramidal pathway segments which project to the motor neurons of the target muscle used for the recording. The corticofacial projections descend from the primary motor cortex to the contralateral facial nucleus, while the facial neurons supplying the forehead muscles also receive projections from other, premotor areas (Morecraft et al. 2001). The corticofacial projections in the brainstem are located at the mesencephalic level in the middle segment of the cerebral peduncle; in the mid-pontine region they are, however, distributed across the entire base of the pons. The fibers cross the midline in the most caudal part of the pons, at the level of the facial nucleus region. Variations of the described course have, however, been described. Some individuals are characterized by so-called aberrant fiber bundles of the pyramidal pathway; they leave the pyramidal pathway at the level of the pontomesencephalic junction, and travel caudally along the border of the tegmentum before reaching the facial nucleus (Yamashita and Yamamoto 2001). In other subjects it may be assumed that corticofacial projections travel with the largest part of the pyramidal pathway through the ventral base of the pons, which they leave in the region of the ventral medulla oblongata only, to cross the midline at the level of the upper medulla oblongata, and continue rostrally to the facial nucleus located in the lower pontine dorsolateral tegmentum (Urban et al. 2001). A lesion location after decussation of the projections in the lateral medulla, and before arrival at the facial nucleus serves to explain the clinical picture of an ipsilaterally located central facial paresis (Urban et al. 1998, 1999; Urban and Hopf 2002). The corticolingual projections descend, by and large symmetrically, from the primary motor cortex to both hypoglossal nuclei; this can be documented electrophysiologically with the use of transcranial magnetic stimulation, which enables the demonstration of bilaterally symmetrical CMAPs on cortical stimulation (Urban et al. 1996, 1997). Due to the bilaterally symmetrical excitation of the tongue, a unilateral lesion of the cortical projections does not in all cases lead to a lateral deviation of the tongue, but is routinely associated with dysarthrophonia, caused by a disturbance of the highly complex fine motor requirements of the tongue motor system in the context of articulation (Urban et al. 1997, 1999, 2001). Comparable to corticofacial projections, corticolingual projections course through the middle segment of the cerebral peduncle, subdivide in the base of the pons and cross the midline in the region of the ventromedial segment of the base of the pons. Location variability has also been described for corticolingual projections in the brainstem with “aberrant bundles” in the paralemniscal tegmental position (Urban et al. 1996).
2.3 Electrophysiologic Diagnostics
2.3.7.2 Application Recordings in the cranial nerve region are obtained from the masticatory musculature (trigeminal nerve), the facial mimic musculature (facial nerve), the sternocleidomastoid and trapezius muscle (accessory nerve), and the tongue (hypoglossal nerve). Of clinical importance are thus far principally recordings from the facial mimic musculature and the tongue, which also enable a fractional assessment of the corticomuscular segments.
Corticofacial Projections For stimulation of the motor cortex a circular coil (mean diameter: 90 mm) or a double coil (mean diameter of each coil half: 70 mm) is placed 2 cm lateral to the vertex. In view of the variability of the CMAPs, a minimum of four MEPs are recorded and the shortest latency and largest amplitude are assessed. Recordings of the CMAPs are taken simultaneously, side-related from a facial muscle. A number of different facial muscles have been described as possible recording sites. A systematic comparison of the validity of different target muscles regarding evokability of a response potential, stimulus artefacts, interference with the R1 component of the blink reflex, cross-talk with registration of contralateral side activity, side differences between amplitudes on right-left comparison, and intraindividual reproducibility demonstrated distinct advantages of the buccinator and triangular muscles over other muscles when electrical or magnetic stimulation of the facial nerve is used, and of the buccinator and levator labii superioris muscles when magnetic stimulation of the motor cortex alone is applied (Urban 2002). This correlates with findings of anatomic studies, showing that only the lateral region of the facial nerve nucleus, where the orofacial musculature is represented, receives almost exclusively contralateral projections from the primary motor cortex, while the upper facial muscles are supplied by bilateral projections from the supplementary motor cortex and the rostral segment of the cingulate gyrus (Morecraft et al. 2001). Recordings from the orofacial musculature, most notably from the buccinator muscle via an enoral approach, are therefore particularly suitable for the examination of corticofacial projections (Urban et al. 1997). In addition to cortical stimulation, magnetic stimulation of the proximal, peripheral segment of the facial nerve is applied and enables determination of the peripheral motor conduction time (PMCT). Comparative studies investigating the surgically exposed facial nerve during surgical interventions in the cerebellopontine angle showed the superiority of a stimulation site located in the most proximal segment of the facial canal, approximately 10–15 mm after entry of the nerve into the internal acoustic meatus (Rösler et al. 1989; Schmid et al. 1991). This requires a
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parietotemporal coil placement and relatively low stimulation strength (as a rule 30–50% of the maximum stimulator performance). Attention should be paid that the PMCT is approximately 1–1.5 ms longer than with supramaximal electric stimulation at the stylomastoid foramen. Careful monitoring is required here to avoid accidental magnetic stimulation of the facial nerve at its exit point from the petrous canal. The conduction time difference between corticomuscular conduction time (CCT) and PMCT corresponds to the so-called central motor conduction time (CMCT), which also comprises the infranuclear segment of the facial nerve up to its entry into the petrous canal. The conduction time difference between magnetic stimulation of the proximal segment and electric stimulation at the stylomastoid foramen (= distal motor latency [DML]) corresponds to the transossal conduction time, which has not gained significant diagnostic importance thus far. Electric stimulation at the stylomastoid foramen corresponds to the classical facial excitability test (FET), although this is used principally in CMAP evaluations.
Corticolingual Projections TMS of the motor cortex is applied with a circular or a double coil, placed 4–6 cm lateral to the vertex. Recordings of the CMAPs are taken from each side of the tongue, using a spoon-shaped electrode device made of plastic material, into which two pairs of Ag/AgCl electrodes are embedded (Schmid et al. 1991; Meyer 1992). Light preactivation is achieved by slight pressure of the tongue against the electrode device, with the hard palate serving as a counterpressor. Synchronous with cortical stimulation, magnetic stimulation of the proximal hypoglossal nerve is applied in the hypoglossal canal, with coil placement in a deep occipital position. Due to both the deep anatomic location of the hypoglossal canal at the caudal end of the base of the skull and low magnetic field intensity, at this site the hypoglossal nerve can be reached and PMCT or CMCT determined in only 75% of all healthy subjects (Urban et al. 1997). No further conclusions can be drawn in cases of an unavailable MEP. More distal in the course of the nerve, electric stimulation can be applied to the mandibular angle (Redmond and Di Benedetto 1988).
2.3.7.3 Evaluation TMS of Corticofacial Projections Since even in healthy subjects merely inconstant ipsilateral responses can be achieved after cortical stimulation (Urban et al. 1997; Fischer et al. 2005), only contralateral responses are considered in patients. A lesion of the supranuclear projections is presumed:
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• W hen no CMAP is evoked on cortical stimulation (absence of potential is defined as no reproducible response on four consecutive stimulations and amplification of 200 mV/div) (Rösler et al. 1989; Fig. 2.46). • At an amplitude quotient (amplitude on cortical stimulation: amplitude on electric stimulation of the facial nerve at the stylomastoid foramen) £10%. • In the presence of an abnormally delayed central motor conduction time or a pathologic side difference for the CMCT. n infranuclear facial nerve lesion can be assumed at an ampliA tude reduction of £50% compared to the healthy side (Urban 2002), approximately 10 days after the acute lesion with onset of axonal degeneration. Reference values for the buccinator muscle have been published (Urban et al. 1994, 1997).
TMS of Corticolingual Projections In healthy subjects, bilaterally symmetric muscle responses can be evoked on cortical stimulation at both sides of the tongue (Urban et al. 1994). A lesion of the supranuclear projections is presumed: a
b
• When no CMAP is evoked on cortical stimulation (absence of potential is defined as no reproducible response on four consecutive stimulations and amplification of 200 mV/div) (Rösler et al. 1989; Fig. 2.47). • At an amplitude quotient (amplitude on cortical stimulation: amplitude on electric stimulation of the hypoglossal nerve at the mandibular angle) £10%. • In the presence of an abnormally delayed central motor conduction time or a pathologic side difference for the CMCT. Reference values have been published elsewhere (Urban et al. 1994, 1997).
2.3.7.4 Interpretation of Findings rainstem Ischemia B Prognostic Significance of MEPs Typical characteristics of MEPs after cerebral ischemias comprise a reduced amplitude quotient, in some instances even the absence of CMAPs on cortical stimulation, an increased motor stimulation threshold, and an only slightly delayed CMCT (Weber and Eisen 2002). Only a small number of studies have analyzed TMS for vascular c
Buccinator muscle, right Cortex L
Buccinator muscle, left Cortex R 1 mV
Prox. n. VII R
Prox. n. VII L 2 mV
Distal n. VII R
Distal n. VII L 3 mV 5 ms
Fig. 2.46 Infarction in the dorsal base of the pons right near the medial lemniscus with central facial paresis left. TMS of the motor cortex right does not evoke a contralateral CMAP in the buccinator muscle
a
b
c
Buccinator muscle, right Cortex L Cortex R Prox. n. XII R Distal n. XII R
Buccinator muscle, left Cortex L 1 mV
Cortex R Prox. n. XII L 1 mV
Distal n. XII L 3 mV 5 ms
Fig. 2.47 Infarction of the left base of the pons, presenting with dysarthria and central facial paresis right. TMS of the motor cortex left does not evoke a CMAP across the two sides of the tongue
2.3 Electrophysiologic Diagnostics
brainstem ischemias. In the largest series, 30 intensive care patients with acute brainstem lesions were investigated 12 h after termination of sedation and muscle relaxation (Schwarz et al. 2000). The causal factor was a brainstem infarction in 15 patients, and a space-occupying cerebellar infarction in five cases. Causes in the remaining patients included brainstem and cerebellar hemorrhages, brainstem contusion, encephalitis and basilar aneurysm, respectively. It was found that the absence of MEPs to the abductor pollicis brevis muscle in the acute phase correlated significantly (p < 0.0001) with a motor deficit persisting after 3 months. Bassetti et al. (1994) reported on six patients with locked-in-syndrome and recording of MEPs from the upper and lower extremities. Four patients with an initial absence of MEP did not show clinical motor recovery, while two patients with still obtainable muscle responses had a nearly complete regression of paresis. Ferbert et al. (1992) investigated MEPs to the abductor pollicis brevis muscle in 20 patients with hemiparesis due to a circumscribed pontine infarction. TMS in the acute phase was, however, carried out in only seven patients, and was used in the chronic infarction study of 13 patients. CMCT was pathologically prolonged in patients with moderate to severe pareses, while the amplitude quotient between cortical and electric stimulation of the peripheral nerves did not permit differentiation between the paretic and non-affected side. From these studies it can be concluded that MEPs in the acute phase of brainstem infarctions are of prognostic significance with respect to paretic regression. This finding is in accordance with reports on investigations of MEPs at other infarct locations (Escudero et al. 1998; Trompetto et al. 2000).
Topodiagnostic Significance of MEPs On principle, the findings reported by TMS studies permit only tentative conclusions regarding the height of the lesion. In all cases the lesion has to be located rostral to the body segment showing pathologically changed MEPs. The possibility of level diagnostics arises only in the presence of a pathologic finding, since a normal MEP does not permit the exclusion of a partial lesion, e.g. of the slow conducting fiber segments. The investigation of MEPs does, however, permit a statement with respect to a lesion location at the axial level (Urban et al. 1996, 1997). Multiple Sclerosis Typical changes in MEP characteristics in multiple sclerosis (MS) include a markedly prolonged CMCT,
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potential dispersion on cortical stimulation, and a reduction in the amplitude quotient. MS lesions located in the brainstem, as well as ischemias, can mediate functional impairment of corticobulbar and corticospinal projections. Singular lesions exist only rarely in the brainstem, chiefly at the onset of the disease, which qualifies the utility of TMS for topodiagnostic mapping. Of greater importance for meeting the diagnostic criterion of topical dissemination is the possibility of identifying clinically silent lesions by means of TMS. The examination of corticospinal and corticobulbar projections can make a valuable contribution to this procedure (Riepe and Ludolph 1993; Urban et al. 1994). In individual cases, the investigation of corticofacial projections with TMS can also provide topodiagnostic information. The occurrence of incomplete peripheral facial paresis with preserved excitability of the proximal facial nerve on magnetic stimulation, and prolonged CMCT suggests the presence of an infranuclear, but more proximally located, e.g. intra-axial, lesion, for example a demyelinating lesion of the dorsolateral pons (Fig. 2.48). Amyotrophic Lateral Sclerosis Typical changes in MEP characteristics in amyotrophic lateral sclerosis (ALS) comprise a reduction in the amplitude quotient, frequently in form of an absent potential on cortical stimulation, and in some instances a slightly prolonged CMCT. In ALS, corticobulbar functions are often affected early in the course of the disease. In 51 patients with different clinical courses of ALS, a lesion of the corticolingual projections was detected in 53% of cases, of the corticofacial projections in 47%, and of the corticospinal projections to the upper or lower extremities in 25% and 43% of patients, respectively (Urban et al. 1998, 2001). Similar incidences of function disturbances of the corticobulbar projections have been reported for recordings from the masseter muscle (Trompetto et al. 2000) and from the trapezius muscle (Truffert et al. 2000). Additional examination of the corticobulbar projections can be helpful, in particular in the differential diagnosis of cervical myelopathy (Truffert et al. 2000).
Hereditary Spastic Spinal Paralysis In patients with hereditary spastic spinal paralysis, in particular MEPs to the lower extremities are absent or amplitude-reduced, while, depending on the clinical findings, the upper extremities are less often and less severely affected. The corticobulbar projections may, however, also be affected in the absence of a clinical correlate (Visbeck et al. 2000).
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a
b
Buccinator muscle, right
Buccinator muscle, left Cortex R
Cortex L
1 mV
Prox. n. VII R
Prox. n. VII L 2 mV
Distal n. VII R
Distal n. VII L 3 mV
c
5 ms
Buccinator muscle, right
Cortex L
Buccinator muscle, left
Cortex R 1 mV
Prox. n. VII R
Prox. n. VII L 2 mV
Distal n. VII R
Distal n. VII L 3 mV
5 ms
Fig. 2.48 Multiple sclerosis. MRJ: Demyelinating lesion in the region of the dorsolateral pons left, presenting with peripheral facial paresis left. TMS (upper right figure) On day 2 absence of CMAP on cortical stimulation of the right motor cortex and recording from the left buc-
cinator muscle. The peripheral facial nerve showed a normal excitability at canalicular stimulation. Lower right figure: Corresponding to clinical improvement, CMAP reappeared following cortical stimulation on day 14
2.3.8 Laser Evoked Potentials
20–100 ms) or a thulium (Tm) laser (wavelength 2.01 mm, stimulation time 3 ms). Stimulation strength is 1.5- to twofold the pain threshold (Treede et al. 2003). These pulses are conducted via a glass fiber where they can be directed to any user-defined skin surface area by means of a mirror handpiece. The laser beams do not cause skin damage. Strong laser stimulation may lead to some transitory reddening of the skin. The interval between two stimulations applied in a random order ranges from 8 to 12 s. Forty laser stimulations are applied per train.
Peter P. Urban 2.3.8.1 Anatomic and Physiologic Principles A number of similarities exist between the method of laser evoked potentials (LEP) and somatosensory evoked potentials, but only the LEPs enable an objective examination of nociceptive pathways. The term nociceptive pathway refers to the entire distance from the peripheral receptor to the cortex. The peripheral pain receptors (nociceptors) are so-called free nerve endings of Að- and C-fibers. These fibers enter the dorsal horn via the dorsal root and synapse in the dorsal horn upon the second neuron. The second neuron crosses at the spinal level through the anterior commissure to the contralateral side and courses within the spinothalamic tract in the anterior part of the spinal cord to cranial. 2.3.8.2 Application Stimulation Stimulation is applied with short repeated heat impulses generated by a CO2 laser (wavelength 10.6 mm, stimulation time
Recording The LEPs are recorded using Ag/AgCl cup electrodes and electrode impedances below 5 kW. A minimum of two channels is required for the assembly: vertex (Cz) against connected earlobes, and a vertical oculogram for the identification of eye movements and blinking. The amplifier sensitivity is 100 mV for the oculography and 25 mV for the remaining channels. At a bandpass of 0.2–70 Hz, the recording rate is set at 200 Hz and the time window at 1 s before and up to 3.5 s after onset of the stimulation. To increase the amplitude of LEPs, the attention of the study subject is directed toward the stimulations (e.g. by counting of stimulations, etc.).
2.3 Electrophysiologic Diagnostics
In patients, two areas are examined by left-right comparison (e.g. both hands or both feet), only one of which has pathologic change. Both areas are subjected to two stimulations each, applied in balanced succession to compensate for habituation effects.
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2.3.8.4 Interpretation of Findings While pathologic latency delays, reduced amplitudes on right–left comparison, or the absence of a potential document the presence of a lesion involving the nociceptive pathways, they do not initially enable the differentiation between a lesion of the peripheral and the central nervous system.
2.3.8.3 Evaluation The principal LEP component used for evaluation in view of its good reproducibility is a negative-positive complex within a latency range of approximately 200–400 ms, derived from stimulation to the dorsum of the hand. On application of the Tm laser, negativity (N2) occurs at a latency of 210 ms, positivity (P2) occurs at a latency of 330 ms, and the peak-topeak amplitude ranges from 10 to 60 mV. The long latency of LEPs is attributable to the slow nerve conduction velocity of nociceptive fibers (Að: 15 m/s), and the fact that these are late potentials which are not generated in the primary sensomotor cortex. Positivity represents the LEP component with the most reliable reproducibility, making it the most frequently assessed factor in the evaluation process. Absolute amplitude values are not considered for diagnostic purposes because of their high interindividual variability and numerous influential factors (subjective pain sensation following laser stimulation, vigilance, age, etc.). A complete absence of the cortical potential constitutes the only factor for evaluation (Treede 1996). Side-to-side differences in amplitudes ³35% have been described as pathologic (Beydoun et al. 1993). The absolute latencies are only rarely prolonged; a 2.5-fold excess of the standard deviation from the mean values in a normal collective documents evidence of pathology (Treede 1996). The latency delay following stimulation of the dorsal foot ranges from 30 to 70 ms compared to stimulation to the dorsum of the hand. Maximum amplitudes are observed above the vertex.
a
b
Central Lesions The first application of LEPs was described in patients with syringomyelia (Kakigi et al. 1991; Treede et al. 1991). These patients had the typical symptoms of sensory dissociation, i.e. the absence of pain and temperature perception at preserved tactile sensitivity. LEPs showed pathologic latency delays, amplitude reductions, or the absence of potentials.
Brainstem Ischemia/Hemorrhage In patients with brainstem infarction and absent or diminished pain perception owing to a lesion of the spinothalamic tract, good correlation has been found between clinical and electrophysiologic findings, which also reflect the clinical course (Hansen et al. 1996). Patients with a lesion of the lateral spinothalamic tract due to a dorsolateral medullary brainstem infarction (Kanda et al. 1996), or a distinctly lateral caudal medullary infarction (Urban et al. 1999) are characterized by contralateral sensory dissociation that can be objectified with LEPs. The absence of LEPs on stimulation to the ipsilateral side of the face has been reported in patients with dorsolateral medulla oblongata infarction and the clinical picture of Wallenberg’s Syndrome (Cruccu et al. 2003; Figs. 2.49 and 2.50).
c
d
Fig. 2.49 MRIs of two patients with an infarction of the right lateral medulla oblongata. (a, b) Patient 1 presented with dissociated sensory deficits on the left side of the body caudal to C3. (c, d) Patient 2 presented with dissociated sensory deficits of the left half of the body caudal to Th4
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Fig. 2.50 Laser evoked potentials of the patients from Fig. 2.49 with dissociated sensory deficits caudal to C3 (patient 1) and caudal to Th4 (patient 2). LEPs were absent from the affected sides, but could be obtained on the control side
Patient 1
Patient 2
Control site (right hand)
Control site (right foot)
− 10 µV + 0.000
0.500 t (s) Affected site (left hand)
2.3.9 Recording of Eye Movements Frank Thömke Electrooculography enables quantitative, accurate recording of different types of eye movements. A number of different, more or less complex, methods are available for this purpose, whose advantages and disadvantages are discussed below. The cooperation of the patient is a basic requirement of all electrooculographic methods. In an inattentive or tired patient, disturbances of smooth pursuit eye movements may occur, and saccades may be characterized by varying degrees of target inaccuracies, or they may be slowed. These irregularities can, on principle, also occur through the influence of centrally acting substances. 2.3.9.1 Direct Current Recording Direct current electrooculography is the longest known (and probably most widely used) method for recording different types of eye movements. It enables quantitative, relatively accurate recording, and is capable of providing sufficient information to answer most clinical questions. The method is based on the so-called corneoretinal potential, a difference of potential between the cornea and the retina, with a positive corneal against a negative retinal potential. On movements in the direction of the electrode, a positive deflection is observed (the positive cornea is located closer to the electrode than the negative cornea); on movements away from the electrode a negative deflection is noted (the negative retina lies closer to the electrode than the positive cornea). The eye thus functions as a flexible dipole, so that every eye movement mediates changes in the electric field, which can
1.000
0.000
0.500 t (s)
1.000
Affected site (left foot)
be recorded as changes of potentials between two surface electrodes. This can be achieved with the subject’s eyes either open or closed. Adhesive electrodes for recording of horizontal eye movements are placed at the lateral and the medial corner of the eye, respectively; for recording of vertical eye movements, the electrodes are affixed above or below the respective eye (Fig. 2.51). There is a linear correlation between the amplitudes of these deflections and those of eye movements for amplitudes of up to 40°. Within this range (±40° from the primary position), direct current electrooculography permits evaluation of different eye movements with a resolution of about 1°. Due to the fact that eye movements can be recorded from closed eyes, investigations of the vestibular system, e.g. caloric excitability of the horizontal semicircular canals on warm and cold water stimulation, or rotational testing may be performed and followed by quantitative evaluation of the recorded caloric and postrotatory nystagmus (Table 2.7).
2.3.9.2 Infrared Reflective Oculography Infrared reflective oculography is based on the finding that the intensity of light reflection of the white sclera is greater than that of the darker iris, which, in turn, is greater than light reflection of the pupil. Movements of the eye exposed to invisible infrared light cause the iris-sclera border and the iris-pupil border to shift in the direction of the eye movement, i.e. the positions of areas with strong, moderate, and mild reflection of the infrared light change commensurate with the eye movement. The infrared light reflected from the eyes and changes over time, which are proportional to the respective eye movement, are measured during this process. Modern systems comprise more than 1,700 photosensitive
2.3 Electrophysiologic Diagnostics
a
Right eye
91 Left eye
b
30°-Saccades to the right Right eye 30°-Saccades to the left Left eye Right eye Left eye
c
0.1 s
Smooth pursuit Right eye
Left eye 1s
d
Optokinetic nystagmus Optokinetic nystagmus target velocity: 60°/s to the right target velocity: 60°/s to the left
Right eye
Amplifier
Left eye Printer 1s
Fig. 2.51 Direct current recording of eye movements. (a) The eye functions as a flexible dipole, with the cornea relating to the positive and the retina relating to the negative pole. Eye movements function as “dipole movements” and mediate changes in the electric field which are
recorded as changes of potentials between two surface electrodes. (b–d) Different types of eye movements: saccades (b); smooth pursuit eye movements (c); optokinetic nystagmus (d) (see Thömke: Eye movement disturbances. Stuttgart: Thieme 2001)
diodes (e.g. AMTech Eyetracker E.T.3: 1,728 diodes, height 13 mm, distance 10 mm) arranged in a linear array opposite each eye. The mode of operation of this diode array is comparable to that of a television camera recording only a single image line, while here the reflection of infrared light is determined by what may be imagined as a line proceeding across the eye. From these data the computer calculates the changes in infrared light reflection recorded during the respective eye movement. The infrared light sources and photosensitive diodes can be integrated into a helmet or a ring mounted on the head. They may also be installed in a frame furnished with a head and chin support for the patient. Eye movement recordings obtained with this method can only be done with open eyes and are within a range of approximately ±20° proportional to the eye position and have a resolution of less than 0.5°. Comparable to direct current recording, infrared reflective oculography does not permit recording of rotational eye movements (Table 2.7).
2.3.9.3 Videooculography Videooculography uses video cameras to record eye movements, in addition to a system for computer-based data evaluation. The study subject wears head-mounted goggles with an integrated camera system and semi-translucent mirrors, weighing less than 500 g (progressively lighter models are becoming available). The eyes are illuminated with infrared light emitted by diodes integrated into the goggle frame. Horizontal and vertical eye positions are calculated by back-transformation after the respective image processing system has mapped the pixel coordinates of the pupil center and calibration of the system. The torsional components are determined based on individual characteristic iris patterns in a selected segment of the iris (alternatively, a mark is made on the iris using a tissue-compatible make-up pencil). The degree of torsion and the eye speed are again calculated by back-transformation of the achieved eye position with consideration of the time domain. The spatial resolution of
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Table 2.7 Advantages and disadvantages of different eye movement recording methods Method Characteristics Advantages Direct current recording
Recording area: approximately ±40° Spatial resolution about 1° Temporal resolution about 40 Hz
Non-invasive Low patient discomfort Recording from open and closed eyes possible
Disadvantages Prone to artefacts (muscle artefacts, blink artefacts, baseline fluctuations) Lower reliability in recording of vertical eye movements Recording of torsional eye movements not possible
Infrared reflective oculography
Recording area: approximately ±20° Spatial resolution below 0.5° Temporal resolution about 100 Hz
Non-invasive Low patient discomfort Reliable recording of horizontal and vertical eye movements
Videooculography
Recording area: approximately ±25° horizontal and ± approximately 20° vertical Spatial resolution up to 0.02° Temporal resolution 500 Hz
Non-invasive Low patient discomfort Reliable recording of horizontal, vertical and torsional eye movements
Recording possible from open eye, only (influence of fixation as a result of recording in complete darkness is assessable) Limited recording area (±25° horizontal or ±20° vertical)
Scleral search coil technique
Recording area: always ±180° Spatial resolution up to 0.01° Temporal resolution 500 Hz
Recording possible from open and closed eyes Reliable recording of horizontal, vertical and torsional eye movements
The cornea must be anesthetized A contact lens with an opening at the center and an integrated coil must be affixed Very cost-intensive and complex technology
currently available systems are within a range of 0.02° horizontal, 0.03° vertical and 0.1° torsional; temporal resolution ranges up to 500 Hz (Table 2.7).
2.3.9.4 Scleral Search Coil Technique The scleral search coil technique is by far the most precise and accurate technique for eye movement recordings in a three-dimensional space, which also permits recording of rotational eye movements. It is based on the principle that voltage is induced in an electrically conductive material while this conductor moves within a magnetic field (or the strength of the magnetic field changes). A contact lens with a small opening at its center and an embedded coil of very thin wire is fixed on the anesthetized cornea (instead of the described contact lens, older systems based on the method developed by Robinson (1963) used a flat metal ring fixed to the cornea). The head of the patient is placed in the center of a strong magnetic field elicited by large magnetic coils. During eye movements in the magnetic field, a voltage is induced in the metal ring, which is proportional to the amplitude of the eye movement. The method is not widely available and employed predominantly in scientific experimentation. It enables three-dimensional recording of horizontal, vertical and rotational eye movements from open and closed eyes at a very high resolution of up to 1 min of angle (0.01°) (Table 2.7).
Recording possible from open eyes only Limited recording area (±20°) Recording of torsional eye movements not possible
2.3.10 Other Electrophysiologic Methods for the Investigation of Brainstem Reflexes Peter P. Urban 2.3.10.1 Stapedius Reflex The stapedius reflex (Fig. 2.52) is an acousticofacial reflex with the cochlear part of the vestibulocochlear nerve functioning as the afferent, and the facial nerve as the efferent branch. Proceeding from the cochlear nucleus, the neurons to the stapedius muscle in both facial nuclei are accessed, Rechts: 226 Hz 1.5 (ml)
1.0
0.5
Fig. 2.52 Stapedius reflex in a healthy subject
0 −400
−200
0 (dapa)200
2.3 Electrophysiologic Diagnostics
inducing bilateral contraction of the stapedius muscle after unilateral stimulation. Synapsing occurs at the pontomedullary level. The stapedius reflex is used primarily by ENT clinicians as an objective audiometric test method. While the examination of the stapedius reflex permits a qualitative assessment, a quantitative evaluation of latencies or amplitudes is not possible. Pathologic findings of the stapedius reflex may, on principle, be expected in the presence of tegmental pontomedullary lesions; an inference as to the lesion topography may be drawn from the pattern of the pathologic findings (ipsilateral/contralateral) (Lehnhardt 1993). How ever, other important influences also need to be considered in the interpretation of abnormal findings. Mechanical damage to the auditory ossicle chain, e.g. as a result of stapes ankylosis, or peripheral facial paresis are further possible pathologies responsible for the absence of a reflex response.
2.3.10.2 Trigemino-Cervical Reflex The trigeminocervical reflex (head retraction reflex) was first described as a clinical reflex by (Wartenberg 1941). In a positive case, a light tap with the reflex hammer to the region below the nose elicits a brief head jerking reaction in the seated patient. The reflex may also be examined neurophysiologically. With the patient in a seated position, the exit sites of the supraorbital or intraorbital nerves are stimulated electrically at the pain threshold and the reflex response is recorded from the sternocleidomastoid and/or semispinalis capitis muscle, using surface or needle electrodes (Ertekin et al. 2001; Serrao et al. 2003). The trigeminocervical reflex is a polysynaptic interconnected nociceptive protective reflex between the sensory trigeminal and the accessory nucleus, or the cervical motor neurons. At low stimulation strengths, inconstant stimulus responses with
a
Fig. 2.53 Stimulation and recording device for unilateral electric stimulation of the hard palate. Recording of CMAPs is achieved from surface area of the tongue using Ag/AgCl-electrodes. (a) View from
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latencies of about 40 ms are elicited in the spinal musculature (Ertekin et al. 2001). Conversely, several reflex responses with different latencies can be recorded at higher stimulation strengths. Short latency responses are obtained after approximately 10 ms, while later response latencies of about 40 ms are associated with the mechanical reflex response (Sartucci et al. 1986; Di Lazzaro et al. 1996; Serrao et al. 2003). Absent or abnormally prolonged reflex responses have been described in patients with tegmental medullary infarctions, cervical myelopathy, and multiple sclerosis (Rossi et al. 1989; Di Lazzaro et al. 1996).
2.3.10.3 Trigemino-Hypoglossal Silent Period Inhibitory connections between sensory trigeminal afferents and hypoglossal neurons have been described in animal models (Tomioka et al. 1999; Zhang et al. 2003). Similar projections have also been shown in humans (Urban et al. 2005). Analogous to the masseter silent period, the trigeminohypoglossal silent period may be assumed to be an antinociceptive protective reflex. Examination of the trigeminohypoglossal silent period is performed with a specially prepared enoral stimulation and recording device, which permits right–left unilateral electric stimulation of the trigeminal (V2) innervated palatine mucosa and simultaneous recording of EMG activity from both sides of the tongue surface (Fig. 2.53). Stimulation is applied to each side of the palate with the fivefold sensory stimulation threshold, while the study subject is asked to maximally activate the tongue muscle. Five trains are recorded and EMG activity is averaged. Filter settings are 20 Hz and 2 kHz, respectively.
b
above showing stimulation electrodes. (b) View from below showing recording electrodes
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In 18 of 20 subjects, monophasic bilateral suppression of tongue activity was observed on right-left unilateral stimulation, starting at 41.1 ± 4.7 ms and terminating at 82.4 ± 12.5 ms. Mean duration of the silent period ranged at 41.4 ± 10.2 ms. Tongue muscle activity was not suppressed after bilateral palatal stimulation in two of the subjects (Fig. 2.54).
Fig. 2.54 Trigeminohypoglossal silent period in a healthy subject. Unilateral electric stimulation of the hard palate induces bilateral suppression of muscle activity at both halves of the tongue
(0.4 mV)
Initial investigations in individual patients with circumscribed tegmental brainstem lesions of the caudal pons and the dorsolateral medulla oblongata showed the absence of a silent period on the ipsilateral side of the lesion location, although no sensory abnormality was found on clinical examination (Figs. 2.55 and 2.56). In individual patients with multiple sclerosis, a unilateral clinically silent lesion was
V2-I, tongue l
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(15 ms)
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Fig. 2.55 Patient with dorsolateral infarction involving the right medulla oblongata. (a) Axial MRI. (b) Sagittal MRI. (c) Electrical stimulation of the hard palate at the right side shows no suppression of muscle activity at both halves of the tongue, while stimulation to the left side of the palate leads to bilateral suppression of tongue muscle activity
Lat.1
Lat.2
Literature Fig. 2.56 Patient with hemorrhage into a cavernoma in the left pontine tegmentum. (a) Axial MRI. (b) Sagittal MRI. (c) Electrical stimulation of the hard palate at the left side shows no suppression of muscle activity at both halves of the tongue, while stimulation of the right side of the palate leads to bilateral suppression of tongue muscle activity
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V2r, tongue r
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detected. Further studies in a larger patient population and in patients with circumscribed brainstem lesions will be conducted to determine the diagnostic validity of this method.
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eumann-Haefelin T, Pilgram-Pastor S, Sitzer M, Sonnberger N M, Tietke M, Trenkler J, Turowski B, INTRASTENT Study Group (2010 March) In-hospital complication rates after stent treatment of 388 symptomatic intracranial stenoses: results from the INTRASTENT multicentric registry. Stroke 41(3):494–498, Epub 2010 Jan 14 Weber W, Mayer TE, Henkes H, Kis B, Hamann GF, SchulteAltedornebug G, Brückmann H, Kuehne D (2005a) Stentangioplasty of intracranial vertebral and basilar artery stenoses in symptomatic patients. Eur J Radiol 55:231–236 Lauterbur PC (1973) Image formation by induced local interactions: examples employing nuclear magnetic resonance. Nature 242:190–191 Liu HM, Wang YH, Chen YF, Tu YK, Huang KM (2003) Endovascular treatment of brainstem arteriovenous malformations: safety and efficacy. Neuroradiology 45:644–649 Livingstone RS, Raghuram L, Korah IP, Raj DV (2003) Evaluation of radiation risk and work practices dural cerebral interventions. J Radiol Prot 23:327–336 Loewy J, Loewy A, Kendall EJ (2004) Reconsideration of pacemakers and MR imaging. Radiographics 24:1257–1267 Maclennan AC, Hadley DM (1995) Radiation dose to the lens from computed tomography scanning in a neuroradiology department. Br J Radiol 68:19–22 Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R (2002) International subarachnoid aneurysm trial (ISAT) on neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. Lancet 360:1267–1274 Pfefferkorn T, Mayer TE, Schulte-Altedorneburg G, Brückmann H, Hamann GF, Dichgans M (2006) Diagnosis and therapy of basilar artery occlusion. Nervenarzt 77:416–422 Saatci I, Cekirge HS, Ozturk MH, Arat A, Ergungor F, Sekerci Z, Senveli E, Er U, Turkoglu S, Ozcan OE, Ozgen T (2004) Treatment of internal carotid artery aneurysms with a covered stent: experience in 24 patients with mid-term follow-up results. Am J Neuroradiol AJNR 25:1742–1749 Saigal G, Bhatia R, Bhatia S, Wakhloo AK (2004) MR findings of cortical blindness following cerebral angiography: Is this entity related to posterior reversible leukoencephalopathy? Am J Neuroradiol AJNR 25:252–256 Schonewille WJ, Algra A, Serena J, Molina CA, Kappelle LJ (2005) Outcome in patients with basilar artery occlusion treated conventionally. J Neurol Neurosurg Psychiatry 76:1238–1241 Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle HP, Engelter ST, Tanne D, Muir KW, Molina CA, Thijs V, Audebert H, Pfefferkorn T, Szabo K, Lindsberg PJ, de Freitas G, Kappelle LJ, Algra A, BASICS study group (2009 Aug) Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study. Lancet Neurol 8(8):724–730, Epub 2009 Jul 3 SSYLVIA Study Investigators (2004) Stenting of symptomatic atherosclerotic lesions in the vertebral or intracranial arteries (SSYLVIA). Study results. Stroke 35:1388–13392 Szikora I (2004) Dural arteriovenous malformations. In: Forsting M (ed) Intracranial vascular malformations and aneurysms. From diagnostic work-up to endovascular therapy. Springer, Berlin, pp 101–141 Schulte-Altedorneburg G, Liebig T, Brückmann H, Jansen O (2009 Dec) Treatment of basilar artery occlusion: a prospective randomised therapeutic study is needed. Lancet Neurol 8(12):1084–1085 Pfefferkorn T, Mayer TE, Schulte-Altedorneburg G, Brückmann H, Hamann GF, Dichgans M (2005) Diagnostik und Therapie der Basilaristhrombose (Epub ahead of print) Tintera J, Gawehn J, Bauermann T, Vucurevic G, Stoeter P (2004) New partially parallel acquisition technique in cerebral imaging: preliminary findings. Eur J Radiol 14:2273–2281
Vindlacheruvu RR, Mendelow AD, Mitchell P (2005) Risk-benefit analysis of the treatment of unruptured intracranial aneurysms. J Neurol Neurosurg Psychiatry 76:234–249 Weber W, Mayer TE, Henkes H, Kis B, Hamann GF, SchulteAltedorneburg G, Brückmann H, Kuehne D (2005) Stent-angioplasty of intracranial vertebral and basilar artery stenoses in symptomatic patients. Eur J Radiol 55:231–236 Willinsky RA, Taylor S, terBrugge K, Farb RI, Tomlinson G, Montanera W (2003) Neurologic complications of cerebral angiography: prospective analysis of 2899 procedures and review of the literature. Radiology 227:522–528
2.2 “Ultrasound Diagnostics” Bartels E (1991) Duplexsonographie der Vertebralarterien, 1. Teil. Praktische Durchführung, Möglichkeiten und Grenzen der Methode, 2. Teil. Klinische Anwendungen. Ultraschall Med 12:54–69 Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K (1995a) Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real-time sonography. Neurology 45:182–184 Becker G, Becker T, Struck M, Lindner A, Burzer K, Retz W, Bogdahn U, Beckmann H (1995b) Reduced echogenicity of brainstem raphe specific to unipolar depression: a transcranial color-coded real-time sonography study. Biol Psychiatry 38:180–184 Berg D, Supprian T, Hofmann E, Zeiler B, Jager A, Lange KW, Reiners K, Becker T, Becker G (1999a) Depression in Parkinson’s disease: brainstem midline alteration on transcranial sonography and magnetic resonance imaging. J Neurol 246:1186–1193 Berg D, Becker G, Zeiler B, Tucha O, Hofmann E, Preier M, Benz P, Jost W, Reiners K, Lange KW (1999b) Vulnerability of the nigrostriatal system as detected by transcranial ultrasound. Neurology 53:1026–1031 Berg D, Siefker C, Ruprecht-Dorfler P, Becker G (2001a) Relationship of substantia nigra echogenicity and motor function in elderly subjects. Neurology 56:13–17 Berg D, Siefker C, Becker G (2001b) Echogenicity of the substantia nigra in Parkinson’s disease and its relation to clinical findings. J Neurol 8:684–689 Brunner-Beeg F, von Reutern GM (1999) Farbduplexsonographie des intrakraniellen vertebrobasilären Systems: Verbesserung der Darstel lung durch Echosignalverstärkung. Ultraschall Med 20:83–86 Iglseder B, Huemer M, Staffen W, Ladurner G (2000) Imaging the basilar artery by contrast-enhanced color-coded ultrasound. J Neuroimaging 10:195–199 Netuka D, Benes V, Mikulik R, Kuba R (2005) Symptomatic rotational occlusion of the vertebral artery. Case report and review of the literature. Zentralbl Neurochir 66:217–222 Ringelstein EB, Koschorke B, Niggemeyer E, Otis SM (1990) Transcranial Doppler sonography: anatomical landmarks and normal velocity values. Ultrasound Med Biol 16:745–761 Schweitzer K, Hilker R, Walter U, Burghaus L, Berg D (2006) Substantia nigra hyperechogenicity as a marker of predisposition and slower progression in Parkinson’s disease. Mov Disord 21:94–98 von Büdingen HJ, Staudacher T (1987) Die Identifizierung der Arteria basilaris mit der transkraniellen Doppler-Sonographie. Ultraschall 8:95–101 Walter U, Niehaus L, Probst T, Benecke R, Meyer BU, Dressler D (2003) Brain parenchyma sonography discriminates Parkinson’s disease and atypical parkinsonian syndromes. Neurology 60:74–77 Walter U, Dressler D, Benecke R (2004) Hirnparenchym-Sonographie zur Früh- und Differenzialdiagnostik der Parkinson-Krankheit. Akt Neurol 31:325–332
Literature Walter U, Dressler D, Wolters A, Wittstock M, Greim B, Benecke R (2006a) Sonographic discrimination of dementia with Lewy bodies and Parkinson’s disease with dementia. J Neurol 253:448–454 Walter U, Morrissey L, Herpertz S, Benecke R, Höppner J (2006b) Brainstem raphe echogenicity predicts response to selective serotonin reuptake inhibitors in depressive states: a transcranial sonography study. Klin Neurophysiol 37:97 Widder B (1999) Verschlussprozesse im vertebrobasilären Gefäßsystem. In: Widder B (ed) Doppler- und Duplexsonographie der hirnver sorgenden Gefäße. 5. Aufl. Springer, Berlin/Heidelberg/New York, pp 265–289
2.3 “Electrophysiologic Diagnostics” 2.3.1 “Blink Reflex” Aramideh M, Ongerboer de Visser BW, Koelman JH, Majoie CB, Holstege G (1997) Late blink reflex response abnormality due to lesion of the lateral tegmental field. Brain 120:1685–1692 Cruccu G, Iannetti GD, Marx JJ, Thömke F, Truini A, Fitzek S, Galeotti F, Urban PP, Romaniello A, Stoeter P, Manfredi M, Hopf HC (2005) Brainstem reflex circuits revisited. Brain 128:386–394 Hopf HC (1994a) Topodiagnostic value of brainstem reflexes. Muscle Nerve 17:475–484 Hopf HC, Thömke F, Gutman L (1991) Midbrain versus pontine medial longitudinal fasciculus lesions: the utilization of masseter and blink reflexes. Muscle Nerve 14:326–330 Hopf HC, Ellrich J, Hundemer H (1992) The pterygoid reflex in man and its clinical application. Muscle Nerve 15:1278–1283 Kimura J (1975) Electrically elicited blink reflex in diagnosis of multiple sclerosis. Brain 98:413–426 Kimura J (1989) Electrodiagnosis in diseases of nerve and muscle: principles and practices. 2. Aufl. F.A. Davis, Philadelphia, pp 307–331 Kugelberg E (1952) Facial reflexes. Brain 75:385–396 Marx JJ, Thoemke F, Fitzek S, Vucurevic G, Fitzek C, Mika-Grüttner A, Urban PP, Stoeter P, Hopf HC (2001) Topodiagnostic value of blink reflex R1 changes – a digital postprocessing MRI correlation study. Muscle Nerve 24:1327–1331 Metha AJ, Seshia SS (1976) Orbicularis oculi reflex in brain death. J Neurol Neurosurg Psychiatry 39:784–787 Ongerboer de Visser BW (1983) Anatomical and functional organisation of reflexes involving the trigeminal system in man: Jaw reflex, blink reflex, corneal reflex and exteroceptive suppression. Adv Neurol 39:729–738 Rossi B, Pasca SL, Sartucci F, Siciliano G, Murri L (1989) Trigeminocervical reflex in pathology of the brain stem and of the first cervical cord segments. Electromyogr Clin Neurophysiol 29:67–71 Tackmann W, Ettlin T, Barth R (1982) Blink reflexes elicited by electrical, acoustic and visual stimuli. Eur Neurol 21:210–216 Valls-Solé J, Graus F, Font J, Pou A, Tolosa ES (1990) Normal proprioceptive afferents in patients with Sjögren’s syndrome and sensory neuropathy. Ann Neurol 28:786–790
2.3.2 “Masseter Reflex” Ben Ghezala K, Hundemer HP, Koehler J, Urban PP, Connemann B, Hopf HC (1996) The variance of masseter reflex (MassR) latencies and amplitudes with different recording techniques and follow-up with weekly intervals. Electroencephal Clin Neurophysiol 99:334
97 Bremer T (1993) Der Eigenreflex des Musculus masseter: Erstellung der Normwerttabelle. Thesis, Mainz Cruccu G, Inghileri M, Fraioli B, Guidetti B, Manfredi M (1987a) Neurophysiologic assessment of trigeminal function after surgery for trigeminal neuralgia. Neurology 37:631–638 Ferguson IT (1978) Electrical study of jaw and orbicularis oculi reflexes after trigeminal nerve surgery. J Neurol Neurosurg Psychiatry 41:819–823 Fitzek S, Fitzek C, Hopf HC (2001) The masseter reflex: postprocessing methods and influence of age and gender. Eur Neurol 46:202–205 Goodwill CJ (1968) The normal jaw reflex: measurement of the action potential in the masseter muscles. Ann Phys Med 9:183–188 Görömbey Z, Csecsei G, Klug N (1986) Veränderungen des MasseterReflexes bei primären und sekundären Hirnstammschädigungen. In: Lowitzsch (Hrsg) Hirnstammreflexe. Methodik und klinische Anwendung. Thieme, Stuttgart, pp 204–210 Hassler O (1967) Arterial pattern of human brainstem. Normal appearance and deformation in expanding supratentorial conditions. Neurology 17:368–375 Hopf HC (1994) Topodiagnostic value of brainstem reflexes. Muscle Nerve 17:475–484 Hopf HC, Gutmann L (1990) Diabetic 3rd nerve palsy: evidence for a mesencephalic lesion. Neurology 40:1041–1045 Hopf HC, Hinrichs C, Stoeter P, Urban PP, Marx J, Thömke F (2000) Masseter reflex latencies and amplitudes are not influenced by supratentorial and cerebellar lesions. Muscle Nerve 23:86–89 Kimura J, Rodnitzky RL, Van Allen MW (1970) Electrodiagnostic study of trigeminal nerve. Orbicularis oculi reflex and masseter reflex in trigeminal neuralgia, paratrigeminal syndrome, and other lesions of the trigeminal nerve. Neurology 20:574–583 Koehler J, Schwarz M, Urban PP, Voth D, Hölker C, Hopf HC (2001) Masseter reflex and blink reflex abnormalities in Chiari II malformation. Muscle Nerve 24:425–427 Krämer G, Bremer T, Hubrich P, Lüder G, Hopf HC (1992) Altersabhängige Normwerte des Masseter Reflexes. Akt Neurol 19: XVIII Lowitzsch K, Marzi I (1986) Multimodale Hirnstammreflexe in der Prognose des Koma. In: Lowitzsch (Hrsg) Hirnstammreflexe. Methodik und klinische Anwendung. Thieme, Stuttgart, pp 237–251 Marx JJ, Mika-Gruettner A, Thoemke F, Fitzek S, Fitzek C, Vucurevic G, Urban PP, Stoeter P, Hopf HC (2002) Electrophysiological brainstem testing in the diagnosis of reversible brainstem ischemia. J Neurol 249:1041–1047 Mika-Grüttner A, Marx J, Thömke F, Fitzek S, Fitzek C, Urban PP, Stoeter P, Hopf HC (2001) Wertigkeit der Elektrophysiologie bei Hirnstammischämien und normalem diffusionsgewichteten und hochauflösenden MRT. Klin Neurophysiol 32:135–140 Mika-Grüttner A, Thömke F, Marx JJ, Urban PP, Ringel K, Hopf HC (2002) Magnetic resonance imaging versus electrophysiological testing in internuclear ophthalmoplegia. Mov Disord 17:S92 Nieuwenhuys R, Voogd J, van Huijzen C (1989) The human central nervous system, 3rd edn. Springer, Berlin Ongerboer de Visser BW, Goor C (1974) Electromyographic and reflex study in idiopathic and symptomatic trigeminal neuralgias: latency of the jaw and blink reflexes. J Neurol Neurosurg Psychiatry 37: 1225–1230 Thömke F (1999) Isolated cranial nerve palsies due to brainstem lesions. Muscle Nerve 22:1168–1176 Thömke F (2003) Die elektrophysiologische Untersuchung des Masseter-Reflexes. Ableittechnik, klinischer Einsatz und topodiagnostische Bedeutung. Klin Neurophysiol 34:1–6 Thömke F, Hopf HC (1999) Pontine lesions mimicking acute peripheral vestibulopathy. J Neurol Neurosurg Psychiatry 66: 340–349
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Thömke F, Gutmann L, Stoeter P, Hopf HC (2002) Cerebrovascular brainstem diseases with isolated cranial nerve palsies. Cerebrovasc Dis 13:147–155 Yates SK, Brown WF (1981) The human jaw jerk: electrophysiologic methods to measure latency, normal values and changes in multiple sclerosis. Neurology 31:632–634
2.3.3 “Early Acoustic Evoked Potentials” Bassetti C, Mathis J, Hess CW (1994a) Multimodal electrophysiological studies including motor evoked potentials in patients with locked-in syndrome: report of six patients. J Neurol Neurosurg Psychiatry 57:1403–1406 Buchner H (2000) Frühe akustisch evozierte Potentiale (FAEP). In: Lowitzsch K, Hopf HC, Buchner H, Claus D, Jörg J, Rappelsberger P, Tackmann W (eds) Das EP-Buch. Thieme, Stuttgart Chia L-G, Shen W-C (1993) Wallenberg’s lateral medullary syndrome with loss of pain and temperature sensation on the contralateral face: clinical, MRI and electrophysiological studies. J Neurol 240:462–467 Chiappa KH (ed) (1997) Evoked potentials in clinical medicine, 3rd edn. Lippincott-Raven, Philadelphia Cho T-H, Fischer C, Nighoghossian N, Hermier M, Sindou M, Maugière F (2005) Auditory and electrophysiological patterns of a unilateral lesion of the lateral lemniscus. Audiol Neurotol 10:153–158 Drulovic B, Ribaric-Jankes K, Kostic VS, Sternic N (1993) Sudden hearing loss as the initial monosymptom of multiple sclerosis. Neurology 43:2703–2705 Egan CA, Davies L, Halmagyi GM (1996) Bilateral total deafness due to pontine haematoma. J Neurol Neurosurg Psychiatry 61:628–631 Ferbert A, Buchner H, Brückmann H (1990a) Brainstem auditory evoked potentials and somatosensory evoked potentials in pontine haemorrhage. Brain 113:49–63 Fischer C, Bognar L, Turjman F, Lapras C (1995) Auditory evoked potentials in a patient with a unilateral lesion of the inferior colliculus and medial geniculate body. Electroencephal Clin Neurophysiol 96:261–267 Friedli WG, Fuhr P (1990) Electrocutaneous reflexes and multimodality evoked potentials in multiple sclerosis. J Neurol Neurosurg Psych 53:391–397 Hammond SR, Yiannikas C, Chan YW (1986) A comparison of brainstem auditory evoked responses evoked by rarefication and condensation stimulation in control subjects and in patients with Wernicke-Korsakoff syndrome and multiple sclerosis. J Neurol Sci 74:177–190 Häusler R, Levine RA (2000) Auditory dysfunction in stroke. Acta Oto-Laryngol 120:689–703 Hoistad DL, Hain TC (2003) Central hearing loss with a bilateral inferior colliculus lesion. Audiol Neurootol 8:111–113 Kaga K, Shinoda Y, Suzuki JI (1997) Origin of auditory brainstem responses in cats: whole brainstem mapping, and a lesion and HRP study of the inferior colliculus. Acta Otolaryngol 117:197–201 Krieger D, Adams H-P, Rieke K, Hacke W (1993) Monitoring therapeutic efficacy of decompressive craniotomy in space occupying cerebellar infarcts using brainstem auditory evoked potentials. Electroencephal Clin Neurophysiol 88:261–270 Lee H, Ahn B-H, Baloh RW (2004) Sudden deafness with vertigo as a sole manifestation of anterior inferior cerebellar artery infarction. J Neurol Sci 222:105–107 Levine RA, Gardner JC, Fullerton BC, Stufflerbeam SM, Carlislc EW, Furst M, Rosen BR, Kiang NYS (1993) Effects of multiple sclerosis brainstem lesions on sound lateralization and brainstem auditory evoked potentials. Hear Res 68:73–88
Lopez-Escamez JA, Salguero G, Salinero J (1999) Age and sex differences in latencies of waves i, III and V in auditory brainstem responses of normal hearing subjects. Acta Otorhinolaryngol Belg 53:109–115 Markand ON (1994) Btainstem auditory evoked potentials. J clin Nevrophysiol 11: 319–342 Martin WH, Pratt H, Schwegler JW (1995) The origin of the human auditory brainstem response wave II. Electroencephal Clin Neuro physiol 96:357–370 Maurer K (1985) Uncertainties of topodiagnosis of auditory nerve and brainstem auditory evoked potentials due to rarefication and condensation stimuli. Electroencephal Clin Neurophysiol 62: 135–140 Pratt H, Aminoff M, Nuwer MR, Starr A (1999) Short-latency auditory evoked potentials. Electroencephal Clin Neurophysiol 52:69–77 Scientific committee BĂK (1998) Richtlinien zur Feststellung des Hirntodes. Dritte Fortschreibung 1997. Dtsch Ärztebl 95: 1509–1516 Vitte E, Tankere F, Bernat I, Zouaoui A, Lamas G, Soudant J (2002) Midbrain deafness with normal brainstem auditory evoked potentials. Neurology 58:970–973
2.3.4 “Vestibulocollic Reflex” Baier B, Dieterich M (2009) Vestibular-evoked myogenic potentials in “vestibular migraine” and Menière`s Disease. A sign of an electrophysiological link? Ann NY Acad Sci 1164:324–327 Baier B, Stieber N, Dieterich M (2009) Vestibular evoked myogenic potentials in “vestibular” migraine. J Neurol (256; 1447–54) Bandini F, Beronio A, Ghiglione E, Solaro C, Parodi RC, Mazzella L (2004) The diagnsotic value of vestibular evoked myogenic potentials in mutliple sclerosis. J Neurol 251:621–671 Basta D, Todt I, Ernst A (2005) Normative data for P1/N1-latencies of vestibular evoked myogenic potentials induced by air- or bone- conducted tone bursts. Clin Neurophysiol 116: 2216–2219 Chen CH, Young YH (2003) Vestibular evoked myogenic potentials in brainstem stroke. Laryngoscope 113:990–993 Chen CW, Young YH, Wu CH (2000) Vestibular neuritis: three- dimensioal videonystagmography and vestibular evoked potential results. Acta Otolaryngeol 120:845–848 Colebatch JG, Halmagyi GM (2000) Vestibular evoked myogenic potentials in humans. Acta Otolaryngeol 120:12 De Waele C, Tran Ba Huy P, Diard JP, Freyss G, Vidal PP (1999) Saccular dysfunction in Menière`s patients. A vestibular-evoked myogenic potential study. Ann NY Acad Sci 871:205–208 Heide G, Freitag S, Wollenberg I, Ivo H, Schimrigk K, Dillmann U (1999) Click evoked myogenic potentials in the differential diagnosis of vertigo. J Neurol Neurosurg Psychiatry 66: 787–790 Itoh A, Kim YS, Yoshioka K, Yoshioka K, Kanaya M, Enomoto H, Hiraiwa F, Mizuno M (2001) Clinical study of vestibular-evoked myogenic potentials and auditory brainstem responses in pati ents with brainstem lesions. Acta Otolaryngeol 545(Suppl): 116–119 Lim CL, Clouston P, Sheean G, Yiannikas C (1995) The influence of voluntary EMG activity and click intensity on the vestibular click evoked potential. Muscle Nerve 18:1210–1213 Minor LB, Cremer PD, Carey JP, Della Santana CC, Streubel SO, Weg N (2001) Symptoms and signs in superior canal dehiscence syndrome. Ann NY Acad Sci 942:259–273 Murofushi T, Halmagyi GM, Yavor RA, Colebatch JG (1996) Absent vestibular evoked myogenic potentials in vestibular
Literature n eurolabyrinthitis. An indicator of inferior vestibular nerve involvement? Arch Otolaryngeol Head Neck Surg 122:845–818 Murofushi T, Shimizu K, Takegoshi H, Cheng PW (2001) Diagno stic value of prolonged latencies in the vestibular evoked myogenic potential. Arch Otolaryngeol Head Neck Surg 127: 1069–1072 Ochi K, Ohashi T, Watanabe S (2003) Vestibular-evoked myogenic potential in patients with unilateral vestibular neuritis: abnormal VEMP and ist recovery. J Laryngeol Otol 117:104–108 Patko T, Vidal PP, Vibert N, Tran Ba Huy P, de Waele C (2003) Vestibular evoked myogenic potentials in patients suffering from an unilateral acoustic neurinoma: a study of 170 patients. Clin Neurophysiol 114:1344–1350 Sartucci F, Logi F (2002) Vestibular-evoked myogenic potentials: a method to assess vestibulo-spinal conduction in multiple sclerosis. Brain Res Bull 59:59–63 Versino M, Colnaghi S, Callieco R, Bergamaschi R, Romani A, Cosi V (2002) Vestibular evoked myogenic potential in multiple sclerosis patients. Clin Neurophysiol 113:1464–1469 Watson SR, Halmagyi GM, Colebatch JG (2000) Vestibular hypersensitivity to sound (Tullio phenomenon): structural and functional assessment. Neurology 54:722–728 Welgampola MS, Colebatch JG (2001) Vestibulocollic reflexes: normal values and the effect of age. Clin Neurophysiol 112: 1971–1979 Welgampola MS, Colebatch JG (2005) Characteristics and application of vestibular-evoked myogenic potentials. Neurology 64: 1682–1688 Zingler V, Weintz E, Jahn K, Bötzel K, Wagner J, Huppert D, Mike A, Brandt T, Strupp M (2008) Saccular function less affected than canal function in bilateral vestibulopathy. J Neurol 255: 1332–1336
2.3.5 “Exteroceptive Suppression of Masticatory Muscle Activity” Bendtsen L, Jensen R, Olesen J (1996) Amytrytiline, a combined serotonin and noradrenaline re-uptake inhibitor, reduces exteroceptive suppression of temporal muscle activity in patients with chronic tension-type headache. Electroencephal Clin Neurophysiol 101: 418–422 Connemann BJ, Urban PP, Lüttkopf V, Hopf HC (1997) A fully automated system for the evaluation of masseter silent periods. Electroencephal Clin Neurophysiol 105:53–57 Cruccu G, Inghileri M, Fraioli B, Guidetti B, Manfredi M (1987) Neurophysiologic assessment of trgeminal function after surgery for trigeminal neuralgia. Neurology 37: 631–638 Cruccu G, Fornarelli M, Manfredi M (1988) Impairment of masticatory function in hemiplegia. Neurology 38:301–306 Ellrich J, Hopf HC, Treede R-D (1997) Nociceptive masseter inhibitory reflexes evoked by laser radiant heat and electrical stimuli. Brain Res 764:214–220 Göbel H (1996) Die Kopfschmerzen. Ursache, Mechanismen, Diagnostik und Therapie in der Praxis. Springer, Berlin/Heidelberg /New York Göbel H, Dworschak M (1996) Die exterozeptive Suppression der Aktivität des M. temporalis. Nervenarzt 67:846–859 Göbel H, Schoenen J (1993) Exteroceptive suppression in headache research. Cephalalgia 13:20 Göbel H, Ernst M, Jeschke J, Weigle L (1992) Acetylsalicylic acid activates antinociceptive brainstem reflex activity in headache patients and in healthy subjects. Pain 48:187–195
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2.3.6 “Somatosensory Evoked Potentials” Besser R, Dillmann U, Henn M (1988) Somatosensory evoked potentials aiding the diagnosis of brain death. Neurosurg Rev 11:171–175 Buchner H, Ferbert A, Hacke W (1988) Serial recordings of median nerve stimulated subcortical somatosensory evoked potentials (SEPs) in developing brain death. Electroencephalogr Clin Neurophysiol 69:14–23 Christophis P (2004) The prognostic value of somatosensory evoked potentials in traumatic primary and secondary brain stem lesions. Zentralbl Neurochir 65:25–31
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Claß R, Buettner UW (1993) Correlation of somatosensory evoked potentials and somatosensory findings in patients with brainstem lesions. In: Caplan LR, Hopf HC (eds) Brainstem localization and function. Springer, Heidelberg, pp 161–164 Dillmann U, Besser R, Eghbal R, Koehler J, Ludwig B (1990) SEP and MRI findings in patients with localized brainstem lesions. Electroencephal Clin Neurophysiol 41:314–319 Ferbert A, Buchner H, Brückmann H, Zeumer H, Hacke W (1988) Evoked potentials in basilar artery thrombosis: correlation with clinical and angiographic findings. Electroencephalogr Clin Neuro physiol 69:136–147 Ferbert A, Buchner H, Brückmann H (1990) Brainstem auditory evoked potentials and somatosensory evoked potentials in pontine haemor rhage. Brain 113:49–63 Jacobson GP, Tew JM (1988) The origin of the scalp recorded P14 following electrical stimulation of the median nerve: intraoperative observations. Electroencephalogr Clin Neurophysiol 71:73–76 Koehler J, Besser R, Stoeter P, Urban PP, Hopf HC (2000) Scalp, basal epidural and intravascular far field recordings after median nerve stimulation: evidence for a separate N18a potential. Somatosens Mot Res 17:239–243 Lueders H, Lesser R, Hahn J, Little J, Klem G (1983) Subcortical somatosensory evoked potentials to median nerve stimulation. Brain 106:341–372 Manzano GM, Schultz RR, Barsottini OG, Zukerman E, Nobrega JA (1999) Median nerve SEP after a high medullary lesion. Preserved N18 and absent P14 components. Arq Neuropsiquiatr 57: 292–295 Maugière F, Allison T, Babiloni C, Buchner H, Eisen AA, Goodin DS, Jones SJ, Kagigi R, Matsuoka S, Nuwer M, Rossini PM, Shibasaki H (1999) Somatosensory evoked potentials. Electroencephalogr Clin Neurophysiol (Suppl):52 Noel P, Ozaki I, Desmedt JE (1996) Origin of N18 and P14 far-fields of median nerve somatosensory evoked potentials studied in patients with a brainstem lesion. Electroencephalogr Clin Neurophysiol 98:167–170 Raroque HG, Batjer H, White C, Bell WL, Bowman G, Greenlee R (1994) Lower brainstem origin of the median nerve N18 potential. Electroencephalogr Clin Neurophysiol 90:170–172 Sonoo M, sakuta M, Shimpo T, Genba K, Mannen T (1991) Widespread N18 in median nerve SEP is preserved in a pontine lesion. Electroencephalogr Clin Neurophysiol 80:238–240 Sonoo M, Genba K, Zai W, Iwata M, Mannen T, Kanazawa J (1992) Origin of the widespread N18 in median nerve SEP. Electroe ncephalogr Clin Neurophysiol 84:418–425 Sonoo M, Hagiwara H, Motoyoshi Y, Shimizu T (1996) Preserved widespread N18 and progressive loss of P13/14 of median nerve SEPs in a patient with unilateral medial medullary syndrome. Electroencephalogr Clin Neurophysiol 100:488–492 Sonoo M, Tsai-Shozawa Y, Aoki M, Nakatani T, Hatanaka Y, Mochizuki A, Sawada M, Kobayashi K, Shimizu T (1999) N18 in median somatosensory evoked potentials: a new indicator of medullary function useful for the diagnosis of brain death. J Neurol Neurosurg Psychiatry 67:374–378 Stöhr M, Petruch F, Scheglmann K (1981) Somatosensory evoked potentials following trigeminal nerve stimulation in trigeminal neuralgia. Ann Neurol 9:63–66 Stöhr M, Riffel B, Ullrich A (1987) Short latency somatosensory evoked potentials in brain death. J Neurol 234:211–214 Tackmann W (2000) Somatosensorisch evozierte Potentiale. In: Lowitzsch K, Hopf HC, Buchner H, Claus D, Jörg J, Rappelsberger P, Tackmann W (eds) Das EP-Buch. Thieme, Stuttgart, pp 127–172 Wagner W (1996) Scalp, earlobe and nasopharyngeal recordings of the median nerve somatosensory evoked P14 potential in coma and brain death: detailed latency and amplitude analysis in 181 patients. Brain 119:1507–1521 Wissenschaftlicher Beirat der Bundesärztekammer (1998) Richtlinien zur Feststellung des Hirntodes. Dritte Fortschreibung 1997. Dtsch Ärztebl 95:1509–1516
2.3.7 “Transcranial Magnetic Stimulation” Bassetti C, Mathis J, Hess CW (1994) Multimodal electrophysiological studies including motor evoked potentials in patients with locked-in syndrome: report of six patients. J Neurol Neurosurg Psychiatry 57:1403–1406 Escudero JV, Sancho J, Bautista D, Escudero M, Lopez-Trigo J (1998) Prognostic value of motor evoked potential obtained by transcranial magnetic brain stimulation in motor function recovery in patients with acute ischemic stroke. Stroke 29:1854–1859 Ferbert A, Vielhaber S, Meincke U, Buchner H (1992) Transcranial magnetic stimulation in pontine infarction: correlation to degree of paresis. J Neurol Neurosurg Psychiatry 55:294–299 Fischer U, Hess CW, Rösler KM (2005) Uncrossed cortico-muscular projections in humans are abundant to facial muscles of the upper and lower face, but may differ between sexes. J Neurol 252: 21–26 Meyer BU (ed) (1992) Die Magnetstimulation des Nervensystems. Springer, Heidelberg Morecraft RJ, Louie JL, Herrick JL, Stilwell-Morecraft KS (2001) Cortical innervation of the facial nucleus in the non-human primate: a new interpretation of the effects of stroke and related subtotal brain trauma on the muscles of facial expression. Brain 124: 176–208 Redmond MD, Di Benedetto M (1988) Hypoglossal nerve conduction in normal subjects. Muscle Nerve 11:447–452 Riepe M, Ludolph AC (1993) Untersuchungen kortikobulbärer Bahnen und peripherer Hirnnerven bei Normalpersonen und Patienten mit multipler Sklerose: Ergebnisse nach nichtinvasiver elektro magnetischer Reizung. Z EEG EMG 24:269–273 Rösler KM, Hess CW, Schmid UD (1989) Investigation of facial motor pathways by electrical and magnetic stimulation: sites and mechanisms of excitation. J Neurol Neurosurg Psychiatry 52: 1149–1156 Schmid UD, Moller AR, Schmid J (1991) Transcranial magnetic stimulation excites the labyrinthine segment of the facial nerve: an intraoperative electrophysiological study in man. Neurosci Lett 124:273–276 Schwarz S, Hacke W, Schwab S (2000) Magnetic evoked potentials in neurocritical care patients with acute brainstem lesions. J Neurol Sci 172:30–37 Trompetto C, Assini A, Buccolieri A, Marchese R, Abbruzzese G (2000) Motor recovery following stroke: a transcranial magnetic stimulation study. Clin Neurophysiol 111:1860–1867 Truffert A, Rösler KM, Magistris MR (2000) Amyotrophic lateral sclerosis versus cervical spondylotic myelopathy: a study using transcranial magnetic stimulation with recordings from the trapezius and limb muscles. Clin Neurophysiol 111:1031–1038 Urban PP (2002) Vergleichende Untersuchung elektrisch und magnetisch evozierter Potentiale aus unterschiedlichen Fazialis-inner vierten Muskeln. Klin Neurophysiol 33:A27 Urban PP, Hopf HC (2002) Verlauf kortiko-fazialer und kortiko- lingualer Projektionen im Hirnstamm des Menschen. In: Bohl J (ed) Neuropathology. Shaker, Achen, pp 1–18 Urban PP, Heimgärtner I, Hopf HC (1994) Transkranielle Stimulation der Zungenmuskulatur bei Gesunden und Patienten mit Encepha lomyelitis disseminata. Z EEG EMG 25:254–258 Urban PP, Hopf HC, Connemann B, Hundemer HP, Koehler J (1996) The course of cortico-hypoglossal projections in the human brainstem. Functional testing using transcranial magnetic stimulation. Brain 119:1031–1038 Urban PP, Beer S, Hopf HC (1997a) Cortico-bulbar fibers to orofacial muscles: recordings with enoral surface electrodes. Electroencephalogr Clin Neurophysiol 105:8–14 Urban PP, Hopf HC, Fleischer S, Zorowka PG, Müller-Forell W (1997b) Impaired cortico-bulbar tract function in dysarthria due to hemispheric stroke. Brain 120:1077–1084 Urban PP, Connemann B, Hundemer HP, Koehler J, Hopf HC (1997c) Technical considerations of electromyographic tongue muscle
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2.3.8 “Laser-Evoked Potentials” Beydoun A, Morrow TJ, Shen JF, Casey KL (1993) Variability of laserevoked potentials attention, arousal and lateralized differences. Electroencephalogr Clin Neurophysiol 88:173 Cruccu G, Pennisi E, Truini A, Ianetti GD, Romaniello A, Le Pera D, De Armas L, Leandri M, Manfredi M, Valeriani M (2003) Unmyelinated trigeminal pathways as assessed by laser stimuli in humans. Brain 126:2246–2256 Hansen C, Treede RD (1995) Laser-evozierte Potentiale: eine neue klinisch neurophysiologische Untersuchungsmethode für die Schmerzbahnen. EEG Labor 17:76–85 Hansen HC, Treede RD, Lorenz J, Kunze K, Bromm B (1996) Recovery from brainstem lesions involving the nociceptive pathways: comparison of clinical findings with laser-evoked potentials. J Clin Neurophysiol 13:330–338 Kakigi R, Shibasaki H, Kuroda Y, Neshige R, Endo C, Tabuchi K, Kishikawa T (1991) Pain-related somatosensory evoked potentials in syringomyelia. Brain 114:1871–1889 Kanda M, Mima T, Xu X, Fujiwara N, Shindo K, Nagamine T, Ikeda A, Shibasaki H (1996) Pain-related somatosensory evoked potentials can quantitatively evaluate hypalgesia in Wallenberg’s syndrome. Acta Neurol Scand 94:131–136 Treede RD (1996) Funktionsprüfung nozizeptiver Bahnen durch SEP nach schmerzhaften Laser-Reizen. Z EEG EMG 27:16–18
101 Treede RD, Lankers J, Frieling A, Zangemeister WH, Kunze K, Bromm B (1991) Cerebral potentials evoked by painful laser stimuli in patients with syringomyelia. Brain 114:1595–1607 Treede RD, Lorenz J, Baumgärtner U (2003) Clinical usefulness of laser-evoked potentials. Neurophysiol Clin 33:303–314 Urban PP, Hansen C, Baumgärtner U, Fitzek S, Marx J, Fitzek C, Treede RD, Hopf HC (1999d) Abolished laser-evoked potentials and normal blink reflex in midlateral medullary infarction. J Neurol 246:347–352
2.3.9 “Recording of Eye Movements” Leigh RJ, Zee DS (2006) Method available for measuring eye movements. In: The neurology of eye movements. Oxford University Press, New York, pp 722–725 Robinson DA (1963) A new method of measuring eye movement using a scleral search coil in a magnetic field. JEEE Trans Biomed Engng 10:137–145 Rottach K, Heide W (1998) Elektrookulographie. In: Huber A, Kömpf D (eds) Klinische Neuroophthalmologie. Thieme, Stuttgart, pp 191–199
2.3.10 “Other Electrophysiologic Methods for the Investigation of Brainstem Reflexes” Di Lazzaro V, Restuccia D, Nardone R, Tartaglione T, Quartarone A, Tonali P, Rothwell JC (1996) Preliminary clinical observations on a new trigeminal reflex: the trigemino-cervical reflex. Neurology 46:479–485 Ertekin C, Celebisoy N, Uludag B (2001) Trigeminocervical reflexes elicited by stimulation of the infraorbital nerve: head retraction reflex. J Clin Neurophysiol 18:378–385 Lehnhardt E (1993) The stapedial reflex in pontine lesions. In: Caplan LR, Hopf HC (eds) Brainstem localization and function. Springer, Heidelberg, pp 243–250 Rossi B, Pasca SL, Sartucci F, Siciliano G, Murri L (1989) Trigemino-cervical reflex in pathology of the brain stem and of the first cervical cord segments. Electromyogr Clin Neurophysiol 29:67–71 Sartucci F, Rossi A, Rossi B (1986) Trigemino cervical reflex in man. Electromyogr Clin Neurophysiol 26:123–129 Serrao M, Rossi P, Parisi L, Perrotta A, Bartolo M, Cardinali P, Ama-bile G, Pierelli F (2003) Trigemino-cervical-spinal reflexes in humans. Clin Neurophysiol 114:1697–1703 Tomioka S, Nakajo N, Takata M (1999) Inhibition of styloglossus motoneurons during the palatally induced jaw-closing reflex. Neuroscience 92:353–360 Urban PP, Pittermann P, Kirchhoff I, Wahlmann U, Dieterich M (2005) Trigemino-hypoglossal silent period-a new pontomedullary brainstem reflex. J Neurol 252:13 Wartenberg R (1941) Head reatraction reflex. Am J Msc 201:553 Zhang J, Pendlebury W, Luo P (2003) Synaptic organization of monosynaptic connections from mesencephalic trigeminal nucleus neurons to hypoglossal motoneurons in the rat. Synapse 49:157–169
3
Diagnostic Findings
Contents 3.1 Disorders of Ocular Motility . . . . . . . . . . . . . . . . . . . . 3.1.1 Basic Principles of Eye Movements . . . . . . . . . . . . . . . . 3.1.1.1 Versions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1.2 Vergences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1.3 Neural Integrator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1.4 Brainstem Structures for Eye Movement Generation . . . 3.1.2 Disorders of Horizontal Eye Movements . . . . . . . . . . . . 3.1.2.1 Internuclear Ophthalmoplegia . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . “Posterior” Internuclear Ophthalmoplegia . . . . . . . . . . . Convergence Spasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2.2 Horizontal Gaze Paresis . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomic Principles and Clinical Findings . . . . . . . . . . 3.1.2.3 One-and-a-Half Syndrome . . . . . . . . . . . . . . . . . . . . . . . 3.1.2.4 Convergence and Divergence Paresis . . . . . . . . . . . . . . . 3.1.2.5 Disturbances of Horizontal Smooth Pursuit Eye Movements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2.6 Lateropulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3 Disorders of Vertical Eye Movements . . . . . . . . . . . . . . 3.1.3.1 Vertical Gaze Palsies and Vertical One-and-a-Half Syndrome . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomic Principles and Clinic . . . . . . . . . . . . . . . . . . . 3.1.3.2 Oculomotor Nucleus Lesion . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3.3 Dorsal Midbrain Syndrome . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3.4 Monocular Elevation Paresis . . . . . . . . . . . . . . . . . . . . . 3.1.3.5 Monocular Depression Deficiency (Old “Double Depressor Palsy”) . . . . . . . . . . . . . . . . . . . 3.1.3.6 Crossed Vertical Gaze Palsy . . . . . . . . . . . . . . . . . . . . . . 3.1.3.7 Oculogyric Crisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3.8 Abnormalities of Vertical Smooth Pursuit Eye Movements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3.9 Ocular Tilt Reaction and Skew Deviation . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathomechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4 Acquired Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4.1 Nystagmus Occurring on Gaze in a Certain Direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gaze-Evoked Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . Rebound Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . . .
105 105 105 105 106 106 106 106 106 108 109 110 110 110 110 111 111 111 112 112 112 112 112 113 113 113 114 114 114 114 115 115 115 115 115 115 117 117 117 118 118 118 119
Dissociated Nystagmus in Internuclear Ophthalmoplegia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4.2 Spontaneous Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . Upbeat and Downbeat Nystagmus . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Torsional Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . . Horizontal Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . Seesaw Nystagmus and Hemi-Seesaw Nystagmus . . . . . Periodic Alternating Nystagmus . . . . . . . . . . . . . . . . . . . Convergence Nystagmus with and Without Retraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Divergence Nystagmus . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4.3 Nystagmus with Imbalances of the Pursuit System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4.4 Nystagmus Occurring (or Increasing) with Fixation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acquired Pendular Nystagmus . . . . . . . . . . . . . . . . . . . . 3.1.4.5 Central Position and Positioning Nystagmus . . . . . . . . . 3.1.4.6 Pharmacotherapy of Acquired Nystagmus . . . . . . . . . . . 3.1.4.7 Topodiagnostic Value of Acquired Nystagmus . . . . . . . 3.1.4.8 Saccadic Oscillations That May Mimic Nystagmus . . . . Opsoclonus and Ocular Flutter . . . . . . . . . . . . . . . . . . . . Square Wave Jerks and Macro Square Wave Jerks . . . . .
120 120 121 122 122 123 123 124
124 125 126
126 126 127 127 128 128 128 129
3.2 Horner’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3 Ethiopathogenesis and Epidemiology . . . . . . . . . . . . . . . 3.2.4 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.5 Functional Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.6 Pharmacologic Pupillary Drop Test . . . . . . . . . . . . . . . . 3.2.7 Sweat Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.8 Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . .
130 130 130 131 131 132 132 132 133
3.3 Central Vestibular Disturbances . . . . . . . . . . . . . . . . . 3.3.1 Central Vestibular Syndromes . . . . . . . . . . . . . . . . . . . . 3.3.1.1 Neuroanatomy and Classification . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sagittal Plane (Pitch Plane) . . . . . . . . . . . . . . . . . . . . . . Frontal Plane (Roll Plane) . . . . . . . . . . . . . . . . . . . . . . . Horizontal Plane (Yaw Plane) . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostics and Differential Diagnosis . . . . . . . . . . . . . 3.3.2 Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2.1 Pitch Plane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2.2 Roll and Yaw Plane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3 Special Nystagmus Syndromes . . . . . . . . . . . . . . . . . . . .
133 133 133 134 135 135 135 135 136 137 137 137 137
3.4 Tinnitus and Auditory Disturbances . . . . . . . . . . . . . . 3.4.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 3.4.1.1 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1.2 Diagnostic and Differential Diagnosis . . . . . . . . . . . . . .
138 138 138 139
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3 Diagnostic Findings
3.4.1.3 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 3.4.1.4 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
3.11.2 Physiology and Neuroanatomy of Micturition . . . . . . . . 160 3.11.3 Ethiopathogenesis and Clinical Findings . . . . . . . . . . . . 161
3.5 Intra-axial Cranial Nerve Lesions . . . . . . . . . . . . . . . . 3.5.1 Epidemiology and Etiopathogenesis . . . . . . . . . . . . . . . . 3.5.2 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.3 Oculomotor Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . 3.5.4 Trochlear Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.5 Trigeminal Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . . 3.5.6 Abducens Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . . 3.5.7 Facial Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.8 Vestibulocochlear Nerve Lesions . . . . . . . . . . . . . . . . . . 3.5.9 Glossopharyngeal and Vagus Nerve Lesions . . . . . . . . . 3.5.10 Accessory Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . . 3.5.11 Hypoglossal Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . 3.5.12 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.13 Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.14 Electrophysiologic Techniques . . . . . . . . . . . . . . . . . . . . 3.5.15 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.16 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.17 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.18 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
140 141 142 142 142 142 143 143 144 144 144 145 145 145 145 145 146 146 146
3.12 Drop Attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 3.12.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 161 3.12.2 Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
3.6 Speech Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 3.6.2 Neuroanatomy of Speech . . . . . . . . . . . . . . . . . . . . . . . . 3.6.3 Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.4 Clinical Picture and Functional Diagnostics . . . . . . . . . . 3.6.5 Paroxysmal Dysarthria . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.6 Anarthria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.7 Mutism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.8 Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . .
147 147 147 147 147 148 148 148 149
3.7 Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 3.7.2 Neuroanatomy of the Physiologic Act of Swallowing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.3 Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.4 Clinical Picture and Functional Diagnostic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.5 Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . .
149 149
3.8 Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 3.8.2 Neuroanatomy and Etiopathogenesis . . . . . . . . . . . . . . . 3.8.3 Types of Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.4 Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . .
151 151 151 151 153
3.9 Pareses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 3.9.2 Neuroanatomy and Etiopathogenesis . . . . . . . . . . . . . . . 3.9.2.1 Peripheral Pareses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.2.2 Central Pareses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.2.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.3 Functional Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.4 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9.5 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
153 153 153 153 154 154 156 156 157
3.10 Sensory Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 3.10.2 Neuroanatomy and Etiopathogenesis . . . . . . . . . . . . . . . 3.10.3 Lesions of the Dorsal Column . . . . . . . . . . . . . . . . . . . . 3.10.4 Lesions of the Medial Lemniscus . . . . . . . . . . . . . . . . . . 3.10.5 Lesions in the Region of the Lemniscal Decussation . . . 3.10.6 Lesions in the Region of the Lateral Spinothalamic Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10.7 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10.8 Functional Diagnostic Evaluation . . . . . . . . . . . . . . . . . . 3.10.9 Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . .
157 157 157 157 157 158
158 158 160 160
149 150 150 150
3.11 Bladder Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . 160 3.11.1 Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 160
3.13 Respiratory Disturbances . . . . . . . . . . . . . . . . . . . . . . 3.13.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.13.2 Etiopathogenesis and Clinic . . . . . . . . . . . . . . . . . . . . . . 3.13.3 Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . .
162 162 162 163
3.14 Disturbances of Consciousness . . . . . . . . . . . . . . . . . . 3.14.1 Ethiopathogenesis and Classification . . . . . . . . . . . . . . . 3.14.2 Clinical Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.2.1 Disorders of Pupillary Function . . . . . . . . . . . . . . . . . . . 3.14.2.2 Respiratory Disturbances . . . . . . . . . . . . . . . . . . . . . . . . 3.14.2.3 Abnormal Eye Positions and Spontaneous Eye Movements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.2.4 Conjugate Deviations of the Eyes . . . . . . . . . . . . . . . . . . 3.14.2.5 Disconjugate Eye Deviations . . . . . . . . . . . . . . . . . . . . . 3.14.2.6 Spontaneous Horizontal Eye Movements . . . . . . . . . . . . 3.14.2.7 Spontaneous Vertical Eye Movements . . . . . . . . . . . . . . 3.14.2.8 Changes in Motor Function . . . . . . . . . . . . . . . . . . . . . .
164 164 165 166 166
167 167 167 167 168 168
3.15 Brain Death Diagnosis in Primary Brainstem Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15.2 Clinical Signs of Brain Death (and Brainstem Death) . . 3.15.2.1 Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15.2.2 Loss of Brainstem Reflexes . . . . . . . . . . . . . . . . . . . . . . 3.15.2.3 Absence of Respiration . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15.3 Confirmatory Laboratory Tests . . . . . . . . . . . . . . . . . . . . 3.15.3.1 Determination of Electrocerebral Inactivity . . . . . . . . . . 3.15.3.2 Determination of Cerebral Circulatory Arrest . . . . . . . . 3.15.3.3 Transcranial Doppler Ultrasonography . . . . . . . . . . . . . . 3.15.3.4 Brain Perfusion Scintigraphy . . . . . . . . . . . . . . . . . . . . . 3.15.3.5 Conventional Angiography . . . . . . . . . . . . . . . . . . . . . . . 3.15.3.6 Somatosensory Evoked Potentials . . . . . . . . . . . . . . . . .
168 168 169 169 169 169 170 170 170 170 170 170 170
3.16 Clinical Brainstem Reflexes . . . . . . . . . . . . . . . . . . . . . 3.16.1 Light Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.1.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.1.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.1.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.2 Convergence Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.2.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.2.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.2.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.3 Corneal Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.3.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.3.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.3.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.4 Orbicularis Oculi Reflex . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.4.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.4.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.4.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.5 Masseter Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.5.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.5.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.5.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.6 Oculocephalic Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.6.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.6.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.6.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.7 Gag Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.7.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.7.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.7.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.8 Cough Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16.8.1 Neuroanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
170 170 170 170 171 171 171 171 171 171 171 172 172 172 172 172 172 172 172 172 172 172 172 172 173 173 173 173 173 173 173
3.1 Disorders of Ocular Motility
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3.16.8.2 Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 3.16.8.3 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 3.17 Rare Findings/Symptoms . . . . . . . . . . . . . . . . . . . . . . . 3.17.1 Hallucinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.1.1 Visual Hallucinations . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.1.2 Acoustic Hallucinations . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.2 Gustatory Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.3 Sneezing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.4 Singultus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.5 Nausea and Emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.6 Tonic Brainstem Attacks . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.7 Disturbances of Automatic Function . . . . . . . . . . . . . . . 3.17.7.1 Disturbances of Sweat Secretion . . . . . . . . . . . . . . . . . . Ipsilateral Hemihypohidrosis . . . . . . . . . . . . . . . . . . . . .
173 173 173 174 174 174 174 174 175 175 175 175
3.1 Disorders of Ocular Motility Frank Thömke
3.1.1 Basic Principles of Eye Movements Brainstem lesions are often accompanied by disorders of ocular motility. This may be accounted for by the fact that functionally different types of eye movements are generated in different neuronal networks localized primarily in the brainstem. The most important function of the oculomotor system is to stabilize images of the visual world on the retina, especially on the fovea centralis, the site of sharpest vision. Retinal image shift during voluntary head movements or movements in the surrounding world have to be avoided, since these shifts would disturb vision and constant spatial perception. These functions are fulfilled by six different oculomotor subsystems involved in generating different eye movement types. A general distinction can be made between two modalities: rapid and slow eye movements that can be divided into two classes from a functional view point: • Eye movements that change the line of sight, so that −− The image of a new object of interest is brought into the fovea, or −− A moving object of interest is kept stable on the fovea • Eye movements that stabilize the line of sight, so that −− The image of an object of interest remains stable on the retina despite movements of the head and/or body. Eye movements in which both eyes move in the same direction are called versions, and those in which each eye moves in opposite directions are named vergences.
3.1.1.1 Versions Versions comprise the following types of eye movements: • Saccades: These are rapid conjugate eye movements with increasing velocity at increasing amplitudes (up to
Contralateral Hemihyperhidrosis . . . . . . . . . . . . . . . . . . Dysrhythmia and Blood Pressure Disturbances . . . . . . . Disturbances of Gastrointestinal Function . . . . . . . . . . . 3.17.8 Extrapyramidal Motor Symptoms . . . . . . . . . . . . . . . . . 3.17.8.1 Parkinson’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.8.2 Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.8.3 Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.9 Pseudoathetosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.10 Paradoxical Activation of the Masticatory Musculature . . . . . . . . . . . . . . . . . . . . . . . . 3.17.11 Pathologic Laughter and Crying . . . . . . . . . . . . . . . . . . . 3.17.12 Pathologic Yawning . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17.13 Gaze Evoked Symptoms . . . . . . . . . . . . . . . . . . . . . . . . .
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700°/s). Saccades are preprogrammed as to direction, amplitude and velocity and cannot be corrected during their course. A differentiation can be made between voluntary and involuntary saccades. −− Voluntary saccades serve to bring new objects of interest on the fovea centralis. −− Reflectory saccades are generated to correct preceding slow deviations of the eyes from target following vestibular or optokinetic stimulation (= rapid phases of the vestibular and optokinetic nystagmus). • Smooth pursuit or following eye movements: These are voluntary, slow conjugate eye movements that keep moving objects of interest stable on the retina. Velocities range from 30°/s to 50°/s and may reach a maximum of 100°/s. They are significantly slower than saccades and, in contrast to those, their direction and velocity can be continuously corrected during their course. • Vestibuloocular reflex (VOR): On movement of the head and/or body, the VOR generates reflexive slow, conjugate eye movements in three-dimensional space, whose direction, amplitude and velocity adapt to the respective head movement. So, the image of the fixated object remains stable on the retina during head and/or body movements. • Opticokinetic eye movements: These are reflexive, slow, conjugate eye movements generated during prolonged movements of the visual surrounding. Prolonged stimulation in one direction induces an opticokinetic nystagmus with smooth pursuit movement in the direction of the stimulus movement, and a rapid saccadic eye movement in the opposite direction.
3.1.1.2 Vergences Vergences comprise convergence and divergence movements. Vergence eye movements are slow and disconjugate, i.e. the two eyes move in different directions. During
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convergence both eyes move in the nasal direction, i.e. the visual axes fuse; in divergence both eyes move in a temporal direction, i.e. the visual axes deviate. Vergence capability ensures that fixated objects of interest moving towards or away from the observer can be kept stable on the fovea centralis.
3.1.1.3 Neural Integrator All conjugate eye movements in which both eyes are moved into a new position in the orbits are based on a change between phasic and tonic innervation. When the eyes are moved into a new position, the viscous resistance of the orbital tissue and the elastic restoring forces of the extended respective antagonistic eye muscles have to be surmounted. The eyes then have to be held in the new position against the elastic restoring forces, to ensure that the images of objects of interest remain stable on the retina. For this purpose the respective agonistic eye muscles have to be tonically innervated, while, at the same time, the antagonistic muscles are inhibited. This tonic innervation signal is generated in a neuronal network, which – in its entirety – is called the neural integrator. The preceding phasic innervation signal serving as the basis for the movement of eyes toward the new position is transmitted with a time delay via a parallel projection to the neural integrator, which integrates, in the mathematical sense, a velocity-coded signal into a position-coded signal. For horizontal eye movements this integration occurs mainly in the prepositus hypoglossal nucleus and the adjacent medial vestibular nucleus, and for vertical and torsional eye movements primarily in the mesencephalic interstitial nucleus of Cajal. A significant contribution is also made by cerebellar structures (dorsal vermis, the fastigial nuclei, flocculus, and paraflocculus) with the dual purpose of avoiding the occurrence of inadequate high or low phasic innervation signals, and achieving precise coordination between the tonic and the preceding phasic innervation.
3.1.1.4 Brainstem Structures for Eye Movement Generation Different types of eye movements are generated by various neuronal networks located primarily in the brainstem. All oculomotor subsystems finally converge on three paired oculomotor nuclear regions in the brainstem: the oculomotor and trochlear nuclei in the midbrain, and the abducens nuclei in the pons (Fig. 3.1). The innervation signals for the respective eye movements are relayed from there via the oculomotor cranial nerves – the oculomotor, trochlear and abducens nerves – to the six extraocular muscles responsible for the movement of each eye. Since the discussion of
3 Diagnostic Findings Rostral interstitial nucleus of the medial longitudinal fasciculus
Interstitial nucleus (Cajal)
Posterior commissure
III
Lamina quadrigemina Paramedian pontine reticular formation IV
N. III
VI
Pontine nuclei
Nucleus reticularis tegmenti pontis
Nucleus prepositus hypoglossi
N. VI Inferior olive
Fig. 3.1 Schematic representation of brainstem structure locations of particular importance for the generation of eye movements. III = oculomotor nucleus; IV = trochlear nucleus; VI = abducens nucleus
all important structures involved in eye movement generation is outside the scope of this chapter, the most important nuclear regions, their pathways and principal functions are shown in Table 3.1 (overview and further reading,see Leigh and Zee 2006).
3.1.2 Disorders of Horizontal Eye Movements 3.1.2.1 Internuclear Ophthalmoplegia Etiopathogenesis Internuclear ophthalmoplegia (better: ophthalmoparesis, INO) is one of the most frequently occurring and widely investigated disorders of ocular motility. Approximately 80% of all INOs occur in patients with multiple sclerosis and brainstem infarcts. The frequently expressed assumption that unilateral INO is virtually pathogonomic for brainstem infarcts and bilateral INO for multiple sclerosis, however, needs to be placed in a nuanced light. Multiple sclerosis is the most frequent cause of unilateral and bilateral INOs (Thömke 1997). Although brainstem infarctions are more often the cause of unilateral than bilateral INOs, in large patient collectives they have been identified as the causal factor of bilateral INO in 20–30% of patients. Patient age therefore also serves as an important parameter for the cause of INO, i.e. inflammatory INO is observed more often in younger, and ischemic INO in older patients. Further comparatively rarer causes include tumors, bleeding, contusions of the brainstem, brainstem encephalitis, Arnold–Chiari malformation (Chiari malformation type II), Wernicke’s encephalopathy, hepatic encephalopathy, as well as intoxications (tricyclic antidepressants, barbiturates, phenothiazine, propanolol, lithium).
3.1 Disorders of Ocular Motility
Adduction paresis is a sequela of a medial longitudinal f asciculus (MLF) lesion, causing dysfunction of the axons of internuclear neurons of the contralateral abducens nucleus, which cross completely at the nuclear level and ascend to the motor neurons of the medial rectus muscle (Fig. 3.2). The medial rectus motor neurons therefore receive no or insufficient prenuclear innervation signals for lateral gaze. Pathoanatomic and electrophysiologic investigations have identified a location in the rostral pons or the midbrain for the majority of MLF lesions (Thömke 1993), so that the rostral mesencephalic convergence neurons are generally not
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affected. This serves to explain preserved adduction during convergence. Adduction may however be abnormal in convergence in patients with more rarely occurring MLF lesions at the level of the oculomotor nucleus, because some of the motor neurons to the medial rectus muscle are located between the MLF fibers. In these circumstances differentiation cannot be made between INO and medial rectus muscle paresis of different etiologies. Abduction nystagmus and overshooting abduction saccades are not attributable to an MLF lesion, but are most likely the expression of increased phasic innervation
Table 3.1 Brainstem structures of particular importance for the generation of eye movements Brainstem Nuclear regions and connections Function segment Medulla oblongata
Pontomedullary junction
Pons
Intercalated nucleus of Staderini caudal continuation of the prepositus hypoglossal nucleus between the hypoglossal nucleus (medial to intercalated nucleus) and the dorsal vagus nucleus (lateral to the intercalated nucleus)
Probably involved in the control of the vestibuloocular reflex and may contribute to the vertical “neural integrator”
Inferior olive nuclear region located dorsolateral to the pyramid
Neurons of the inferior olive influence the vestibuloocular reflex via their connections to the flocculus (adaptive changes, vestibulovisual interactions)
Nucleus prepositus hypoglossi cell group located between the abducens and hypoglossal nucleus in the floor of the fourth ventricle
Forms the “neural integrator” for horizontal eye movements jointly with the medial vestibular nucleus and contributes to the integration of vertical eye movements, although this occurs primarily in the interstitial nucleus of Cajal
Vestibular nuclei extended pontomedullary nuclear complex (superior, lateral, medial and inferior vestibular nuclei) containing the second neuron of the three neuron-containing vestibuloocular reflex onto which synapse afferents of the semicircular canals
Important relay station for the vestibulo-ocular reflex – the medial vestibular nuclear also makes a significant contribution to the neuronal integrator for horizontal eye movements
Abducens nerve nucleus cell group near midline in the tegmentum of the caudal pons in the floor of the fourth ventricle
Innervation of the lateral rectus muscle Center for all types of conjugate horizontal eye movements (= “pontine gaze center”)
Paramedian pontine reticular formation (PPRF) physiologi- Generation of ipsiverse horizontal saccades cally (not anatomically) defined segment of the pontine reticular formation, whose stimulation induces conjugate ipsiverse horizontal saccades
Pontomesencephalic junction
Dorsolateral and dorsomedial pontine nuclei cell group located between the descending corticopontine and corticospinal fibers
Generation of ipsiverse smooth pursuit eye movements
Nucleus of the reticularis tegmenti pontis (NRTP) Cell group located ventral to PPRF and MLF
(Like adjacent pontine nuclei) involved in the generation of smooth pursuit eye movements – mediodorsal caudal segments of the NRTP involved in saccade generation
Medial longitudinal fasciculus (MLF) near-midline structure interconnecting various nuclear regions (e.g. vestibular, abducens,trochlear and oculomotor nuclei, interstitial nucleus of Cajal
Transmits signals for different types of horizontal and vertical eye movements (primarily horizontal saccades, vestibuloocular reflex in all directions, horizontal and vertical smooth pursuit movements; coordination of medial and lateral rectus muscle functions
Ascending tract (Deiters) near-midline connection between vestibular and oculomotor nuclei
Transmits signals for the vestibuloocular reflex in all directions
Brachium conjunctivum contains, among others, projections from the vestibular nuclei to oculomotor nuclei
Transmits signals for the vestibuloocular reflex in all directions (continued)
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3 Diagnostic Findings
Table 3.1 (continued) Brainstem Nuclear regions and connections segment Mesencephalon
Function
Nucleus of the oculomotor nerve near midline in midbrain tegmentum, ventral to the aqueduct located nuclear complex
Innervation of the ipsilateral medial rectus muscle, inferior rectus muscle, inferior oblique muscle, and the contralateral superior rectus muscle – innervation of the levator palpebrae muscle of both sides (caudal central nucleus) –innervation (via ciliary ganglion) of ipsilateral sphincter pupillae muscle and the ciliary muscle (accessory oculomotor nucleus, Edinger-Westphal)
Trochlear nerve nucleus cell complex near midline caudal to the oculomotor nucleus in the midbrain tegmentum
Innervation of contralateral superior oblique muscle
Rostral interstitial nucleus of the medial longitudinal fasciclus (riMLF) wing-shaped nuclear region embedded in the fibers of the medial longitudinal fasciclus, dorsomedial to the rostral red nucleus and rostral to the interstitial nucleus of Cajal
Generation of vertical and torsional saccades (torsional saccades to right [clockwise from patient’s viewpoint] are generated in the right, torsional saccades to left in left riMLF)
Interstitial nucleus of Cajal (INC) cell group dorsolateral to rostral oculomotor nucleus embedded in the fibers of the medial longitudinal fasciclus
Neural integrator for vertical and torsional eye movements – center for eye-head coordination about the roll axis
Superior colliculus paired cell groups consisting of seven layers located dorsolateral to the aqueduct
Deep layers involved in the generation of contralateral saccades (latency, accuracy)
Central mesencephalic reticular formation (cMRF)
Involvement in generating horizontal and vertical saccades Reciprocal connection to superior colliculus
Posterior commissure
adjusted to the degree of the adduction paresis as an attempt to minimize the adduction paresis (Zee et al. 1987; Thömke et al. 2000). The phasic innervation signal for agonistic eye muscles is the basis for an eye movement into a new position. This facilitates overcoming the viscous resistance of the orbital tissue and the elastic restoring forces of the extended antagonistic eye muscles. The eyes then have to be held against the elastic restoring forces in the new position. For this purpose the respective agonistic eye muscles need a tonic innervation signal. When the oculomotor system generates an increased phasic innervation to minimize the adduction paresis, the lateral rectus muscle of the healthy eye receives an abnormally high phasic innervation signal, as agonistic muscles of both eyes are always equally innervated (Hering’s law). This causes overshooting (hypermetric) abduction saccades of the healthy eye with subsequent nasal backdrift. If the paretic adducting eye is still at a considerable distance from the intended position, another saccade is generated. In the contralesional abducting eye, this saccade will again be hypermetric due to the increased phasic innervation. The sequence of these compensation processes is clinically seen as an abduction nystagmus. This assumption is supported by a number of findings, in particular by the
Conducts signals for coordinated eye muscle innervation with all types of vertical eye movements – connection located dorsal to the aqueduct with axons of interstitial nucleus of Cajal (INC) crossing to the oculomotor and trochlear nuclei and to the contralateral INC, as well as with axons of posterior commissure nuclei crossing to the respective contralateral INC and riMLF
change observed after covering the paretic or non-paretic eye (Thömke 1996). The cause of slowed abduction saccades, which can often only be shown with electrooculography, has been controversially discussed (e.g. lesion of the intrapontine abducens nerve, additional horizontal gaze palsy, disturbed inhibition of the medial rectus muscle in lateral gaze). The most probable of these assumptions appears to be disturbed inhibition of the tonic resting activity of the medial rectus muscle in lateral gaze, since it is consistent with the majority of additional findings in INO (Thömke 1997). The neuroanatomic-neurophysiologic background of medial rectus inhibition, however, is not yet fully understood (Thömke and Hopf 2001).
Clinical Findings The principal clinical sign in patients with INO is adduction paresis on lateral gaze with usually spared adduction during convergence. The severity of adduction paresis ranges from slowed adduction saccades without restricted adduction on clinical examination to an inability to adduct the eye beyond
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a Right eye
Left eye
20° 100 ms
Medial rectus muscle
Lateral rectus muscle
gaze-evoked nystagmus exclusively or markedly more pronounced in the non-paretic abducting eye (abduction nystagmus), almost always associated with overshooting abduction saccades (Fig. 3.2). Abduction nystagmus increases with increasing amplitude of lateral gaze in the direction of action of the paretic medial rectus muscle. Patients with unilateral INO frequently also have skew deviation, a vertical misalignment of the visual axes (see p. 13) mainly causing an ipsilateral hypertropia, i.e. an upward deviation of the paretic eye. Patients with bilateral INO almost always have a concomitant vertical gazeevoked nystagmus, as well as impaired vertical smooth pursuit eye movement and vertical vestibuloocular reflex abnormalities. Finally, in more than 50% of patients slowed abduction saccades are found on electrooculography. In unilateral INO these develop primarily in the paretic eye, while they occur preferentially in the more severely affected eye in bilateral INO.
Oculomotor nerve Oculomotor nucleus
Medial longitudinal fasciclus
“Posterior” Internuclear Ophthalmoplegia Abducens nerve Pontine reticular formation
Abducens nucleus
b
Fig. 3.2 (a) Top: Direct current recording of saccades to right in internuclear ophthalmoplegia left. Slowed adduction saccades of the left eye, overshooting abduction saccades of the right eye and exhaustible abduction nystagmus. Bottom: Schematic presentation of horizontal eye movement organization; (detailed description s. text). (b) MRI of small infarction in the median region of the pontine tegmentum left, including the left medial longitudinal fascicle (MLF)
the midline. Outward deviation of the paretic eye (exophoria) is observed only occasionally. (Extremely pronounced outward deviation of both eyes causing the virtual absence of voluntary horizontal eye movements may very rarely be seen in bilateral INO [wall-eyed bilateral INO = WEBINO].) On lateral gaze in the direction of action of the paretic medial rectus muscle, most patients show a dissociated
In 1923 Anton Lutz postulated the existence of an internuclear (or prenuclear) abduction paresis, ophthalmoplegia internuclearis posterior (“posterior” INO), which was based on inaccurate anatomic perceptions and without presenting new observations. Since then the existence of a prenuclear abduction paresis continues to be controversially discussed. Its presence was always assumed when the respective authors felt that certain findings were not compatible with a lesion of the abducens nerve. Such findings included absent diplopia, absent esotropia, nystagmus of the contralateral adducting eye, slowed abduction saccades with otherwise unrestricted abduction movements, or preserved abduction saccades during rapid phases of vestibular nystagmus. In individual patients, however, none of these signs permit conclusive exclusion of a sixth nerve paresis (Thömke et al. 1992). A number of reports on abduction paresis in association with acute mesodiencephalic lesions (infarctions, hemorrhage, tumor compression, mesencephalotomy) have been published. In addition to the demonstration of a mesencephalic lesion (radiologic and pathologic investigations), electrophysiologic abnormalities were also described as indicators of mesencephalic lesions in some of these patients (Thömke and Hopf 2001). The reported abduction pareses with mesencephalic and meso-diencephalic lesions named sixth nerve pseudopalsy, pseudo-sixth, or pseudoabducens palsy cannot be attributed to an impaired excitation of the lateral rectus muscle: such lesions would affect supranuclear excitatory pathways descending through the midbrain to the abducens nucleus (and the paramedian pontine reticular formation) and would be followed by impaired excitation of both, the lateral rectus muscle on one and the medial rectus muscle on the other eye thereby
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causing conjugate disturbances of horizontal saccades and pursuit movements (= horizontal gaze paresis). The most likely cause of mesodiencephalic abduction pareses are abnormal convergence impulses to the medial rectus muscle (Pullicino et al. 2000), or impaired inhibition of medial rectus muscle during lateral gaze (Thömke et al. 1992). An alternative explanation is that the patient fixates with the hyperadducted eye and so does not abduct fully the other eye. This can be shown by covering the hyperadducted eye and encouraging further lateral movement of the abducting eye. Further clarification can be obtained by eye muscle EMG, which is not justifiable in view of the risks of this examination and the absence of therapeutic consequences. Prenuclear abduction pareses are, as a whole, rare dis orders of ocular motility without uniform localization and pathophysiology. This diagnosis should be considered only in patients with an incomplete abduction paresis and clinical, morphologic and/or electrophysiologic evidence of an ipsilateral ponto-mesencephalic, mesencephalic, or meso- diencephalic lesion.
Convergence Spasm Convergence spasm (spasm of the near reflex) (Miller and Keane 1998) is due to abnormal convergence impulses during lateral gaze. Clinically, these patients show a bilateral abduction paresis accompanied by miosis in lateral gaze, which enables the differentiation from abducens palsy. In rare cases miosis may be absent. During prolonged lateral gaze the abducting eye is frequently observed to be “pulled” back in the direction of the nose as a consequence of a persistent abnormal convergence tone. Spasm of the near reflex is said to occur mainly in “hysterical” or “neurotic” patients as a sign of a psychosomatic disorder, although they may be only intermittently pronounced. Organic causes are rare (Wernicke’s encephalopathy, mesodiencephalcic tumors and hemorrhage, metabolic encephalopathies, phenytoin intoxications).
3.1.2.2 Horizontal Gaze Paresis Etiology Infarctions, hemorrhage, tumors, and areas of demyelination in multiple sclerosis are the most frequent causes of horizontal gaze paresis in pontine lesions. Anatomic Principles and Clinical Findings Unilateral pontine lesions may be followed by an ipsilateral horizontal gaze paresis. All types of eye movements are affected in cases of abducens nucleus lesions. The abducens
3 Diagnostic Findings
nucleus corresponds to the “pontine gaze center” described in the older clinical literature. All oculomotor subsystems converge on the abducens nucleus, which contains two populations of neurons without a strict spatial separation: • The lateral rectus motor neurons, whose axons project in the abducens nerve to the ipsilateral lateral rectus muscle • The internuclear neurons, whose axons cross at the level of the sixth nerve nucleus to the contralateral side and course in the MLF to the medial rectus motor neurons in the oculomotor nucleus of the contralateral side A unilateral lesion of the abducens nucleus affects both types of neurons causing an ipsilateral gaze paresis: • A lesion of lateral rectus motor neurons causes ipsilesional abduction paresis • A lesion of internuclear neurons impairs prenuclear excitatory innervation of medial rectus motor neurons causing contralateral adduction paresis Direct premotor signals for all types of horizontal eye movements are generated in the abducens nucleus, so that all types of ipsilesional horizontal eye movements (saccades, smooth pursuit eye movements, vestibuloocular reflex) are affected by abducens nucleus injury. A “nuclear” abduction paresis does not exist! Lesions of adjacent pontine structures that spare the abducens nucleus, may only affect certain types of eye movements: • Isolated damage to the PPRF is responsible for slowed or absent ipsilateral saccades, but does not impair ipsilesional smooth pursuit eye movements and the ipsilesional horizontal vestibuloocular reflex. • Damage to the PPRF and the dorsolateral pontine nuclei will induce ipsilesional slowed saccades and disturbed smooth pursuit eye movements, but does not impair the ipsilesional horizontal vestibuloocular reflex, provided the medial vestibular nucleus and the MLF are intact. • Bilateral lesions of the PPRF cause slowed or absent horizontal saccades in both directions, and also transient disturbances of vertical saccades. Isolated slowed or even absent horizontal saccades in both directions are highly suspect for neurodegenerative diseases (e.g. olivopontocerebellar atrophy, autosomal dominant cerebellar ataxia, Huntington’s chorea), storage diseases (e.g. Tay-Sachs disease, Gaucher disease), or neuromuscular or myogenic disturbances (e.g. ocular myasthenia, early chronic progressive external ophthalmoplegia). Midbrain lesions may also induce horizontal gaze paresis (midbrain paresis of horizontal gaze) when the descending
3.1 Disorders of Ocular Motility
excitatory pathways to the pons are damaged. Ipsilesional pareses of horizontal pursuit eye movements can occur following injury to descending fibers to the dorsolateral pontine nuclei. Slowed horizontal saccades occur when descending fibers to the PPRF are affected. Contralesional saccadic slowing may occur when the lesion is located rostral to the crossing of the descending fibers at the oculomotor and trochlear nerve nuclei, while ipsilesional deceleration develops in the presence of a lesion caudal to this crossing. Ipsilesional pareses of horizontal smooth pursuit movements may be associated with either ipsilesional or contralesional slowed horizontal saccades.
3.1.2.3 One-and-a-Half Syndrome In the one-and-a-half syndrome all horizontal eye movements are absent, with the exception of abduction of one eye. The eye with spared abduction is often deviated outward an (exophoria). The disturbance usually results from a lesion in the region of the abducens nucleus affecting the sixth nerve nucleus and crossed axons of the internuclear neurons of the contralateral abducens nucleus, which ascend in the MLF to the medial rectus motor neurons. This is the cause of both, an ipsilesional horizontal gaze paresis (abducens nucleus lesion) and an ipsilesional adduction paresis (INO due to lesion of the crossed axons of the internuclear neurons) (Wall and Wray 1983). This combination of a “whole” ipsilesional horizontal gaze paresis and a “half” – affecting only the ipsilesional adduction – contralesional gaze paresis was thus named oneand-a-half syndrome (Fisher 1967). The most common causes are infarctions, demyelinating lesions in multiple sclerosis, pontine hemorrhage or tumors (Wall and Wray 1983).
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midbrain dysfunction and without a quantifiable impairment of stereoscopic vision needs to be viewed with reservation and is often explained by psychogenically mediated convergence paresis. The most frequent cause of an “isolated convergence paresis” may be a lack of cooperation (Leigh and Zee 2006). Divergence paresis – a rare condition – is characterized by horizontal diplopia when fixating on distant objects. The distance of the double images increases with increasing distance of the object of regard, but remains the same at the same distance in lateral gaze. The clinical examination of horizontal eye movements shows no indication of an abduction paresis. There is no horizontal misalignment of the visual axes during lateral gaze, when the patient fixates near objects. Esophoria, however, becomes manifest in distance vision. The most important differential diagnosis is a mild bilateral abducens palsy, raising concern for intracranial pressure. A divergence paresis should be diagnosed only if slowed abduction saccades can be excluded (Smith 1998).
3.1.2.5 Disturbances of Horizontal Smooth Pursuit Eye Movements The principal clinical sign of impaired following eye movements is so-called saccadic smooth pursuit. With impaired following eye movements, the eyes lag behind the moving object of interest causing a retinal slip and the retinal image moves continuously away from the fovea. This induces generation of a catch-up saccade to bring the object of interest back on the fovea. So, the otherwise “smooth” pursuit eye movements become “saccadic”, i.e. are continually interrupted by small saccades in the direction of the pursued object (Fig. 3.3).
3.1.2.4 Convergence and Divergence Paresis Rostral midbrain lesions with damage to vergence neurons may induce convergence and divergence abnormalities, which are frequently associated with other signs of midbrain lesions (e.g. vertical gaze paresis) and rarely occur in isolation. The most common causes include hydrocephalus, tumor, infarction, hemorrhage, multiple sclerosis and craniocerebral trauma. The incidence of convergence pareses is significantly higher than that of divergence pareses. Convergence paresis manifests as a disturbance of stereoscopic vision and may, if asymmetrical, also cause diplopia during fixation of near objects. A basic requirement for the diagnosis of a convergence paresis is the cooperation of the patient, since lacking cooperation may simulate a convergence paresis. The fact that a certain degree of convergence weakness is frequently found in older individuals further needs to be considered. The finding of an isolated convergence weakness without additional clinical signs of
Movement of the object of regard
Right eye
Left eye
20° 1s
Fig. 3.3 Saccaded horizontal smooth pursuit eye movements of a patient with olivopontocerebellar atrophy
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During clinical examinations of smooth pursuit movements, the examiner must consider that following eye movements are very susceptible to interference. Inattentiveness may also cause saccadic following eye movements. In distracted patients, the frequency of catch-up saccades varies significantly on repeated examinations, which can be satisfactorily documented with electro-oculographic methods. Saccadic pursuit can further be induced by a number of different pharmaceutical agents. Finally, a certain degree of saccadic pursuit is a physiologic phenomenon in older persons: The borderline between an age-related and an abnormal finding is fuzzy. The finding of saccadic following eye movements in the absence of other oculomotor abnormalities requires careful diagnostic consideration in older persons. Impaired smooth pursuit eye movements in only one direction provides information as to the side but not the site of the lesion: pursuit eye movement abnormalities occur on the side of the lesion. The responsible lesion may involve the parietooccipital/parietotemporal cortex, projections from these areas descending to the pons, the dorsolateral pontine nuclei, or the cerebellum. The clinical examination may also show an asymmetry of optokinetic nystagmus to the healthy side. An ipsilesional disturbance of following eye movements is often accompanied by impaired ipsilesional slow phases of optokinetic nystagmus because they are generated by the same neuronal network.
3 Diagnostic Findings
indicated by experimental findings: microinjections of the GABAergic muscimol result in hypermetric saccades to the side of the injection and in hypometric saccades to the contralateral side. The commonest type of abnormality is characterized by ipsilesional hypermetry and contralesional hypometry (=ipsipulsion) but there is another more rare reversed form (=contrapulsion) with contralesional hypermetry and ipsilesional hypometry, as well as contralesional deviation of vertical saccades. It is due to infarctions in the territory of the superior cerebellar artery involving the rostral cerebellum, including the rostral vermis and the superior cerebellar peduncle. Such infarcts may also involve projections of the fastigial nucleus, which cross in the cerebellum to travel in the uncinate fasciculus to the PPRF, after their crossing. Conversely, functional impairment of the fastigial nucleus in ipsipulsion represents a disturbance occurring at a location before the crossing of its efferent projections.
3.1.3 Disorders of Vertical Eye Movements 3.1.3.1 Vertical Gaze Palsies and Vertical One-and-a-Half Syndrome Etiopathogenesis
3.1.2.6 Lateropulsion The term lateropulsion was originally used to describe a tendency to fall or to past-point to one side (e.g. in unilateral brainstem lesions). It was later employed by Kommerell and Hoyt (1973) to describe a characteristic saccade disturbance in patients with Wallenberg’s syndrome (dorsolateral oblongata syndrome). Horizontal saccades to the side of the lesion are overshooting (hypermetric) and those to the opposite side are hyopometric (undershooting). Attempts to perform vertical saccades results in oblique saccades, because the vertical component is superimposed by a horizontal deviation to the side of the lesion. This phenomenon differentiates oblique vertical saccades in patients with lateropulsion from “simple” dysmetric saccades, which are also not accurately targeted, but are exact regarding the intended direction. Lateropulsion has been attributed to a functional impairment of the nucleus fastigii (Helmchen et al. 1994). A lesion of the dorsolateral medulla oblongata may disrupt the climbing fibers on their path from the contralesional inferior olive to the ipsilesional vermis and so cause enhanced activity of GABAergic Purkinje-cells at this location. This would result in inhibition of the nucleus fastigii, which also projects to the contralateral PPRF, and may cause lateropulsion as
Vertical gaze palsies usually result from bilateral, and less frequently from unilateral lesions of the rostral midbrain tegmentum. Anatomic unilateral midbrain lesions may cause vertical gaze palsies, when they are followed by a functional bilateral disturbance. A unilateral lesion in the region of the rostral interstitial nucleus of the medial longitudinal fasciculus and the interstitial nucleus of Cajal can simultaneously involve the described nuclear regions and the crossed fibers of the respective contralateral nuclear regions. The most frequent causes are unilateral or bilateral mesencephalic or mesodiencephalic infarctions, tumors (primarily pineal body tumors with midbrain compression), mesencephalic or mesodiencephalic hemorrhage. Rarer causes comprise demyelination in multiple sclerosis, brainstem encephalitis, aqueductal stenoses, and arteriovenous vascular malformations. Vertical gaze pareses may also occur in the context of systemic degenerations (e.g. Steele–Richardson–Olszewski syndrome) or storage diseases (e.g. Niemann–Pick disease).
Anatomic Principles and Clinic Significant structures for the generation of vertical eye movements are located in the rostral paramedian midbrain tegmentum:
3.1 Disorders of Ocular Motility
• Rostral interstitial nucleus of the medial longitudinal fasciclus (riMLF) • Interstitial nucleus of Cajal (INC) • Posterior commissure Burst neurons of the riMLF generate the phasic innervation signal for vertical and ipsitorsional, i.e. to the side of the active riMLF, saccades. The respective tonic innervation signals emanate from INC-neurons (neural integrator). The INC is also involved in the generation of vertical smooth pursuit eye movements and the vertical vestibuloocular reflex (VOR). All conjugate vertical eye movements require a concurrent impulse transmission to the motor neurons of the respective agonistic eye muscles in the oculomotor and trochlear nuclei of both sides. The respective projections from the riMLF and INC cross primarily in the posterior commissure, although the course of these pathways is still only incompletely known. The pathways for upward eye movements cross in the posterior commissure and proceed through or alongside the riMLF in a caudal direction to the oculomotor and the trochlear nuclei. The precise course of the pathways for downward eye movements as well as the level of their crossing is not well defined. They may course more medially and cross at a more caudal location than the interconnections for upward eye movements. A unilateral or bilateral lesion of the riMLF and the adjacent structures, in particular the posterior commissure, induce an upgaze palsy, while more extensive lesions are associated with a combined up- and downgaze paresis. An isolated downgaze palsy is significantly less common than either upgaze or combined up- and downgaze palsies. All patients with a downgaze palsy investigated thus far had bilateral midbrain lesions in the region of both the riMLF and the periaqueductal grey matter. The close anatomical relationship between the riMLF, INC and the posterior commissure clearly shows that lesions localized in these regions have an effect on nearly all types of vertical eye movements (saccades, smooth pursuit, VOR). Individual or several types may, however, be spared (“dissociated” vertical gaze palsies, e.g. paresis of vertical saccades with preserved pursuit eye movements and normal VOR, or pareses of saccades and pursuit eye movements with preserved VOR. Unilateral or bilateral midbrain lesions may, depending on the degree of the involvement of the different structured located in this area, also cause a vertical one-and-a-half syndrome, in which all vertical eye movements are absent except upward and downward movements in one eye: • Conjugate upgaze palsy plus monocular depressor paresis (= preserved depression of one eye) • Conjugate downgaze palsy plus a monocular elevation paresis (= preserved elevation of one eye)
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3.1.3.2 Oculomotor Nucleus Lesion Etiology Oculomotor nucleus lesions generally result from midbrain infarcts, and less frequently from hemorrhage or tumors. Clinical Findings In addition to an ipsilesional third nerve palsy, lesions of the oculomotor nucleus are associated with a contralesional – overall thus bilateral – superior rectus paresis and a contralesional – overall thus bilateral – ptosis: • Ipsilateral oculomotor palsy: This is generally, but not in all cases, complete and caused by an injury of the ipsilesional medial rectus, inferior rectus, and inferior oblique motor neurons, whose axons course in the ipsilesional oculomotor nerve. The axons for the ipsilesional superior rectus muscle are damaged in parallel. Although their motor neurons lie in the contralesional oculomotor nucleus, the axons cross and then travel through the ipsilesional superior rectus subnucleus to the ipsilesional oculomotor nerve. The levator palpebrae muscle and pupillary sphincter may be spared if the caudal or rostral segments of the oculomotor nuclear complex are not involved. • Bilateral superior rectus paresis: The axons of the superior rectus motor neurons cross and travel through the superior rectus subnucleus to the contralateral side. A unilateral nuclear lesion therefore involves the ipsilesional superior rectus motor neurons for the contralesional superior rectus muscle, and the crossed axons of the contralesional superior rectus motor neurons for the ipsilesional superior rectus muscle. The result is a bilateral superior rectus paresis, with the clinical appearance of a supranuclear upgaze palsy. • Bilateral ptosis: The motor neurons for the superior levator palpebrae muscle of both sides lie in the central caudal nucleus, a single nucleus located medially and dorsally at the caudal end of the oculomotor nuclear complex. Damage to this nucleus involves the motor neurons for the levator palpebrae muscles on both sides thereby causing a bilateral ptosis. With incomplete third nerve nucleus lesions involving only its rostral parts, the caudal central nucleus may be spared, and bilateral ptosis does not occur. More than half of the patients with an oculomotor nuclear lesion reported so far had bilateral superior rectus paresis and bilateral ptosis; approximately one third had bilateral superior rectus paresis without contralesional ptosis, i.e. without bilateral ptosis. Bilateral ptosis without contralesional, i.e. bilateral superior rectus paresis, was only seen occasionally. There are a number of additional reports of
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individual patients with MRI evidence of infarctions or metastases in the region of the oculomotor nucleus, and clinical findings of an isolated complete or partial ipsilesional oculomotor palsy (overview and further reading – see Thömke 2002; case reports see Lee et al. 2000; Kwon et al. 2003). 3.1.3.3 Dorsal Midbrain Syndrome Etiology The most frequent causes of the dorsal midbrain syndrome are hydrocephalus and mesodiencephalic infarctions. Hydrocephalus is most often caused by aqueductal stenosis or external compression of the aqueduct, e.g. by a pinealoma, leading to enlargement of the third ventricle, exerting pre ssure on the posterior commissure and the rostral midbrain. Rare causes comprise thalamic and midbrain tumors or tentorial herniation, as well as encephalitis, arteriovenous vascular malformations, and craniocerebral trauma. Clinical Findings Lesions of the rostral midbrain may cause vertical gaze palsies in addition to a number of other disorders of ocular motility, which may occur in different, mutually interrelated combinations. These disturbances are collectively subsumed as the “dorsal midbrain syndrome” or “pretectal syndrome”. As a whole, they represent an etiologically and clinically heterogeneous group. In addition to the most common signs of pupillary dysfunction (absent light reaction, light-near dissociation, anisocoria), and vertical gaze palsies (upgaze, downgaze, or in both directions), various other abnormalities may occur in different combinations. In order of decreasing frequency these include (Keane 1990): • Horizontal misalignment of the visual axes (exotropia, esotropia) • Upper eye lid retraction (Collier’s sign) • Vertical misalignment of the visual axes (skew deviation [see p. 13], in some instances with alternating hypertropia or hypotropia of the adducting eye) • Convergence-retraction nystagmus • Spontaneous or gaze-evoked vertical nystagmus • Disorders of convergence (convergence paresis, convergence spasm, pseudo-abducens paresis) A number of different names, sometimes designating different combinations of symptoms, have, unfortunately, lead to some confusion (Parinaud’s syndrome, Koerber–Salus– Elschnig syndrome, posterior commissural syndrome, Sylvian aqueduct syndrome). In particular the most widely known of these terms, Parinaud’s syndrome, is not uniformly applied. The majority of patients with this diagnosis showed
3 Diagnostic Findings
the combination of a convergence paresis with an upgaze palsy, in some cases also with up- and downgaze palsies, or only a downgaze palsy. These symptom constellations may also be found in the dorsal midbrain syndrome group, so that it does not seem to make sense to adhere to the term Parinaud’s syndrome. More important, attention should be given to a detailed description of the individual oculomotor symptoms.
3.1.3.4 Monocular Elevation Paresis The rare monocular elevation paresis is characterized by the acute occurrence of vertical diplopia in upward gaze with the clinical finding of a restricted upward movement of one eye. Misalignment of the visual axes is typically absent in the primary position (=looking straight ahead), which was already thought to indicate a central, supranuclear lesion in the first description of this disorder (Jampel and Fells 1968). The symmetrical elevation of the eyes in Bell’s phenomenon (tested on forced lid closure against resistance) observed in individual patients is a strong indication of a prenuclear origin of this abnormality (Lessell 1975). It was originally thought that both muscles involved in the elevation of the eye, the superior rectus muscle and the inferior oblique muscle, are involved (thus double elevator palsy). Elevation of the eye in abduction and the primary position, however, depends exclusively, or primarily, on the superior rectus muscle. Similarly, in adduction, where the inferior oblique muscle has the strongest elevation effect, the contribution of the superior rectus muscle is almost identical to that of the inferior oblique muscle. So, the clinical sign of monocular elevation paresis can be attributed mainly to a superior rectus palsy. Electrooculographic investigations have further shown that monocular elevation paresis may also be the clinical manifestation of asymmetric upgaze palsy, in which the disturbance of the less affected eye escapes clinical observation (Thömke and Hopf 1992). Based on the associated clinical signs of their patients and anatomic considerations Jampel and Fells (1968) attributed monocular elevation paresis to a lesion of the contralateral midbrain tegmentum. This location has since then been confirmed by different authors (Lessell 1975; Thömke and Hopf 1992). Monocular elevation paresis has also been observed in patients with an ipsilateral mesodiencephalic infarct (Hommel and Bogousslavsky 1991) and also in an ipsilateral tumor (Ford et al. 1984). These patients, however, also had an ipsilesional internuclear ophthalmoplegia confirming an extension of the lesion to the level of the oculomotor nucleus. So, a partial lesion of the intramesencephalic oculomotor nerve can not be excluded. Finally, a patient with a small infarct in the intramesencephalic course of the oculomotor nerve has been described, who showed a monocular elevation paresis with restricted elevation in Bell’s phenomenon (Gauntt et al. 1995).
3.1 Disorders of Ocular Motility
A monocular elevation paresis is a rare sign of mesencephalic dysfunction. A supranuclear origin can only be assumed in patients with preserved elevation in Bell’s phenomenon, which differentiates this condition from a partial third nerve palsy. 3.1.3.5 Monocular Depression Deficiency (Old “Double Depressor Palsy”) An even rarer condition associated with midbrain lesions than monocular elevation paresis is a monocular paresis of depression as the only clinical sign. In addition to a small midbrain infarct involving parts of the infranuclear intramesencephalic oculomotor nerve (Negoro et al. 1993) this condition was also seen with metastases in the region of the oculomotor nucleus (Pusateri et al. 1987; Chou and Demer 1998). 3.1.3.6 Crossed Vertical Gaze Palsy The rare combination of an elevation paresis of one eye with a depressor palsy on the other eye has been reported as a crossed vertical gaze palsy (Wiest et al. 1996). The supranuclear origin was indicated by a symmetric elevation of the eyes in Bell’s phenomenon and the preserved vertical vestibuloocular reflex. The cause was a mesodiencephalic infarction on the side of the depressor palsy. There are another two patients with monocular elevation paresis who had electrooculographically documented slowed downward saccades in the other eye; this may represent a subclinical variant of a crossed vertical gaze palsy (Thömke and Hopf 1992). Wiest et al. (1996) proposed a causative lesion that was located close to the third nerve nucleus affecting excitatory supranuclear projections from the ipsilesional riMLF to the inferior rectus motor neurons and from the contralesional riMLF to the superior rectus motor neurons. Other authors (Thömke and Hopf 1992) posited a bilateral, although mainly ipsilateral, projection from the riMLF to the oculomotor nucleus. A unilateral lesion of such a projection would be followed by decreased excitation of the ipsilesional inferior rectus and superior rectus motor neurons. In both instances an ipsilesional depressor palsy (uncrossed projections of the inferior rectus motor neurons) and a contralesional elevator palsy (crossed projections of the superior rectus motor neurons) would be expected. 3.1.3.7 Oculogyric Crisis Oculogyric crises were reported as a characteristic symptom of the postencephalitic Parkinson’s syndrome, which was of particular importance in the 1920s. Today it mainly occurs as a side effect of neuroleptics, most often in the context of
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so-called early dyskinesias. They may, however, also be seen after long-term neuroleptic drug treatment with other signs of tardive dyskinesia. Clinically episodes are characterized by involuntary conjugate tonic upward deviations of both eyes, less often to the side, and only in exceptional cases downward. The degree of the upward deviations vary considerably being only mild or so severe, that the pupils are no longer visible. During the upward deviation, eye movements in the upper visual field appear intact, downward pursuit eye movements are usually possible to the primary position only, and downward saccades are slowed. Oculogyric crises may last from a few minutes, in some cases also less than a minute, to several hours (sometimes even a few days). Initial symptoms of the attack are frequently, but not always, transient mood changes (anxiety, sadness) that may be followed by slowed thought processes or obsessive fixation on one idea (Leigh et al. 1987). Possible causes include a tonic imbalance in the vertical neural integrator, the mesencephalic INC. Neuroleptic-induced oculogyric crises in early dyskinesia respond favourably to anticholinergic therapy (e.g. biperiden 5 [-10] mg i.v.); good results have been reported for clonazepam in the therapy of oculogyric crisis in tardive dyskinesia.
3.1.3.8 Abnormalities of Vertical Smooth Pursuit Eye Movements Comparable to disturbances of horizontal smooth pursuit eye movements, abnormalities of vertical smooth pursuit are completely nonspecific, although pronounced saccadic pursuit may be observed in a number of different conditions (e.g. vascular encephalopathy, all types of cerebral atrophic processes, systemic degeneration, hepatic and uremic ence phalopathy, degenerative cerebellar diseases, Chiari malformation, schizophrenia). At the level of the brainstem, the nucleus reticularis tegmenti pontis seems to be of central importance for the performance of smooth vertical eye movements (Suzuki et al. 1999; Rambold et al. 2004).
3.1.3.9 Ocular Tilt Reaction and Skew Deviation Definition The ocular tilt reaction (OTR) (Fig. 3.4) represents an oculocephalic synkinesia of • Vertical divergence of the eyes. • Ocular torsion to the side of the lower eye (i.e. outward rotation of the lower and inward rotation of the higher eye). • Head tilt toward the lower eye. • There is also a tilt of the subjective visual vertical toward the lower eye in almost all patients.
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3 Diagnostic Findings
Head tilt to the lower eye Ocular tilt reaction Skew deviation Ocular torsion to the lower eye
Skew torsion sign
Fig. 3.4 Schematic representation of an ocular tilt reaction. Vertical divergence of the eyes, head tilt to the lower eye and ocular torsion toward the lower eye, i.e. outward rotation of the lower and inward rotation of the higher eye
The OTR is a basic pattern of eye-head coordination in the roll plane. It is interpreted as a compensatory response to an apparent head tilt caused by a lesion of graviceptive pathways, which, in turn, is usually the result of a brainstem lesion, and less frequently of a peripheral vestibular lesion. Vertical divergence of the eyes alone is called skew deviation and is typically constant for all directions of gaze. It may, however, vary and even alternate with different directions of gaze (alternating skew deviation). Skew deviations are characteristically associated with an extorsion of the lower eye and intorsion of the higher eye (skew torsion sign = STS) (Brodsky et al 2006). The first detailed description of the OTR was by Westheimer and Blair (1975), who stimulated the rostral midbrain near the INC in monkeys. Initially, it was only rarely reported in humans, but today the OTR is known to be a frequent sign of brainstem lesions occurring in over 20% of patients with unilateral brainstem infarcts (Dieterich and Brandt 1993a). A slightly higher incidence has been found for the STS, which occurs in one third of all patients with unilateral brainstem infarcts (Brandt and Dieterich 1993); it is often accompanied by a head tilt toward the lower eye in two of three patients (=OTR) (Dieterich and Brandt 1993a). All of the patients with skew deviation investigated by Brandt and Dieterich (1993) also had unilateral or bilateral ocular torsion, thus the name “skew-torsion sign”. Ocular torsion always occurs in the direction of the lower eye and affects both eyes in 50% of patients, the lower eye
only in 31%, and the higher eye only in 19% (Brandt and Dieterich 1993). Ocular torsion, which can only be detected using fundus photography, occurs significantly more often alone than in association with an STS or OTR. Ocular torsion was seen in more than 80% (in 71 of 86) of patients with unilateral brainstem infarcts, affecting both eyes in 47% and one eye in 36% of patients. All of these patients also showed a tilt of the subjective visual vertical in the direction of the ocular torsion (Dieterich and Brandt 1993a). OTR and STS are usually associated with additional clinical signs of brainstem dysfunction (e.g. horizontal and vertical gaze-evoked nystagmus, INO, Horner’s syndrome, dorsal midbrain syndrome, hemiparesis and tetraparesis, hemiataxia, dysarthrophonia, dysphagia). In rare cases they may also constitute the only or the main clinical sign of a brainstem lesion; in this setting, an isolated STS has to be differentiated from partial oculomotor or trochlear paresis (see differential diagnosis). Special types of OTR and skew deviation are: • Paroxysmal OTR: Paroxysmal OTR represents an extre mely rare disorder with a non-specific location, which has thus far been observed in only a small number of patients. The site of the lesion was unknown in a patient with multiple sclerosis (Rabinovich et al. 1977), one patient had an abscess at the mesodiencephalic junction (Hedges and Hoyt 1982), and another a MRI-documented hamartoma in the area of the vestibular nuclear region with a paroxysmal contralesional OTR (F. Thömke, unpublished observation). Occasionally, an otolithic Tullio phenomenon may be triggered by a loud noise in patients with stapes subluxation (Brandt et al. 1988). • Alternating skew deviation: Alternating skew deviations are vertical divergences in which the respective higher and lower eye changes with the direction of gaze, i.e. if the right eye is higher in right gaze, the left eye will be higher during left gaze. Both, the respective abducting eye (bilateral abducting hypertropia, Moster et al. 1989) and the respective adducting eye (bilateral adducting hypertropia) can be higher. The incidence rate for both forms is similar, and together they represent slightly more than 10% of all vertical divergences (Keane 1975). • Slowly/periodic alternating skew deviation: In some patients, the positions of the respective higher and lower eye slowly change at regular (periodic) or irregular intervals. The eyes remain in the respective vertical deviation for 30–60 s, before changing their positions again within 10–30 s (slowly alternating skew deviation, Schatz et al. 1981; periodic alternating skew deviation, Mitchell et al. 1981).
3.1 Disorders of Ocular Motility
Etiology Unilateral brainstem lesions are the most frequent causes of OTR and STS, in the order of importance: brainstem infarctions, brainstem hemorrhages, brainstem tumors, and inflammatory plaques in multiple sclerosis. An OTR may also be observed in unilateral lesions of the utricle, the vertical semicircular canals, the vestibulocochlear nerve, and the cerebellum (Brandt 1999; Brandt and Dieterich 1993). Medullary, pontomedullary, and caudal pontine lesions may cause ipsilesional OTR or STS with an ipsilesional lower eye, ipsilesional head tilt and ipsilesional ocular torsions, whereas rostral pontine, pontomesencephalic and mesencephalic lesions may be associated with a contralesional OTR or STS. An OTR or STS therefore may help to localize the side and the location of the responsible brainstem lesion. • When the side of the brainstem lesion is evident from clinical signs, the direction of the head tilt and the side of the lower eye indicate the level of the brainstem lesion. • When the level of the brainstem lesion is evident from the clinical signs, the direction of the head tilt and the side of the lower eye indicate the side of the lesion. Alternating skew deviation alone has no specific localizing value (Keane 1985; Moster et al. 1988). Most of the small number of patients with periodic alternating skew deviation showed lesions in the rostral midbrain.
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Graviceptive afferents from the utricle and the vertical semicircular canals converge in the medial vestibular nucleus and travel together in the medial longitudinal fasciclus to the oculomotor motor neurons in the third and fourth nerve nuclei. Lesions of this graviceptive pathway may cause two basic types of an OTR (Brandt and Dieterich 1993): • An ascending pontomedullary form (ascending pontomedullary VOR-OTR) with ipsilateral head tilt and disconjugate ocular torsion (more pronounced or exclusively involving the lower eye) • A descending mesencephalic form (descending mesencephalic integrator OTR) with contralesional head tilt and conjugate ocular torsion Alternating skew deviation cannot easily be explained on the basis of the models discussed above. Keane (1975) proposed a bilateral lesions of the otolithic-ocular pathways affecting primarily the projections to the oblique muscles. Zee, on the other hand, suggested a disturbed inhibition of developmentally old reflex eye movements. Animals with laterally positioned eyes generate torsional eye movements as well as vertical divergence with head tilts. The latter has to be suppressed by frontal-eyed animals. Alternating skew deviations may occur when there is an impaired inhibition of the vertical divergence and an imbalance in the otolithic-ocular pathways (Zee 1996). In periodic or slowly alternating skew deviation, dysfunction in the region of the interstitial nucleus of Cajal seems likely, because stimulation of this region elicits an OTR with a head tilt in the direction of the stimulation. Oscillations – regardless of their origin – in the INC (or adjacent structures) can therefore produce periodic or aperiodic alternating skew deviation.
Pathomechanism OTR and STS are generally attributed to a lesion of the “graviceptive” pathways. Both, unilateral lesions of the tonic otolithic-ocular pathway (Keane 1975) as well as combined lesions of “graviceptive” afferents from the utricle and the vertical semicircular canals are possible causes (Brandt and Dieterich 1993). An OTR may be interpreted as a tonic imbalance of the vestibuloocular reflex (VOR) in the roll plane, in which the semicircular canal and otolith systems cooperate with some functional overlap (Brandt and Dieterich 1993): • With low frequency rotations or static rotations around the visual axis, the torsional VOR mainly depends on utricular signals with only minor contributions of the vertical semicircular canals. • With high frequency rotations of the head, signals from the vertical semicircular canals mainly generate the torsional VOR, whereas impulses from the otoliths are of minor importance because of their delayed transmission.
Differential Diagnosis Diagnosis of “typical” skew deviation or STS should not pose a major problem because of the constant (or almost constant) vertical divergence in all directions of gaze. But whenever the degree of the vertical divergence varies in different gaze directions and/or additional clinical signs of brainstem dysfunction, which are usually associated with a STS, are absent, partial third nerve palsies with weakness of individual muscles (superior rectus muscle, inferior rectus muscle, inferior oblique muscle) and, in particular, a fourth nerve palsy have to be differentiated. It may be impossible to differentiate an OTR with varying degrees of vertical divergence and maximal hypertropia of the adducting eye from an isolated superior oblique palsy with the widely used three-step test of Parks (1958) (Donahue et al. 1999). This also applies to an OTR with a maximal vertical divergence of the abducting eye and an inferior oblique palsy (Donahue et al. 2001). In these – and all other
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problematic – cases, investigation of ocular torsion by fundus photography and determination of the subjective visual vertical may prove useful. Demonstration of binocular torsion may serve as evidence of an STS, because in oculomotor and trochlear palsies ocular torsion occurs – if at all – in only one eye, in which case not only the paretic, but also the healthy eye may be affected (Dieterich and Brandt 1993b). If ocular torsion in STS is present in only one eye, the lower eye shows extortion while the upper eye is intorted. Conversely, in superior oblique palsy the upper (paretic) eye is extorted, and in inferior oblique palsy the lower (paretic) eye is intorted. In an alternating skew deviation with hypertropia of the respective abducting eye, the principal differential diagnostic consideration is a bilateral inferior rectus paresis. In hypertropia of the respective adducting eye, differentiation from the bilateral superior oblique palsy is difficult. In this case determination of ocular torsion can make an important contribution to the differential diagnosis.
3.1.4 Acquired Nystagmus Nystagmus is an involuntary repetitive, rhythmic to-and-fro movement of the eyes with horizontal, vertical, oblique or torsional directions. It is one of the most frequent clinical signs of brainstem and/or cerebellar dysfunction. There are two main types: • Jerk nystagmus with alternations of slow drifts of the eyes in one direction and fast (corrective) eye movements in the opposite direction. The direction of the nystagmus is defined by the direction of its fast phase. • Pendular nystagmus with sinusoidal oscillations of the eyes. Most types of acquired nystagmus involve both eyes, which usually move in the same direction (conjugate nystagmus) and less often in different directions (disconjugate nystagmus). Nystagmus always occurs when there is impaired fixation or gaze stability, which is achieved by the interaction of several oculomotor subsystems. These systems ensure that the direction of gaze or fixation is held steady, so that the retinal image of the visual world remains stable on the retina despite head and/or body or object movements. Dysfunction of one (or more) of the oculomotor subsystems (e.g. vestibuloocular reflex, smooth pursuit, neural integrator) may cause a slow deviation of the eyes from the position in which they should be held (= slow nystagmus phase). This induces generation of rapid corrective saccades in the opposite direction, i.e. in the direction of the original position (= fast nystagmus phase). So, it is the slow deviation of the eyes from the
3 Diagnostic Findings
desired position, which is abnormal, whereas the fast eye movement in the opposite direction is aimed to bring the eyes back to their original position. Dysfunction of the neural integrator and lesions of central vestibular connections with impairment of the vestibuloocular reflexes are of particular clinical importance for the development of acquired nystagmus. Circumstances in which an acquired nystagmus occur or change its intensity can provide valuable information on the underlying condition: • Nystagmus observed only in a certain direction of gaze (gaze-evoked nystagmus) mainly reflect dysfunction of the neural integrator. • Nystagmus occurring spontaneously, i.e. without fixation (e.g. under Frenzel goggles or in darkness) (=spontaneous nystagmus) are usually seen with disorders of the vestibular system. • Possible effects of fixation on the nystagmus permit further conclusions: –– Spontaneous nystagmus due to peripheral-vestibular lesions decrease in amplitude and frequency or may even cease on fixation. –– Spontaneous nystagmus with central-vestibular lesions are typically not influenced by fixation. • Nystagmus that occur with fixation or are more pronounced in straight-ahead fixation than under Frenzel goggles (=fixation nystagmus) are the manifestation of a central disturbance. • Nystagmus that occur with positioning to a certain position (= positioning nystagmus) are due to a peripheralvestibular dysfunction. • Nystagmus that occur only in a certain position (= position nystagmus) usually reflect a central disturbance of the vestibular system. This allows a rough, clinically useful classification of acquired nystagmus (Table 3.2). The most important forms observed in acquired brainstem (and/or cerebellar) lesions are described in greater detail in the following sections.
3.1.4.1 Nystagmus Occurring on Gaze in a Certain Direction Gaze-Evoked Nystagmus Gaze-evoked nystagmus (GEN) is the most frequently observed acquired nystagmus. It is a conjugate jerk nystagmus that occurs only on gaze in one (or more) direction(s). The rapid phase beats in the respective direction of gaze.
3.1 Disorders of Ocular Motility Table 3.2 Clinical classification of the most important kinds of nystagmus in acquired brainstem (and/or cerebellar) lesions Nystagmus occurring on gaze in a certian nystagmus Gaze-evoked nystagmus Rebound nystagmus Dissociated nystagmus in internuclear ophthalmoplegia Spontaneous nystagmus Downbeat nystagmus Upbeat nystagmus Torsional nystagmus Sidebeat nystagmus Seesaw nystagmus Periodic alternating nystagmus Pendular nystagmus Convergence nystagmus with and without retraction Divergence nystagmus
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the orbital tissue), which leads to the generation of corrective (centrifugal) saccades back to the original position. Here, the eyes cannot be held due to the impaired integrator function and slowly drift back to the primary position, which, in turn, leads to the generation of corrective saccades, etc. The sequential progression of these processes presents clinically as gaze-evoked nystagmus. The impaired integrator function is more clearly and distinctly perceived, the farther the eyes are to be held away from the primary position (Fig. 3.5). With increasing distance from the primary position, the work of the respective agonistic muscles to maintain eye position increases, which causes the required tonic innervation signal to increase proportionally. The effects of the disturbed integrator function are becoming more and more clearly apparent under the described conditions. Since the role of the neural integrator is least important for gaze stability in forward gaze, impaired neural integrator function does not elicit nystagmus (or only a discrete form) in this setting.
Nystagmus in imbalances in the smooth pursuit system Nystagmus occurring (or markedly increasing) with fixation
Clinical Findings
Fixation pendular nystagmus
GEN occurs on gaze in a certain direction, becomes increasingly pronounced with increasing amplitude of gaze (Alexander’s law), and is inexhaustible in sustained lateral or vertical gaze. Its quick phases beat in the direction of gaze, i.e. away from the primary position. An exponentially decreasing velocity of the slow nystagmus phases can typically be demonstrated on electrooculography (Fig. 3.5). In healthy individuals a conjugate horizontal jerk nystagmus may also frequently occur on lateral gaze reaching a maximum or near maximum lateral gaze position (“endpoint nystagmus”). In contrast to GEN this nystagmus usually is of lower intensity, i.e. smaller amplitude and higher frequency, and exhaustible (Shallo-Hoffmann et al. 1990). The remaining clinical findings are normal in these persons, whereas patients with a GEN often have additional clinical signs of brainstem and/or cerebellar dysfunction.
Positioning or position-dependent nystagmus Central position nystagmus Central positioning nystagmus
Etiology The most common causes of GEN include multiple sclerosis, infarctions in the territory of the vertebrobasilar arterial system, as well as overdosing or side-effects of certain medications (e.g. anticonvulsives and sedatives). Further causes are anomalies at the craniocervical junction (Chiari malfor mation), degenerative cerebellar disorders, hemorrhages and tumors in the posterior cranial fossa, encephalitis, craniocerebral trauma, and Wernicke’s encephalopathy.
Rebound Nystagmus Pathomechanism The cause of a GEN is an impaired function of the neural integrator (leaky integrator; see Sect. 3.1.1). In horizontal GEN the disturbance involves the nucleus prepositus hypoglossi and the adjacent medial vestibular nucleus (Cannon and Robinson 1987), and in vertical GEN the interstitial nucleus of Cajal (Crawford et al. 1991). On lateral gaze or up- and downgaze the eyes cannot be held in the desired eccentric position because of an inadequate (or absent) tonic innervation. The eyes slowly drift back to the primary position (centripetal drift) due to elastic restoring forces (extended antagonistic eye muscles, viscous resistance of
If a patient with horizontal (exhaustible) GEN in lateral gaze with quick phases away from the primary position has horizontal jerk nystagmus with quick phases in the opposite direction after the eyes are returned to the primary position, this is described as rebound nystagmus. Etiology Rebound nystagmus is observed particularly in degenerative cerebellar disorders, but may also occur in multiple sclerosis, infarctions in the territory of the vertebrobasilar arterial system, and lesions in the region of the foramen magnum.
120 Fig. 3.5 (a) Gaze-evoked nystagmus on right gaze with exponentially decreasing slow phase velocity, and (b) characteristic increase in intensity of the nystagmus at incremental lateral gaze direction (20°, 30° and 40° in right gaze)
3 Diagnostic Findings
a Right eye
Left eye
20°
20° 1s
40°
0,1 s
b
30° 20°
1s
Pathomechanism Rebound nystagmus is attributed to central compensation mechanisms aimed to minimize impaired integrator function. In the presence of a leaky integrator, increased tonic innervation has to be generated on lateral gaze to maintain the eyes in the lateral position. This would decrease the slow nasal (centripetal) drift of the eyes back in the direction of the primary position and thus cause a decrease in the centrifugal GEN. Increased tonic innervation in the centrifugal direction will elicit slow centrifugal drift of the eyes immediately on return of the eyes to the primary position. This would induce the generation of corrective saccades in the opposite direction, and elicit a centripetally beating rebound nystagmus. Clinical Findings Horizontal GEN on lateral gaze occurring in patients with rebound nystagmus is characteristically not inexhaustible, but decreases or ceases on sustained lateral gaze after approximately 10–20 s. In healthy individuals with end-point nystagmus, rebound nystagmus may occasionally be seen, whose intensity is nevertheless markedly lower than that of the pathologic rebound nystagmus, and ceases after a few seconds (Shallo-Hoffmann et al. 1990).
Dissociated Nystagmus in Internuclear Ophthalmoplegia Internuclear ophthalmoplegia (INO) is characterized by an adduction paresis on lateral gaze with preserved adduction during convergence. The majority of patients show a jerk nystagmus in lateral gaze, which is exclusively, or more
markedly, pronounced on the abducting, non-paretic eye (=abduction nystagmus) (Fig. 3.2). Abduction nystagmus increases with increasing amplitude of the lateral eye movements gaze in the direction of action of the paretic medial rectus muscle and is almost always associated with overshooting abduction saccades. Particularly in cases of only mild adduction pareses, the intensity of this abduction nystagmus decreases in sustained lateral gaze, or the nystagmus ceases. An exponentially decreasing velocity of the slow nystagmus phases is observed on electrooculography (Fig. 3.2). The adduction paresis is the consequence of a lesion of the medial longitudinal fasciclus on the side of the paresis. Abduction nystagmus, however, is not attributable to an MLF lesion. The most probable pathomechanism is increased phasic innervation adjusted to the degree of the adduction paresis as an attempt to minimize this paresis (Zee et al. 1987; Thömke 1996; Thömke et al. 2000). 3.1.4.2 Spontaneous Nystagmus Spontaneous nystagmus occurs by definition spontaneously, i.e. without a relationship to gaze in certain directions, changes in head position or head movements, and without fixation (e.g. under frenzel goggles, with eyes closed, or in darkness). Some authors have also referred to nystagmus occurring in straight-ahead gaze as spontaneous nystagmus. This also applies to nystagmus manifesting purely on fixation, which cease, in contrast to spontaneous nystagmus, on removal of visual fixation (frenzel goggles, in darkness). To avoid confusion produced by imprecise terminology, fixation nystagmus should not be classified as spontaneous nystagmus, since it does not occur spontaneously but only with fixation.
3.1 Disorders of Ocular Motility
Most cases of spontaneous nystagmus are the result of peripheral or central vestibular disturbances, and are generally attributed to impairment or imbalances of the vestibuloocular reflex (VOR). On movements of the head and/or body, the VOR generates reflexive slow, conjugate eye movements in the opposite direction. Ideally, the amplitude and velocity are adjusted to the head movement in such a way that the line of sight is not changed. This enables the image of an object of interest to remain stable on the retina despite movements of the head and/or body. The VOR is mediated via a 3-neuron reflex arc: the first neuron is in the vestibular ganglion. It receives the primary vestibular afferents from the semicircular canals and the otoliths and projects to the second neuron in the vestibular nucleus, which in turn projects to the motor neurons in the third, fourth, and sixth nerve nuclei. Every semicircular canal has excitatory connections with one agonistic eye muscle pair (one muscle per eye), which moves the eyes in the same direction. • Horizontal canal: medial rectus muscle ipsilateral and lateral rectus muscle contralateral. • Posterior canal: superior oblique muscle ipsilateral and inferior rectus muscle contralateral. • Anterior canal: superior rectus muscle ipsilateral and inferior oblique muscle contralateral. The spatial plane of one semicircular canal corresponds approximately to the functional planes of the eye muscles connected with that semicircular canal. The VOR generates eye movements around the following main axes: • Horizontal eye movements during rotations of the head around the vertical body axis (yaw) • Vertical eye movements during flexion and retroflexion of the head around a horizontal axis (to be thought as passing through both ears) (pitch) • Torsional (rotational) eye movements during movement of the head around the visual axis (roll) Eye movements in the yaw plane are mediated via the horizontal semicircular canals, and those in the pitch and roll plane are mediated via the vertical semicircular canals. Fixation typically does not significantly change spontaneous nystagmus due to dysfunction of the central vestibular system. Conversely, spontaneous nystagmus in peripheral vestibular lesions, which affect the labyrinth or the vestibular segment of the vestibulocochlear nerve, are markedly less pronounced or cease during fixation and increase significantly under frenzel goggles, or can only be demonstrated under these conditions. Spontaneous nystagmus due to dysfunction of the vestibular system follows Alexander’s law, i.e. the nystagmus becomes more intense when the
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patient looks in the direction of the quick phase of the nystagmus.
Upbeat and Downbeat Nystagmus Upbeat nystagmus as well as downbeat nystagmus is a conjugate spontaneous jerk nystagmus that may be associated with disturbing oscillopsia (illusionary motion of the stationary environment). Etiology The most important causes of downbeat or upbeat nystagmus comprise acquired and degenerative cerebellar disorders, as well as anomalies of the craniocervical junction, in particular Chiari malformation. Further possible causes include brainstem and/or cerebellar infarctions or hemorrhages, tumors, multiple sclerosis, paraneoplastic brainstem encephalitis, and Wernicke’s encephalopathy. Vertical nystagmus due to intoxications or side effects of drugs (e.g. lithium, anticonvulsives, alcohol, toluene) usually manifest as downbeat nystagmus, while upbeat nystagmus has thus far only be described for organophosphate poisoning. Pathomechanism Brainstem lesions which cause downbeat nystagmus are at the paramedian pontomedullary junction and affect projections from the posterior canals from both sides. Upbeat nystagmus may occur with paramedian pontomedullary or pontomesencephalic lesions, as well as unilateral injuries to the medulla oblongata, affecting the nucleus intercalatus (Staderini). Upbeat and downbeat nystagmus is usually attributed to an imbalance of the VOR in the pitch plane, which is, however, only one of several possible mechanisms. Downbeat Nystagmus An injury to the excitatory central projections of the two posterior semicircular canals would impair excitation of the inferior rectus muscles. This would cause a slow upward drift of the eyes, which gives rise to the generation of corrective downward saccades. Disinhibition of central excitatory projections from the anterior semicircular is another possible mechanism of downbeat nystagmus, as it may be followed by increased excitation of the superior rectus muscles. This would also cause a slow upward drift of the eyes with subsequent generation of corrective downward saccades. Investigation of a group of patients with downbeat nystagmus, however, failed to reveal an impairment of the vertical VOR, So, downbeat nystagmus was, at least in this group of patients, not the result of a VOR imbalance in the pitch plane (Glasauer et al. 2004).
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Alternative causative mechanisms discussed were imbalances in the system of vertical smooth pursuit eye movements or in the vestibulootolithic reflex (Marti et al. 2002, 2005; Kalla et al. 2006). Both mechanisms may also be followed by an upward drift of the eyes, leading to the generation of corrective downward saccades.
3 Diagnostic Findings
a
30° upward
Straight-ahead gaze
Upeat Nystagmus Disruption of the excitatory central projections of the two anterior semicircular canals would impair excitation of the superior rectus muscles. This could cause a slow downward drift of the eyes, which gives rise to the generation of corrective upward saccades.
10° 1s 30° downward
b Clinical Findings Upbeat and downbeat nystagmus usually follow Alexander’s law, i.e. the nystagmus becomes more intense when the patient looks in the direction of the quick phase of the nystagmus. Occasionally, both types of vertical nystagmus may decrease with gaze in direction of the fast phase, and in rare cases may even reverse directions, i.e. downbeat nystagmus beats upward in downgaze and an upbeat nystagmus changes into a downbeating nystagmus in upgaze. Downbeat nystagmus typically also increases in lateral gaze. In some patients, upbeat and downbeat nystagmus become more intense with convergence, and may rarely even reverse directions. Sometimes, upbeat nystagmus may also decrease due to convergence. Fixation typically does not have a significant influence on the intensity of upbeat and downbeat nystagmus. Electrooculography typically demonstrates a linear velocity of the slow phases of upbeat and downbeat nystagmus (Fig. 3.6). Upbeat and downbeat nystagmus are usually associated with impaired vertical smooth pursuit and gaze-evoked nystagmus on lateral gaze. Most patients also have a tendency to fall backward (downbeat nystagmus), or forward (upbeat nystagmus, occasionally also associated with a tendency to fall backward). Patients with spontaneous vertical nystagmus, especially downbeat nystagmus, often complain of disabling oscillopsia.
Straight-ahead gaze
Lateral gaze 5° 1s
Fig. 3.6 (a) Spontaneous downbeat nystagmus with linear velocity of the slow phase and increase in downgaze and decrease in upgaze; (b) typical increase in downbeat nystagmus intensity in lateral gaze
direction that is followed by a rapid torsional eye movement in the opposite, i.e. back to the initial position.
Cause The most frequent causes are multiple sclerosis and brainstem infarcts; less frequently observed causes include tumors of the posterior fossa, brainstem encephalitis, syringobulbia, and craniocerebral trauma. The causal lesions are primarily located in the medullary or pontomedullary regions of the – with regard to the direction of the fast phase – contralateral vestibular nucleus (Lopez et al. 1992).
Pathomechanism Analogous to upbeat and downbeat nystagmus, torsional nystagmus is attributed to a VOR imbalance in the roll plane.
Therapy See Sect. on “Pharmacotherapy of Acquired Nystagmus”.
Torsional Nystagmus Torsional nystagmus refers to the sequence of a slow conjugate torsional eye movement around the visual axis in one
Clinical Findings In contrast to horizontal or vertical nystagmus, which are associated with a change in the eye position in the horizontal or vertical plane, pure torsional nystagmus can easily be missed, in particular if the movements have small amplitudes, as rotations about the visual axis do not lead to a change in the
3.1 Disorders of Ocular Motility
position of the eyes in the orbits. Demonstration of conjunctival vessel movements (or retinal vessel movements on ophthalmoscopy) can be helpful in establishing the diagnosis. Rotation of the head around the visual axis in the direction of the quick phase of torsional nystagmus usually increases nystagmus intensity. In some patients torsional nystagmus occurs only in lateral gaze. Approximately one fourth of these patients show an additional skew deviation, with the nystagmus almost always beating in the direction of the higher eye. Differential Diagnostics In mesencephalic and pontomesencephalic lesions a vertical– torsional nystagmus may occur, whose clinical differentiation from a conjugate torsional nystagmus is difficult, or may even be impossible, if it has a comparatively small vertical component. Such nystagmus is observed after unilateral microinjection of muscimol into the interstitial nucleus of Cajal (INC). It is characterized by an ipsilesional torsional component that is more pronounced on the ipsilesional eye, and a downward vertical component more pronounced in the contralesional eye. A central vestibular imbalance has been posited, because nystagmus with such directions of the quick phases would develop on stimulation of the anterior semicircular canal (Helmchen et al. 1998; Rambold et al. 1999). This nystagmus is very rarely found under “natural” conditions, as an isolated lesion of the INC is highly unlikely because lesions at that site would also involve the adjacent riMLF in most cases. So the ipsilesional rapid torsional components would no longer be generated, as these are known to depend on an intact riMLF. Another rare type of torsional nystagmus with midbrain lesions and contralesional quick phases was attributed to an injury to the riMLF (Helmchen et al. 1996). Therapy See Sect. on “Pharmacotherapy of Acquired Nystagmus”. Horizontal Nystagmus Conjugate, purely horizontal spontaneous jerk nystagmus without suppression on fixation (sidebeat nystagmus) is extremely rare. This nystagmus may occur with unilateral damage to central projections of a horizontal semicircular canal, which would be followed by a VOR imbalance in the yaw plane. The only site, where an isolated injury of these projections may occur, is in the entry zone of the vestibulocochlear nerve at the pontomedullary junction. At that site, however, additional lesions of the afferent connections of other semicircular canals are likely to occur, as they are closely related to the horizontal canal projections. So, horizontal– rotational nystagmus – similar to that in vestibular neuritis – is frequently observed with such localized lesions (“vestibular
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pseudoneuritis”). Imbalance in the system of horizontal smooth pursuit eye movements may also cause purely horizontal nystagmus, although this would be a rarity at the brainstem level. (Such pursuit defect nystagmus may be seen occasionally with lesions of the cerebral hemispheres).
Seesaw Nystagmus and Hemi-Seesaw Nystagmus Seesaw and hemi-seesaw nystagmus are spontaneous vertical-torsional oscillations of the eyes with disconjugate vertical and conjugate torsional components associated with intorsion of the upper and extorsion of the lower eye. Etiology The most frequent cause of pendular seesaw nystagmus are tumors of the sellar region with bilateral compression or infiltration of the mesodiencephalic brainstem and/or the visual tract. It can also be observed with severe visual impairment (e.g. retinitis pigmentosa), and may occasionally occur in multiple sclerosis, brainstem infarcts, syringobulbia, and Chiari malformation. Jerky hemi-seesaw nystagmus is due to unilateral mesodiencephalic, mainly ischemic lesions, and occasionally also hemorrhages, tumors, and stereotactic lesions. Pathomechanism Pendular seesaw nystagmus is, among other causes, attributed to oscillations in the region of the interstitial nucleus of Cajal (INC), whose stimulation results in a skew deviation or a skew torsion sign. These oscillations can develop either directly in the INC or result from oscillating excitations of the INC by central projections of the vertical semicircular canals (Rambold et al. 1998). Unilateral lesions of the INC were discussed as a cause of jerky hemi-seesaw nystagmus, which may lead to slow vertical–torsional eye movements finally leading to skew deviation (with intorsion of the ipsilesional higher eye and extorsion of the contralesional lower eye). The subsequent quick vertical– torsional eye movements in the opposite direction are generated by the oculomotor system to bring the eyes back to their original position (Halmagyi et al. 1994). This depends on the integrity of the adjacent rostral interstitial nucleus of the medial longitudinal fasciculus, which is the direct premotor structure for generation of vertical and torsional saccades. It has been shown in monkeys that inactivation of the INC with muscimol injections does not produce seesaw nystagmus, but a dissociated vertical–torsional nystagmus with downward vertical and ipsilesional torsional components. Downward components are more pronounced in the contralesional eye and the torsional component in the ipsilesional eye.
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3 Diagnostic Findings
Clinical Findings
Etiology
Pendular seesaw nystagmus is a very rare type of nystagmus with disconjugate vertical and conjugate torsional components, i.e. vertical components are directed in opposite and torsional components in the same directions with intorsion of the upward moving eye and extorsion of the downward moving eye. These conditions are reversed after every hemicycle, i.e. the previously higher intorted eye is then lowered and extorted, and the previously lowered extorted eye becomes higher and intorted (Fig. 3.7). So, at the end of each hemicycle a brief episode of a skew torsion sign is observed. Hemi-seesaw nystagmus is also a very rarely occurring jerk nystagmus, which has to be differentiated from pendular seesaw nystagmus. It is characterized by slow disconjugate vertical drifts of the eyes from the midposition finally leading to a skew deviation (with intorsion of the higher and extorsion of the lower eye) followed by fast eye movements in the opposite position, i.e. back to the primary position.
A PAN is often encountered in patients with multiple sclerosis and abnormalities in the region of the posterior cranial fossa, in particular Chiari malformation. More rarely found causes include cerebellar disorders (degeneration, inflammation, tumor), brainstem infarcts and phenytoin intoxication.
Therapy See Sect. on “Pharmacotherapy of Acquired Nystagmus”.
Pathomechanism Disinhibition of the velocity storage mechanism due to damage of inhibitory GABAergic projections from the nodulus to the nucleus prepositus hypoglossi vestibular nucleus is proposed as the most likely pathomechanism of PAN. Velocity storage refers to a network of cerebellar and pontomedullary neurons that act to increase the time constant of afferent vestibular neurons. This enables reliable recording of continuing head movements with constant velocity over an extended period of time. The decrease or cessation of this nystagmus is again attributed to normal vestibular “repair mechanisms”. The PAN might therefore be understood as the result of the central compensation of a central-vestibular imbalance caused by velocity storage instabilities. Clinical Findings
Periodic Alternating Nystagmus Periodic alternating nystagmus (PAN) is a spontaneous horizontal jerk nystagmus that periodically reverses its direction.
The PAN is a spontaneous, conjugate horizontal jerk nystagmus present already in gaze straight ahead. It reverses its direction at regular intervals (typically every 1.5–2 min) with a short (or also without) latency. The intensity of the respective nystagmus initially increases slowly, reaches its individual maximum, begins to decrease, and finally ceases (Fig. 3.8). The time of a complete cycle is 3–4 min, but it may also be either shorter or longer. Direction asymmetries up to a periodic nystagmus in one direction are occasionally observed. Therapy See Sect. on “Pharmacotherapy of Acquired Nystagmus”.
Convergence Nystagmus with and Without Retraction Convergence nystagmus is a rare disconjugate horizontal jerk nystagmus with fast phases in the nasal direction (opposed adduction saccades). Fig. 3.7 Schematic representation of a seesaw nystagmus with disconjugate vertical and conjugate torsional components. This is associated with intorsion of the upward moving eye, and extorsion of the eye moving in a downward direction. A skew torsion sign is observed after each hemicycle – and the previously higher intorted eye is in a lower outward rotated position; the previously extorted eye is now in a higher inward rotated position
Etiology The most common cause is a pineal tumor with compression of the dorsal midbrain; less frequently encountered are demyelinization plaques in multiple sclerosis, or midbrain tumors and hemorrhages.
3.1 Disorders of Ocular Motility Fig. 3.8 Periodic alternating nystagmus. (a) Diagram of the complete cycle; (b) depiction of the velocity changes of the slow nystagmus phases over time
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a
b Velocity of the slow nystagmus phases to the left [°/s)
25 50 s
150 s Time [S)
25
Velocity of the slow nystagmus phases to the right [°/s)
Pathomechanism
Clinical Findings
The following pathomechanism have been adequately demonstrated:
Convergence nystagmus is a rare disconjugate horizontal jerk nystagmus with fast phases in the nasal direction (opposed adduction saccades). It may be associated with synchronous retraction of the eyes (convergence-retraction nystagmus). A pure convergence nystagmus as well as a pure retraction nystagmus may also occur. Convergence-retraction nystagmus is usually elicited by upward saccades – on occasion also by saccades in each direction or by pursuit movements. It may also occur spontaneously. Other frequent findings include pupillary abnormalities, vertical gaze palsies, upbeat and/or downbeat nystagmus, and skew deviation.
• Convergence nystagmus without retraction: An imbalance in the vergence system with excessive divergence tone may cause disconjugate slow deviations of the eyes in a temporal direction giving rise to the generation of fast corrective saccades in the nasal direction (Rambold et al. 2007). • Convergence nystagmus with retraction: An abnormal concurrent co-contraction of the medial and lateral rectus muscles of both eyes, and therefore pathologic prenuclear phasic innervation signals, is a prerequisite for such a disorder. An imbalance in the saccadic system was discussed as a possible cause (Ochs et al. 1979). Here, the fast phases themselves would be abnormal, instead of representing correction of a preceding deviation of the eyes.
Divergence Nystagmus Divergence nystagmus is very rarely encountered. It is a disconjugate horizontal jerk nystagmus with slow
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deviations of the eyes in the nasal direction followed by fast eye movements in the opposite, i.e. temporal direction. Such nystagmus might, on principle, be regarded as the consequence of a disturbance in the vergence system, e.g. as a result of a disinhibition of mesencephalic convergence neurons. This would create an increased convergence tone causing slow adduction movements of the eyes followed by quick abduction movements to bring the eyes back to their previous positions. To the best of my knowledge, however, such nystagmus has thus far not been described in the literature. Patients with a Chiari malformation or, less frequently, with cerebellar degeneration occasionally have downbeat nystagmus with an additional divergent component, i.e. oblique slow phases with upward and nasal components (Baloh and Spooner 1981). This type of nystagmus has been explained by the presence of a central vestibular disturbance. In rabbits, floccular projections to the vestibular nucleus inhibit only the adduction component of the horizontal VOR. Damage to these projections may be followed by a disinhibition of the adduction component of the VOR causing slow nasal drift of the eye with subsequent generation of fast abduction movements to bring the eyes back to their previous positions (Ito et al. 1977).
3.1.4.3 Nystagmus with Imbalances of the Pursuit System This type of nystagmus is somewhat controversial. On principle, a pursuit imbalance is a possible mechanism of a spontaneous, purely horizontal or purely vertical jerk nystagmus, which follow Alexander’s law. An imbalance in the pursuit system may cause a slow horizontal or vertical drift of the eyes followed by generation of fast corrective saccades in the opposite direction. Electrooculography would demonstrate a constant (linear) velocity of the slow nystagmus phases, which also characterizes central vestibular nystagmus. This implies that nystagmus due to pursuit imbalances can not be differentiated from central vestibular nystagmus either clinically or electrooculographically. Possible causes are lesions (e.g. infarcts, hemorrhages, tumors, demyelinizations) at any level of the smooth pursuit system (cerebral hemispheres, midbrain, pons, cerebellum) (Zee et al. 1974; Abel et al. 1979). A pursuit imbalance as the cause of acquired spontaneous nystagmus, however, should only be considered when (a) the presence of a vestibular lesion can be excluded, and (b) there is impaired pursuit eye movements in the direction of the fast phase of nystagmus. The clinical significance of this type of nystagmus can not be conclusively defined. More recent studies have again discussed pursuit imbalances as a possible cause of downbeat nystagmus (Marti et al. 2005; Kalla et al. 2006).
3 Diagnostic Findings
3.1.4.4 Nystagmus Occurring (or Increasing) with Fixation Acquired Pendular Nystagmus Patients with acquired pendular nystagmus have mainly conjugate to-and-fro movements of the eyes with approximately equal velocity and amplitudes, but may also show disconjugate pendular oscillations. Etiology Multiple sclerosis is the most frequent cause of acquired pendular nystagmus. Pendular nystagmus may also occur with a latency of a few months after brainstem infarcts or hemorrhages, and is often associated with palatal tremor. It has occasionally also been described in patients with brainstem tumors, Whipple’s disease, as well as with demyelinizations occurring with Pelizaeus–Merzbacher disease or Cockayne syndrome. Pathomechanism Most patients show (multiple) lesions in the region of the dentato-rubro-olivary pathway i.e. red nucleus, inferior olive, central tegmental tract, and the medial vestibular nucleus (Lopez et al. 1996). These lesions are thought to cause deafferentiation of neurons of the inferior olive, which develops rhythmic spontaneous activity under these conditions. These oscillations are transmitted to Purkinje cells in the flocculus. Oscillating discharges of these Purkinje cells, in turn, mediate oscillating VOR instabilities that clinically manifest as pendular nystagmus. Impairment (at least additional) of visual input has been suggested as possible cause of an asymmetric pendular nystagmus, which is more pronounced in the eye with reduced, or more markedly reduced vision (Barton et al. 1993). Acquired pendular nystagmus with convergent-divergent oscillations has been attributed to instabilities of the vergence system (Averbuch-Heller et al. 1995). Clinical Findings Acquired pendular nystagmus mainly occurs with conjugate to-and-fro movements of the eyes with an approximately equal velocity and amplitude and, in optimal conditions, sinusoidal oscillations (Fig. 3.9). The median frequency ranges from 2 to 7 Hz. The trajectories of the eyes vary considerably and may be purely horizontal or purely vertical. More commonly, however, are those with horizontal and vertical components. If these components are in phase, the trajectory of the nystagmus is oblique, but will be elliptical, when there is a phase shift. A phase shift of 90° with equal
3.1 Disorders of Ocular Motility
a
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Right eye Left eye
5° 1s
b
Right eye 5° Left eye
1s
Fig. 3.9 Acquired pendular nystagmus with (a) conjugate and (b) disconjugate (convergent-divergent) beat direction
amplitudes of the horizontal and vertical component is a special case resulting in a circular trajectory. Purely horizontal or vertical pendular nystagmus with different trajectories of both eyes (convergent-divergent; see Fig. 3.9) are less often observed. Acquired pendular nystagmus is occasionally asymmetric or even monocular. Acquired pendular nystagmus is typically more intense during fixation, and may also occur during fixation only (fixation pendular nystagmus). The affected patients often have severely disabling oscillopsia (illusionary motion of the stationary environment). In rare cases acquired pendular nystagmus may occur after eye closure, i.e. in the absence of fixation, and has to be observed under Frenzel goggles (or be recorded electrooculographically with the patient’s eyes closed).
compensated at rest, have been considered. This imbalance is unmasked by normal afferent signals from the graviceptive otolith organs that are generated, when the patient is in the respective nystagmus-eliciting position. This causes a slow deviation of the eyes in the direction of the respective imbalance with the subsequent generation of corrective saccades in the opposite direction. Clinical Findings Central position and positioning nystagmus constitute a group of conjugate jerk nystagmus, which occur in a certain position only (e.g. head down position, lateral position). The nystagmus typically occurs immediately after the patient has reached the respective nystagmus-eliciting position, and the intensity does not decrease with repeated elicitations. The direction of the quick phase varies, e.g. in the lateral position toward upper as well as the lower ear, or even vertical direction. A characteristic feature is the discrepancy between the nystagmus intensity and the comparatively mild vertiginous symptoms. Occasionally, a central paroxysmal position and positioning nystagmus may also occur with severe vertigo and concomitant vegetative symptoms, and has been described with lesions in the region of the fourth ventricle (Brandt 1990), the dorsal vermis (Sakata et al. 1991), or with diffuse cerebellar damage (Büttner et al. 1999).
3.1.4.6 Pharmacotherapy of Acquired Nystagmus Therapy See Sect. on “Pharmacotherapy of Acquired Nystagmus”. 3.1.4.5 Central Position and Positioning Nystagmus Central position and positioning nystagmus refer to a group of conjugate jerk nystagmus, which occur only in a certain position or during positioning to a certain position. The direction of the quick phases is variable. Etiology The most frequent causes of a central position nystagmus include multiple sclerosis, cerebellar degeneration, vertebrobasilar ischemia, and anomalies of the craniocervical junction, in particular Chiari malformation. This nystagmus may also occur with tumors in the posterior fossa. Pathomechanisms Lesions of the vestibulocerebellum and/or the caudal brainstem causing a latent imbalance of the VOR, which is
Many different substances have been successfully used to treat specific types of nystagmus. Previous studies were mainly based on single or only a small number of patients, and were not performed under controlled conditions (overview and further reading, see Straube et al. 2004). Larger randomized placebo-controlled studies are currently only available for downbeat nystagmus (Strupp et al. 2003), and acquired pendular nystagmus (Averbuch-Heller et al. 1997). From a pragmatic view the following procedures are recommended: Central Vestibular Nystagmus Baclofen (3 × 5–20 mg/day), and clonazepam (3 × 0.5–2 mg/day) have been shown to be effective in single or small numbers of patients with different types of central vestibular nystagmus (downbeat/upbeat nystagmus, torsional nystagmus, horizontal nystagmus, seesaw/hemi-seesaw nystagmus, periodic alternating nystagmus, central position and positioning nystagmus). In some instances gabapentin (3–4 × 300–600 mg/day) was also effective. Downbeat nystagmus: The effectiveness of 3, 4-diaminopyridine has been shown in a placebo-controlled study (Strupp et al. 2003), and in a number of subsequent reports in
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3 Diagnostic Findings
smaller numbers of patients. Individual doses – according to clinical and side effects –ranged from 5 to 10 mg for single doses and four to five daily doses. 4-aminopyridine may be even more effective and better tolerated than 3, 4-diaminopyridine (Kalla et al. 2007). Periodic alternating nystagmus: Baclofen (between 3 × 5 and 3 × 20 mg/day) was repeatedly reported to be particularly effective in this type of nystagmus.
3.1.4.8 Saccadic Oscillations That May Mimic Nystagmus Opsoclonus and Ocular Flutter Opsoclonus and ocular flutter are involuntary, irregularly occurring, “chaotic”, rapid conjugate to-and-fro movements of the eyes, whose directions are entirely irregular (opsoclonus), or horizontal (ocular flutter).
(Fixation-) Pendular Nystagmus Gabapentin (3–4 × 300–600 mg/day) and memantine (3 × 5–20 mg/day) have been shown to control this type of nystagmus in most patients. Scopolamine (1–2 ScopodermTTS 1.5 mg/day patches) may also be effective. 3.1.4.7 Topodiagnostic Value of Acquired Nystagmus The topodiagnostic value of acquired nystagmus in brainstem lesions varies widely. Some types are highly specific for the site of a certain lesion (e.g. seesaw nystagmus, convergence-retraction nystagmus), and others are not (e.g. acquired pendular nystagmus, torsional nystagmus, gaze-evoked nystagmus). Some types clearly indicate the side of the lesion (e.g. gaze-evoked nystagmus, dissociated nystagmus as part of internuclear ophthalmoplegia), whereas others are without side-localising value (e.g. upbeat and downbeat nystagmus, periodic alternating nystagmus) (Table 3.3). In general, frequently occurring types of nystagmus are of little topodiagnostic value, and those with high topodiagnostic value are rare.
Etiology While opsoclonus has been repeatedly described as a paraneoplastic disorder, usually associated with small cell bronchial carcinoma or neuroblastomas in children, it may also occur in multiple sclerosis, brainstem encephalitis, cerebellitis, para-infectious encephalitis, metabolic disturbances, tumors, or pontine and mesodiencephalic hemorrhages. Pathomechanism Neither the neurons nor the neurotransmitters involved in opsoclonus/ocular flutter are known. Both types of oscillations are composed of saccades without an intersaccadic interval. The normal relationship between the amplitude and the velocity of these saccades strongly indicate a normal phasic innervation (pulse command). Opsoclonus/ ocular flutter may be interpreted as a consequence of abnormally occurring, but otherwise normal burst neuron
Table 3.3 Topodiagnostic significance of the most important kinds of nystagmus Medulla
Pons
Horizontal gaze-evoked nystagmus
+ Ipsilesional
+ Ipsilesional
Dissociated gaze-evoked nystagmus in internuclear ophthalmoplegia
+
+
Upbeat nystagmus
Midbrain
Contralesional
Contralesional
+
Pontomedullary
Pontomesencephalic
Downbeat nystagmus
+
Pontomedullary
Torsional nystagmus
+
+
Periodic alternating nystagmus
+
+
Rebound nystagmus
+
+
Central position nystagmus
+
+
Central positioning nystagmus
+
+
Acquired pendular nystagmus
+
+
+
+
Seesaw nystagmus
+
Convergence retraction nystagmus
+
Divergence nystagmus
+
3.1 Disorders of Ocular Motility
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discharges without the generation of a tonic innervation signal (step command) by the neural integrator. The cause of the abnormal burst neuron discharges remains unknown. The different possibilities considered include a disinhibition of burst neurons due to pause neuron dysfunction (Zee and Robinson 1979; Ashe et al. 1991), and a disinhibition of the fastigial oculomotor region (Wong et al. 2001). In accordance, functional MRI of two patients revealed an increased bilateral activation of the paramedian cerebellar segments dorsal to the fourth ventricle during opsoclonus, which also involved the region of the fastigial nucleus (Helmchen et al. 2004). Considering the number of different disorders that may cause opsoclonus/ocular flutter, a single pathomechanism is very questionable. More likely, opsoclonus/ocular flutter reflect dysfunctions in a scattered network of brainstem and cerebellar neurons that can occur at different levels finally causing abnormal discharges of burst neurons. Such dys function may involve the burst neurons themselves, or may be the consequence of disinhibition or abnormal excitation of otherwise normal burst neurons.
Square Wave Jerks and Macro Square Wave Jerks
Clinical Findings
Pathomechanism
Common characteristics of opsoclonus and ocular flutter are involuntary, irregularly occurring, “chaotic”, rapid conjugate to-and-fro movements of the eyes that are electrooculographically demonstrable as saccades without an intersaccadic interval. The frequencies of these oscillations range from 5 to 15 Hz. The oscillations may be continuous or occur repeatedly with series of saccades. The main difference between opsoclonus and ocular flutter is the direction of the saccades, which is horizontal in ocular flutter and entirely irregular in opsoclonus. Opsoclonus is elicited or enhanced in particular by preceding saccades or by eye closure. Patients complain of impaired visual acuity ranging from blurred to severely compromised vision. This is the consequence of the inability to hold the visual environment stable on the retina, as every attempted fixation is immediately interrupted by involuntary saccades.
Several mechanisms have been proposed. A lesion of pontine omnipause neurons, or impaired/absent excitation of omnipause neurons, would be followed by an impaired/absent inhibition of burst neurons, which may cause involuntary saccades (Averbuch-Heller et al. 1996). Saccades back to the previous position, which are generated after a normal intersaccadic interval, should be viewed as a central correction of the abnormal foregoing saccade. Onnipause neuron dysfunction may – among others – be the consequence of a lesions of fixation neurons in the superior colliculus or the frontal eye field, which project to omnipause neurons. Lesions of the afferent connection of fixation neurons in the frontal eye field or the superior colliculus may create an imbalance in the fixation system thereby causing square wave jerks/macro square wave jerks (Averbuch-Heller et al. 1996). Another possible cause is a lesion of the nucleus fastigii or its projections to the burst neurons.
Therapy A number of different substances with varying effectiveness have been reported for individual patients. This includes steroids, ACTH, baclofen, clonazepam, nitrazepam, propanolol, thiamine, 5-hydroxytryptophan, and valproine acid. The course of a paraneoplastic opsoclonus seems to be largely independent of the underlying cancer. Intravenous administration of immunoglobulins (e.g. 0.4 g/kg body weight on 5 consecutive days), or plasma separation were favorable in individual patients (Cher et al. 1995; Pless and Ronthal 1996).
Square wave jerks and macro square wave jerks are involuntary saccades that interrupt fixation. The eyes are involuntarily moved away from the point of fixation and are brought back by another saccade after a short interval.
Etiology Square wave jerks have been observed in a number of different conditions including cerebellar diseases, Parkinson’s disease, progressive supranuclear palsy, Huntington’s disease, cerebral lesions, Alzheimer’s disease, side effects of tricyclic antidepressants and monoaminoxidase inhibitors. They may also be observed in particular in very young and old, healthy individuals, where they occur primarily in the form of small amplitude square wave jerks. Macro square wave jerks are mainly seen in patients with multiple sclerosis and cerebellar diseases, most notably with olivopontocerebellar atrophies.
Clinical Findings Square wave jerks and macro square wave jerks are involuntary saccades that interrupt fixation. The eyes are involuntarily moved away from the point of fixation and brought back by another saccade after a short interval. (In contrast to nystagmus in which the eyes slowly drift away from the point of fixation, here the eyes are moved away by a saccade). The amplitudes of square wave jerks range from 1° to 5° and the intersaccadic intervals from 150 to 200 ms. Square wave oscillations is a series of successive square wave jerks
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3 Diagnostic Findings
Right eye
3.2.2 Neuroanatomy
Left eye
Horner’s syndrome represents a lesion of the sympathoexcitatory innervation, in which a brainstem lesion can involve the fibers of the first preganglionic sympathetic neuron descending from the hypothalamus, as well as the sympathetic integration centers at different localizations. The central first order neurons descend together from the hypothalamus through the brainstem and course to the neurons of the intermediolateral horn of the spinal gray matter at the level of segments C8-Th3. Projections of the neurons, in turn, terminate in the superior cervical ganglion, whose axons travel principally in the internal carotid artery wall to the base of the skull and finally to the orbit and the facial skin (Amonoo-Kuofi 1999) (Fig. 3.12). While multiple neurophysiologic and neuroanatomic studies have focussed on the topography of preganglionic and postganglionic neurons, far fewer comprehensive data are available on the course of the central segment of the sympathetic pathway. According to results obtained by animal studies and mapping investigations, the central neurons of the sympathoexcitatory system are localized in the posterolateral region of the hypothalamus (Carpenter 1985; Marx et al. 2003). Hypothalamospinal fibers from the paraventricular, lateral and posterior hypothalamic nuclei appear to
10° 1s
Fig. 3.10 Square wave oscillations
(Fig. 3.10). Macro square wave jerks are differentiated from square wave jerks by a shorter intersaccadic interval of 70–150 ms and significantly larger amplitudes of up to 40°. They occur more frequently in groups with a frequency of 2–3 Hz. Macrosaccadic Oscillations Macrosaccadic oscillations are hypermetric saccades that overshoot the intended target that are followed by refixation saccades in the opposite direction, which also overshoot the target, so that new refixation saccades have to be generated, which again overshoot the target etc. The result is a sequence of saccades in opposite directions, during which the eyes oscillate around the point of fixation with decreasing amplitudes. Hypermetric saccades and macrosaccadic oscillations may occur with cerebellar lesions near the midline particularly affecting the posterior vermis and the nucleus fastigii. They may also be found in patients who have unilateral pontine lesions (Averbuch-Heller et al. 1996).
Tarsal (Müller’s) muscle
Central sympathetic pathway (1st sympathetic neuron)
3.2 Horner’s Syndrome Jürgen Marx
3.2.1 Definition The symptom complex first published in 1869 by Johann Friedrich Horner, the Swiss ophthalmologist, comprises an ipsilateral partial ptosis mediated by a superior tarsal muscle paresis, miosis with normal pupillary light response, enophthalmus, cutaneous vasodilation in the face with a hemifacial transient rise in skin temperature, and ipsilateral hypohidrosis (Fig. 3.11).
Pupillary dilator muscle
Carotid plexus
Superior cervical ganglion (3rd sympathetic neuron)
Ciliospinal center (C8-Th2) (2nd sympathetic neuron)
Fig. 3.11 Horner syndrome right with dorsolateral medulla oblongata infarction
Fig. 3.12 Simplified schematic representation of the sympathoexcitatory pathway to the orbita (acc. to Thömke F. Eye movement disturbances. Stuttgart: Thieme 2001)
3.2 Horner’s Syndrome
descend ipsilaterally through the brainstem and the lateral funiculus of the spinal cord, before terminating in the region of the intermediolateral column of the spinal gray matter at the level of segments C8-Th3. The precise location of this segment of the sympathetic pathway of relevance for a Horner’s syndrome associated with brainstem infarctions is not yet fully understood. Investigations of the pupillodilator pathway in cats indicate a course through the lateral medullary tegmentum (Loewy et al. 1973). Hypothalamic neurons further project to the pontine parabrachial nucleus, to the solitary tract nucleus and to the ventrolateral medulla oblongata. Reciprocally interlinked sympathetic relay structures comprise the insular cortex, the amygdala, the hypothalamus, the parabrachial nucleus, the solitary tract nucleus, and the ventrolateral medullary tegmentum (Nathan and Smith 1986; Mosqueda-Garcia 1996). In this context, the ventrolateral medullary tegmentum appears to be a particularly sensitive area for the occurrence of a clinical Horner’s syndrome (Marx et al. 2003). Although in a topographic diagnostic study including more than 300 patients with brainstem infarctions, an affection of the medulla was found in most intraparenchymatous lesions (63%), only 4 patients with ischemic Horner’s syndrome had pontine infarct (Marx et al. 2003). The course of the sympathoexcitatory fibers suggested by these findings is in a dorsal location through the pontine tegmentum and therefore remote from the ventral pontine regions, which are preferential sites of infarctions due to the vascular brainstem anatomy. This is further supported by single reports of combined occurrence of ischemic Horner’s syndrome and trochlear nerve lesion (Hopf et al. 2000a).
3.2.3 Ethiopathogenesis and Epidemiology On principle, any lesion of the three neurons comprising sympathoexcitatory pathway in its course from the hypothalamus to the face may cause Horner’s syndrome. A central Horner’s syndrome represents a classical symptom of a dorsolateral medulla oblongata ischemia and constitutes a determining symptom in Wallenberg`s syndrome (Saper et al. 1976; Nagy et al. 1997). Further etiologies associated with brainstem lesions include demyelinating lesions, although these are less frequently found in the region of the lateral medulla oblongata, and syringobulbia (Nagy et al. 1997). Only in isolated cases are middle cerebral artery infarctions extending into the hypothalamus responsible for a central Horner’s syndrome. Additional causes are space-occupying lesions, e.g. craniopharyngiomas or prolactinomas and – rarely – neoplasms or myelitic patches in the upper spinal cord, cervical disk herniations affecting the first thoracic root, and cervical spinal cord trauma, that may cause lesion
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of the central preganglionic neurons below the brainstem (Lee et al. 1996; Nagy et al. 1997). Although no precise prevalence data have been cited in the literature, lesions of the peripheral crus, in particular of the second postganglionic neuron, are significantly more frequently encountered than central Horner’s syndromes. Here the most prevalent etiologies comprise neoplasms in the region of the apex of the lung, at the level of the sympathetic trunk and the brachial plexus, internal carotid artery dissections, pathologic processes in the cavernous sinus and rarely – compressing structures directly in the orbital region (Jaffe 1950; Carpenter 1985). A Horner’s syndrome without further clinical abnormalities is almost always attributable to an injury to the postganglionic neuron. When additional investigations do not show a causal pathology, the Horner’s syndrome is referred to as idiopathic.
3.2.4 Clinical Findings The most prominent clinical sign of the classical symptom complex is ptosis, which measures rarely more than 2 mm, and may be completely absent in 10–15% of patients. Anisocoria ranges on average at 1 mm and seldom at more than 2 mm. The initially described enophthalmus is frequently only simulated by a narrowed palpebral fissure. A real enophthalmus is not necessarily present, as the sympathetically innervated orbital muscle constitutes only a thin smooth muscle layer at the dorsal aspect in the orbital periosteum (Wilhelm 1988). Due to the particularly close neighborhood of the central sympathoexcitatory neurons and other eloquent nuclear regions and fibre tracts in the brainstem, a Horner’s syndrome due to a brainstem lesion is almost never found as an isolated symptom. The concomitant clinical symptoms can often provide vital information on the localization of the pathology. Frequent concomitant symptoms include ataxia of gait and posture, ipsilateral hemiataxia, or a contralateral dissociated sensory disturbance. The findings of a study in more than 300 patients with acute brainstem infarction have identified Horner’s syndrome as a clinical sign of medulla oblongata infarctions in more than 80% of cases, at an incidence rate of more than 20% for all patients with brainstem ischemias (Marx et al. 2003). Horner’s syndrome is, however, very rarely associated with lesions in other brainstem regions. Outside the brainstem “pseudo-crossed” symptoms can also develop after carotid artery dissection, with a resulting postganglionic Horner’s syndrome on the side of the dissection and, in the presence of a middle cerebral artery territory infarction, an accompanying contralateral sensorimotor hemiparesis.
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3.2.5 Functional Diagnostics Pharmacologic pupillary and sweat tests have proven to be useful in the primary differentiation between a central and a peripheral pathogenesis of Horner’s syndrome.
3.2.6 Pharmacologic Pupillary Drop Test This test is based on the ability of intact sympathetic neurons to synthesize and then discharge norepinephrine via the nerve terminals (Pilley and Thompson 1975). In a first step, one to two drops of a weak cocaine solution (4–10%) are placed in the conjunctival sac of the affected and the healthy eye to enable the basic decision as to whether the detected miosis is due to Horner’s syndrome mediated by damage to the sympathetic excitatory innervation. After the initial drop application the pupils are observed over a period of 45 min. Cocaine blocks the reuptake of norepinephrine, and thus leads to pronounced mydriasis in the healthy eye. This effect is not observed in the affected eye when the lesion involves the second preganglionic or postganglionic neuron. In the presence of the described lesions, the neuron no longer receives the impulses capable of stimulating the release of norepinephrine from the sympathetic nerve endings. With a lesion to the central neuron, e.g. in the brainstem, the damage to the sympathetic pathway is, however, never complete and mild dilatation of the pupil can generally be achieved, although this is less pronounced here than on the contralateral side. Differentiation between a preganglionic and a postganglionic lesion can be achieved by using a hydroxyamphetamine hydrochloride 1% or a pholedrine 5% solution. This stimulates the release of norepinephrine from the sympathetic terminals. The pupil will fail to dilate due to the degeneration of terminals mediated by a postganglionic lesion, whereas intact postganglionic neurons associated with preganglionic lesions will continue to produce norepinephrine. If a normal reaction is present in the hydroxyamphetamine test, the impairment can be presumed to be due to a first- or second-order preganglionic neuron lesion. In view of their poor reproducibility, additional pharmacologic pupillary motor function tests have not become an integral part of routine clinical diagnostic practice (Maloney et al. 1980). Infrared videography or computerized pupillometry enable a greatly superior quantification of the described changes, in addition to showing previously undetected less severe findings. Furthermore, pupillometry frequently permits the detection of a Horner’s syndrome based on the dilatation lag observed in the first few seconds of darkness (Smith and Smith 1999).
3 Diagnostic Findings
3.2.7 Sweat Tests The extension and distribution of an anhidrotic skin area can provide information on the localization of the causal lesion. An injury to the central neuron leads to unilateral hypo-/anhidrosis associated with vasomotor disturbances that are manifest by warmer and more reddened skin on the side affected with Horner’s syndrome. In contrast, a lesion of the second preganglionic neuron is associated with ipsilaterally impaired sweat secretion of the face and neck only; if a proximal lesion is present, this extends to the level of the stellate ganglion and includes the upper body, arm and hand (quadrant hypo-/-anhidrosis). Finally, a lesion to the postganglionic neuron in the superior cervical ganglion causes a hypo-/anhidrosis of the ipsilateral side of the face only. The more distally the lesion involving the carotid plexus is located, the more pronounced is the decrease in the area of hypohidrosis or anhidrosis in the direction of the face. Localizational information is further provided by the course of the sudomotor fibers which ascend along the external carotid artery and are therefore not, or only partially, affected by an internal carotid artery dissection. Lesions occurring in the region of the cavernous sinus are associated with a disturbance of sweat secretion in the periorbital region only, while retroorbital and orbital lesions mediate a Horner’s syndrome without sudomotor impairment (Amonoo-Kuofi 1999). The described disturbances of temperature regulation are rarely observed or reported by the patient. An anhidrotic skin area is, however, frequently identified already on right-left comparison of the sides of the face during clinical examination. A number of tests are available to objectify the localization of the sweat secretion disturbance. The most widely used of these methods is the measurement of sweat secretion using Minor’s iodine starch test (Minor 1927). In this test an alcoholic iodine solution (2%) is applied and allowed to dry, and starch in powder form is then brushed on the area. The starch turns dark blue on moist mixing with iodine. Thermal loading through muscle work or infrared radiation stimulates symmetrical sweat production in which the anhidrotic skin areas remain unstained, whitish yellow. In the context of a screening procedure, larger body areas can be topographically mapped with this method (Fig. 3.13). A less time consuming test procedure based on the same principle involves the use of an indicator powder, e.g. Alizarin Red. While sweat causes the indicator powder to turn purple, it has an orange color on dry skin (Low et al. 1975). The Ninhydrin sweat test represents a method for the assessment of sudomotor function, primarily in the palm and the sole of the foot (Schliack 1976). The test is based on selective staining of amino acids contained in the secreted sweat with 1% ninhydrin reagent in acetic acid. In a bilateral comparison the respective body surface is pressed on a sheet of paper, which is then sprayed with ninhydrin. Sweating skin areas can be identified by a bluish color appearing on the paper after drying. Further evaporimetric test procedures
3.3 Central Vestibular Disturbances
Fig. 3.13 Demonstration of right upper quadrant hidrosis in ischemic Horner’s syndrome using Minor’s iodine starch test
are not used in routine clinical diagnostics due to the required amount of time and effort.
3.2.8 Therapy and Prognosis No results obtained by controlled studies on the therapeutic options for patients with Horner’s syndrome are available to date. Ptosis is often found to be mild because of the only incomplete lid raising function of the superior tarsal muscle and the generally intact superior levator palpebrae muscle, so that a therapeutic intervention as, e.g. lid tightening is usually not required. Described disturbances in accommodation associated with miosis can be improved with the use of appropriate vision aids. Only insufficient data are currently available on the effects of physiotherapeutic methods on lid raising function and pupillary motor function.
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dorsolateral thalamus, and to the multisensory vestibular cortex in the temporoparietal cerebrum (Brandt and Dieterich 1994, 1995; Brandt et al. 2003). The pathways from the peripheral labyrinth via the vestibular nuclei to the eye muscle nuclei mediate the vestibuloocular reflex (VOR). This three-neuron reflex arc, enables compensatory eye movements during active head or body movements and thus maintains gaze stabilization (Fig. 3.14). The perception of position and movement is mediated by pathways from the dorsolateral thalamus to the multisensory vestibular cortex, while vestibuloocular, vestibulocollic and vestibulospinal reflexes regulate head position and body posture. Clinical classification of the vestibular brainstem syndromes is established according to the three major planes of action of the VOR: pitch, roll and yaw (Fig. 3.15). Unilateral function losses as the result of a lesion as well as unilateral excitation mediate a deflection of the central vestibular tone balance in one or more of these planes.
Perception
OS Vestibuloocular Reflex
III IV
Brainstem A
3.3 Central Vestibular Disturbances
RI
P H
VIII
UT
Marianne Dieterich and Sandra Bense
3.3.1 Central Vestibular Syndromes 3.3.1.1 Neuroanatomy and Classification The central vestibular neuronal pathways course from the vestibular nuclear regions in the medulla oblongata via the oculomotor nuclus in the pons and the midbrain (abducens, oculomotor and trochlear nerve nuclei) to the integration centers in the midbrain (interstitial nucleus of Cajal [INC] and the rostral interstitial nucleus of the medial longitudinal fascicle [riMLF]), as well as to the vestibulocerebellum, the
Vestibulospinal Reflex
Lateral vestibulospinal tract
Medial vestibulospinal tract
Fig. 3.14 Schematic representation of the vestibuloocular reflex (VOR), the three-neuron reflex arc from the hair cells in the peripheral labyrinth via the vestibular nuclei to the eye muscle nuclei in the brainstem. Also shown are afferent pathways of the vestibular system via the dorsolateral thalamus to the vestibular cortex (perception) and efferents for the mediation of vestibulospinal reflexes. A = anterior semicircular canal; H = horizontal semicircular canal; OS = superior oblique muscle; P = posterior semicircular canal; RI = inferior rectus muscle; UT = utricle; III = oculomotor nucleus; IV = trochlear nucleus; VIII = vestibular nuclear region
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3 Diagnostic Findings
VOR syndromes YAW
YAW III IV
VIII
VI VIII
PITCH
PITCH III IV
VIII
VI
up down
ROLL
ROLL III riMLF INC
IV
MLF VIII
VI VIII
Fig. 3.15 Schematic and MRI representation of typical lesion sites in the brainstem and the cerebellum with central vestibular disturbances in the three VOR planes
Etiology Central vestibular syndromes and vertigo are primarily due to brainstem and vestibulocerebellar lesions, while cortical vertigo (e.g. vestibular epilepsy) is rarely observed. Central vestibular disturbances are clearly defined clinical syndromes associated with typical disturbances in the three vestibular function areas, i.e. perception (vertigo), regulation of body posture (falling tendency, ataxia), and
oculomotor function (defective eye position, nystagmus), which enable a topographic brainstem diagnosis. But they may also be part of a complex infratentorial syndrome with additional supranuclear or nuclear oculomotor abnormalities and/or additional brainstem signs (e.g. in Wallenberg’s syndrome). Possible causes of central-vestibular syndromes are many. The abnormalities along the central-vestibular pathways can – in frequency of occurrence – be of vascular (ischemic
3.3 Central Vestibular Disturbances
infarctions, hemorrhages, cavernomas), inflammatory (e.g. MS plaque), traumatic (e.g. brainstem contusion), neoplastic/paraneoplastic (e.g. tumors), metabolic, congenital, or drug/toxicity origin. Episodes of (rotatory) vertigo attacks associated with vertebrobasilar ischemia increase with age, due to the fact that the vestibular nuclei in the brainstem represent terminal distribution territories of the circumferential arteries of the pontomedullary tegmentum. Central-vestibular vertigo and central-vestibular signs can also be a partial cause or principal sign of basilar or vestibular migraine. Pathologic excitations due to paroxysmal brainstem attacks or vestibular epilepsy are only rarely observed. There are typical causes for the different target structures of the individual central-vestibular syndromes.
Sagittal Plane (Pitch Plane) Abnormalities in the pitch plane are always the result of paramedian bilateral pontomedullary, pontomesencephalic, or bilateral flocculus/paraflocculus lesions in the cerebellum. In downbeat nystagmus the flocculus/paraflocculus appears to have a special role in the control system between the vestibular nucleus and the cerebellum (Bense et al. 2006; Hüfner et al. 2007; Kalla et al. 2006). The most frequent causes of downbeat nystagmus include bilateral injuries to the flocculus/paraflocculus in the context of structural lesions in the region of the floor of the fourth ventricle, or intoxications (e.g. with lithium or antiepileptics as, e.g. carbamazepine and phenytoin). Approximately 50% of the causes remain elusive (Halmagyi et al. 1983; Halamgyi and Leigh 2004; Wagner et al. 2008). Craniocervical junction anomalies are found in 20–30% (Chiari malformations), and cerebellar degenerations in 20% (hereditary, sporadic, or paraneoplastic) of patients, while MS plaques are less frequently observed. Increased intracranial pressure, and magnesium and vitamin B12 deficiencies have also been described as possible causes. Downbeat nystagmus can also occur in episodic ataxia Type II, a congenital canal disorder. In isolated patients, a paramedian lesion in the rostral medulla oblongata may also be the cause of downbeat nystagmus syndrome (Cox et al. 1981). Upbeat nystagmus is most often mediated by paramedian acute brainstem lesions, located along the ascending pathway from the anterior semicircular canals and/or the otolith organs via the superior vestibular nucleus to the contralateral oculomotor nucleus in the cerebellum. The site of the lesion is either in the paramedian medulla oblongata, adjacent to the caudal segment of the prepositus hypoglossal nucleus (MS plaque in Fig. 3.15) and the medial vestibular nucleus (Janssen et al. 1998); Baloh et al. 1989, Ranalli and Sharpe 1988; Stahl et al. 2000) or – less frequently in the paramedian pontomesencephalic tegmentum (here often in combination with internuclear ophthalmoplegia as an indicator of medial longitudinal fasciculus (MLF)
135
involvement). A lacunar lesion in the rostral paramedian pons at the level of the crossing of the ventral tegmental tract has been described recently as the site of the lesion in an isolated nystagmus (Pierrot-Deseilligny et al. 2005). The most common causes comprise MS plaques, brainstem ischemias or brainstem tumors, Wernicke’s encephalopathy, degenerative cerebellar disorders and intoxications (e.g. nicotine in tobacco). Medications do not play a role in the etiology of upbeat nystagmus. Frontal Plane (Roll Plane) Causal factors of unilateral lesions along the graviceptive pathway with an effect on the roll plane are chiefly acute brainstem and paramedian thalamic infarcts extending up into the rostral midbrain (INC, riMLF) (Dieterich and Brandt 1993c, d, 1992) (Fig. 3.15). Significantly less frequent are MS plaques, hemorrhages and tumors. Horizontal Plane (Yaw Plane) Central vestibular syndromes manifesting purely in the yaw plane are rare and, according to current knowledge, are mediated solely by circumscribed lesions in the region of the entry zone of the vestibular nerve in the medulla oblongata, the medial and/or superior vestibular nucleus, as well as in the adjacent integration centers for horizontal eye movements (prepositus hypoglossal nucleus = PHN; paramedian pontine reticular formation = PPRF). Possible causes of the majority of lesions in the vesti bular nuclear region or one of its fascicles are ischemic infarctions (approx. 50%) and MS plaques (approx. 25%) (Fig. 3.15), in addition to, although less frequently, hemorrhages or tumors. Clinical Findings A tonic imbalance in the pitch plane leads to clinical syndromes in the vertical plane with predominantly acquired fixation nystagmus (downbeat or upbeat nystagmus), postural instability, forward/backward falls, as well as vertical deviation of the subjective horizontal in an opposite direction to the nystagmus (Janssen et al. 1998; Leigh and Zee 2006). While downbeat nystagmus beats downward in primary position, increases its amplitude in the head-hanging position as well as on side and downward gaze, frequently has a rotatory component and is persistent. Upbeat nystagmus is rarer, generally transient, beats jerkily upward in primary position, and is associated with defective vertical smooth pursuit movement. Vestibular syndromes in the roll plane indicate an acute unilateral injury to the “graviceptive” vestibular pathways
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from the vertical semicircular canals and otoliths. They manifest with oculomotor (vertical divergence of the eyes [skew deviation], ocular torsion), perceptual (deviation of the subjective visual vertical), and postural signs (head tilt, tendency to fall to one side), occurring individually or simultaneously as an ocular tilt reaction. Torsional nystagmus may occur in the acute phase, whose fast component will be in the opposite direction of the tonic skew deviation and ocular torsion. The crossing of the ascending pathways at the pontine level is of crucial importance for topographic diagnosis. All signs of involvement of the roll plane in unilateral pontomedullary lesions (e.g. of the medial and superior vestibular nucleus) are represented by an ipsiversive, those with pontomesencephalic lesions by a contraversive, and in cerebellar lesions by an ipsiversive or contraversive tilt (Brandt and Dieterich 1994, 1995; Baier et al. 2008). Unilateral pontomesencephalic lesions are attributable to injury to the MLF or the INC (e.g. in paramedian thalamic infarctions). Unilateral vestibular lesions located rostral to the INC lead to isolated perceptual deficits without oculomotor deficits, in most cases with a contraversive tilt (e.g. damage to the parietoinsular vestibular cortex, thalamic astasia in lesions of the dorsolateral thalamus). Vestibular syndromes in the yaw plane manifest clinically with oculomotor abnormalities in the horizontal plane (e.g. horizontal spontaneous nystagmus, horizontal gaze deviation), horizontal past-pointing (subjective straight-ahead), ipsiversive falling tendency to the side, and ipsilateral caloric hypoexcitability). Additional signs of a mild central oculomotor deficit are often also present (like lateral gaze-evoked direction nystagmus in the opposite direction to the spontaneous nystagmus or upward, or saccadic dysmetria). Due to the anatomic proximity and partial overlapping in the vestibular nucleus with structures for the roll plane, there are often “mixed patterns” with disturbances in the yaw and roll plane. In an acute unilateral peripheral-vestibular injury disorder as, e.g. vestibular neuritis, similar symptoms to those of lesions in the vestibular nucleus zone are detected, although vestibular neuritis is characteristically also associated with a mixed pattern in the form of horizontal-rotatory nystagmus, while the typical additional central oculomotor deficits are absent. In many cases the lesions are not confined to the vestibular nucleus zone or its fascicles, so that further brainstem signs are found.
Diagnostics and Differential Diagnosis Of importance for the diagnostic evaluation and differential diagnosis of central-vestibular deficits in addition to the history are a complete diagnostic neurologic and a detailed neuroophthalmologic workup, including an investigation of postural regulation, oculomotor function
3 Diagnostic Findings
and perception. A comprehensive clinical-neurologic examination is of particular importance, to differentiate defined central-vestibular syndromes from complex infratentorial syndromes, peripheral abnormalities, or mixed patterns. The clinical examination with respect to oculomotor function should comprise the following aspects: • Head and body position • Stance and posture regulation • Eye position (e.g. vertical devergence of the eyes – skew deviation) • Ocular motility in all eight positions of gaze • Occurrence of spontaneous, provoked (by head-shaking, hyperventilation) or position nystagmus (Frenzel goggles) • Performance of dynamic oculomotor functions (e.g. fixation, gaze holding, saccades, smooth pursuit eye movements, optokinetic nystagmus) • Examination of the vestibuloocular reflex (VOR) with the Halmagyi-Curthoys test, and visual fixation suppression of VOR or vestibular nystagmus (Halmagyi and Curthoys 1988) The clinical examination is supplemented – provided these are available – by diagnostic investigations such as neuroorthoptic and psychophysical test procedures (fundus photography for the measurement of ocular torsion, examination of the subjective visual vertical as an otolith function test) for an extended topographic diagnosis. Perceptual deficits in the sense of pathologic deviations of the subjective visual vertical constitute one of the most sensitive signs in acute brainstem and cerebellar lesions that is found in approx. 90% of acute unilateral infarctions (Dieterich and Brandt 1993; Baier et al. 2008). Electronystagmography (ENG) and videooculography (VOG) enable noninvasive recording and quantification of eye movements (e.g. velocities of spontaneous nystagmus or saccades), which is expedient not only for the diagnosis, but also documentation during the course, e.g. recovery under medical therapy. The three-dimensional VOG further offers the possibility of recording torsional eye movements. ENG is used to evaluate peripheral-vestibular functions by thermic stimulation of the horizontal semicircular canals. Indispensable for clarification of the etiology of centralvestibular deficits (DD = differential diagnosis, ischemia, hemorrhage, tumor, inflammation) are cranial imaging techniques, preferably high resolution magnetic resonance imaging with fine-slices through the brainstem and possible contrast administration. Cranial computed tomography is of no significance for brainstem diagnostics. Depending upon the etiology, the use of further standard diagnostic imaging techniques (e.g. Doppler sonography/Doppler duplex sonography of cerebral arteries, cerebrospinal fluid analysis, evoked potentials) may be useful.
3.3 Central Vestibular Disturbances
3.3.2 Therapy and Prognosis 3.3.2.1 Pitch Plane Downbeat and upbeat nystagmus: Course and prognosis are dependent upon the underlying disease. Oscillopsia (illusionary motion of the visual scene) is very distressing due to the mostly larger amplitude of the nystagmus, although, in contrast to downbeat nystagmus, the symptoms generally do not persist. Drug therapy should be considered for the symptoms of persisting downbeat or upbeat nystagmus. Individually effective are gabapentin (2 × 200–600 mg/day), memantine (2 × 10–20 mg/day), the GABA-agonist baclofen (3 × 5–15 mg/day), and clonazepam (3 × 0.5 mg/day) (Averbuch-Heller et al. 1997; Starck et al. 1997; Straube et al. 2004). Recent placebo controlled studies showed a beneficial effect of the potassium channel blockers 3.4-diaminopyridine (3 × 20 mg/day), and 4-aminopyridine (2–3 × 5 mg/day) in a small number of patients with downbeat nystagmus (Strupp et al. 2003; Kalla et al. 2004); 4-aminopyridine was also found to be effective in an individual patient who had upbeat nystagmus (Glasauer et al. 2005). In selected patients with downbeat nystagmus caused by a craniocervical junction anomaly, surgical treatment with enlargement of the foramen magnum and decompression of the caudal cerebellum has led to improvement of the symptoms. In patients with an improvement of downbeat nystagmus in convergence, the nystagmus amplitude can be lowered and oscillopsy reduced with the use of prism glasses, which guide the eyes to an artificial convergence position. 3.3.2.2 Roll and Yaw Plane The course and therapy here also depend on the etiology of the underlying disease. Because the lesions are unilateral, central compensation mechanisms via the healthy contralateral side often lead to a complete recovery from the symptoms within days to a few weeks (Cnyrim et al. 2007). This recovery is aided by early physiotherapy with particular emphasis on balance training (Dieterich and Brandt 1992). The prognosis of unilateral lesions with symptoms in the roll or yaw plane can be viewed as favorable overall.
3.3.3 Special Nystagmus Syndromes As outlined above, a pure horizontal nystagmus is only rarely of central-vestibular genesis. However, pure vertical or pure torsional nystagmus is mostly of central origin. Vertical and torsional components, but most notably the classical downbeat and upbeat nystagmus syndromes, predominate in central types of nystagmus. There are, rare nystagmus syndromes
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that are currently assumed to be of central-vestibular origin. These will be described briefly below, as they are both clinically impressive and of topodiagnostic interest. Seesaw or pendular nystagmus consists of an alternating elevation and intorsion of one eye, with the simultaneous depression and extorsion of the fellow eye and vice versa. A half cycle therefore corresponds to an ocular tilt reaction (OTR) with vertical divergence of the eyeballs (skew deviation) and ocular torsion in the same direction. This spontaneous nystagmus is generally pendular, although it can also be jerky with a fast nystagmus phase followed by a slow return movement. The frequency is lower for the pendular (2–4 Hz) than the jerk type nystagmus. Causal lesions in pendular nystagmus are located in the region of the rostral midbrain or the caudal diencephalon at the level of the INC as the integration center for the roll plane (Leigh and Zee 2006), and consist primarily of parasellar space occupying lesions compressing the brainstem (Halmagyi and Hoyt 1991). A concomitant bitemporal hemianopsia is therefore frequently present. Rare causes include trauma, infarctions, multiple sclerosis, Chiari malformations, syringobulbia, as well as congenital forms. The dysfunction of crossed visual pathways appears to have a crucial role in the pathophysiology of the pendular seesaw nystagmus (Stahl et al. 2000). The jerky form may be associated with a unilateral mesodiencephalic lesion of the INC and its vestibular afferents arising from the vertical semicircular canals, sparing the riMLF (Halmagyi et al. 1994b; Endres et al. 1996). Case reports describing therapeutic measures in individual or few patients have reported the beneficial effect of alcohol (1.2 g/kg BW), baclofen, clonazepam, or gabapentin (Straube et al. 2004). Periodic alternating nystagmus is a rare, spontaneous, horizontal jerk nystagmus. In this type of nystagmus the direction of beat changes periodically, typically every 1–2 min. As the nystagmus amplitude decreases in crescendo fashion, it changes direction, usually interrupted by a nystagmus-free phase of approx. 10 s, before it increases again in crescendo fashion. The patients complain of oscillopsia of varying intensity, and in most cases disturbed visual fixation. The most common cause is a lesion of the vestibulocerebellum in the inferior vermis (nodulus and uvula), structures assumed to cause disinhibition of the GABAergic velocity storage, which is mediated via the vestibular nuclei (Waespe et al. 1985; Furmann et al. 1990). Craniocervical junction anomalies, multiple sclerosis, cerebellar degenerations or tumors, brainstem infarctions and antiepileptic intoxications are the most frequent causes of acquired nystagmus types. Periodic alternating nystagmus does not usually resolve spontaneously, unless the causal bilateral vision loss recedes. A number of case reports have obtained beneficial effects following the administration of the GABA(B)-agonist baclofen (3 × 5–10 mg/day). A double-blind study performed by
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Averbuch-Heller et al. (1997) showed a significant improvement under therapy with gabapentin (3 × 300–600 mg/day), but did not find baclofen therapy beneficial. Improvements in individual patients have further been described under therapy with memantine, phenothiazines, and barbiturates (Straube et al. 2004). Central position nystagmus is elicited when certain positions of the head are present (head-hanging position, lateral position). This nystagmus (often diagonal, horizontal or vertical) can change beat directions depending on the head position. Different from benign paroxysmal positional vertigo (BPPV), central position nystagmus typically manifests without or with only a short latency (<5 s), has a low frequency, often lasts longer than 60 s, or is inexhaustible, as long as the body position is maintained, and does not habituate, even on repeated position changes. Lesions of the caudal brainstem or vestibulocerebellum (chiefly MS plaques, ischemic infarctions, craniocervical junction anomalies, cerebellar degenerations or cerebellar tumors, intoxications) can elicit central position nystagmus. Currently, these often small lesions can not always be conclusively identified on brainstem imaging. Pathogenetically it is assumed that the afferent signals from the graviceptive otolith organs produce a tonus imbalance as a result of damage to the central vestibular pathways (Glasauer et al. 2001). The therapeutic regimen is dependent upon the underlying illness. In the majority of cases, the central position nystagmus resolves spontaneously within weeks. Acquired pendular nystagmus refers to a quasi sinusoidal oscillation of one or both eyes that may have a dominant (horizontal, vertical or torsional) or mixed beat direction (e.g. elliptic, diagonal or circular) (Leigh and Zee 2006). The different components of this oscillation often have the same frequency, ranging from 2 to 8 Hz, while the amplitudes may vary. Acquired pendular nystagmus is frequently associated with head shaking, trunk or limb ataxia, palatal tremor, or visual disturbance. Causal factors of acquired pendular nystagmus include extended or multiple central lesions, predominantly in the dentatorubroolivary pathway system, i.e. in the region of the red nucleus, the inferior olive, the central tegmental tract, and the vestibular nucleus (Lopez et al. 1996). It is therefore most frequently mediated by multiple sclerosis, brainstem ischemias/hemorrhages or Whipple’s disease. Possible pathophysiological factors discussed are an injury in the region of the oculomotor cranial nerve nuclei, an inhibition of the inferior olive, and an instability in the gaze-holding system (neuronal integrator), with the latter hypothesis being corroborated by an experimental mathematical model (Das et al. 2000). Older publications have reported therapeutic success using the anticholinergic trihexyphenidyl (20–40 mg/day), although this was supported by a beneficial result obtained in only one of six patients of a double-blind study (Leigh et al. 1991). In a double-blind study carried out by Averbuch-Heller (1997), the use of
3 Diagnostic Findings
gabapentin (3 × 300–400 mg/day) was shown to have a significant effect. A further study reported the alleviation of oscillations in all nine patients included in the investigation following the administration of memantine (15–60 mg/day), a NMDA receptor blocker with a dopaminergic effect (Starck et al. 1997, 2010), so that gabapentin and memantine may be regarded as the drugs of first choice. A beneficial effect of cannabinoids has been reported for individual patients with multiple sclerosis (Straube et al. 2004).
3.4 Tinnitus and Auditory Disturbances Marianne Dieterich and Sandra Bense
3.4.1 Definition and Epidemiology Tinnitus is a frequent, thus far only incompletely understood disturbance, in which a subjective sound is perceived by the patient, even though no external sound is present. It is often a reversible phenomenon lasting from several seconds to a few days, although it becomes chronic in 5–15% of the population (Heller 2003). The prevalence of tinnitus increases with advancing years (Adams et al. 1999). About 12% of adults older than 60 years, compared to only 5% of the 20- to 30-year-olds are affected. In most cases, chronic tinnitus is associated with an auditory disturbance, which may be induced by noise exposure or ageing processes. In approximately 1–3% of the population, the quality of life of tinnitus patients is reduced, e.g. due to sleep disturbance, incapacity to work, or (secondary) psychiatric disorders (Dobie 2003).
3.4.1.1 Etiology Although tinnitus with associated auditory disturbance is usually lateralized to one ear, the current pathophysiologic concept favours an alteration of the central auditory system due to cochlear receptor or auditory afferent dysfunction as the causal factor (Lockwood et al. 2002; Eggermont and Roberts 2004). The reduced input via the auditory nerve results in a reduced inhibition of central auditory structures – presumably of the dorsal cochlear nucleus and/or the inferior colliculus – (Levine 1999; Kaltenbach et al. 2005), with subsequent hyperexcitability in the central auditory system, which is perceived as tinnitus (Salvi et al. 1990, 2000). In animal experiments, reduced inhibition of these structures as the result of increased inferior colliculus and secondary auditory cortex neuron activity in tinnitus was indirectly shown after salicylate application (Jastreboff and Sasaki 1994; Eggermont and Kenmochi
3.4 Tinnitus and Auditory Disturbances
1998). However, there is only limited evidence supporting the assumption of an increased spontaneous activity of peripheral auditory nerve fibers (Müller et al. 2003). Functional imaging studies in different patient populations have corroborated the hypothesis of a central origin (Lockwood et al. 1998, 2001; Giraud et al. 1999; Melcher et al. 2000; Reyes et al. 2002). Reorganization of central auditory pathways as the expression of a high plasticity was shown in patients with different auditory disturbances (Lockwood et al. 1998, 2001; Mühlnickel et al. 1998; Andersson et al. 2000). The following possible causes of tinnitus have been described (Lockwood et al. 2002): • Otogenic processes (e.g. noise trauma, presbyacousis, otosclerosis, Menière’s disease) • Neurologic disorders (e.g. vestibular (acoustic) schwan nomas, cerebellopontine angle tumor, migraine, meni ngioma) • Infections (e.g. otitis media, meningitis, viral infection) • Toxins (e.g. arsenic poisoning, heavy metals) or medications (e.g. aminoglycosides, diuretics, chemotherapeutics, carbamazepine, salicylate) • Rare causes as, e.g. temporomandibular joint disorders, labyrinthine trauma, barotrauma
3.4.1.2 Diagnostic and Differential Diagnosis The diagnostic approach to tinnitus and auditory disturbances comprises a detailed history including characterization of the noise (episodic or permanent, unilateral or bilateral, onset, type, time course), determination of its impact on everyday life, identification of concomitant and secondary symptoms, previous noise exposure, intake of ototoxic medications, and the presence of relevant previous illnesses (particularly in the ENT region), followed by a clinical-neurologic and otologic-otoscopic examination. The focus of the clinical examination should be on the throat-neck region and include inspection of the oral cavity, the outer ear and eardrums, as well as cranial nerve (in particular the trigeminal, facial and vestibulocochlear nerves) and masticatory apparatus examination. In addition, auscultation of the heart, carotid arteries, and the periaural region should be performed. The clinician should attempt to differentiate between objective and subjective ear noises (Lockwood et al. 2002). In subjective tinnitus, false sound information is formed in the auditory system in the absence of an outside acoustic stimulus. Patients with objective tinnitus, in contrast, hear real noises, generated by a physical sound source within the body, in the neighborhood of the ear as, e.g. vibrations associated with blood flow turbulences. In these
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circumstances, a temporal relationship between tinnitus pulsations and cardiac rhythm is expected. Pulsatile ear noises are suggestive of a vascular genesis, e.g. carotid stenosis, arteriovenous malformation, fistulation, angioma, glomus tumor, heart valve alteration, or increased cardiac output (e.g. in anemia or hyperthyroidism), and require appropriate further, often interdisciplinary diagnostic evaluation. Clicking sounds or low frequency hissing may indicate palatomyoclonus, tensor tympani or stapedius muscle contractions. Spontaneous otoacoustic emissions of hair cells only rarely produce audible noises, and their diagnosis requires a special examination device. In most patients (>95%), auditory disturbances result from inner ear injury. Retrocochlear lesions are rare and difficult to differentiate based on clinical symptoms alone. A comprehensive examination using diagnostic audiology devices is essential to differentiate between cochlear and retrocochlear lesions, to quantify hearing loss, and detect treatable causes. The standard test battery should include tone audiometry with air and bone conduction, assessment of the discomfort threshold, loudness of tinnitus and masking level, tympanometry and stapedial reflex testing, electronystagmography with oculomotor and vestibular testing, vestibular evoked myogenic potentials (VEMP), and – where available – the derivation of otoacoustic emissions, as well as brainstem evoked response audiometry (BERA). The most common causes of the rare retrocochlear auditory disturbances constitute schwannomas of the vestibulocochlear nerve or other tumors of the cerebellar pontine angle. Tinnitus or auditory disturbances are rarely the only symptom of a brainstem lesion as, e.g. multiple sclerosis plaque (Schweri and Geusing 1996; Häusler and Levine 2000; Zaffaroni et al. 2001), ischemia, or hemorrhage in the vertebrobasilar distribution (Lee and Baloh 2005). Brainstem ischemia at the level or rostral to the trapezoid body usually lead to non-lateralized lesions of the acoustic striae, those of the cochlear nuclear region to ipsilateral auditory symptoms (Häusler and Levine 2000). Cortical deafness, hemianacousia and auditory agnosia in hemispheric infarctions have been described as central auditory syndromes. Their precise anatomic localization has thus far not been determined despite the availability of modern imaging modalities. Patients with retrocochlear auditory disturbances therefore still have to undergo further imaging examinations (e.g. petrousal bone CT, cranial MRI or angiography) (Weissmann and Hirsch 2000), while cochlear disturbances usually do not require any additional radiologic diagnostics. Depending on the respective history and findings of the basic diagnosis, additional tests can be suitable (e.g. ultrasound of the cervico-cranial arteries, diagnostic laboratory testing, testing of brainstem reflexes, psychosomatic evaluation). Despite the described
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detailed efforts, the underlying cause of tinnitus frequently remains elusive.
3 Diagnostic Findings
3.5 Intra-axial Cranial Nerve Lesions Frank Thömke and Peter P. Urban
3.4.1.3 Therapy Therapy of tinnitus and auditory disturbances is geared to the cause, time course, and degree of severity (see respective guidelines of the different associations for rhinootolaryngology and neurology). Identification of the endogenous sound source and its elimination is of major importance in patients with objective ear noises. In particular, therapy of a patient with chronic tinnitus represents a challenge, because a reduction in the sound intensity is only rarely achieved. The aims of counselling and the therapeutic regimes are therefore the patient’s acceptance of the ear sound and its integration into everyday life. Although many medications are known to elicit tinnitus, only a small number of studies with a special focus on the therapy of tinnitus have been conducted. Dobie (1999) carried out an overview of 69 randomized clinical studies and concluded that none of the available therapeutic regimens inclusive of carbamazepine, tricyclic antidepressants, psychotherapy, acupuncture, masking, biofeedback, hypnosis, or electric or magnetic stimulation have led to a sustainable improvement of subjective tinnitus beyond a placebo effect. Tinnitus counselling and medical care are in the foreground treatment. In individual patients, particularly in the decompensated stage of tinnitus, consideration of fitting of a hearing aid, habituation training, retraining therapy, sleep aids, prescription medication (e.g. for depression/anxiety), and multimodal therapeutic concepts with a psychological-psychotherapeutic approach are important. The prescription of pharmaceuticals is to be avoided in patients with decompensated tinnitus. Polypragmatic tinnitus therapies without scientific substantiation should be rejected.
3.4.1.4 Prognosis The findings of the basic diagnostic examinations serve to alleviate the fear of tinnitus patients to be affected by a severe or life-threatening illness. As long as aspects of the patient’s quality of life are placed at the center of the therapeutic efforts, many patients can be provided with satisfactory support in coping with their problems. The current therapeutic situation must, still be characterized as unsatisfactory. With increasing understanding of the pathophysiology of tinnitus, hopefully, controlled future therapeutic studies will uncover better treatments.
Lesions involving the cranial nerve segments coursing in the brainstem are typically also associated with signs of injury to the long tracts, as the cranial nerve segments running transversely through the brainstem and the adjacent long tracts ascending and descending through the brainstem in a longitudinal direction are mostly conjointly affected. In addition to an ipsilesional cranial nerve dysfunction which provides information on the rostro-caudal location of the lesion, this results in a contralesional motor and/or sensory hemisyndrome as well as, although more rarely, in a contralesional hemiataxia. These crossed symptom constellations are characteristic of the classic brainstem syndromes, most of which were first described already in the nineteenth century (e.g. Millard-Gubler syndrome [1856]; Weber syndrome [1865]; Nothnagel syndrome [1879]; Benedikt syndrome [1889]; Raymond syndrome [1895]; Claude syndrome [1912]) (literature overviews and further reading, see (Liu et al. 1992; Krasnianski et al. 2003a, 2004). However, except for Wallenbergs syndrome, in clinical practice the classic brainstem syndromes are quite rare (Marx and Thömke 2009). In 1901, Achard and Lévi described a patient with a clinically predominant total left oculomotor paresis (and mild dysarthria) and pathologically confirmed mesodiencephalic infarction. The authors were the first to suggest that cranial nerve dysfunction may, on principle be the only symptom of a circumscribed brainstem lesion. Despite this description, cranial nerve dysfunctions, in particular disturbances of oculomotor cranial nerves, were attributed until only a few years ago primarily to an injury to the nerve segments traveling outside of the brainstem (Burde et al. 1992; Richards et al. 1992). Especially isolated oculomotor pareses in patients with vascular risk factors were ascribed to microvascular infarctions of the nerve after its exit from the brainstem (Dreyfus et al. 1957; Asbury et al. 1970; Weber et al. 1970). During the past 15 years, the number of reported patients with unilateral cranial nerve dysfunctions and brainstem lesions as the only correlate has been increasing. Predominantly involved were the oculomotor and abducens nerves, and less frequently the trochlear, trigeminal, facial, as well as the vestibulocochlear nerves (Table 3.4) (overviews and further reading, see Thömke 2002; Thömke et al. 2002). An –although bilateral – hypoglossal nerve dysfunction as the only symptom of a medulla oblongata infarction has been described in only one patient thus far (Benito-Léon and Alvarez-Cermeño 2003). The demonstration of these lesions that involved the course of the respective intra-axial cranial nerve segment was accomplished with magnetic resonance imaging (MRI) and in some instances also using computed tomography (CT).
3.5 Intra-axial Cranial Nerve Lesions
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Table 3.4 Reported patients with isolated cranial nerve lesions due to brainstem lesions of different origin Affected cranial Type of brainstem Number of nerve lesion patients Oculomotor nerve
Midbrain infarction
30
Midbrain hemorrhage
9
Midbrain tumor
6
Midbrain demyelinating focus in multiple sclerosis
3
Other causes (vascular malformations, cysts, tuberculoma, gumma
6
54 Trochlear nerve
Midbrain hemorrhage
6
Midbrain infarction
4
Pontine hemorrhage
5
Pontine infarction
3
Inflammatory pontine lesions
2
10 Trigeminal nerve
10 Abducens nerve
Pontine infarction
15
Pontine demyelinating focus in multiple sclerosis
7
Pontine hemorrhage
2
Pontine tumor
2
Other causes (borreliosis, chronic inflammatory demyelinating polyneuropathy = CIDP)
2
Pontine demyelinating focus in multiple sclerosis
6
Pontine infarction
3
Pontine bleeding
1
28 Facial nerve
10 Vestibulocochlear nerve Vestibular segment
Cochlear segment
Pontine demyelinating focus in multiple sclerosis
6
Pontine infarction
2
Pontine tumor
1
Pontine demyelinating focus in multiple sclerosis
2
11
3.5.1 Epidemiology and Etiopathogenesis Cranial nerve dysfunctions as the sole symptom of brainstem lesions are chiefly mediated by circumscribed infarctions, hemorrhages, and demyelinating lesions in multiple sclerosis (MS), less often by tumors, vascular malformations, and inflammations other than MS (Table 3.4). They may occur more often than generally assumed, although currently only a rough estimate of the incidence rate can be made of oculomotor and abducens pareses based on reports by a small number of studies with divergent results. The basis of the occurrence of cranial nerve dysfunctions as an isolated finding in patients with brainstem infarcts is the complex vascular architecture of the brainstem. In addition to blood supply from the long penetrating branches arising directly from basilar artery, the midbrain is supplied by paramedian lateral, as well as dorsolateral branches of the superior cerebellar artery and the posterior cerebral artery; the pons is supplied via lateral as well as dorsolateral branches from the circumferential pontine arteries and the anterior inferior cerebellar artery (Hassler 1967; Duvernoy 1978). Located between the areas supplied by the described arterial vessels are a number of so-called border zone areas through which the intramesencephalic or intrapontine cranial nerve segments pass. In the presence of decreased or absent perfusion in the areas supplied by one of these small vessels a critical, functionally relevant underperfusion may be expected to occur in the border zone areas only, due to preserved blood supply from the other vessels. The degree of underperfusion is determined by interindividually greatly varying contributions from the affected and intact vessels to the arterial supply to this region. This finding serves to explain why only the intraaxial cranial nerve segments are affected, while the surrounding structures are spared. In a study of 282 patients with ischemia of the vertebrobasilar circulation territory undergoing routine MRI, Bogousslavsky et al. (1994), identified only 2 patients with an isolated oculomotor paresis mediated by a midbrain infarct. This corresponds to approx. 0.7% of all posterior circulation infarctions. Conversely, Kumral et al. (2002b) did not find an isolated oculomotor paresis in 41 of their patients with an MRI documented midbrain infarction. Our own findings based on the results of MRI investigations are in accordance with those reported by Bogousslavsky et al. Abnormal electrophysiologic findings nevertheless suggest a substantially higher rate than the one reported by Bogousslavsky et al. (1994), Thömke 2002; Thömke et al. 2002); on a cautionary note it needs to be pointed out that neither diffusion-weighted nor high-resolution MRI were used in our investigations. Conflicting results were also reported for patients with diabetic oculomotor paresis. Keane and Ahmadi (1998) found a circumscribed midbrain infarction in only one of 50
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consecutive patients undergoing MR imaging, while other authors reported causal ipsilateral midbrain infarctions in 5 of 29 patients using MR imaging (Thömke et al. 1995). Six out of 150 patients with a pontine infarction confirmed on imaging had an abducens paresis only (Kumral et al. 2002a). In view of the finding that at least one third of all vertebrobasilar infarctions involve the pons (Marx et al. 2004), the expected rate of isolated abducens pareses based on the total number of posterior circulation infarctions would range at 1.3%. This rate is consistent with our own experience of MRI-documented lesions, although we emphasize that a large number of our MRI examinations were done without highresolution slice imaging, so that the actual rate may be higher. This assumption is further supported by the presence of abnormal electrophysiologic findings (Thömke 1999, 2002). Abnormal electrophysiologic findings strongly suggest that small midbrain or pontine infarcts may represent the most significant cause of oculomotor and abducens pareses in middle and advanced age patients with vascular risk factors like diabetes mellitus and/or arterial hypertension. The electrophysiological examination showed a causal midbrain or pontine lesion in 40 out of 50 consecutive patients with an oculomotor, and in 20 of 30 patients with an abducens nerve paresis, (Thömke 2002). Microvascular infarctions of peripheral nerve segments outside the brainstem may therefore be a less important causal factor of oculomotor and abducens pareses than previously assumed. Isolated cranial nerve dysfunctions in patients with multiple sclerosis are attributable to demyelinating lesions in the brainstem associated with the primary disease, a finding which was repeatedly confirmed both on MRI and electrophysiologic examination (Thömke et al. 1999, 2002). Unilateral cranial nerve dysfunction represented the only symptom of an episode in 24 (16%) out of a series of 1,489 multiple sclerosis patients; most frequently affected – in 14 out of 24 of these patients – was the abducens nerve (Thömke 1997). Less often involved were the vestibular segment of the vestibulocochlear nerve (six patients), the facial nerve (three patients) and – in one patient each – the oculomotor nerve, the trochlear nerve, and the cochlear segment of the vestibulocochlear nerve. In 14 of these 24 patients this was the first episode, in 6 the second, and in the remaining 4 patients the third episode of multiple sclerosis (Thömke et al. 1997). The probability of an isolated cranial nerve dysfunction in multiple sclerosis therefore appears to decrease progressively at an increasing number of individually experienced episodes, with an isolated cranial nerve paresis occurring concurrently with the first episode in 5% of patients in our study group.
3 Diagnostic Findings
from cranial nerve disturbances mediated by damage to nerve segments traveling outside the brainstem. Furthermore, injuries to the respective cranial nerve nuclei – with the exception of oculomotor and abducens nuclei lesions – result in the same clinically observed deficits as a lesion of the nerve itself.
3.5.3 Oculomotor Nerve Lesions Clinical symptoms of a lesion of the intramesencephalic segment of the oculomotor nerve range from complete pareses, affecting all muscles innervated by the oculomotor nerve, to pareses that mimic an injury to the superior or inferior ramus, and to isolated pareses of individual extraocular muscles or the pupillary sphincter muscle. The most common causes are midbrain infarcts (Fig. 3.16) and hemorrhages, rare tumors, demyelination foci and vascular malformations.
3.5.4 Trochlear Nerve Lesions Superior oblique paresis as an isolated symptom of a mesencephalic lesion in the course of the trochlear nerve has thus far been observed primarily in hemorrhages, less frequently in infarctions (Table 3.4) (further reading, see Thömke 2002).
3.5.5 Trigeminal Nerve Lesions Reports of pontine lesions with the clinical finding of a sensory, in some cases painful trigeminal neuropathy as the only symptom describe hemorrhages, infarctions and demyelinating foci in multiple sclerosis (Fig. 3.17; Table 3.4) (further reading, see Thömke et al. 2002). The described deficits may also involve the distribution area of individual branches of the trigeminal nerve only (Kamitani et al. 2004).
3.5.2 Clinical Findings Cranial nerve dysfunction as an isolated symptom of circumscribed brainstem lesions can, clinically, not be differentiated
Fig. 3.16 Midbrain infarction presenting with acute oculomotor nerve palsy at the right side as sole deficit. (a) MRI-DWI; (b) MRI-FLAIR
3.5 Intra-axial Cranial Nerve Lesions
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sclerosis, less frequently in hemorrhages or tumors (Table 3.4). In individual patients T2 weighted MRI revealed signal intensive lesions in the course of the intrapontine abducens nerve in chronic inflammatory demyelinating polyneuropathy (CIDP) and borreliosis that were interpreted as an acute central demyelinating or inflammatory lesion (further reading, see Thömke 2002). Fig. 3.17 Subacute numbness with hypesthesia/-algesia in the territory of the trigeminal nerve affecting V2 and V3 at the left side. Clinically isolated syndrome (CIS) as initial manifestation of multiple sclerosis which was established in the further course. MRI: Hyperintensity at the nerve entry zone of the left trigeminal nerve
3.5.6 Abducens Nerve Lesions Isolated lateral rectus pareses due to lesions involving the intrapontine abducens nerve have been observed mostly in cases of infarctions and demyelinating foci in multiple
a
3.5.7 Facial Nerve Lesions Clinically, lesions in the intrapontine segment of the facial nerve can lead solely to pareses of muscles innervated by the facial nerve (Novy et al. 2008). Here – as in the presence of damage to the nerve outside the brainstem – all muscles are similarly affected. The described pareses have thus far been observed in infarctions, demyelinating foci in multiple sclerosis (Fig. 3.18), and in one patient with a hemorrhage (Table 3.4) (further reading, see Thömke 2002).
b
50 [ms] 100 0 50 [ms] 100 0 Stimulation left, recording left Stimulation left, recording right
Fig. 3.18 Subacute peripheral facial paresis at the left side in multiple sclerosis. (a) MRI: Hyperintensity at the dorsolateral tegmentum of the left pons. (b) Absent blink reflex responses at the paretic side
0 50 [ms] 100 0 50 [ms] 100 Stimulation right, recording left Stimulation right, recording right
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Fig. 3.19 Subacute myokymias involving the left side of the face mainly affecting the periocular region and the cheek as initial manifestation of multiple sclerosis (CIS). MRI: Hyperintensity of the left middle
Facial myokymias constitute a special form of a paramedian facial nerve lesion (Fig. 3.19). They are characterized by wormlike or undulating movements that cannot be influenced by voluntary activity and cease during sleep. Distinctive features demonstrated on electromyography are repetitive and grouped, spontaneous discharges in the form of individual potentials, doublets, triplets or multiplets firing at a frequency of 2–60 Hz over a period of up to several seconds. Myokymias may be accompanied by a mild to moderate facial paresis. Although facial myokymias can, on principle, be mediated by lesions in the course of the entire facial nerve, they are typically due to lesions in the dorsolateral tegmental brainstem in the region of the facial nucleus; myokymia found in young adults is suggestive of multiple sclerosis (Jacobs et al. 1994; Yoritaka 2001).
3.5.8 Vestibulocochlear Nerve Lesions Intrapontine injuries to the vestibulocochlear nerve affect primarily the vestibular segment. There are currently no reports of an injury affecting both the vestibular and cochlear segments as the only symptom of a pontine lesion. The clinical examination shows injuries to the intrapontine vestibular nerve such as an acute peripheral vestibulopathy (“vestibular neuritis”), also called “vestibular pseudoneuritis”. The patients have a horizontal-rotary spontaneous nystagmus with a beat direction towards the healthy side, a falling tendency to the ipsilesional side, ipsilesional past-pointing on Bárány’s test, as well as nausea with and without emesis. The principal causes include demyelinating foci in multiple sclerosis (Fig. 3.20), while hemorrhages, infarcts and pontine tumors are less frequently observed (Table 3.4) (Thömke et al. 2002). In addition to the occurrence of these lesions in the intrapontine segment of the vestibular nerve, they were also found to involve the vestibular nuclear region (Francis et al. 1992; Thömke and Hopf 1999). Lesions of the cochlear segment have thus far been reported only for pontine demyelinations in multiple sclerosis and are associated with ipsilesionally impaired auditory function (Thömke et al. 2002).
3 Diagnostic Findings
cerebellar peduncle, (a) sagittal plane; (b) axial plane; (c) EMG with concentric needle electrode from the left orbicularis oculi muscle showing spontaneous repetitive bursts as doublets and multiplets
Fig. 3.20 Pseudovestibular syndrome presenting with subacute rotatory vertigo, nausea, vomiting, lateropulsion to the left side, and rotatory spontaneous nystagmus to the right side. MRI: Hyperintensity at the left pontomedullary junction at the base of the middle cerebellar peduncle
3.5.9 Glossopharyngeal and Vagus Nerve Lesions Lesions of the dorsolateral medulla oblongata often involve both cranial nerves concurrently, with resulting diminished pharyngeal wall sensitivity (N. IX), positive uvular deviation as the expression of unilateral paresis of the pharyngeal musculature (N. X), and recurrent pharyngeal nerve paralysis with hypophonia (N. X). These paralyses have to date not been described as an isolated brainstem lesion symptom, and were observed only in conjunction with other signs of a medulla oblongata lesion. The most common causes are brainstem infarcts, in which the complete picture of the so-called Wallenberg’s syndrome always also involves N. IX and N. X (Fig. 3.21). Additional rare causes include multiple sclerosis, tumors, and anomalies of the craniocervical junction.
3.5.10 Accessory Nerve Lesions In the brainstem region, lesions to the intramedullary fibers of the accessory nerve may occur in the context of syringobulbia, brainstem tumors, brainstem encephalitis, and vascular lesions, and be a causal factor of ipsilateral sternocleidomastoid muscle paresis, or paresis of the upper segment of the trapezius muscle.
3.5 Intra-axial Cranial Nerve Lesions
a
b
145
the blink and the masseter reflex, acoustic evoked potentials, as well as saccades and smooth pursuit eye movements did not show a corresponding lesion on MRI (Thömke 1999, Thömke 2002).
3.5.14 Electrophysiologic Techniques Fig. 3.21 Right dorsolateral medullary infarction with acute hoarseness and dysphagia presenting with further signs of Wallenberg’s syndrome. (a) MRI-DWI; (b) MRI-FLAIR
Brainstem lesions can be shown with the assessment of brainstem reflexes and/or electrooculographic recordings of eye movements provided the following two basic requirements are fulfilled:
These pareses have thus far not been described as an isolated symptom of a medulla oblongata lesion, but been observed only in conjunction with other signs of a medullary lesion.
• A close anatomic relationship is required between the central brainstem reflex arcs or brainstem networks involved in the generation of specific forms of eye movements and the respective cranial nerve segments coursing in the brainstem (Hopf 1994; Thömke 1999). –– The central masseter reflex arc has a close anatomic relationship with the oculomotor and trochlear nerves, as well as with the inner knee of the facial nerve in the lower pons and the proximal vestibular segment of the vestibulocochlear nerve. –– The central reflex arc of the blink reflex R1 component travels in the lower pons in the immediate neighborhood of the abducens, facial and vestibulocochlear nerves. –– The “saccadic network” in the brainstem comprises a descending excitatory pathway to the paramedian pontine reticular formation (PPRF), the PPRF itself and the medial longitudinal fasciculus. There are thus topographic relationships at different brainstem levels to the oculomotor, trochlear, abducens, facial and vestibulocochlear nerves. –– The network for generation of smooth pursuit movements, which includes among other brainstem structures the dorsolateral pontine nuclei, the vestibular nuclei, the prepositus hypoglossal nucleus, oculomotor cranial nerve nuclei and the connective pathways between these structures has relationships to all intramesencephalic and intrapontine cranial nerve segments. • Abnormal electrophysiologic findings serve as evidence of an acute brainstem lesion only when improvement or regression can be demonstrated in the further course. In the presence of concurrent improvement or regression of the respective cranial nerve disturbance, a causal relationship between the electrophysiologic and the clinical abnormalities may be assumed.
3.5.11 Hypoglossal Nerve Lesions There have been no reports of patients with an isolated unilateral lesion to the hypoglossal nerve mediated by an injury to the medulla oblongata to date. There has, however, been one report of a patient with total tongue paralysis and bilateral infarctions in the hypoglossal nuclear region (BenitoLéon and Alvarez-Cermeño 2003).
3.5.12 Diagnosis In patients with intra-axial cranial nerve lesions, the diagnosis of causal brainstem lesions is chiefly established using magnetic resonance imaging and electrophysiologic techniques.
3.5.13 Imaging Techniques The MRI-demonstration of a lesion in the intraaxial course of the respective involved cranial nerve is convincing proof of a brainstem lesion as the cause of an isolated cranial nerve dysfunction. Investigations using thinner slices (2–3 mm) and the introduction of new techniques (e.g. diffusionweighted MRI, FLAIR) have made a definite contribution to the improved detection rate of these lesions. Despite these advances, not all functionally relevant brainstem lesions can be imaged on MRI, although their presence cannot be excluded (Marx et al. 2002, 2004a). These lesions may be too small to be viewed on MRI, or they may only impair the function of certain brainstem structures without necessarily damaging their structural integrity, so that no morphologic changes are demonstrable using MRI. This has been confirmed by a number of studies, in which patients with electrophysiologically identified central-pathologic changes in
3.5.15 Differential Diagnosis The clinical symptoms of a cranial nerve injury are independent of the lesion localization, and thus do not permit clinical
146
differentiation of a paranuclear cranial nerve lesion from an injury to the nerve after its exit from or entry into the brainstem. The location of a cranial nerve lesion is therefore without significance for the differential diagnosis, i.e. possible disturbances in isolated cranial nerve dysfunctions due to brainstem lesions correspond to those of cranial nerve dysfunctions found in nerve injuries outside the brainstem. Also virtually impossible is the clinical differentiation – excepting the oculomotor and abducens nerves – of a nuclear from an infranuclear lesion. Clinical findings in oculomotor or abducens nuclear lesions other than oculomotor or abducens pareses have been discussed elsewhere in this book (see Sects. 3.1.2.2 and 3.1.3.2). Pseudovestibular cerebellar infarctions represent a possible differential diagnosis of a vestibular lesion. These are unilateral cerebellar infarctions with the chief clinical symptoms of vertigo with nystagmus and a falling tendency, while other signs associated with cerebellar lesions, such as kinetic ataxia or dysarthrophonia, are absent (Brandt 1999a). Some of these patients can already be clinically differentiated from patients with a peripheral-vestibular lesion, since their nystagmus and falling tendency are directed towards the side with the cerebellar infarction, i.e. both an ipsilesional nystagmus and ipsilesional falling tendency are present. Although a patient with a peripheral-vestibular lesion also falls to the side of the injury, the nystagmus nevertheless beats to the healthy side, i.e. a contralesional nystagmus as well as an ipsilesional falling tendency are present. Patients with cerebellar infarctions frequently have additional abnormal findings which do not occur in isolation in patients with peripheral-vestibular lesions, e.g. saccadic gaze shifts, saccadic dysmetria, kinetic ataxia, dysarthria. Infarctions in the supply area of the posterior inferior and anterior inferior cerebellar arteries can, in addition to the cerebellum, concurrently involve the intrapontine and intramedullary segments of the vestibular nerve and/or vestibular nuclear region and be the causal factor of a combined peripheral-vestibular cerebellar symptomatic complex. In addition to an ipsilesional falling tendency (peripheral-vestibular and cerebellum) and a contralesional horizontal-rotatory nystagmus (peripheral-vestibular), the patient has an ipsilesional horizontal gaze direction nystagmus (cerebellum) and other cerebellar symptoms as, e.g. kinetic ataxia, dysarthria, saccadic gaze shifts, and dysmetric saccades. There have also been reports of individual patients with an isolated infarction in the nodulus region who had a contralesional falling tendency and an ipsilesional horizontalrotatory nystagmus (Lee et al. 2003; Lee and Cho 2004). Clinically predominant in this setting were the principal signs of a unilateral peripheral injury (on the contralateral side to the nodulus infarction). In these patients, differentiation from an acute peripheral-vestibular lesion suggested by the clinical findings was achieved alone based on the
3 Diagnostic Findings
bilaterally equal normal excitability of the semicircular canals demonstrated using caloric testing. The proposed explanation of this finding was the loss of inhibitory projections from the nodulus to the ipsilesional vestibular nucleus. This would lead to an imbalance of the tonic resting activity in favor of the ipsilesional “non-inhibited” side, or to a disadvantage of the contralesional side, which was suggested as an explanation of the clinical signs of a unilateral peripheralvestibular injury contralesional to the nodulus infarction (Lee et al. 2003; Lee and Cho 2004). The incidence of the described disturbances can currently be estimated only based on the results of the study by Lee et al. (2003), who observed two patients with the disorder among a group of 374 patients with posterior circulation infarcts, which would correspond to a rate of 0.5% and therefore range below the incidence rate for abducens or oculomotor pareses due to circumscribed pons or midbrain infarctions.
3.5.16 Therapy With the exception of isolated cranial nerve dysfunction in multiple sclerosis, each episode of which is generally treated with an intravenous steroid pulse (e.g. prednisolone 1,000 mg i.v./day on 5 successive days), there is no specific treatment regimen. In patients (chiefly of middle and advanced age) with vascular risk factors and/or confirmed small acute or older brainstem infarctions, the inhibition of platelet aggregation with acetylsalicylic acid 100 mg/day is indicated to reduce the risk of additional brain ischemia. In patients with brainstem stroke and an embolic lesion pattern due to atrial fibrillation warfarin is recommended.
3.5.17 Prognosis In the majority of cases, cranial nerve dysfunctions resulting from circumscribed brainstem infarctions resolve almost completely within a period from 1 week to several (maximum 6) months. To our knowledge there are no descriptions of pathologic synkineses, otherwise characteristic signs of peripheral nerve lesions, and currently there is only an isolated report thereof in midbrain infarctions (Messé et al. 2001). Cranial nerve dysfunctions mediated by demyelinating foci in the intraaxial course of the nerve generally also resolve completely within a few weeks (to months).
3.5.18 Summary The large number of reports describing patients with brainstem dysfunctions as an isolated symptom of circumscribed,
3.6 Speech Disorders
chiefly ischemic brainstem lesions appears to justify the allocation of vascular brainstem syndromes to the following three groups: • Classical crossed brainstem syndromes with concurrent involvement of cranial nerve segments traveling transversely through the brainstem and the adjacent ascending and descending long tracts coursing in a longitudinal direction (Liu et al. 1992; Krasnianski et al. 2003a, 2004). • Lacunar brainstem syndromes owing to circumscribed ischemic injury to the ascending and descending long tracts running in the longitudinal direction of the brainstem, while cranial nerve segments coursing transversely through the brainstem are spared (e.g. pure motor hemiparesis with and without involvement of the face, purely sensory hemisymptoms, ataxic hemiparesis, dysarthriaclumsy hand symptom (Mohr 1982). • Isolated cranial nerve dysfunctions due to a lesion involving the cranial nerve segments proceeding transversely through the brainstem, while the ascending and descending cranial nerve segments traveling in a longitudinal direction through the brainstem are spared (Thömke 2002; Thömke et al. 2002).
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is blurred, as mutism is also characterized by inability to voluntarily produce speech. A narrower definition of mutism further calls for the suspended ability of emotional speech sound production (Ziegler and Ackermann 1994). In a strict sense, dysarthria means only impairment of articulation. In view of the fact that in central lesions the voice is almost always also affected, the term dysarthrophonia, however, is also used.
3.6.2 Neuroanatomy of Speech Speech is produced by activation of the motor functions of articulation, phonation and breathing. The most important articulatory muscles are the tongue and the orofacial musculature. Airflow and voice production are regulated by the laryngeal musculature. The most constant subglottal pressure possible is required for speech production, and is created during expiration by contraction of the intercostal and abdominal musculature. The speech musculature receives input via the primary motor cortex (Urban et al. 1997b). The task of coordination falls to the paravermal cerebellar regions (Urban et al. 2003).
3.6.3 Etiopathogenesis 3.6 Speech Disorders Peter P. Urban
3.6.1 Definition and Epidemiology Speech disorders are a common finding in patients with brainstem lesions. An analysis of the German Stroke Foundation databank showed that 56.2% of 340 patients with isolated brainstem infarction had dysarthria (Weimar et al. 2002). An extreme form of dysarthria is the complete inability to perform volitional articulation and phonation, so-called anarthria, in which only emotional sounds (sighing, crying, or laughing) can be produced. The differentiation from mutism
Fig. 3.22 Lesion topography of 18 patients with acute dysarthria due to brainstem infarction. The lesions are located along the pyramidal tract
In the presence of injuries to the ventral brainstem, dysarthria can be mediated by a single unilateral lesion to the pathways descending from the sensorimotor cortex, i.e. to the corticobulbar segments of the pyramidal tract (Urban et al. 1996a, 1997a, 1999a, 2001a). Thereby affected are primarily the corticolingual projections of the pyramidal tract (Fig. 3.22).
3.6.4 Clinical Picture and Functional Diagnostics Dysarthria is characterized by impaired articulation with unclear and slurred speech, chiefly regarding consonants, impaired laryngeal function with altered voice quality,
148
3 Diagnostic Findings
impaired speech performance, modified sound production, as well as prosodic and breathing deficits with deviations of breathing rhythm and frequency. The finding of an isolated dysarthria as the result of a brainstem lesion is extremely rare. Most patients with dysarthria caused by a brainstem infarction have additional symptoms or clinical findings (Table 3.5; Urban et al. 2001a). An analysis of the associated clinical findings indicates that primarily the ventral brainstem segments containing the pyramidal tract are involved. When dysarthria is caused by brainstem infarction, in 91% and 63% of patients a lesion of the corticolingual and corticofacial projections to the tongue and orofacial musculature identifies these areas as the most important articulation organs. This finding is confirmed by an examination of motor evoked potentials (MEPs). The technique for recording MEPs from the tongue and orofacial musculature has been described in Sect. 2.3.7. Table 3.5 Clinical findings associated with a dysarthrophonia mediated by a brainstem infarction Clinical finding Incidence in % Pyramidal pathway sign
96
Central paresis of upper extremities
91
Central paresis of lower extremities
83
Central facial paresis
83
Central lingual paresis
39
Gait ataxia
39
Posture ataxia
38
Hemihypesthsia/hemialgesia
22
Limb-kinetic ataxia
22
Horner’s syndrome
4
Nystagmus
4
Central palatal paresis
4
Dysphagia
4
a
3.6.5 Paroxysmal Dysarthria Paroxysmal dysarthrophonia and ataxia are characterized by attacks that frequently occur several times a day, each lasting for a few seconds. This symptom is characteristic of multiple sclerosis, in which the patients may have a demyelinating lesion in the cerebellar peduncle, or at a paravermal site in the cerebellum (Kammer et al. 1993). Paroxysmal dysarthria has also been described with a brainstem infarction of the mesencephalic tegmentum, suggestive of a lesion to the cerebellar efferents (Matsui et al. 2004) (Fig. 3.23).
3.6.6 Anarthria Bilateral lesions lead to more pronounced and poorly improving dysarthrias, or, as in locked-in syndrome, to anarthria. An initial anarthria was found in 29%, and dysarthria in 86% of all patients with a bilateral anteromedial pontine infarction (Kumral et al. 2002c).
3.6.7 Mutism A number of studies, primarily in animals, showed that lesions in the region of the periaqueductal gray of the midbrain can mediate mutism. More extended lesions of the periaqueductal gray are frequently the cause of varying degrees of disturbance of consciousness that do not permit speech assessment. Isolated, smaller lesions in this region in patients with intact consciousness are very rare. The role of the periaqueductal gray in human vocalization and phonation is therefore still only incompletely understood (Schulz et al. 2005). There
b
Tongue, right
Tongue, left Cortex L
Cortex L 1 mV
Cortex R
Prox. n. XII R
Cortex R
Prox. n. XII L 1 mV
Distal n. XII R
Distal n. XII L 3 mV 5 ms
Fig. 3.23 (a) MRI-T2 showing a paramedian ventral pontine infarction left. The clinical picture was an acute dysarthria-clumsy hand syndrome. (b) The motor evoked potentials of the tongue musculature
showed a loss of CMAPs to both halves of the tongue on stimulation over the affected left hemisphere
3.7 Dysphagia
have, nevertheless, been reports of individual patients, in whom a small lesion in the region of the mesodiencephalic junction was associated with the clinical picture of akinetic mutism, and whose inability of speech production – in the presence of intact speech comprehension – is accompanied by the complete absence of any spontaneous or reactive motor activity (Esposito et al. 1999; Alexander 2001). In patients with pontomesencephalic lesions, an initial mutism was found to be followed by dysarthria (Orefice et al. 1999). Furthermore, in lesions of the mesencephalic tegmentum involving the periaqueductal gray, an injury to the cerebellar efferents may also have a role in the occurrence of dysarthria. Transient mutism (from several days to 4 months) was observed in up to 13% of children after surgical interventions in the cerebellar region (Ozimek et al. 2004). Although the cerebellum has an important role in speech movement coordination, and unilateral paravermal lesions of the superior cerebellum alone are capable of mediating dysarthria, an intraoperative lesion to the mesencephalic tegmentum has also been discussed as a possible causal factor in addition to a purely cerebellar cause.
3.6.8 Therapy and Prognosis Therapy consists of logopedic exercises aimed at the restitution and compensation of the function deficits.The prognosis of solitary ischemic lesions is favorable. At the time of the logopedic follow-up examination 10 months after the onset of infarction, dysarthria had resolved completely in more than half of the patients, while a significant improvement over the findings of the initial examination was noted in the remaining patients; intelligibility was unimpaired in all patients (Urban et al. 1999a). An impressive improvement was observed following the administration of dopamimetics in one patient with chronic akinetic mutism after a mesodiencephalic infarct (Alexander 2001).
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3.7.2 Neuroanatomy of the Physiologic Act of Swallowing Based on the results of stimulation and lesion studies in animal models, as well as on the evaluation of focal lesions in patients, and of current functional imaging findings in healthy subjects, the cortical representation of swallowing has been shown to involve the following areas: the caudal segment of the precentral and postcentral gyrus, the premotor cortex, the frontoparietal operculum and the insula. Corticobulbar fibers project from these supratentorial regions to the cranial nerves relevant to swallowing, which, in turn, project to the 50 pairs of muscles participating in the act of swallowing. There are additional projections to the so-called central pattern generators in the tegmental region of the caudal pons and the rostral medulla oblongata, as well as to numerous sensory cranial nerve nuclei (solitary tract nucleus, trigeminal spinal tract nucleus) (Fig. 3.24). The medullary central pattern generators are located bilaterally near the solitary tract nucleus and the nucleus ambiguous (Jean 2001; Prosiegel et al. 2005). During volitional swallowing, the supratentorial areas relevant to swallowing are primarily activated, although these are responsible only for a part of the oral phase of swallowing. As soon as the bolus is transported from the posterior tongue to the pharynx, stimulation of sensory afferents in the palatopharyngeal region triggers the swallowing reflex, which – once initiated – proceeds automatically and is coordinated exclusively in the brainstem. The swallowing process is modulated by sensory afferent influences and adjusted to the size and consistence of the bolus.
Nucleus motorius n. trigemini 4
Nucleus n. facialis
Pons
3.7 Dysphagia
3 1
Peter P. Urban
2 Medulla oblongata
3.7.1 Definition and Epidemiology Swallowing disturbances are a frequent symptom of brainstem lesions, independent of their etiology. Neurogenic swallowing disturbances may affect volitional, cortically induced and/or involuntary swallowing, i.e. reflexive swallowing triggered by sensory afferents. In addition to nutritional deficits, neurogenic dysphagia poses a risk for aspiration, a frequent complication following acute brainstem lesions.
Nucleus tractus solitarii Nucleus dorsalis n. vagi Nucleus n. hypoglossi Nucleus ambiguus
“Swallowing centers” 1 = Dorsomedial “Pattern generator” 2 = Ventrolateral “Pattern generator” 3 = “Pattern generator” at the pontomedullary junction 4 = Pontine “Swallowing centers”
Fig. 3.24 Schematic representation of the location of brainstem areas relevant to swallowing (according to Bartolome et al. 1993)
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3.7.3 Etiopathogenesis Due to the localization of the nuclear regions relevant to swallowing and of the central pattern generators, dysphagia occurs most often in lesions of the rostral medulla oblongata. Dorsolateral medullary infarctions lead to swallowing abnormalities in 35–69% of patients (Meng et al. 2000; Kameda et al. 2004) (Fig. 3.25). Following the correlation of the lesion topography with videofluoroscopic findings of swallowing, Kwon et al. (2005) found that lateral medullary infarctions are accompanied by a reduced hyoid-larynx elevation, while this function is delayed in medial medullary infarctions. Brainstem lesions of the pons and the mesencephalon located rostral to the medulla can also lead to dysphagia, in particular when the corticobulbar projections in the ventral brainstem are bilaterally affected (Fig. 3.26). These lesions are typically associated with an impaired initiation of volitional swallowing (Ertekin et al. 2000).
3.7.4 Clinical Picture and Functional Diagnostic Evaluation Patients with neurogenic dysphagia report subjective symptoms such as difficulty in initiating swallow, cough, or a gurgling “wet” tone of voice after drinking, and reswallowing.
3 Diagnostic Findings
These symptoms may indicate penetration or aspiration. In penetration, material enters the laryngeal inlet without passing the glottis; this is in contrast to aspiration, where the material is propelled downward to below the level of the vocal cord. In cases of disturbed laryngeal sensitivity, silent aspiration may further occur, unless the patient reacts by coughing. While persistent swallowing disturbances are absent in unilateral supratentorial lesions, single and unilateral lesions in the region of the pontomedullary tegmentum can cause severe and persistent dysphagia with a negative influence on the prognosis (Kuhlemeier et al. 1989). Factors in the pathogenesis of dysphagia in brainstem lesions, in addition to swallowing musculature paresis (chiefly of the pharyngeal constrictor muscle), include sensory deficits of the oropharyngolaryngeal region, delayed or absent initiation of the swallowing reflex, a delayed or reduced elevation of the hyoid and larynx, and upper esophageal sphincter dysfunction. In most patients a combination of dysfunctions is present, so that complex disturbance pictures are frequently observed. In brainstem lesions, dysphagia is often associated with additional clinical cranial nerve abnormallities, such as dysarthria, paralysis of the recurrent laryngeal nerve, absence of the gag reflex, or oral or pharyngeal sensory disturbances. Neurogenic dysphagia is, however, very rarely the only symptom of a brainstem lesion (Lee et al. 1999; Chiti-Batelli and Delap 2001). An additional, clinically relevant problem in brainstem lesions is caused by attenuated protective reflexes (cough reflex), impaired vigilance, and disturbed coordination of breathing and swallowing (Urban et al. 2004). These accompanying factors of dysphagia further increase the risk for aspiration. Separation of the individual parts of the swallowing process can be established with the use of videoendoscopy and videofluoroscopy.
3.7.5 Therapy and Prognosis Fig. 3.25 Dysphagia in dorsolateral medulla oblongata infarction right. MRI-FLAIR (a) sagittal, (b) transverse with representation of an intramural hematoma of the right vertebral artery in the context of a dissection as the cause of the brainstem infarction
Fig. 3.26 Bilateral infarctions of the rostral pontine base. MRI-T2 (a) transverse, (b) sagittal. In a patient with a preexisting infarction area in the right pontine base, acute dysphagia occurred as a result of an acute left pontine infarction (c) (MRI-DWI)
As a rule, adequate food and liquid intake is ensured by nasogastric tube feeding (weeks 1–3; The FOOD Trial Collaboration 2005). In patients with an expected longer
3.8 Ataxia
151
a lacunar infarction syndrome (Fisher 1978). Ataxia may be completely masked in patients with more severe pareses. The finding of an ataxic hemiparesis is not specific regarding the level of the lesion site and can occur in both supratentorial (e.g. of the internal capsule) and brainstem lesions. If additional clinical findings are suggestive of a brainstem lesion, the accompanying hemiparesis does, however, permit the assumption of a ventral lesion location. An ipsilateral central Horner’s syndrome with contralateral ataxic hemiparesis may, e.g. be the result of a mesodiencephalic lesion (Rossetti et al. 2003). The ataxia is due to a lesion of the corticopontocerebellar projections running either adjacent to the pyramidal tract (mesencephalic cerebral crus) or interspersed with it (pontine base). Because the fibers originating from the pontine nuclei and projecting to the cerebellar cortex via the medial cerebellar peduncle cross the midline already in the pontine base, a unilateral lesion of the pontine base can also lead to bilateral limb ataxia (Withiam-Leitch and Pullicino 1995). Clinically, an ipsilateral limb ataxia usually does not occur despite the described crossing of the pontocerebellar 3.8 Ataxia fibers in the pontine base. The findings of anatomic studies suggest that this is most likely due to the rapid spatial dispersion of the pontine nuclei axons across the entire pontine Peter P. Urban base (Schmahmann et al. 2004a), so that in a unilateral lesion of the pontine base the pontine nuclei are involved, and con3.8.1 Definition and Epidemiology tralateral limb ataxia occurs due to the disconnection of the cerebellar afferents. The same lesion nevertheless affects Ataxia refers to abnormal coordination of movement pro- only a small number of axons projecting from the contralatcesses (ataxis = lack of order). Movements of the extremities eral pontine nuclei, which explains why in an incomplete and the trunk, as well as of the speech musculature (dysar- lesion of the pontine base this is clinically not manifest as an thria) may be affected. Ataxia is a very frequent clinical find- ipsilateral limb ataxia. ing in brainstem lesions, independent of their etiology. Limb ataxia (hemiataxia) associated with brainstem lesions may occur without a concomitant hemiparesis. MRIbased mapping studies have shown that hemiataxia ipsilateral to a lesion is mediated by dorsolateral medulla oblongata 3.8.2 Neuroanatomy and Etiopathogenesis infarctions, which lead to a lesion of the posterior spinocerebellar tract and therefore represent a disturbance of the cereA brainstem lesion can mediate different types of ataxia. In bellar afferents (Fig. 3.27) (Marx et al. 2006). MRI-based bilateral lesions of the dorsal column nuclei or the medial mapping studies have further shown that hemiataxia contralatlemniscus, impaired proprioceptive sensation leads to a seneral to a lesion is associated with ventral infarctions of the rossory ataxia, which is worsened on eye closure. In unilateral tral pons, which mediate a lesion of the corticopontine tract or brainstem lesions, ataxia is more frequently due to a lesion of the pontine nuclei and therefore also constitute a disturbance the cerebellar afferents (corticopontocerebellar projections of the cerebellar afferents (Fig. 3.28) (Marx et al. 2006). and spinocerebellar tract) or efferents (dentato-rubro- Lesion localization follows from the combination of other thalamo-cortical projections) that can not be compensated by ipsilateral deficits associated with crossed symptoms. In visual control. ipsilateral oculomotor paresis and contralateral hemiataxia (Claude’s syndrome), oculomotor paresis supports the assumption of a mesencephalic lesion (Seo et al. 2001). Based on 3.8.3 Types of Ataxia the tegmental localization of the lesion, involvement of the dentato-rubro-thalamo-cortical projections exiting from the If limb ataxia is present in addition to a mild or moderate cerebellum via the superior cerebellar peduncle has been hemiparesis, this is referred to as ataxic hemiparesis. Ataxic hypothesized as the causal factor of the hemiataxia (Arias hemiparesis with an ischemic genesis has been described as et al. 1999). duration of dysphagia, a percutaneous endoscopic gastrostomy (PEG) tube is placed. A tracheostomy is established in patients with attenuated or absent protective reflexes, in particular absent cough reflex and/or reduced vigilance who have clinically relevant aspiration despite non-oral feeding. Exercise therapy (functional swallowing therapy) is carried out in parallel to restore the physiologic swallowing function, or measures to compensate for the remaining deficits are undertaken. The therapeutic measures will be most effective when the therapist is thoroughly informed of the respective individual disturbance patterns. Knowledge of the videoendoscopic or videofluoroscopic findings is therefore of particular importance. The long-term prognosis regarding regression of dysphagia in single brainstem lesions is generally favorable (Kim et al. 2000), although dysphagia may persist in individual patients and does not respond to therapeutic efforts.
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3 Diagnostic Findings
a
b Nucleus globosus and Nucleus emboliformis
Nucleus fastigii Dentate nucleus
Position of sections
Decussation
Corticopontine tract
Superior cerebellar peduncle
Pontine nuclei
Medial cerebellar peduncle
Dentate nucleus Inferior olive
Anterior spinocerebellar tract
Inferior cerebellar peduncle
Olivocerebellar tract Posterior spinocerebellar tract
Fig. 3.27 Areas of infarction in a hemiataxia ipsilateral to the lesion (overlapping the infarction areas of n = 28 patients). (a) The center of the lesions is located in the dorsal medulla oblongata and results from a
posterior spinocerebellar tract lesion. (b) Brainstem connections to the cerebellum
Stance and gait ataxia associated with brainstem lesions occurs as an isolated symptom, but may also be found in combination with limb ataxia. A pronounced gait ataxia, which is usually not associated with limb ataxia, may be observed in medial tegmental lesions of the rostral pons (Mitoma et al. 2000; Bhidayasiri et al. 2003) (Fig. 3.29), and has also been described in medial infarctions localized in the rostral midbrain (Baehring et al. 2008). The clinical picture of gait ataxia and accompanying trunk ataxia is similar to that found in patients with cerebellar vermis lesions, a finding that leads to the assumption of a disruption of the cerebellar influences on the reticulospinal and vestibulospinal tracts. A posited cause is a bilateral lesion of the dentato-rubro-thalamo-cortical projections. The question as to what extent a pontomesencephalic, tegmental “locomotor center” assigned to the tegmental pedunculopontine nucleus exists in humans, analogous to other primates (Eidelberg et al. 1981), has not yet been conclusively answered. The neurons of the tegmental pedunculopontine nucleus are located in the pontomesencephalic reticular formation lateral to the medial lemniscus. A bilateral ischemic lesion in this area has recently been described as the cause of freezing gait (Kuo et al. 2008).
Stance and gait ataxia in connection with bilateral limb ataxia, that was more pronounced ipsilateral to the lesion, has been reported in lesions of the rostral pontine tegmentum (Lee and Cho 2003). The assumed cause of the bilateral limb ataxia is a lesion that involves both dentato-rubro-thalamo-cortical projections in the region of their decussation in the rostral pontine tegmentum. In an MRI-based mapping study, patients with stance ataxia and falling tendency to one side (“lateropulsion”) were examined following a medullary infarction. The patients with stance and gait ataxia without accompanying limb ataxia showed a dorsomedial lesion with lateral vestibulospinal tract involvement, while the infarct had a ventrolateral localization and was more likely to involve the posterior spinocerebellar tract in patients with concomitant limb ataxia (Thömke et al. 2005). Paroxysmal (acute) ataxia is usually accompanied by dysarthria and is characterized by brief – of approx. 10–20 s – recurrent episodes of limb ataxia. Although the most common cause is a multiple sclerosis, it may also occur after brainstem infarction (Matsui et al. 2004). The causal lesions are located in the medial cerebellar peduncle (Kammer et al. 1993) or in the mesencephalic tegmentum near the red nucleus (Matsui et al. 2004).
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a
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this approach leads to a favorable prognosis (Chua and Kong 1996). In individual patients without progressive disorders, in particular severely compromising limb ataxia, positive effects of deep brain stimulation have been reported.
3.9 Pareses Peter P. Urban and Jürgen Marx
3.9.1 Definition and Epidemiology
b
Paresis is defined as a slight or partial loss of voluntary motor functions (palsy). Complete loss of motor functions is described as paralysis or palsy. Brainstem or extremity pareses are frequent clinical findings in brainstem lesions independent of their etiology.
3.9.2 Neuroanatomy and Etiopathogenesis 3.9.2.1 Peripheral Pareses
Fig. 3.28 Areas of infarction in a hemiataxia contralateral to the lesion (overlapping the infarction areas of n = 12 patients). (a) The center of the lesions is located in the rostral ventral pons and results from a corticopontine tract or pontine nuclei lesion. (b) Brainstem connections to the cerebellum
Fig. 3.29 MRI of a patient with acute gait and stance ataxia without lower extremity involvement. The infarction is localized in the dorsal median pontine base. (a) MRI-DWI; (b) MRI-T2
3.8.4 Therapy and Prognosis Physiotherapy represents the treatment of first choice. In most patients with acute incidents (e.g. brainstem infarctions)
Brainstem lesions can cause atrophic pareses of motor cranial nerves resulting from an injury to the motor cranial nerve nuclei or the fascicles coursing in the brainstem (Thömke 1999). Different types of pareses include pareses of the eye movement muscles (oculomotor, trochlear, abducens nerves), masticatory muscles (trigeminal nerve), facial musculature (facial nerve), palatal and pharyngeal musculature (motor parts of the vagus nerve), the sternocleidomastoid and trapezius muscles (accessory nerve), as well as of the tongue musculature (hypoglossal nerve). The pareses occur almost always ipsilateral to the lesion site. An exception from this rule is a contralateral paresis of the superior oblique muscle following a lesion at or near the trochlear nucleus, whose axons cross the midline in the brainstem. Because of the proximity of the trochlear nucleus to the central sympathetic pathway, a contralateral trochlear paresis is frequently associated with an ipsilateral Horner’s syndrome (Müri and Baumgartner 1995). In cases of isolated cranial nerve pareses (e.g. acute oculomotor paresis) without other dysfunctions, a definitive clinical differentiation between an extramedullary and an intraaxial lesion is not possible. An oculomotor paresis mediated by a brainstem infarction can either affect the pupillary motor function or spare it (Hopf and Gutmann 1990). The differentiation is accomplished with high-resolution thin slice MRIs of the brainstem or with additional electrophysiologic techniques like the masseter reflex, the blink reflex and acoustic evoked potentials (Hopf 1994). The most
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common causes are brainstem infarctions followed by demyelinating lesions in multiple sclerosis (Thömke et al. 1997), and brainstem hemorrhages (Sherman and Thompson 2005). The occurrence of isolated cranial nerve pareses permits a reliable topodiagnostic localization of the level of the lesion within the brainstem. 3.9.2.2 Central Pareses The corticobulbar and corticospinal tracts (pyramidal tract) course through the ventral brainstem (mesencephalic: middle part of the cerebral crus; pontine: pontine base; medullar: pyramid). A lesion of the projections in the described areas leads to the occurrence of central pareses in the cranial nerve supply regions and/or the extremities. Clinically relevant central pareses in the cranial nerve region are of importance only for the facial nerve (central facial paresis) and the hypoglossal nerve (dysarthria, tongue deviation). The ocular motor nuclei are, however, not innervated by segments of the pyramidal tract, but activated by superior neuronal networks responsible for the coordination of ocular muscle activity. Oculomotor functions are therefore not affected by pyramidal tract lesions. A lesion of the corticospinal segments of the pyramidal tract results in a contralateral central paresis of the extremities and trunk musculature. The pareses which are most acutely perceived by the patient are those with an effect on the fine motor skills of the hands, although only a few muscle groups may be affected due to the partially preserved somatotopic organization in the brainstem.
3 Diagnostic Findings
Frequent causes of small lesions are lacunar infarctions, which are most often due to a hypertension-induced microangiopathy. These were described by Fisher (1982) as “lacunar infarction syndromes” and comprise among others: isolated facial paresis, pure dysarthria, dysarthria-facial paresis, dysarthria clumsy hand syndrome, and pure motor hemiparesis. A lesion of the corticofacial segments of the pyramidal tract induces a contralateral central facial paresis extending to the midline crossing in the pontomedullary junction (Urban et al. 2001a). A lesion occurring beyond the midline, although before reaching the facial nucleus, can also cause a central ipsilateral facial paresis (Urban et al. 1999b) (Fig. 3.30). Activation of the facial mimic muscles is not only volitional, but also emotional. The anatomic correlates are corticofacial projections from the primary motor cortex and projections from portions of the limbic system (supplementary motor area and thalamus), both of which converge on the neurons of the facial nucleus and may each be affected in isolation in brainstem lesions. A circumscribed lesion to the corticofacial projections, e.g. in the region of the pontine base, leads to a contralateral volitional paresis, i.e. to a contralateral buccal branch weakness on volitional activation, but symmetrical innervation of the mouth during laughter (Urban et al. 1998). In the case of a lesion to the limbic projections in the tegmental region of the brainstem alone, an emotional paresis occurs, i.e. a unilateral buccal branch weakness during laughter, but bilateral activation on volitional innervation. A contralateral emotional paresis has been described in a lesion to the rostral dorsolateral pons associated with infarction in the territory of the superior cerebellar artery (Hopf
3.9.2.3 Clinical Findings Ventral brainstem lesions that include the entire pyramidal tract cause a contralateral motor hemiparesis. If this occurs in isolation, i.e. without other neurologic deficits, it is described as a pure motor hemiparesis (Melo et al. 1992). This finding does, however, not permit localization of the lesion level, but can be caused by a circumscribed lesion in the mesencephalic cerebral crus, the pontine base, or the ventral medulla oblongata. When the lesion is located caudal to the pyramidal decussation, an ipsilateral motor hemiparesis can develop (Kimura et al. 2003). Due to the somatotopic organization of the pyramidal tract only individual segments may be affected by small lesions, which leads to monopareses of individual segments or combinations producing isolated clinical syndromes. An analysis of the “Lausanne Stroke Registry” showed a hemiparesis in 4.1% of all stroke patients (Maeder-Ingvar et al. 2005). The causal factor in 8% of these patients was a brainstem lesion.
2
1 1 3
VII
3
VII
Fig. 3.30 Schematic representation of the course of the corticofacial projections in the brainstem. 1 = usual course of the corticofacial projections in the ventral pontine base: 2 = course of corticofacial projections paralemniscal on the border to the pontine tegmentum observed in some individuals; 3 = course of corticofacial projections through the ventral portion of the medulla oblongata found in some individuals
3.9 Pareses
et al. 2000b), in a lesion to the caudal dorsolateral pons in an anterior inferior cerebellar artery territory infarction (Khurana et al. 2002), as well as in a lesion to the lateral medulla oblongata (Cerrato et al. 2003), which lead to an ipsilateral emotional facial paresis. This gives rise to the assumption that projections from the limbic system responsible for the emotional activation of the facial nucleus cross the midline in the region of the transition from the upper to middle third of the pons. A lesion of the corticolingual projections causes dysarthria, as the tongue is the most important organ of articulation (Urban et al. 2001b). Dysarthrophonia may also be present in the absence of tongue deviation when the tongue is protruded. The corticolingual projections cross the midline at the level of the hypoglossal nuclei (Urban et al. 1996c). Clinically relevant central deficits of the other cranial motor nerve regions (accessory nerve) have so far not been described or cause only discrete, mostly subclinical changes (contralateral soft palate paresis in phonation and changes in the pitch of the voice in dysphonia). Anatomical studies have shown that the strict somatotopic organization of the pyramidal tract is interrupted in the region of the pontomesencephalic junction and is re-established only in the medullary region. The pyramidal tract fibers are interspersed in the pontine base with the pontocerebellar projections that course in a transverse direction and originate from pontine nuclei that are also located in the region of the pontine base. Schmahmann et al. (2004b) describe a predominance of lesion locations depending on the paretic region of the body. Dysarthria was found primarily in ventral medial lesions, central facial paresis in medial lesions of the dorsal pontine base, and central paresis of the hand and arm in mediolateral lesions, while pareses of the leg were associated with more lateral and dorsal lesions of the pontine base. The analysis of the MRI images was, however, based on a relatively small patient population, which may serve as an explanation why the findings of other authors did not support somatotopic organization of the pyramidal pathway at the pontine level (Marx et al. 2005). In another MRI-based mapping analysis, a statistically significant segregation between the topography of lesions in proximal limb pareses located in the medial as well as the dorsal pontine base, and the topography of lesions in distal limb paresis found in the mediolateral pontine base was shown (Marx et al. 2005). This finding is in accord with case reports showing that purely proximal pareses of the arms corresponding to a man-in-the-barrel syndrome can develop in bilateral lesions of the medial and dorsal pontine base (Paulin et al. 2005). In the study by Marx et al. (2005) no significant difference was found between the lesion areas leading to paresis of the upper and lower extremities. Furthermore, analysis of central facial pareses did not show predominance of a specific lesion pattern in the pontine base,
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although the medial cerebral crus was found to be involved in mesencephalic lesions (Urban et al. 2001a). The rostrocaudal extension of the pyramidal pathway permits only very limited conclusions regarding the site of the lesion. A central facial paresis may therefore be due to a lesion in the caudal motor cortex, in the corona radiata, in the internal capsule, in the mesencephalic cerebral crus, or in the ventral pons extending to the region of the pontomedullary junction. A more caudal lesion site is, however, not possible. Bilateral lesions of the corticobulbar or corticospinal projections, e.g. in extended bilateral infarctions of the pontine base, lead to a locked-in syndrome (Fig. 3.31). Patients with this condition are virtually “locked in” their own body and, excepting eye movements, no volitional movements of the extremities or of other muscles with cranial nerve innervation are possible. If there is additional involvement of the tegmental region, oculomotor disturbances may also be present. Verbal communication is rendered impossible due to bulbar muscle paresis, a causal factor of anarthria. In this setting, communication is possible only with the use of a yes/ no code via the usually still preserved vertical ocular motility, which is controlled by structures in the mesencephalic tegmentum (riMLF = rostral interstitial nucleus of the medial longitudinal fascicle). Because the tegmentum is, as a rule, preserved, involuntary movements of the musculature that can not be activated volitionally may occur and are usually mediated by emotional stimuli as, e.g. yawning and swallowing (Bauer et al. 1980; Krasnianski et al. 2003b). The most frequent causal lesion site is the pons. Causal factors are usually bilateral infarctions, e.g. due to basilar artery thrombosis, or extended pontine hemorrhages. In rare patients bilateral mesencephalic lesions of both cerebral crura can lead to a locked-in syndrome (Zakaria and Flaherty 2006). More caudally located bilateral lesions, e.g. in a bilateral ventral medulla oblongata infarction, can cause tetraparesis sparing the cranial nerves (Zickler et al. 2005). Milder forms associated with bilateral lesions of the pontine base may result in tetraparesis, i.e. residual limited extremity function and dysarthria that still permits communication. The most common causes include brainstem infarctions, brainstem encephalitis, gliomas, as well as central pontine myelinolysis (Fig. 3.32). An isolated lesion in the region of the pyramidal decussation can result in different combinations of central extremity pareses of both sides of the body, so that, e.g. the clinical picture of a central paresis of the ipsilateral arm and the contralateral leg in the form of a hemiplegia cruciata develops. The clinical differentiation from concurrently existing bilateral lesions of the pyramidal pathway is, however, not possible. Crossed syndromes are the result of a combination of ipsilateral cranial nerve lesions (e.g. ipsilateral peripheral
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3 Diagnostic Findings
a
b
Fig. 3.31 Schematic representation of typical paresis distribution patterns in brainstem lesions. (a) Crossed symptom with ipsilateral cranial nerve dysfunction (e.g. N III, N VI, N VII) or an internuclear ophthalmoplegia and a contralateral hemiparesis. (b) Crossed hemiplegia:
Fig. 3.32 (a and b) Central pontine myelinolysis in a 35-year-old patient with chronic excessive alcohol abuse. Clinically, a tetraparesis with bilateral limb-kinetic ataxia, a pronounced dysarthrophonia and a bilateral saccadic gaze pursuit developed over several days. The serum sodium concentration on admission ranged at 119 mmol/L
facial paresis and contralateral hemiparesis: Millard-Gubler syndrome), or a lesion of ipsilateral projections and contralateral central deficits (e.g. an ipsilateral lesion of the medial longitudinal fascicle with internuclear ophthalmoplegia and contralateral hemiparesis: Raymond-Cestan syndrome). While an ipsilateral Horner’s syndrome and a contralateral lesion of the long tracts may be associated with a brainstem lesion (Rossetti et al. 2003), they may also be explained by a carotid artery dissection and a supratentorial infarction with involvement of the hypothalamus. Clinical differentiation is possible with a pharmacological assessment of the presence of a peripheral or central Horner’s syndrome. A contralateral hemiparesis is also described as alternate hemiplegia. The crossed syndromes enable the clinical localization of the lesion level based on existing ipsilateral dysfunctions.
c
lesion in the region of the pyramidal pathway crossing with unilateral central paresis of the arm and contralateral central paresis of the leg. (c) Locked-in syndrome with anarthria, dysphagia, bilateral central facial paresis and tetraplegia
Most “classical” brainstem syndromes (e.g. Millar– Gubler syndrome, Weber syndrome, Nothnagel syndrome, Benedikt syndrome) were already described in the nineteenth century as a combined injury to the cranial nerves or their nuclei passing through the brainstem in a transverse direction and to the ascending and descending pathways coursing in a longitudinal direction in the brainstem. Involvement of the cerebellar afferents are common in brainstem lesions in view of the close proximity of the corticopontocerebellar projections to the pyramidal tract. Provided only a partial lesion of the pyramidal tract with incomplete paresis is present, the clinical demonstration of involvement of these cerebellar projections due to a superimposed limb ataxia (ataxic hemiparesis) can be accomplished. Highergrade pareses mask an involvement of these projections.
3.9.3 Functional Diagnosis Functional non-invasive assessment of pyramidal tract function can be made by an examination of motor evoked potentials (MEP) using transcranial magnetic stimulation (TMS) (see Sect. 2.3.7).
3.9.4 Therapy In addition to physiotherapeutic exercises on a so-called neurophysiologic basis (Bobath, proprioceptive neuromuscular
3.10 Sensory Disturbances
facilitation, Vojta), motor learning concepts are increasingly employed. These concepts are characterized by the repeated active performance of a motor task or its components, preferably in a contextual, sensory-proprioceptive environment. A special form of the task-oriented therapy is the so-called forced-use method, in which the non-affected arm is immobilized in a splint, and the paretic arm is subjected to a 2-week intensive exercise therapy (1993). The results of animal studies indicate that initiation of active exercise therapy should be no earlier than 2 weeks after the onset of the brain injury, because the increased neuronal activity can maintain the still continuing apoptotic cascade due to the excitotoxicity resulting from an activation of the excitatory transmitters (Humm et al. 1998). Residual functional deficits can also be partially compensated by the use of suitable adjuvants. The rehabilitation success can also be enhanced by optimal motivation and mental activation (drive) of the patient. It is therefore important to treat an accompanying post-stroke depression with appropriate drug therapy, in particular with selective serotonin reuptake inhibitors (SSRI). A beneficial effect has been shown following L-dopa administration for gait rehabilitation in hemiparetic patients after stroke (Scheidtmann et al. 2001).
3.9.5 Prognosis The prognosis of motor deficits associated with brainstem lesions may be somewhat less favorable than in cortical or medullary lesions, because the likelihood of a lesion to additional descending projections is increased due to the dense bundling of motor efferents and so limiting the possibilities of compensation. However, no studies aimed at the systematic investigation of the prognosis of motor deficits in brainstem lesions have been performed to date. The prognosis of locked-in syndrome is extremely poor, since an extension of the lesion to caudal levels with impairment of the respiratory centers often occurs already in the acute phase. Provided the patients survive the acute phase, their life expectancy is markedly impaired due to aspiration and respiratory tract infections (Ruff et al. 1987).
3.10 Sensory Disturbances Peter P. Urban
3.10.1 Definition and Epidemiology The term sensory disturbance is used to describe impairment of the subjective perception of sensory stimulation through touch, pain, temperature, vibration and changes in the position of a joint. These qualities may be affected collectively or individu-
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ally and have a different topographic distribution. Sensory disturbances are frequently associated with brainstem lesions.
3.10.2 Neuroanatomy and Etiopathogenesis A brainstem lesion can cause sensory disturbances in the distribution area of the sensory supply of the cranial nerves (trigeminal nerve, glossopharyngeal nerve) mediated by a lesion to their nuclear regions or to the nerves in their intramedullary course. The sensory nuclear region of the trigeminal nerve extends from the medulla oblongata to the mid-pontine region. The nerve fibers that carry sensations of pain and temperature travel as far caudal as the spinal trigeminal tract before terminating on the second sensory neuron in the caudal subnucleus of the spinal trigeminal nucleus, which extends into the cervical spinal cord. The spinal trigeminal nucleus forms the cranial continuation of the gelatinous substance of the cervical dorsal horn which receives pain impulses from the upper cervical segments. In contrast, the trigeminal fibers mediating touch sensations end in the pontine principal sensory trigeminal nucleus. Somatosensory afferents from the region innervated by the glossopharyngeal nerve end in the medullary solitary tract nucleus. A lesion to the sensory cranial nerves in their intramedullary course results in impairment of all sensory qualities. Sensory disturbances may also be due to a lesion to the ascending sensory projections (medial lemniscus, spinothalamic tract, trigeminal lemniscus, trigeminothalamic tract) on their way to the thalamus. Which of the sensory qualities are impaired depends on the pathways that are involved. The somatotopic organization of the sensory projections may further be responsible for sensory disturbances in circumscribed regions of the body resulting from partial lesions.
3.10.3 Lesions of the Dorsal Column An injury to the gracile and cuneate nuclei in the region of the dorsal caudal medulla oblongata is associated with an ipsilateral impairment of dorsal column function (position and touch perception, vibration perception). The posterior funiculus is organized somatotopically so that fibers from the sacral and lumbar segments of the spinal cord travel within the medial gracile nucleus (Goll), while fibers from the cervical and thoracic segments project to the lateral cuneate nucleus (Burdach).
3.10.4 Lesions of the Medial Lemniscus Damage to the nerve cell processes that originate from the dorsal column and collectively form the medial lemniscus
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also leads to impairment of ipsilateral dorsal column function. Because the medial lemniscus crosses the midline in the upper medulla shortly after its exit from the dorsal column nuclei, lesions in structures (pons, mesencephalon) located rostrally cause a contralateral sensory disturbance. An isolated lesion of the medial lemniscus leads to a contralateral hemihypesthesia with diminished touch perception, as well as to impairment of vibration and position perception (Kim and Jo 1992). The medial lemniscus is also organized somatotopically so that even the smallest lesions can cause an apparent segmental hypesthesia (Lee et al. 2001).
3.10.5 Lesions in the Region of the Lemniscal Decussation A lesion in the region of the lemniscal crossing can lead to bilateral sensory disturbances as, e.g. a cheiro-oral syndrome or oral sensory deficits (Yasuda et al. 1988). After crossing the midline, sensory projections from the spinal trigeminal tract and nucleus terminate in the medial lemniscus. Lesions of the medial lemniscus rostral to the spinal trigeminal nucleus therefore also produce a sensory disturbance in the contralateral half of the face.
3.10.6 Lesions in the Region of the Lateral Spinothalamic Tract These lesions are accompanied by contralateral impairment of pain and temperature sensation. The lateral spinothalamic tract is located in the region of the caudal medulla oblongata, ventral and lateral to the dorsal column nuclei. An extended unilateral lesion of the caudal medulla oblongata can thus, comparable to a spinal lesion, cause the clinical picture of a Brown-Séquard syndrome with an ipsilateral loss of dorsal column function and a contralateral dissociated sensory disturbance (Cerrato et al. 2000). The lateral spinothalamic tract is located rostral to the dorsal column nuclei, lateral and dorsal to the medial lemniscus. Circumscribed brainstem lesions in this area lead to the clinical picture of a contralateral dissociated sensory disturbance, i.e. to a loss of pain and temperature perception with preserved tactile sensation. Due to the somatotopic organization of the lateral spinothalamic tract, incomplete lesions cause sensory disturbances in circumscribed regions and may even lead to an unilateral sensory level on the trunk, which have been described in lateral medulla oblongata infarctions (Urban et al. 1999c).
3 Diagnostic Findings
3.10.7 Clinical Findings In some patients, the distribution pattern of sensory disturbances allows conclusions to be drawn about the presence of a brainstem lesion. Crossed symptoms with ipsilateral sensory disturbances in the innervation area of the trigeminal nerve and contralateral dissociated sensory disturbances – often sparing the contralateral face – are evidence of a brainstem lesion and are found, e.g. in a lesion of the dorsolateral medulla oblongata (Wallenberg’s syndrome) (Fig. 3.33a). A causal factor is a lesion of the ipsilateral trigeminal nucleus (spinal trigeminal nucleus) and the lateral spinothalamic tract. Less often a dissociated sensory disturbance attributable to trigeminothalamic tract involvement may also be present in the contralateral half of the face (Fig. 3.33b). A crossed distribution pattern of sensory disturbances has also been described with lesions in the caudal dorsolateral pons, e.g. following intraparenchymal hemorrhage (Combarros et al. 1996). Another characteristic indicative of a brainstem lesion is an oral sensory disturbance. An unilateral oral sensory disturbance is suggestive of a lesion to the rostral aspect of the spinal trigeminal nucleus (Graham et al. 1988), while bilateral oral and perioral sensory disturbances, the latter with an onion-skin-like distribution (Sölder-lines), are an indication of a lesion to the medial lemnicus in the region of the lemniscal decussation of the sensory trigeminal afferent fibers (Kim et al. 1997; Fig. 3.33c). Due to the somatotopic organization of the medial lemniscus, unilateral perioral onion-skin-like sensory disturbances can also be caused by lesions rostral to the brainstem. A bilateral cheiro-oral distribution pattern, involving the mouth and enfolding the hands like a glove, represents a further indication of a brainstem lesion in the region of the lemniscal decussation (Ikeda et al. 1995; Yasuda et al. 1998; Fig. 3.33d). An unilateral cheiro-oral syndrome may, however, also occur in lesions with a more rostral location in the ventral posterolateral nucleus of the thalamus and the postcentral gyrus region. An isolated sensory disturbance in the area innervated by the trigeminal nerve can also be associated with a brainstem lesion. Most frequently involved are the maxillary and mandibular portions of the trigeminal nerve. Acute occurrences are most often small pontine hemorrhages in the dorsolateral tegmentum, commonly from a cavernoma (Kim et al. 1994), or lacunar infarctions. A lesion of the spinal trigeminal nucleus in medullary diseases (Nakamura et al. 1996) is usually accompanied by loss of pain and temperature perception or, in midpontine lesions, an injury of the principal sensory trigeminal nucleus (Kamitani et al. 2004) is accompanied by diminished touch sensation. All sensory modalities may be impaired in a lesion in the nerve entry zone of the trigeminal
3.10 Sensory Disturbances
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Thermohypesthesia and hypalgesia
a
Hypesthesia
b
c
d
Fig. 3.33 Schematic representation of the distribution pattern of sensory deficits typical of a brainstem lesion. (a) Ipsilateral thermohypesthesia, hypalgesia, and hypesthesia of the face and enorally, as well as a dissociated sensory disturbance of the contralateral half of the body sparing the face. (b) Ipsilateral thermohypesthesia, hypalgesia, and
hypesthesia of the face and enorally, as well as a dissociated sensory disturbance of the contralateral half of the body with involvement of the face. (c) Bilateral enoral and perioral hypesthesia. (d) Bilateral enoral and perioral hypesthesia as well as bilateral hypesthesia of the hands (cheiro-oral syndrome)
nerve with the nerve still coursing within the medulla. But sensory disturbances may also occur in the trigeminal innervation area alone due to a lesion of the trigeminothalamic tract, e.g. in the mesencephalon (Kim 1993). Brainstem lesions are significantly more often associated with sustained hemihypesthesia/hemialgesia, which does not enable any conclusions about the lesion site. A possible lesion site rostral to the trigeminal nuclear complex may be presumed if involvement of the face is present. The most rostrally located lesion that is consistent with a sustained sensory deficit with involvement of the face corresponds to a lesion in the rostral lateral medulla oblongata (Vuadens and Bogousslavsky 1998). A “pseudoathetosis” analogous to the so-called thalamic hand represents a rare condition associated with lesions to the medial lemniscus in the brainstem and has most often been observed in patients with impaired joint position sense (Shiga et al. 2003). Sensory disturbances mediated by a brainstem lesion can also be accompanied by a number of different pain syndromes. If the lesion is located in the nerve entry zone, the result may be a trigeminal neuralgia (Iizuka et al. 2006) or, less frequently, glossopharyngeal neuralgia (Minagar and Sheremata 2000).
Patients with lesions in the dorsolateral medulla oblongata frequently (up to 70% of patients) develop pain in the ipsilateral face, which is more pronounced in the periorbital region and/ or the contralateral body half and manifests with a latency from 2 weeks to 24 months (Fitzek et al. 2001). The pain is generally chronic, has a superficial localization and a burning, stinging character, and is often also associated with thermal sensation. Touch frequently exacerbates or elicits pain (allodynia) (Peyron et al. 1998). The causal factor identified in an MRI-mapping study by Fitzek et al. (2001) was a lesion at the level of the oral and interpolar trigeminal nuclei. In view of the finding that the nociceptive fibers terminate on the caudal subnucleus, the data support the assumption of a deafferentiation of the nociceptive neurons in the caudal subnucleus. Neither lesions of the second neurons in the caudal subnucleus region, nor lesions in the course of the trigeminothalamic tract were associated with facial pain. Trophic disturbances can also develop, particularly in the facial region (Schommer et al. 2000), whose origin has not been conclusively identified. Repeated self-traumatization (e.g. nose-rubbing, scratching) due to dysesthesias and disturbed sensitivity are posited to lead to infections that further cause trophic changes (Pedicelli et al. 2009).
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3.10.8 Functional Diagnostic Evaluation Confirmation of sensory disturbances can be accomplished with an investigation of early somatosensory evoked potentials (SEP) and laser evoked potentials (LEP). Somatosen sory evoked potentials are defined as changes in potentials resulting from electric stimulation of peripheral sensory nerves, which can be recorded from the scalp, the cervical region and – depending on the stimulation site – from the extremities (see Sect. 2.3.6). Due to the anatomic course of the central somatosensory projections, median SEPs (stimulation of the median nerve) are suitable for detection of circumscribed brainstem lesions, affecting the rostral segments of the posterior columns and the medial lemniscus. In some settings, stimulation of the trigeminal nerve is used in addition to median SEPs in order to examine the integrity of the sensory afferences in this innervation area (Stöhr et al. 1981). LEPs are a similar method to SEPs in that the selective stimulation of nociceptors (free nerve endings of Að- and C-fibers) enables an examination of the entire nociceptive pathway from the peripheral receptor of the cortex (see Sect. 2.3.8; Treede et al. 2003). A lesion of the spinothalamic tract is associated with pathologic latency delays, amplitude decreases or a loss of potentials (Cruccu et al. 2003). Analysis of the blink reflex is expedient when lesion patterns suggestive of an injury in the region of the dorsolateral pontomedullary tegmentum are present (see Sect. 2.3.1). In the blink reflex electric stimulation of the supraorbital nerve (N. V1) is applied supraorbitally at the exit point of the nerve, and the reflex response, consisting of bilateral eye closure, is recorded by means of a surface electromyogram of the orbicularis oculi muscle. A unilateral afferent disturbance, e.g. in the context of a lesion in the trigeminal nuclear region comprising N. V1, results in a pathologic delay or a loss of the early ipsilateral reflex response (R1) and of the late bilateral responses (R2) (Valls-Solé 2005).
3.10.9 Therapy and Prognosis Only a small number of systematic investigations on the therapy of sensory deficits after cerebral lesions are currently available. A controlled study of 20 patients with a stable sensory deficit more than 2 years after a brain insult showed the superiority of results obtained in patients undergoing a retraining program of the sensory function of the hand over those in an untreated control group on the basis of different tests designed to assess surface and depth sensitivity (Yekutiel and Guttman 1993). The prognosis of sensory disturbances with a view to their regression is usually favorable. Within the first 3 months
3 Diagnostic Findings
after a brain insult a complete or incomplete recovery of the sensory deficits, independent of a supra- or infratentorial localization, is frequently observed, as shown by the results of quantitative sensory testing (Julkunen et al. 2005). SEPs provide important information in the acute phase, as the obtained cortical responses have a favorable prognosis (Julkunen et al. 2005). Sensory deficits may be associated with a central neuropathic pain syndrome that sometimes responds favorably or at least partially to drug therapy. Intermittent neuralgias (e.g. trigeminal neuralgia) respond to treatment with carbamazepine or gabapentin. In patients with chronic pain, e.g. due to a lesion to the spinal trigeminal tract after Wallenberg’s syndrome, therapy with amitriptyline, lamotrigine, and gabapentin have been effective (MacGowan et al. 1997; Frese et al. 2006).
3.11 Bladder Disturbances Peter P. Urban
3.11.1 Definition and Epidemiology Neurogenic bladder disturbances can manifest as urinary frequency or urinary urgency, incontinence, difficult and incomplete bladder voiding, or recurrent urinary tract infections and are often noted in patients with brainstem lesions.
3.11.2 Physiology and Neuroanatomy of Micturition The parasympathetic nervous system is largely responsible for urinary bladder motor control. The pelvic splanchnic nerves ascend from the sacral segments (S2-4) to the ganglia in the urinary bladder wall and to the smooth muscle of the internal urethral sphincter. Stimulation of the parasympathetic nervous system results in contraction of the detrusor smooth muscle and relaxation of the internal urethral sphincter muscle. Bladder voiding then occurs. The sympathetic urinary bladder fibers originate from the lateral column cells of the lumbar spinal cord (Th12, L1-2, intermediolateral nucleus). They travel through the caudal segment of the sympathetic trunk and reach the inferior mesenteric ganglion via the inferior splanchnic nerves. Sympathetic nervous system impulses are transferred from there via the inferior hypogastric plexus to the bladder wall (tunica muscularis) and the smooth muscle of the internal urethral sphincter.
3.12 Drop Attacks
The somatomotor fibers originate from the motor cells in the anterior column of the sacral spinal cord (S2-4). They proceed within the pudendal nerve to the external bladder sphincter muscle, so that the striated muscle of the external urethral sphincter is subject to voluntary motor function. Sensory innervation occurs via afferent fibers (nociceptors and proprioceptors) in the bladder wall that respond to distension. At increasing bladder filling volumes, there is a reflex increase in muscle tone of the bladder musculature and the internal sphincter muscle via the sacral segments (S2-4) and the pelvic splanchnic nerves. Increasing bladder filling volume is also consciously perceived, because a number of the impulses via the dorsal columns are transferred to the periaqueductal grey (midbrain) (Vanderhorst et al. 1996) and from there to the paracentral lobule at the medial aspect of the hemispheres, as well as to other areas of the brain. The results of different PET studies have shown that although micturition activity is initiated at the sacral level primarily by sensory afferents of the bladder mucosa that reflect the bladder filling volume, micturition is also controlled by a complex supraspinal neuronal network (Blok et al. 1997; Nour et al. 2000; Athwal et al. 2001). According to these findings, brain structures like the premotor cortex, the cingulate gyrus, the hypothalamus, periacqueductal gray, and the pontine tegmentum are involved during micturition. The periacqueductal gray projects to the pontine tegmentum (Blok and Holstege 1994) also referred to as the “pontine bladder center”. After the existence of a pontine bladder center had already been postulated in 1925 (Barrington) on the basis of lesion studies in the cat, tracer studies enabled description of a direct connection between the medial neurons (M-Region) of the pontine tegmentum and the parasympathetic intermediolateral cell column of the sacral spinal cord, which contains neurons of the vesical detrusor muscle. The activation of this pathway mediates micturition. Another connection exists between the more laterally located neurons of the pontine tegmentum (L-Region) and the also laterally located Onuf’s nucleus, whose neurons control the external urethral sphincter muscle and are important for continence (Grifiths et al. 1990). The current model of micturition control in the brainstem hypothesizes a tonic influence of the periacqueductal gray on the “continence”-neurons in the pontine L-region. At various bladder filling volumes, the information is relayed within the pontine bladder center to the M-Region (Athwal et al. 2001).
3.11.3 Ethiopathogenesis and Clinical Findings Micturition disturbances are expected in tegmental brainstem lesions due to the important role of pontine neurons in micturition control. Nevertheless, only a limited number of
161
case studies describing micturition changes in circumscribed brainstem lesions are currently available. Most of the studies did not carry out urodynamic examinations, so that information on the exact type of bladder disturbance is scarce and milder function disturbances may not have been recorded. In patients with acute urinary retention which, in some cases, represented the only micturition symptom, the lesions affected the right periacqueductal gray (Yaguchi et al. 2004), the right dorsolateral pontine tegmentum (Manente et al. 1996; Deleu et al. 2004), and the left (Naganuma et al. 2005) and right (Lee et al. 2008) dorsolateral medulla oblongata. In all patients, complete regression of the micturition disturbance occurred within a period of 4 weeks. In view of the finding that urinary retention was present in all patients, on the basis of the above mentioned model it may pathophysiologically be assumed that the impaired relay from the L- to the M-region of the pontine bladder center was due to the brainstem lesion. No studies designed to investigate if the pattern of micturition disturbances in lesions rostral or caudal to the pontine micturition centers is different from that in pontine lesions have been performed thus far.
3.12 Drop Attacks Peter P. Urban
3.12.1 Definition and Epidemiology The clinical phenomenology of drop attacks consists of an abrupt loss of leg muscle tone and a sudden fall. Drop attacks occur without warning signs or discernible causes while standing or walking. In contrast to syncopes, there is no loss of consciousness. Drop attacks are not accompanied by head movements, posture changes, or focal neurologic signs. The patient gets up immediately without requiring help, but may have fall-related injuries. Drop attacks typically occur in elderly patients, and women are more often affected than men for still unknown reasons.
3.12.2 Etiopathogenesis The etiology of drop attacks is initially nonspecific and can have different causes. A transient ischemia in the vertebrobasilar territory is the most frequent presumed cause and may lead to functional impairment of the corticospinal pathways or the reticular formation (Kubala and Milikan 1964). This may be assumed if, at various times, the patients also show other distinct brainstem symptoms like vertigo, diplopia, perioral paresthesias, ataxia and dysarthria, or a vascular
162
pathology in the vertebrobasilar territory. An autopsy report of a patient with drop attacks and subsequent quadriplegia showed an infarction in the region of the corticospinal tracts (Brust et al. 1979). A cautionary remark is needed regarding the hypothesis of a vertebrobasilar ischemia as the cause of drop attacks is that these occur very rarely in patients with confirmed vertebrobasilar stenoses or a subclavian steal syndrome. Syncopes have significantly more often been reported in connection with a subclavian steal syndrome. Drop attacks have further been described in perfusion disturbances of the parasagittal premotor or motor cortex (Meisner et al. 1986; Gerstner et al. 2005). The question as to whether an intermittent spinal hypoperfusion in terms of spinal transient ischemic attacks can also lead to drop attacks has not been answered yet. Although a vascular genesis is generally assumed, other causes also need to be taken into consideration, e.g. tumors in the region of the third ventricle or in the posterior cranial fossa, possibly mediated by an intermittent cerebrospinal fluid flow disturbance, may lead to drop attacks (Lee et al. 1994). As a rule, the affected patients have additional signs of an intermittent increase in intracranial pressure as, e.g. headaches and blurred vision. Drop attacks of vestibular origin (Turmarkin’s otolith crisis) are rare and occur primarily in the late stages of Menière’s disease, although in individual cases these may be the initial manifestation (Baloh et al. 1990). In these patients, sudden recurrent falls mediated by changes in endolymphatic fluid pressure occur in the absence of a specific trigger, premonitory symptoms, or loss of consciousness. The unilateral otolith stimulation then results in an impaired vestibulospinal posture reaction. The differentiation from vertebrobasilar drop attacks is particularly difficult, since Menière’s disease is associated with recurrent rotatory vertigo attacks, a falling tendency, and tinnitus. In these cases the identification of “ear symptoms”, i.e. hearing impairment, feelings of pressure or fullness in the affected ear, which occur primarily in Menière’s disease, can be helpful. An internal perilymph fistula of the anterior semicircular arch (dehiscence of the superior semicircular canal) as a result of a bony defect in the apical aspect toward the epidural space (Brantberg et al. 2005) may be an additional vestibular cause of drop attacks. The attacks are frequently, but not always, associated with rotatory and vestibular vertigo, and are triggered by coughing, pressing or loud noises. Drop attacks are usually a diagnosis by exclusion and should include a detailed medical history from an eye-witness. An additional type of drop attacks, where even a very detailed diagnostic procedure does not yield an explanatory correlate, are the so-called cryptogenetic drop attacks (also known as “maladie des genoux bleus” or blue knee disorder) in older women (Stevens and Mathews 1973; Mumenthaler 1984). Cataplexy is a condition characterized by an abrupt loss of muscle tone in the leg musculature with preserved
3 Diagnostic Findings
consciousness. It always occurs in connection with emotional stimuli (e.g. joy, anger) and is associated with additional symptoms of narcolepsy (obligatory: excessive daytime sleepiness with sleep attacks; possible: sleep paralysis, hypnagogic hallucinations). Some epileptic attacks can also be associated with falls (Tinuper et al. 1998). These are most often myoclonic attacks in juvenile myoclonic epilepsy, primary and secondary generalized tonic-clonic attacks, as well as atonic and myoclonic-atonic attacks in Lennox-Gastaut syndrome (Grunwald et al. 2005). Falls without loss of consciousness are also a characteristic of the extremely rare paroxysmal kinesigenic dyskinesias, which are marked by sudden dystonic, ballistic and choreic movements of the extremities, including the legs. Unless these are observed by a physician, they may be mistaken for drop attacks (Schelosky 2005).
3.13 Respiratory Disturbances Peter P. Urban
3.13.1 Neuroanatomy The respiratory neurons identified by animal studies to generate respiratory rhythm (Smith et al. 1991) are located within an area in the ventrolateral medulla oblongata extending from the caudal pole of the facial nucleus to the level of the rostral cervical spine (the so-called Pre-Bötzinger complex or ventral respiratory group). The neurons are located immediately ventral to the nucleus ambiguus. While the cell columns of both sides are each capable of generating respiratory rhythm, in vivo there are distinct connections between both sides that are responsible for synchronizing their activity. The described respiratory neurons constitute the anatomic correlate of automatic respiration and are modulated by chemoceptive and vagal afferent fibers (Hering–Breuer reflex). Projections of these fibers travel to the motor neurons that innervate the diaphragm and the intercostal musculature (Holstege 1991). Automatic respiration can be voluntarily modulated and controlled in the awake state, although this occurs via the cortico-respiratory projections of the pyramidal tract.
3.13.2 Etiopathogenesis and Clinic Central respiratory function disturbances in brainstem lesions usually manifest as apnea phases (= respiratory arrest of longer than 10 s duration) (Lassman and Mayer 2005). These occur primarily during sleep and are described as central
3.13 Respiratory Disturbances
sleep apnea syndrome. Causal factors comprise acute medulla oblongata lesions due to infarctions, hemorrhages, as well as slowly progressing lesions as, e.g. brainstem gliomas (Hui et al. 2000), although the idiopathic central sleep apnea syndrome predominates. An extreme form of central sleep apnea syndrome is the complete arrest of automatic respiration during sleep (= Ondine’s curse). These patients achieve sufficient oxygenation only in the awake state by volitional activation of the respiratory musculature via the corticospinal projections, while the control of automatic respiration during sleep does not lead to an adequate depth of respiration, or long apnea phases culminate in hypoventilation (Schestatsky and Fernandes 2004). Although a satisfactory vital capacity is measured during the day, the nocturnal hypoventilation results in hypercapnia, which, however, does not provide an adequate respiratory stimulus. Smaller injuries, in particular unilateral lesions of the lateral medulla oblongata, usually do not lead to clinically relevant respiratory function disturbances. Caution is nevertheless indicated, since transient apnea phases have also been described in the acute phase of a unilateral lateral medulla oblongata infarction (Oya et al. 2001; Lanczik et al. 2006). Bilateral lesions of the tegmental medulla oblongata can, on the other hand, mediate significant function disturbances ranging from hypoventilation to disturbances with the need for artificial respiration already in the initial stage. Sleep-phase related changes in breathing patterns have been shown in 90% of patients even weeks to months after a brainstem infarction. These become manifest as NREM sleep dependent hypercapnia and hypoventilation. In individual patients, changes in the breathing patterns like periodic breathing, pharyngeal obstructions and marked hypoventilations with central apneas may be present (Schäfer et al. 1996). Extended bilateral ventral lesions of the brainstem with interruption of the cortico-respiratory projections may be associated with impaired volitional but preserved automatic respiration as can, for example, be found in the locked-in syndrome (Munschauer et al. 1991; Urban et al. 2002). In addition to the respiratory changes mentioned above, further pathologic breathing patterns may be observed in brainstem lesions, which are frequently accompanied by consciousness disturbances of varying severity, including coma (Fig. 3.34). These comprise Cheyne–Stokes respiration (period breathing), an abnormal breathing pattern characterized by a periodically increasing and decreasing tidal volume that occurs in both diffuse hemispheric injuries and diencephalic lesions, central hyperventilation (automatic respiration) in lesions of the pontomesencephalic tegmentum, apneic respiration with inspiratory pauses and a prolonged inspiratory cramp with lesions of the dorsolateral middle or caudal pons, and ataxic breathing
163 Cheyne–Stokes respiration
Automatic respiration
Apneic respiration
Cluster respiration
Atactic respiration
Fig. 3.34 Schematic representation of respiratory patterns (according to Plum and Posner 1982)
(Biot’s breathing) characterized by an irregular change from shallow to deep breathing with irregular pauses occurring in lesions to the dorsomedial medulla oblongata. An analysis of the respiratory patterns can therefore contribute to the localization of brainstem lesions.
3.13.3 Therapy and Prognosis Progressive respiratory function disturbances can develop in the acute phase due to an extension of the infarction area in a basilar artery thrombosis, or result from caudal extension of a pontine hemorrhage. Especially in the presence of acute medullary lesions, respiratory function should be carefully monitored. In all patients with tumors and recurrent hemorrhages due to cavernomas, resection of the space occupying lesion, or of the source of bleeding is indicated. While symptomatic therapies are geared to the pulmonary situation, additional neurologic deficits, the prognosis of the clinical picture, the wishes and the medical social situation (e.g. home care) of the patient need to always be taken into consideration in evolving a comprehensive therapeutic approach. In patients with central sleep apnea syndrome, the shortterm administration of acetazolamide can be beneficial to stimulate spontaneous breathing (Whit et al. 1982). More invasive therapeutic measures include the implantation of a phrenic nerve stimulator (Lassman and Mayer 2005), or nocturnal endotracheal ventilation.
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Hypoventilation promotes the occurrence of pneumonia, which may lead to a further transient exacerbation of the pulmonary situation. Although the patients require shortterm intensive care therapy, this does not necessarily imply a poor prognosis regarding survival. In particular in patients with infarcts and hemorrhages, complete recovery of respiratory function has been reported after initial ventilatory management (Rao et al. 2005).
3 Diagnostic Findings
rostral parts of the raphe nuclei (Parvizi and Damasio 2003). In most patients these lesions have a bilateral localization (Fig. 3.35). Table 3.6 The most important causes of coma from direct and indirect brain injury Direct brain injuries • Cerebrovascular disorders – Intracerebral hemorrhage – Subarachnoidal hemorrhage
3.14 Disturbances of Consciousness Frank Thömke
3.14.1 Ethiopathogenesis and Classification Disturbances of consciousness are uniform and nonspecific signs of brain dysfunction caused by direct (primary) or indirect (secondary) brain injuries due to a multitude of possible causes (Table 3.6; overview and further reading: (Markowitsch 1999; Posner et al. 2007). Such brain injuries are followed by severe disturbances in a widely ramified interconnected network of brain areas essential to consciousness (reticular formation, thalamus, cerebral cortex). Disorders of consciousness may be caused by bilateral lesions/functional impairment of the cerebral cortex or may be attributed to a direct or indirect brainstem injury (e.g. basilar thrombosis, spaceoccupying cerebellar infarctions, brainstem hemorrhage, brainstem encephalitis). Primarily affected brainstem structures in these settings are the nuclear regions of the reticular formation in the rostral brainstem and their long projections – via thalamus and hypothalamus – to the cerebral cortex. This entire network is summarized as the ascending reticular activating system (ARAS) (Moruzzi and Magoun 1949). Intact function of the ARAS is the basis of any form of consciousness (Markowitsch 1999): • The ARAS of the medial reticular formation controls and determines the general state of wakefulness and attention. • Serotonergic neurons in the median and paramedian parts of the raphe nuclei are connected with almost all neocortical regions, and particularly closely with the limbic system, including the hippocampus. • Noradrenergic neurons in the locus coeruleus also have extensive projections to the limbic system and the neocortex, including the prefrontal cortex. Brainstem injuries leading to coma involve the rostral pons, the pontomesencephalic junction with the locus coeruleus, the nucleus pontis oralis, nucleus parabrachialis, and
– Subdural hematoma – Epidural hematoma – Space occupying infarcts in territory of the medial cerebral artery – Space occupying cerebellar infarcts – Basilar thrombosis – Sinus thrombosis • Craniocerebral trauma – Brain concussion – Brain contusion – Traumatic intracranial bleeding (intracerebral, subarachnoidal, subdural, epidural) • Intracranial space occupying lesions – Brain tumor – Brain metastases – Obstructive hydrocephalus • Inflammatory CNS diseases – Bacterial meningitis/meningoencephalitis – Viral encephalitis, in particular herpes virus-encephalitis – Cerebral abscess • Meningeal carcinomatosis • Epilepsy – Condition after generalized tonic-clonic seizure – Interictual condition in convulsive status epilepticus – Non-convulsive status epilepticus • Basilar migraine (rare) • Multiple sclerosis (rarity) • End-stage of neurodegenerative diseases Indirect brain injuries • Cardiocirculatory diseases – Cardiac arrest – Ventricular fibrillation – Cardiogenic shock (e.g. in myocardial infarction) – Progressive myocardial insufficiency (e.g. severe dilatory cardiomyopathy) • Lung function disturbances – Pulmonary embolism – Pneumonia – Pulmonary edema – Aspiration
3.14 Disturbances of Consciousness
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• Coma: State of unconsciousness from which the individual can not be awakened even with the use of strong painful stimuli.
Table 3.6 (continued) • Metabolic/endocrinologic disturbances – Diabetic coma (hypo- and hyperglycemia) – Hepatic coma
The severity of the condition or the depth of coma is determined by the degree of brainstem dysfunction, i.e. disturbances of brainstem reflexes, respiratory and cardiovascular functions. With increasing depth of coma, focal neurological signs (e.g. hemiparesis, deviation conjugée) may be no longer detectable. The Glasgow Coma Scale (GCS) is widely used to assess the severity of impaired consciousness and is based on a test of three functions (opening of eyes, best motor and best verbal response) that assess the respective performance using a scoring system. In addition, a classification of the coma stages (I–IV) or the correlation of certain clinical constellations with specific brainstem segments (e.g. midbrain syndrome) was also used. A thorough documented assessment of the clinical state of the patient is indispensable for accurate grading of the severity of the disorder and its course. It is preferable to the – not always uniformly applied – coma classifications, or the score of the Glasgow Coma Scale (Tables 3.7 and 3.8).
– Uremic coma – Pituitary coma (hypopituitarism; Sheehan syndrome) – Hypernatremia, hyponatremia – Hypercalcemia, hypocalcemia – Hyperthyreosis, hypothyreosis – Cushing’s disease – Addison’s disease (crisis) – Pheochromocytoma (crisis) • Septic encephalopathy • Hypovitaminoses – Vitamin B1 (Wernicke’s encephalopathy) – Vitamin B12 • Physical causes – Hypothermia – Hyperthermia – Electrotrauma – Lack of ambient oxygen • Intoxications – Hypnotics and other psychopharmaceuticals
3.14.2 Clinical Signs
– Alcohol – Opiates and related substances – CO2 and other ambient gases
• Disturbances of the consciousness level are generally divided into three stages that can not be sharply differentiated, but merge seamlessly. • Somnolence: State of near-sleep or an abnormal desire for sleep; the patient can be aroused with speaking voice or light touch, and caused to produce simple reactions. • Stupor: Sleep-like state, from which the patient can be aroused briefly only by rough touch, or painful stimuli; in some cases, short verbal utterances and a response to simple commands are produced.
Pons
Fig. 3.35 Topography of brainstem lesions associated with coma (according to Parvizi and Damasio 2003). Brainstem lesions followed by coma involved the rostral pons and the pontomesencephalic junction with the locus coeruleus, the oral pontine nucleus and the rostral raphe complex
Mesencephalon
MM
SA
A number of clinical signs, in particular disturbances of pupillary function and respiration, spontaneous eye movements, abnormal eye positions, as well as spontaneous or elicited motor patterns are of particular topodiagnostic significance. However, under conditions of modern everyday clinical practice these signs are increasingly rarely observed, because patients with disordered states of consciousness are often intubated and sedated (e.g. midazolam + fentanyl; propofol + fentanyl or sufentanil) in the prehospital phase. As a result of the analgosedation, the above mentioned signs may no longer be observed, or, like bilateral papillary constriction, may be the consequence of fetanyl/sufentanil and of no diagnostic value.
TG
PH
HR
IP
SM
VS
VR
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3 Diagnostic Findings
Table 3.7 Glasgow coma scale Assessment criteria
3.14.2.1 Disorders of Pupillary Function Points
Opening of eyes Eyes opening spontaneously
4
Eyes opening in response to voice
3
Eyes opening in response to painful stimuli
2
No eye opening to external stimuli
1
Best motor response Patient obeys commands
6
Localizes painful stimuli
5
Purposeful withdrawal from painful stimuli
4
Flexion reaction to painful stimuli
3
Extension reaction to painful stimuli
2
No response to painful stimuli
1
Best verbal response Oriented patient
5
Confused, inappropriate answers, talking at cross-purposes
4
Individual, inappropriate words
3
Incomprehensible sounds
2
No verbal responses
1
Evaluation: 13–15 points: minor brain injury; 9–12 points: moderately severe brain injury; 0–8 points severe brain injury
Table 3.8 Classification of coma depth according to clinical signs Coma stage Clinical signs I (corresponds to the early midbrain syndrome in the older clinical literature) II (corresponds to the late midbrain syndrome in the older clinical literature)
III (corresponds in essence to the medullary (“bulbar”) syndrome in the older clinical literature) IV (corresponds to the clinical brain death symptoms [‘coma dépassée] in the older clinical literature)
• Preserved brainstem reflexes • Purposeful reactions to painful stimuli • Demonstrable focal neurologic signs • Possible flexion synergisms • Possible Cheyne–Stokes respiration • Partial loss of brainstem reflexes • Loss of purposeful reactivity to painful stimuli or flexion synergisms • Spontaneous flexion and/or extension synergisms • Automatic respiration • Focal neurologic signs may be demonstrable • Loss of brainstem reflexes • No reactivity to painful stimuli • Ataxic or gasping respiration • No demonstrable focal neurologic signs • Imminent risk of or already present circulatory failure • Loss of brainstem reflexes • No reaction to painful stimuli • Loss of spontaneous breathing
Pupillary dysfunction may be of topodiagnostic value. In thalamic lesions both pupils are typically narrow and the reaction to light is preserved. This is attributed to involvement of the hypothalamus with bilateral injury to the central sympathoexcitatory pathway (= bilateral central Horner’s syndrome). The bilateral ptosis escapes clinical detection under conditions of coma. Thalamic lesions can also be associated with bilateral dilated pupils, which may be explained by an injury to the descending inhibitory projections to the parasympathetic neurons in the Edinger– Westphal nucleus in the midbrain. Bilateral dilated pupils may also occur in the course of intoxications with parasympatheticolytic drugs like atropine (deadly nightshade, thorn apple, henbane), or with anticholinergics (e.g. tricyclic antidepressants). Midbrain lesions with bilateral damage to the Edinger– Westphal nucleus and/or the intramesencephalic oculomotor nerve may be followed by bilateral maximally dilated pupils that are not reactive to light. Furthermore, an injury to fibers from the olivary pretectal nucleus crossing in the posterior commissure to the Edinger–Westphal nucleus, which typically occurs in conditions of external dorsal midbrain compression, can result in bilateral dilated pupils that are unreactive to light. Unilateral mydriasis may be mediated by compression of the oculomotor nerve at the tentorial notch, and occurs typically with supratentorial space-occupying lesions. Unilateral injury to the Edinger–Westphal nucleus and/or the intramesencephalic oculomotor nerve can also be the cause of a unilateral dilated and not (or only to a limited degree) light reactive pupil. Bilateral maximally constricted pin-point pupils with preserved light reaction are a characteristic symptom of bilateral pontine lesions. Such extensive miosis can, however, not be satisfactorily explained by bilateral damage to the central sympathoexcitatory pathway (=bilateral central Horner’s syndrome). In these conditions, a possible additional disinhibition of the parasympathetic pupillomotor neurons in the midbrain and the intactness of the efferent projections from these neurons was posited. In the differential diagnosis of patients with a disordered state of consciousness and bilateral small pupils, the possibility of an opiate or cholinesterase inhibitor (organophosphate) intoxication has to be weighed.
3.14.2.2 Respiratory Disturbances A number of abnormal respiration patterns have been described in connection with brainstem disorders and will be described briefly below:
3.14 Disturbances of Consciousness
• Cheyne–Stokes respiration: A pattern of breathing characterized by regular breaths with an initial increase followed by a decrease in the depth of respirations. Apnea of varying duration occurs between the individual cycles. Cheyne–Stokes respiration may be associated with lesions of the thalamus and/or the mesodiencephalic junction, as well as with diffuse cerebral injuries. • Automatic respiration: The term refers to a regular very high-frequency respiration pattern (up to 40 breaths/min) with a relatively constant depth of respiration and is mediated by midbrain lesions. • Gasping respiration: This pattern is characterized by individual breaths with prolonged inspiration and intermediate apnea phases of varying length. Gasping respiration is known to occur with pontine lesions. • Cluster respiration: Characteristic of this breathing pattern are groups of breaths of variable frequency, different respiratory depth, and intermediate breathing pauses of varying length. It is associated primarily with pontine lesions. • Ataxic respiration: Ataxic respiration represents a completely irregular pattern of breathing, or groups of individual breaths of different depth, interrupted by breathing pauses of varying length. This breathing pattern is an indication of medulla oblongata lesions.
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unilateral cerebral lesions, but may also occur with brainstem lesions. Cerebral and rostral brainstem lesions (diencephalon, mesodiencephalic junction, rostral midbrain) are followed by an ipsilesional gaze deviation (“the patient is looking to the affected side”). With large space-occupying unilateral cerebral lesions or extended thalamic hemorrhages, a contralesional gaze deviation (wrong-way eyes) was occasionally observed, whose cause is still unknown. Lesions below the level of the oculomotor or trochlear nucleus, i.e. injuries below the crossing of excitatory projections from the frontal eye field (or other areas of the cerebral cortex involved in the generation of eye movements) to the pons may lead to contralesional gaze deviation (“the patient is looking’ away from the lesions”). • Tonic vertical gaze deviations: Tonic downward gaze occurs in comatose patients with bilateral meso-diencephalic or mesencephalic lesions near-midline (hemorrhage, infarction, tumors), but may also occur with metabolic, in particular hepatic disturbances. Tonic upward gaze deviations are less often observed. They may manifest in midbrain lesions, but have also been described in patients with diffuse cerebral hypoxia after cardiopulmonary resuscitation.
3.14.2.5 Disconjugate Eye Deviations 3.14.2.3 Abnormal Eye Positions and Spontaneous Eye Movements In comatose patients, a variety of spontaneous eye movements, gaze deviations, and deviations of one eye may occur. This may provide information on the site of the lesion, the affected structures, and may be of use in assessing coma depth (overview and further reading, Thömke 2001). These signs constitute a highly heterogeneous group of disturbances, some of which have only been described in the literature by one observer. On a cautionary note it needs, however, to be said that spontaneous eye movements in particular may readily be suppressed by substances generally used for analgesia and sedation (e.g. midazolam + fentanyl; propofol + fentanyl, or sufentanil). This may serve to explain why these signs are increasingly rarely observed. In addition, benzodiazepines and opiates may also be the cause of gaze deviations, mainly divergence, but also conjugate gaze deviations, so that these are of only limited value in patients under analgesia and sedation.
3.14.2.4 Conjugate Deviations of the Eyes • Tonic horizontal gaze deviations (déviation conjugée: Tonic gaze deviations to one side occur mainly in large
Unilateral eye deviations are often the consequence of cranial nerve lesion: • Oculomotor nerve lesion: The affected eye deviates outward and downward. A concurrent mydriasis, frequently the earliest clinical sign of constriction at the tentorial notch is due to parasympathetic fiber involvement. • Abducens nerve lesion: The affected eye deviates inward. • One and a half syndrome: The eye contralateral to the pontine lesion is frequently deviated outward. • Skew deviation: Vertical divergence of the eyes due to a lesion of graviceptive pathways: –– Medullary and pontomedullary lesions: the ipsilesional eye is in a lower position. –– Pontomesencephalic and mesencephalic lesions: the contralesional eye is in a lower position.
3.14.2.6 Spontaneous Horizontal Eye Movements • Periodic alternating gaze deviation (ping-pong gaze): Alternating slow horizontal conjugate ocular deviations to the side, with the eyes remaining in this position for a few seconds, rarely longer, before moving slowly to the contralateral side. The most frequent causes are bilateral
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cerebral infarctions, and less often hemorrhages into the posterior cranial fossa. • Roving eye movements: Slow, usually horizontal conjugate or disconjugate eye movements of varying frequency and amplitude. They occur only in patients in light coma and are absent in deep comatose patients. • Repetitive divergence: Disconjugate horizontal oscillations with slow movements of both eyes from the primary to a lateral position; after a brief pause at this divergent position, a rapid return to the primary position occurs. A similar finding has thus far been described only in one patient with hepatic coma.
3.14.2.7 Spontaneous Vertical Eye Movements • Ocular bobbing: abrupt, spontaneous conjugate downward movement of the eyes, followed immediately, or with a latency of a few (up to 10) seconds, by a slow return to the initial position. This sign has an unfavorable prognosis and is most often observed in severe pontine lesions (hemorrhage, infarction, tumor), although it may also occur with cerebellar hemorrhages, metabolic–toxic encephalopathies or severe encephalitis. • Ocular dipping (also named inverse ocular bobbing): slow conjugate downward eye movements followed immediately, or with a latency of a few seconds, by a fast return. Ocular dipping is a comparatively rarer symptom than ocular bobbing and has no specific localization. It has, among others, been observed in diffuse, hypoxic, metabolic or inflammatory brain lesions, and been described as a transient phenomenon after status epilepticus. An individual cycle of ocular bobbing or dipping lasts several (up to 10) seconds. The sequence of the individual cycles is mostly irregular with intervals from 10 to 45 s. The occurrence of these eye movements is unpredictable. • Reverse ocular bobbing: rapid conjugate upward eye movement followed by a slow return to primary position. Reverse ocular bobbing is very rarely observed. • Reverse ocular dipping (converse ocular bobbing): an extremely rare slow conjugate upward eye movement with a subsequent fast return to the primary position. • Ocular floating: an extremely rare condition observed in one patient with pontine hemorrhage. Spontaneous, alternately fast and slow conjugate downward eye movements followed by slow or fast upward eye movements. • Acute vertical ocular myoclonus: large amplitude (up to 45°) conjugate pendular upward and downward eye movements, which have been occasionally observed in the acute phase of extended pontine infarctions and hemorrhages. • Pretectal pseudo-bobbing: spontaneous, rapid conjugate downward and inward eye movements followed by a slow
3 Diagnostic Findings
return to the primary position. The condition has been observed in a small number of patients with acute occlusive hydrocephalus and midbrain compression.
3.14.2.8 Changes in Motor Function Patients in light coma usually lie in a sleep-like unremarkable position on the bed and show purposeful responses of the arms and legs to painful stimuli. The arms may be flexed and the legs extended with increasing coma depth. Painful stimuli may then provoke extension synergisms of the arms and flexion synergism of the legs. With further increasing coma depth there may be spontaneous or pain-evoked responses ranging from extension synergisms to extension spasms. The sequence of motor phenomena in craniocaudal loss of brainstem function may also be influenced by analgesia and sedation or masked by relaxation.
3.15 Brain Death Diagnosis in Primary Brainstem Injury Frank Thömke
3.15.1 Definition Brain death is defined as the irreversible loss of function of the brain, including the brainstem. The presence of an acute brain injury (e.g. aneurysmal subarachnoid hemorrhage, severe head injury, intracerebral hemorrhage) and exclusion of complicating medical conditions that can confound clinical assessment, (e.g. intoxications, hypothermia, circulatory shock, severe metabolic disturbances, influence of sedative agents) are prerequisites for the diagnosis of brain death. First of all, brain death is a clinical diagnosis. Obligatory clinical signs of brain death, i.e. coma, loss of brainstem reflexes, absence of respiration, are the same all over the world. Guidelines concerning the time interval of the recommended repeat clinical evaluations varies between 6 (e.g. USA) and 72 h (e.g. Germany in patients with secondary, i.e. indirect brain injury). Confirmatory laboratory tests such as electroencephalography, conventional angiography, transcranial Doppler ultrasonography, brain scintigraphy, somoatosensory evoked potentials, auditory evoked potentials, are optional in a number of countries (e.g. USA, United Kingdom), but mandatory in others, and the recommended laboratory tests may differ between different countries. Sometimes confirmatory tests are mandatory only in certain conditions (e.g. patients with brainstem and/or cerebellar injuries in Germany). Irreversible loss of brainstem functions usually occurs in patients with an acute severe injury of the whole brain. Isolated damage of the brainstem, which may be seen with basilar artery thrombosis, extensive brainstem hemorrhage
3.15 Brain Death Diagnosis in Primary Brainstem Injury
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or cerebellar hemorrhage with brainstem compression, is rare. Such patients may show all obligatory clinical signs of brain death, i.e. coma, loss of brainstem reflexes, absence of respiration, although their cerebral function are not yet lost. As far as I know, the United Kingdom is the only country with practice parameters for the diagnosis of brain stem death, which are basically the same as for brain death. Other countries (e.g. USA) do not specify this condition in their practice parameters or require confirmatory tests to document electrocerebral inactivity or cerebral circulatory arrest.
3.15.2 Clinical Signs of Brain Death (and Brainstem Death) Many guidelines require that clinical assessment of the obligatory signs of brain death (or brainstem death) (Table 3.9) be done by two physicians with long-term experience in intensive care therapy of patients with severe brain injuries.
3.15.2.1 Coma Coma or unresponsiveness is defined as a state of unconsciousness without cerebral motor response to pain in all extremities and the face. In some brain-dead patients, however, movements of the extremities may occur spontaneously or in response to external stimulation. These are generated within the spinal cord and are ascribed to “disinhibition” of spinal reflex patterns due to the loss of inhibitory projections from the brain. The loss of brainstem reflexes must always be confirmed under these conditions.
3.15.2.2 Loss of Brainstem Reflexes Assessment of the complete loss of the following brainstem reflexes is mandatory: • No response of the pupils to bright light • Size of the pupil: midposition (about 4 mm) or dilated (up to 9 mm) • No oculocephalic reflex during passive movements of the head or no deviation of the eyes to irrigation in each ear with 50 mL of cold (ice) water • No corneal reflex • No grimacing to painful stimuli (e.g. deep pressor on the nose, the supraorbital ridge, the temporomandibular joint) • No response to stimulation of the posterior pharynx • No cough response to bronchial suctioning
3.15.2.3 Absence of Respiration To avoid placing the patient at risk and due to possible physiologic effects of hypercapnia, apnea-testing should be performed as the final clinical examination for clinical assessment of brain death signs. • Hypercapnia caused by disconnection from the ventilator: Preoxygenation with 100% O2 is to obtain an arterial pO2 ³200 mmHg. The ventilator is then turned off (or the patient is disconnected from the ventilator). If respiratory movements are absent, the patient is continuously observed until the pCO2 rises to >60 mmHg, or 20 mmHg over the individual baseline pCO2. (The mean rise in pCO2 under these conditions is about 5 mmHg/min).
Table 3.9 Components of brain death diagnostics in infratentorial (brainstem and/or cerebellar) brain injury in Germany Prerequisites Essential clinical finding Confirmation of irreversibility (ancillary imaging techniques) • Two assessing physicians
• Coma
• Electroencephalography
• Acute brain injury
• Cessation of spontaneous respiration
or
• Exclusion of other causes, e.g.
• Loss of brainstem reflexes
• Doppler sonography
– Intoxications
– No pupillary light reaction
or
– Hypothermia
– No corneal reflex
• Brain scintigraphy
– Circulatory shock
– No vestibuloocular reflex
– Metabolic dysfunctions
– Absence of reaction to pain in the trigeminal distribution area – No gag reflex – No cough reflex
Exception children <2 years • Minimum of two examinations (clinical, imaging) • Delay between the examinations – Full-term newborns (0–28 days): 72 h – Infants (29–365 days) and toddlers (366–730 days): 24 h
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• Hypercapnia caused by hypoventilation: Hyperoxic hypoventilation with 100% oxygen (e.g. reduction in the respiratory rate of 50% or above). The ventilator is switched off (or the patient is disconnected from the ventilator) on reaching a pCO2 ³ 60 mmHg. At that time there is a pO2 of several 100 mmHg. The loss of spontaneous respiration is confirmed when respiratory movements are absent over a period of 1–2 min.
3.15.3 Confirmatory Laboratory Tests 3.15.3.1 Determination of Electrocerebral Inactivity The absence of cerebral electrical activity during at least 30 min of continuous EEG recording confirms the irreversible loss of brain function. Sensitivity of the system has to be 2 mV/mm (German Association of Clinical Neurophysiology 1998). 3.15.3.2 Determination of Cerebral Circulatory Arrest Cerebral circulatory arrest may be assessed by transcranial Doppler ultrasonography, brain perfusion scintigraphy, or conventional angiography (Scientific Council of the German Medical Association 1998). Both of these noninvasive methods, transcranial Doppler ultrasonography and brain perfusion scintigraphy show a 100% agreement with conventional angiography (George 1991; Lemmon et al. 1995).
3.15.3.3 Transcranial Doppler Ultrasonography
3 Diagnostic Findings
3.15.3.5 Conventional Angiography No intracerebral filling at the level of the carotid bifurcation or circle of Willis proves cerebral circulatory arrest. While mandatory in a number of countries (e.g. Switzerland) or judged as the most sensitive test (e.g. USA), conventional angiography is not recommended in other countries (e.g. Germany) because of its potential side effects.
3.15.3.6 Somatosensory Evoked Potentials Bilateral absence of N20 response in the presence of brachial plexus potentials with median nerve stimulation confirms brain death as far as a cervical spinal cord lesion is excluded.
3.16 Clinical Brainstem Reflexes Peter P. Urban Brainstem reflexes enable the clinical diagnosis of various brainstem functions independent of the cooperation of the patient and are therefore also of value in patients with different disturbances of consciousness. Brainstem reflexes further reflect the function of various anatomic brainstem regions and contribute to accurate localization of the lesion.
3.16.1 Light Reflex 3.16.1.1 Neuroanatomy
• The number of patients without a temporal insonation window increases with age and is higher in women. Therefore, the initial absence of Doppler signals cannot be interpreted as consistent with brain death except when Doppler signals were previously conclusively demonstrated by the same investigator • Documentation of small systolic peaks (<50 cm/s) in early systole without diastolic flow or reverberating flow are indicators of high vascular resistance as seen with increased intracranial pressure
3.15.3.4 Brain Perfusion Scintigraphy Absence of uptake of isotope (e.g. Technetium-99m hexamethylpropyleneamineoxime) (“hollow skull phenomenon”) confirms irreversible cerebral circulatory arrest (Goodman et al. 1985; George 1991; Schlake et al. 1992; Bonetti et al. 1995).
The afferent fibers of this reflex course together with fibers of the visual pathway in the optic nerve and tract to the lateral geniculate body, which they bypass to continue in the direction of the superior colliculi, before terminating on the nuclei of the pretectal area. Interneurons travel to the Edinger–Westphal nuclei of both sides and thereby effect the consensual light reflex. The efferent fibers originate in the Edinger–Westphal nuclei and course with the oculomotor nerve before entering the orbits. The parasympathetic preganglionic fibers branch off at this level to synapse in the ciliary ganglion with short postganglionic fibers that innervate the pupillary sphincter muscle (Fig. 3.36).
3.16.1.2 Examination A flashlight or an ophthalmoscope is used to direct a light from the side to the pupil, while the pupillary reaction of
3.16 Clinical Brainstem Reflexes
Pupillary sphincter muscle Ciliary ganglion
171 Pupillary sphincter muscle Ciliary muscle Optic nerve fascicle
Autonomic portion of the oculomotor nerve Optic tract
Medial rectus muscle
Oculomotor nerve parasympathetic portion
Optic nerve
Accessory nucleus (autonomic)
Ciliary ganglion Oculomotor nerve
Geniculate body – Lateral – Medial Pretectal nucleus
Fig. 3.36 Schematic representation of the light reflex circuitry (Modified according to Duus 2003)
both eyes is observed. Constriction of the pupil in response to light stimulation is called the direct light reflex, while constriction of the contralateral pupil without light stimulation is named the consensual or indirect light reflex.
Accessory nucleus (autonomic)
Lateral geniculate body
Nucleus III for medial rectus muscle Perlia’s nucleus Pretectal area
Optic radiation
Visual cortex Area 19
Area 17 Area 18
Fig. 3.37 Schematic representation of the central connections of the convergence reaction (modified according to Duus 2003)
3.16.1.3 Interpretation The absence of the direct and consensual light reflexes is an indication of an afferent disturbance. A loss of alone the direct light reflex is suggestive of an efferent disturbance in the light-stimulated eye.
3.16.2 Convergence Reflex
3.16.2.2 Examination The patient initially fixates a point of reference in the room and is then asked to fixate on the investigator’s index finger, which is held at a distance of approximately 10 cm from the patient’s eyes. The physiologic reaction consists of convergence of the bulbs of the eyes and pupillary constriction.
3.16.2.1 Neuroanatomy
3.16.2.3 Interpretation
The convergence reflex can be triggered volitionally by fixation on a nearby object. It may, however, also occur as a reflex reaction to the sudden approach of a distant object. The impulses are transmitted via afferents from the retina to the visual cortex and from there via efferents through the pretectal area to a parasympathetic nuclear region, described as Perlia’s nucleus, which is located in a mid-position and ventral to the Edinger–Westphal nuclei. The impulses are transmitted from these nuclei to the nuclei of both medial rectus muscles (for convergence movements of both eyes), to the Edinger–Westphal nuclei, and from there via the ciliary ganglion to the ciliary muscles (accommodation), as well as to the pupillary sphincter muscle (pupillary constriction) (Fig. 3.37).
The loss of the convergence reflex is often associated with mesencephalic lesions involving the tegmentum. It may, however, also not be possible to elicit the convergence reflex in some healthy individuals. The diagnostic value of this reflex is therefore limited.
3.16.3 Corneal Reflex 3.16.3.1 Neuroanatomy The neural circuitry of the pontomedullary corneal reflex corresponds to that of the electrically triggered blink reflex
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3 Diagnostic Findings
(see Sect. 2.3.1); the reflex response with bilateral lid closure is consistent with the R2 component of the electrically triggered blink reflex (Ongerboer de Visser 1980).
electrophysiologic diagnostic methods in Chap. 2 (see Sect. 2.3.2). The masseter reflex constitutes the only muscle reflex in the cranial nerve region.
3.16.3.2 Examination
3.16.5.2 Examination
The reflex is evoked by tactile stimulation of the cornea from the side using a cotton swab, which produces bilateral reflex lid closure.
At the start of the examination the patient is asked to open the mouth slightly. The investigator then places the index finger of one hand on the chin of the patient and delivers a short tap to it to elicit the reflex. The reflex response to this activity is the closure of the jaw.
3.16.3.3 Interpretation Bilateral absence of the reflex response is suggestive of an afferent disturbance, i.e. a lesion of the ophthalmic division of the trigeminal nerve on the examined side. If absence or delay of the reflex response is constant on one side, independent of the examined side, the causal factor may be an efferent lesion of the facial nerve.
3.16.5.3 Interpretation Because the masseter reflex may also be absent or weak in healthy subjects, an increased reflex response serves as the only evidence of a lesion of the corticobulbar projections. A comparison between the reflex amplitude and muscle reflexes of the extremities is particularly helpful in this setting.
3.16.4 Orbicularis Oculi Reflex 3.16.4.1 Neuroanatomy The neural circuit underlying the pontomedullary orbicularis oculi reflex (glabellar reflex) corresponds to that of the electrically elicited blink reflex (see Sect. 2.3.1); the reflex response with bilateral lid closure is consistent with the R2 component of the electrically triggered blink reflex.
3.16.4.2 Examination To elicit the reflex, the patient is asked to close the eyes; the examiner then delivers a tap to the patient’s forehead with the finger or reflex hammer to effect a bilateral contraction of the orbicularis oculi muscle.
3.16.4.3 Interpretation The evaluation corresponds to that of the corneal reflex.
3.16.5 Masseter Reflex 3.16.5.1 Neuroanatomy A detailed description of the neural circuitry of the pontomesencephalic masseter reflex is presented in the discussion of
3.16.6 Oculocephalic Reflex 3.16.6.1 Neuroanatomy In the oculocephalic reflex (= vestibuloocular reflex) a rapid rotational head movement induces an excitatory stimulus to the semicircular canals of both labyrinths, which initiates a compensatory conjugate eye movement. The synaptic interconnection with the paramedian pontine reticular formation for horizontal movements, or with the rostral interstitial nucleus of the medial longitudinal fascicle for vertical movements, occurs at the level of the pontomedullary vestibular nuclei.
3.16.6.2 Examination The oculocephalic reflex is of particular importance in comatose patients, as it represents the only clinical possibility to test the eye movements. The investigator holds the head of the patients in both hands, lifts the eye lids, and then rotates the patient’s head to the side. The normal initial reaction of the eyes is to move in the direction of the passive head rotation, before promptly drifting back to the original position (= positive oculocephalic reflex). If the oculocephalic reflex is absent, the eye balls, while remaining in their position in the orbits, follow the rotational movement of the head (= negative oculocephalic reflex). The examination can also be performed in the sagittal plane with the head of the patient either tilted forward or to the back.
3.17 Rare Findings/Symptoms
3.16.6.3 Interpretation In patients with a mesencephalic lesion, a normal oculocephalic reaction can be elicited on rotational head movements, but not with the head tilted forward or back. If a pontine lesion is present, the oculocephalic reflex in both horizontal directions is negative or abnormal. Disconjugate eye movements may be an indication of a supranuclear (e.g. internuclear ophthalmoplegia) or infranuclear disturbance (e.g. abducens paresis).
3.16.7 Gag Reflex 3.16.7.1 Neuroanatomy The afferent limb of the gag reflex is formed by sensory fibers of the glossopharyngeal nerve that terminate in the solitary tract nucleus. Interneurons mediate the synapse with the nucleus ambiguus bilaterally, which forms the efferent limb of the gag reflex via the vagus nerve (pharyngeal rami). The synaptic interconnection occurs exclusively within the medulla oblongata. 3.16.7.2 Examination Stimulation of the posterior pharyngeal wall with the tip of a tongue blade causes a reflexive upward deviation of the uvula.
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“cough center” that also receives cortical impulses (voluntary control of coughing). These impulses are conducted to the respiratory neurons responsible for expiratory muscle function (in the Bötzinger complex), as well as to the motor nucleus of the vagus nerve (nucleus ambiguus), which forms the recurrent laryngeal nerve responsible for glottal closure (Pantaleo et al. 2002). 3.16.8.2 Examination The clinical examination is of importance for an evaluation of the integrity of the medullary brainstem in comatose patients. The cough reflex further represents an essential component of brain death diagnostics and its absence must be confirmed to establish a positive brain death diagnosis. In clinical practice the cough reflex can readily be tested by endotracheal stimulation, e.g. with a suction catheter, of the generally intubated and ventilated patients. A cough reaction will regularly occur in patients without sedation and muscle relaxation.
3.16.8.3 Interpretation The cough reflex is a protective reflex and can be absent in brain lesions at different locations especially with lesions to the dorsolateral medulla oblongata. A weak or absent cough reflex is associated with in increased risk for aspiration and pneumonia, e.g. following brain ischemia (Addington et al. 2005).
3.17 Rare Findings/Symptoms 3.16.7.3 Interpretation The gag reflex may be absent in medullary lesions, although it has been found to be particularly brisk in patients with amyotrophic lateral sclerosis (Hughes and Wiles 1996). The gag reflex may be impossible to elicit in some healthy subjects with normal laryngeal sensation and voluntary activation of the pharyngeal musculature.
3.16.8 Cough Reflex 3.16.8.1 Neuroanatomy The afferent limb of the cough reflex is formed by sensory fibers of the vagus nerve (tracheal and bronchial rami), which innervate the mucosa of the bronchial system and the trachea. The afferent impulses terminate in the solitary tract nucleus, localized in the dorsolateral medulla oblongata. From there the impulses are transmitted along not yet fully understood neural networks and synapse via a medullary
Peter P. Urban
3.17.1 Hallucinations 3.17.1.1 Visual Hallucinations Vivid, complex, visual hallucinations, i.e. scenic hallucinations, may occasionally be a symptom of brainstem lesions. The patients are sometimes aware of the hallucinatory nature of the perceived images (Parisis et al. 2003; Kamalakannan et al. 2004). Although the anatomic substrate remains unknown, the causal lesions usually have a mesencephalic location as well as involving reticular formation nuclei. The French used the term “peduncular hallucinations” to describe this phenomenon but in France the term pedunculaire referred to the thalamus. Because the posterior portions of the thalamus (pulvinar) and the lateral geniculate body are usually also affected by the lesion, these structures may play a crucial role in the
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3 Diagnostic Findings
development of visual hallucinations (Manford and Andermann 1998). The so-called room tilt illusion, in which the surrounding world is seen as tilted 90° to the side or upside down, has to be differentiated from the described scenic visual hallucinations. The causal factor of a room tilt illusion is a lesion involving the central otolith connections (Tiliket et al. 1996).
supported by the loss of ability to sneeze despite adequate sensory stimulation observed in patients with circumscribed lateral medulla oblongata lesions (Hersch 2000; Fink 2001; Seijo-Martinez et al. 2006). Furthermore, as initial symptom of lateral medullary syndrome patients with paroxysmal sneezing have been reported (Swenson and Leira 2007). Sometimes only the ability to complete the sneeze is lost.
3.17.1.2 Acoustic Hallucinations
3.17.4 Singultus
Acute brainstem lesions may cause complex acoustic hallucinations. The affected patients are often aware of the character of their misperception. Acoustic hallucinations are almost always accompanied by auditory disturbances in the form of hypacusia or hyperacusia and tinnitus (Cascino and Adams 1986; Schielke et al. 2000). The patients usually hear songs and melodies they are familiar with. A lesion in the lateral tegmental pons in the course of the auditory pathways was present in all of the patients described in the literature.
3.17.2 Gustatory Disturbances The afferent gustatory neurons are localized in the solitary tract nucleus. The neuroanatomy of the central pathways involved in gustatory perception is only incompletely known. Circumscribed brainstem lesions may cause impaired gustatory perception. A number of informative case reports have been published which describe an ipsilateral hypogeusia with dorsolateral, unilateral pontine lesions (Uesaka et al. 1998; Weidemann and Sparing 2002), and a contralateral gustatory disturbance with lesions of the pontomesencephalic junction (Sunada et al. 1995), or of the mesencephalon up to the level of the inferior colliculi (Cerrato et al. 2005). These findings suggest that the central afferent taste projections cross the midline in the mid-pontine region (Lee et al. 1998).
3.17.3 Sneezing Sneezing is usually triggered by sensory stimulation of the nasal mucosa (afferents: second branch of the trigeminal nerve) and elicits a complex reflexive motor response that requires coordination between respiration and the laryngeal musculature, as well as between the buccal and pharyngeal musculature. This is ensured by a central synapse of afferent and efferent fibers, which, with consideration of the involved structures, is most likely to occur at the pontomedullary level. Although current understanding of the actual connections is incomplete, the assumed existence of a “sneezing center” is
Singultus is defined as involuntary, usually irregular series of contractions of the diaphragm and the intercostal muscles terminated by glottal closure that produce the typical “hiccupping” inspiration. The contractions of the diaphragm during hiccups can be bilateral with one side, usually the left, being the dominant one. However, the contraction occurs most often only on one side, and then chiefly on the left. The afferent limb of the singultus reflex comprises the vagus, glossopharyngeal and the phrenic nerves, as well as the sympathetic nerves at the level of Th6–12. Current knowledge of the localization of the central synaptic interconnection is still incomplete. The existence of a center for the coordination of motor activation or inhibition of the muscles involved in the singultus reflex has been suggested that is independent of the respiratory center. The findings of animal studies have shown that electrical stimulation in the region of the medulla oblongata lateral to the nucleus ambiguus can generate hiccups (Arita et al. 1994). This region may therefore be the most probable location of the described hiccup center. The efferent limb consists of the phrenic nerve, the intercostal nerves and the motor portion of the vagus nerve (recurrent laryngeal nerve) to the glottis. The motor cells of the phrenic nerve are localized at the level of C4, motor neurons that supply the intercostal musculature are localized at the level of Th6–12, and those of the vagus nerve are found in the nucleus ambiguus of the brainstem. Acute brainstem lesions in the region of the rostral dorsolateral medulla oblongata may, independent of their cause (ischemia, hemorrhage, inflammation), lead to intractable singultus. The lesions are localized in the region of the solitary tract nucleus (Al Deeb et al. 1991; Park et al. 2005).
3.17.5 Nausea and Emesis Nausea and emesis in circumscribed brainstem lesions occur chiefly in connection with injuries to the vestibular nuclear
3.17 Rare Findings/Symptoms
complex in the region of the dorsolateral medulla oblongata (Brandt 1999a). In these cases emesis is almost always associated with severe rotatory vertigo and nystagmus. The findings of animal studies show that emesis is not coordinated by an anatomically defined center, but is instead controlled by a widely ramified neural network in terms of a central pattern generator between the obex and the nucleus ambiguus (Hornby 2001). The central pattern generator receives input from the chemosensitive area postrema and via abdominal vagal afferents. The exact anatomic connections between the vestibular nuclear complex and this network have not yet been defined. Vomiting in association with brainstem lesions may also be seen without severe rotatory vertigo and nystagmus and occur, for example, with changes in head position in central positional vertigo syndromes. The causal lesions involve the connections between the vestibular nuclei in the medulla oblongata and near-midline cerebellar structures (vermis) (Brandt et al. 2004). Recurrent vomiting without vertigo may in rare cases also be mediated by an isolated brainstem lesion. The lesions involve the dorsomedial brainstem in the region of the pontomedullary junction near the dorsal nucleus of the vagus nerve and may be accompanied by persistent singultus (Misu et al. 2005; Sawaii et al. 2006). Additional causes of recurrent vomiting include increased intracranial pressure, a space-occupying lesion of the posterior cranial fossa, or meningeal infiltration in leptomeningeal metastasis, while intraparenchymal brainstem lesions are a very rare causal factor.
3.17.6 Tonic Brainstem Attacks Although tonic brainstem attacks were already described in the nineteenth century, the first systematic investigation of the symptomatology was carried out by Mumenthaler and Altermatt in 1967. They also coined the term “tonic brainstem attacks” as characterized by an involuntary, tonic contraction of the muscles of one side – in very rare cases also of both sides – of the body. During the tonic attack the arm is flexed at all joints and adducted to the body, while the leg is usually extended at the knee joint with flexion and supination of the foot. Flexion of the leg at the hip and knee joint is less frequently observed. The tonic contractions are often preceded by pain in one half of the body, but the pain may also persist throughout the attack. The duration of the attacks is from a few seconds to, although rarely, more than 1 min. The attacks characteristically occur up to 100 times per day. They are often precipitated by sudden movements, anxiety, excitement or similar emotions. The attacks are not associated with disturbance of consciousness, and no changes are seen in the EEG of the patient during the attack.
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Contrary to what the name suggests, tonic brainstem attacks may also be due to lesions outside the brainstem (e.g. lesions in the posterior limb of the internal capsule). The lesions are typically localized in the vicinity of the pyramidal pathway, so that ephaptic excitation of these projections may be an important pathophysiologic factor in this setting (Spissu et al. 1999). The most common etiology is multiple sclerosis (MS) (Shibasaki and Kuroiwa 1974). Tonic brainstem attacks in MS belong to the group of paroxysmal disorders. Tonic brainstem attacks may also be the result of brainstem infarctions (Kellett et al. 1997). In these patients, the mesencephalic cerebral crus or the pontine base are affected. Recurrent tonic spasms occurring in individual extremities only have been described in connection with brainstem infarctions (Kaufman et al. 1994).
3.17.7 Disturbances of Automatic Function 3.17.7.1 Disturbances of Sweat Secretion Ipsilateral Hemihypohidrosis The central sympathetic pathway courses from the hypothalamus through the brainstem to the ciliospinal center at the level of the spinal segments C8 – Th3. A lesion involving the central hypothalamic neurons leads to an ipsilateral Horner’s syndrome and unilateral ipsilateral hypohidrosis with vasomotor disturbances, manifested by a slightly warmer, reddened area of skin. Although disturbances of sweat secretion and disturbances of temperature regulation are only rarely observed and spontaneously reported by the patient, they represent a frequent finding in patients who have brainstem infarctions. They are detected in 83% of all patients following the quantitative determination of sweat secretion (e.g. evaporimetry) (Korpelainen et al. 1993). The qualitative confirmation is accomplished using Minor’s iodine-starch test (Marx et al. 2004b). The central sympathetic pathway in the brainstem travels in the dorsolateral tegmentum of the mesencephalon and the pons, as well as in the ventrolateral medulla oblongata (Marx et al. 2004c), so that circumscribed lesions in these areas can cause an ipsilateral Horner’s syndrome and hemihy pohidrosis.
Contralateral Hemihyperhidrosis A contralateral hemihyperhidrosis has also been described in brainstem lesions. The pathophysiology of this disorder is
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only incompletely understood. The absence of an ipsilateral Horner’s syndrome and unimpaired sweat secretion speak against a pure compensatory hyperhidrosis. The existence of an inhibitory connection has therefore been postulated which crosses the midline and is disinhibited by the lesion. The finding that the causal lesions were also localized in the dorsolateral tegmentum of the brainstem has given rise to the assumption that the inhibitory pathway courses in anatomic proximity to the central sympathetic pathway (Kim et al. 1995; Pellecchia et al. 2003).
Dysrhythmia and Blood Pressure Disturbances Acute brainstem lesions of the rostral lateral medulla oblongata can cause a decrease in heart rate variability (Korpelainen et al. 1996) and paroxysmal hypertension (Phillips et al. 2000). A parallel increase in the catecholamine level was observed in medullary, but not in pontine and mesencephalic infarctions (Meglic et al. 2001). The disturbances of cardiac function in lateral medullary infarctions are most likely attributable to a lesion in the entry zone of the baroreceptor afferents or to the solitary tract nucleus (Sved et al. 2003). The question as to what extent compression of the medulla oblongata due to elongated vessels contributes to the genesis of chronic arterial hypertension continues to be controversially discussed (Saglitz and Gaab 2002).
3 Diagnostic Findings
3.17.8.1 Parkinson’s Syndrome In individual patients, an unilateral, ipsilateral Parkinson’s syndrome has been described after substantia nigra infarction (Morgan and Sethi 2003; Orima et al. 2004). These patients typically show hypokinesia and rigor, but no tremor. 3.17.8.2 Dystonia A number of case reports have described a connection between focal dystonia or hemidystonia and brainstem lesions, although the pathophysiologic basis thereof was not determined (LeDoux and Brady 2003; Loher and Krauss 2009). The causal relationship also remains unclear when imaging studies identify a possibly pre-existing lesion in patients with acutely occurring dystonia. On the other hand, there are reports of individual cases suggestive of the existence of a possible relationship, e.g. in the presence of focal dystonia of the hand, precipitated by a contralateral mesencephalic hemorrhage (Esteban Munoz et al. 1996), or hemidystonia in acute pontine infarction (Tan et al. 2005). Acute brainstem lesions that do not primarily involve the basal ganglia may mediate an altered sensory input that promotes the development of dystonia analogous to posttraumatic focal dystonia observed, e.g. in the complex regional pain syndrome (CRPS, Sudeck’s disease).
3.17.8.3 Tremor Disturbances of Gastrointestinal Function Gastrointestinal function disturbances (hypersalivation secondary to dysphagia, gastric emptying disturbances, constipation) play a role primarily in neurodegenerative diseases like Parkinson’s disease and multisystem atrophy. Although the pathogenesis of motility disturbances is usually multifactorial (e.g. medications, reduced fluid intake), neuroanatomic studies have conclusively shown that lesions that involve the dorsal vagal nucleus, which shows histologic involvement early in the course of the disease, are jointly responsible for the development of function disturbances (Braak et al. 2003). No results of studies aimed to determine if acute focal brainstem lesions also lead to disturbances of gastrointestinal functions are currently available.
3.17.8 Extrapyramidal Motor Symptoms Acute brainstem diseases are only very rarely associated with extrapyramidal motor symptoms.
Mesencephalic lesions in the region of the red nucleus can, with a latency of up to 2 years, be a causal factor of the socalled Holmes’ tremor. The older name “rubral tremor” for this condition has been made obsolete by the finding that tegmental pontine lesions lead to a similar clinical picture (Sheperd et al. 1997), showing that mesencephalic pathology is not a necessary precondition for the occurrence of the tremor. Because brainstem lesions in Holmes’ tremor are often associated with ipsilateral olivary hypertrophy, the pathology may be due to an interruption of the inhibitory pathways between the red nucleus and the inferior olive, which form the Guillain– Mollaret triangle together with the dentate nucleus (Sheperd et al. 1997). The clinical manifestation may be a number of different tremor-myoclonus syndromes. These comprise an isolated palatal tremor, palatal tremor in combination with action tremor or an acquired pendular nystagmus (oculopalatal tremor), an isolated pendular nystagmus, tongue tremor, and Holmes’ tremor. Holmes’ tremor is characterized by the combination of a 3.5–4 Hz resting and action tremor and may cause major functional impairment. Beneficial effects have been described for the treatment with deep brain stimulation of the ventral intermediate nucleus.
Literature
3.17.9 Pseudoathetosis Brainstem lesions are only rarely associated with pseudoathetosis. The term describes relatively constant, involuntary athetotic movements of the fingers and toes in the presence of proprioceptive loss. The causal lesions of pseudoathetosis may occur along the entire sensory pathway from the periphery (sensory nerve, spinal ganglion) to the CNS (dorsal columns, thalamus, parietal cortex). Lesions of the pontine medial lemniscus and the mesencephalon can also lead to a pseudoathetosis (Torres et al. 2002; Shiga et al. 2003).
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junction in 6.7% of patients, while the syndrome was absent in pure tegmental pontine infarctions (Kataoka et al. 1997). The pathomechanism of pathologic laughter and crying remains debatable. A disinhibition of limbic, serotonergic projections terminating in a pontomedullary coordination center has been postulated (Wild et al. 2003). The symptoms sometimes respond favorably to serotonin-acting agents (e.g. amitriptylin, serotonin reuptake inhibitors).
3.17.12 Pathologic Yawning 3.17.10 Paradoxical Activation of the Masticatory Musculature A neuronal reorganization in the brainstem leading to the creation of new neural pathways has been observed for circumscribed lesions of the dorsolateral pontine tegmentum. In the described patients this resulted in ipsilesional paradoxical activation of the masticatory muscles during jaw opening (Patzner et al. 2004).
3.17.11 Pathologic Laughter and Crying Pathologic laughter and crying is a syndrome characterized by loud and/or relatively long episodes of laughter and crying that are not commensurate with the provoking stimulus. The laughter and crying are not an expression of a respective inner affect, but represent an agonizing, uncontrollable experience for the patient. Pathologic laughter and crying are often induced by trivial emotional stimuli. Causal factors are mostly bilateral or diffuse cerebral lesions, although single brainstem lesions have also been described. The lesion etiology appears not to be essential, since pathologic laughter and crying have been observed in traumatic injuries, tumors, multiple sclerosis, neurodegenerative diseases and various other causes. In the brainstem, bilateral lesions of the mesencephalic cerebral crus (Okuda et al. 2005) and the pontomesencephalic junction (Dabby et al. 2004), as well as bilateral or unilateral lesions of the pontine base (Kim 1997) have been described as causes of pathologic laughter and crying in one patient with bilateral pontine infarctions and basilar artery dissection with pseudoaneurysm formation (Arif et al. 2005). An analysis of clinical findings in 49 patients with paramedian pontine infarctions showed the presence of pathologic laughter and crying with infarctions of the pontine base in 11%, and of the basotegmental
Transient excessive yawning secondary to infarction in the rostral pontine region or the pontomesencephalic junction on the border between the pontine base and the tegmentum has been reported in two patients (Cattaneo et al. 2006). Yawning was associated with gait ataxia in one and with a brachio facial hemiplegia in the other patient.
3.17.13 Gaze Evoked Symptoms Different directions of gaze, i.e. to the side, upward or downward can all evoke transient symptoms like myoclonus of the extremities or myokymia of the orbicularis oculi muscle (Jacome 1997; Williams 2004). This has been attributed to the ephaptic transmission of impulses from the paramedian pontine reticular formation (horizontal gaze direction), or the rostral nucleus of the medial longitudinal fascicle. Possible causal factors include the transmission of neural impulses in acute brainstem lesions or congenital synkinesias.
Literature 3.1 “Eye Movement Disturbances” Abel LA, Daroff RB, Dell’Osso LF (1979) Horizontal pursuit defect nystagmus. Ann Neurol 5:449–452 Ashe J, Hain TC, Zee DS, Schatz NJ (1991) Microsaccadic flutter. Brain 114:461–472 Averbuch-Heller L, Kori AA, Rottach KG, Dell’Osso LF, Remler BF, Leigh RJ (1996) Dysfunction of pontine omnipause neurons causes impaired fixation: macrosaccadic oscillations with unilateral pontine lesions. Neuroophthalmology 16:99–106 Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach KG, Ganser GL, Heide W, Büttner U, Leigh RJ (1997) A double-blind controlled study of gabapentin and baclofen as treatment for acquired pendular nystagmus. Ann Neurol 41:818–825 Averbuch-Heller L, Zivotofsky AZ, Das VE, DiScenna AO, Leigh RJ (1995) Investigations of the pathogenesis of acquired pendular nystagms. Brain 118:369–378
178 Baloh RW, Spooner JW (1981) Downbeat Nystagmus: a type of central vestibular nystagmus. Neurology 31:304–310 Barton JJS, Cox TA (1993) Acquired pendular nystagmus in multiple sclerosis – clinical observations and the role of optic neuropathy. J Neurol Neurosurg Psychiatry 56:262–267 Bhidayasiri R, Plant GT, Leigh RJ (2000) A hypothetical scheme for brainstem control of vertical gaze. Neurology 54:1985–1993 Brandt T, Dieterich M (1993) Skew deviation with ocular torsion: a vestibular brainstem sign of topographic diagnostic value. Ann Neurol 33:528–534 Brandt T, Dieterich M (1998) Two types of ocular tilt reaction: the ‘ascending’ pontomedullary VOR-OTR and the ‘descending’ mesencephalic integrator-OTR. Neuroophthalmology 19:83–92 Brandt T (1990) Positional and positioning vertigo and nystagmus. J Neurol Sci 95:2–28 Brandt T (1991) Benign paroxysmal positioning vertigo (BPPV). In Vertigo: its multisensory syndromes. 1st ed. London: SpringerVerlag, 39–151 Brodsky MC, Donahue SP, Vaphiades M, Brandt T (2006) Skew deviation revisited. Surv Opthalmol 51:105–128 Büttner U, Brandt T, Helmchen C (1999) The direction of nystagmus is important for the diagnosis of central paroxysmal positioning nystagmus (cPPV). Neuro Ophthalmol 21:97–104 Cannon SC, Robinson DA (1987) Loss of the neural integrator of the oculomotor system from brain stem lesions in monkey. J Neuro physiol 57:1383–1409 Cher LM, Hochberg FH, Teruya J, Nitschke M, Valenzuela RF, Schmahmann JD, Herbert M, Rosas HD, Stowell C (1995) Therapy for paraneoplastic neurologic syndromes in six patients with Protein A Column immunabsorption. Cancer 75:1678–1683 Chou T, Demer JL (1998) Isolated inferior rectus palsy caused by a metastasis to the oculomotor nucleus. Am J Ophthalmol 126: 737–740 Corbett JJ, Schatz NJ, Shults WT, Behrens M, Berry RG (1981) Slowly alternating skew deviation: description of a pretectal syndrome in three patients. Ann Neurol 10:540–546 Crawford JD, Cadera W, Vilis T (1991) Generation of torsional and vertical eye position signals in the interstitial nucleus of Cajal. Science 252:1551–1553 Dieterich M, Brandt T, Fries W (1989) Otolith function in man. Results from a case of otolith Tullio phenomenon. Brain 112: 1377–1392 Dieterich M, Brandt T (1993a) Ocular torsion and tilt of subjective visual vertical are sensitive brainstem signs. Ann Neurol 33: 292–299 Dieterich M, Brandt T (1993b) Ocular torsion and perceived vertical in oculomotor, trochlear and abducens nerve palsies. Brain 116: 1095–1104 Donahue SP, Lavin PJM, Hamed LM (1999) Tonic ocular tilt retraction simulating a superior oblique palsy. Arch Ophthalmol 117: 347–352 Donahue SP, Lavin PJM, Mohney B, Hamed L (2001) Skew deviation and inferior oblique palsy. Am J Ophthalmol 132:751–756 Fisher CM (1967) Some neuro-ophthalmological observations. J Neurol Neurosurg Psychiatry 30:383–392 Ford CS, Schwartze GM, Weaver RG, Troost BT (1984) Monocular elevation paresis caused by an ipsilateral lesion. Neurology 34: 1264–1267 Gauntt CD, Kashii S, Nagata I (1995) Monocular elevation paresis caused by an oculomotor fascicular impairment. J Clin Neuro Ophthalmol 15:11–14 Glasauer S, von Lindeiner H, Siebold C, Büttner U (2004) Vertical vestibular responses to head impulses are symmetric in downbeat nystagmus. Neurology 63:621–625 Halmagyi GM, Aw ST, Dehaene I, Curthoys IS, Todd MJ (1994) Jerkwaveform see-saw nystagmus due to unilateral meso-diencephalic lesions. Brain 117:775–788 Hedges TR, Hoyt WF (1982) Ocular tilt treaction due to an upper brainstem lesion: paroxysmal skew deviation, torsion, and oscillation of the eyes with head tilt. Ann Neurol 11:537–540
3 Diagnostic Findings Helmchen C, Glasauer BK, Büttner U (1996) Contralesionally beating torsional nystagmus in a unilateral rostral midbrain lesion. Neurology 47:482–486 Helmchen C, Rambold H, Fuhry L, Büttner U (1998) Deficits in vertical and torsional eye movements after uni- and bilateral muscimol inactivation of the interstitial nucleus of Cajal of the alert monkey. Exp Brain Res 119:436–452 Helmchen C, Rambold H, Sprenger A, Erdmann C, Binkofski F (2003) Cerebellar activation in opsoclonus. An fMRI study. Neurology 61:412–415 Helmchen C, Straube A, Büttner U (1994) Saccadic lateropulsion in Wallenberg’s syndrome may be caused by a functional lesion of the fastigial nucleus. J Neurol 241:421–426 Hommel M, Bogousslavsky J (1991) The spectrum of vertical gaze palsy following unilateral brainstem stroke. Neurology 41:1229–1234 Ito M, Nisimaru N, Yamamoto M (1977) Specific patterns of connexions involved in the control of the rabbit’s vestibulo-ocular reflexes by the cerebellar flocculus. J Physiol Lond 265:833–854 Jampel RS, Fells P (1968) Monocular elevation paresis caused by a central nervous system lesion. Arch Ophthalmol 80:45–57 Kalla R, Deutschlander A, Hufner K, Stephan T, Jahn K, Glasauer S, Brandt T (2006) Strupp. Detection of floccular hypometabolism in downbeat nystagmus by fMRI. Neurology 66:281–283 Kalla R, Glasauer S, Büttner U, Brandt T, Strupp M (2007) 4-aminopyridine restores vertical and horizontal neural integrator function in downbeat nystagmus. Brain 130:2441–2451 Keane JR (1985) Alternating skew deviation: 47 patients. Neurology 35:725–728 Keane JR (1975) Ocular skew deviation. Analysis of 100 cases. Arch Neurol 32:185–190 Keane JR (1990) The pretectal syndrome. 206 patients. Neurology 40:684–690 Kommerell G, Hoyt WF (1973) Lateropulsion of saccadic eye movements. Electro-oculographic studies in a patient with Wallenberg’s syndrome. Arch Neurol 28:313–318 Kwon JH, Kwon SU, Ahn HS, Sung KB, Kim JS (2003) Isolated superior rectus palsy due to contralateral midbrain infarction. Arch Neurol 60:1633–1635 Lee AG, Tang RA, Wong GG, Schiffman JS, Singh S (2000) Isolated inferior rectus muscle palsy resulting from a nuclear third nerve lesion as the initial manifestation of multiple sclerosis. J Neuro ophthalmol 20:246–247 Leigh RJ, Foley JM, Remler BF, Civil RH (1987) Oculogyric crisis: a syndrome of thought disorder and ocular deviation. Ann Neurol 22: 13–17 Leigh RJ, Zee DS (2006) The neurology of eye movements. Oxford University Press, New York Lessell S (1975) Supranuclear paralysis of monocular elevation. Neurology 25:1134–1136 Lopez L, Bronstein AM, Gresty MA, Du Boulay EP, Rudge P (1996a) Clinical and MRI correlates in 27 patients with acquired pendular nystagmus. Brain 119:465–472 Lopez L, Bronstein AM, Gresty MA, Rudge P, du Boulay EP (1992) Torsional nystagmus. A neuro-otological and MRI study of thirty five cases. Brain 115:1107–1124 Marti S, Palla A, Straumann D (2002) Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus. Ann Neurol 52:712–721 Marti S, Straumann D, Glasauer S (2005) The origin of downbeat nystagmus. An asymmetry in the distribution of on-directions of vertical gazevelocity purkinje cells. Ann NY Acad Sci 1039:548–553 Miller NR, Keane JR (1998) Spasm of the near reflex. In: Miller NR, Newman NJ (eds) Walsh & Hoyt’s clinical neuro-ophthalmology, vol 1. Williams & Wilkins, Baltimore, pp 1780–1782 Mitchell JM, Smith JL, Quencer RM (1981) Periodic alternating skew deviation. J Clin Neuroophthalmol 1:5–7 Moster ML, Schatz NJ, Savino PJ, Benes S, Bosley TM, Sergott RC (1988) Alternating skew on lateral gaze (bilateral abducting hypertropia). Ann Neurol 23:190–192
Literature Negoro K, Sasabe F, Morimatsu M (1993) Isolated inferior rectus paresis from midbrain infarction. Rinsho Shinkeigaku 33: 434–436 Ochs AL, Stark L, Hoyt WF, D’Amico D (1979) Opposed adducting saccades in convergence-retraction nystagmus. A patient with sylvian aqueduct syndrome. Brain 102:497–508 Parks MM (1958) Isolated cyclovertical muscle palsy. Arch Ophthalmol 60:1027–1035 Pless M, Ronthal M (1996) Treatment of opsoclonus-myoclonus with highdose intravenous immunoglobulin. Neurology 46:583–584 Pullicino P, Lincoff N, Truax BT (2000) Abnormal vergence with upper brainstem infarcts. Pseudoabducens palsy. Neurology 55:352–358 Pusateri TJ, Sedwick LA, Margo CE (1987) Isolated inferior rectus muscle palsy from a solitary metastasis to the oculomotor nucleus. Arch Ophthalmol 105:675–677 Rabinovich HE, Sharpe JA, Sylvester TO (1977) The ocular tilt reaction. A paroxysmal dyskinesia asssciated with elliptical nystagmus. Arch Ophthalmol 95:1395–1398 Rambold H, Helmchen C, Büttner U (1999) Unilateral muscimol inactivations of the interstitial nucleus of Cajal in the alert rhesus monkey do not elict seesaw nystagmus. Neurosci Lett 272:75–78 Rambold H, Helmchen C, Straube A, Büttner U (1998) Seesaw nystagmus associated with involuntary torsional head oscillations. Neurology 51:831–837 Rambold H, Kömpf D, Helmchen C (2001) Convergence retraction nystagmus: a disorder of vergence? Ann Neurol 50:679–681 Rambold H, Neumann G, Helmchen C (2004) Vergence deficits in pontine lesions. Neurology 62:1850–1853 Sakata E, Ohtsu K, Itoh Y (1991) Positional nystagmus of benign paroxysmal type (BPPN) due to cerebellar vermis lesions. PseudoBPPN. Acta Otolaryngol 481:254–257 Shallo-Hoffmann J, Schwarze H, Simonsz HJ, Mühlendyck H (1990) A reexamination of end-point and rebound nystagmus in normals. Invest Ophthalmol Vis Sci 31:388–392 Smith CH (1998) Divergence weakness and its relationship to abducens nerve palsy. In: Miller NR, Newman NJ (eds) Walsh & Hoyt‘s clinical neuro-ophthalmology, vol 1. Williams & Wilkins, Baltimore, pp 1257–1258 Straube A, Leigh RJ, Bronstein A, Heide W, Riordan-Eva P, Tijssen CC, Dehaene I, Straumann D (2004) EFNS task force – therapy of nystagmus and oscillopsia. Eur J Neurol 11:83–89 Strupp M, Schuler O, Krafczyk S, Jahn K, Schautzer F, Buttner U, Brandt T (2003) Treatment of downbeat nystagmus with 3, 4-diaminopyridine: a placebo-controlled study. Neurology 61: 165–170 Suzuki DA, Yamada T, Hoedema R, Yee RD (1999) Smooth-pursuit eye-movement deficits with chemical lesions in macaque nucleus reticularis tegmenti pontis. J Neurophysiol 82:1178–1186 Thömke F, Hopf HC, Krämer G (1992) Internuclear ophthalmoplegia of abduction: clinical and electrophysiological data on the existence of an abduction paresis of prenuclear origin. J Neurol Neurosurg Psychiatry 55:105–111 Thömke F, Hopf HC (2001) Abduction paresis with rostral pontine and/ or mesencephalic lesions: Pseudoabducens palsy and its relation to the so-called posterior internuclear ophthalmoplegia of Lutz. BMC Neurol 1:4 Thömke F, Hopf HC (1992) Aquired monocular elevation paresis – an asymmetric upgaze palsy. Brain 115:1901–1910 Thömke F, Strothjohann M, Mika-Grüttner A (2000) Adaptive Phänome bei internukleärer Ophthalmoplegie. Klin Neurophysiol 31:16–20 Thömke F (2002) Brainstem diseases causing isolated ocular motor nerve palsies. Neuroophthalmology 28:53–67 Thömke F (1993) The internuclear ophthalmoplegias. In: Caplan LR, Hopf HC (eds) Brain-stem Localization and function. Springer, Berlin pp 119–132 Thömke F (1996) Some observations on abduction nystagmus in internuclear ophthalmoplegia. Neuroophthalmologie 16:27–37
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3.2 “Horner’s Syndrome” Amonoo-Kuofi HS (1999) Horner’s syndrome revisited: With an update of the central pathway. Clin Anat 12:345–361 Birklein F, Spitzer A, Riedl B (1999) Die Schweißmessung zur Diagnostik autonomer Störungen. Fortschr Neurol Psychiatry 67:287–295 Carpenter MB (1985) Core text of neuroanatomy. Williams & Wilkins, Baltimore, pp 266–279 Hopf HC, Fitzek C, Marx J, Urban PP, Thömke F (2000a) Isolated emotional facial paresis in pontine pathology. Neurology 54:1217 Horner JF (1869) Über eine Form von Ptosis. Klin Monatsbl Augenheilkunde 7:193–198 Jaffe NS (1950) Localization of lesions causing Horner’s syndrome. Arch Ophthalmol 44:710–728 Lee AG, Hayman LA, Tang RA, Schiffman JS, Nagy AN (1996) An imaging guide for Horner’s syndrome. Int J Neurorad 2:196–200 Loewy AD, Araujo JC, Kerr FW (1973) Pupillodilatator pathways in the brain stem of the cat: anatomical and electrophysiological identification of a central autonomic pathway. Brain Res 60: 65–91 Low PA, Walsh JC, Huang CJ, McLeod G (1975) The sympathetic nervous system in diabetic neuropathy. A clinical and pathological study. Brain 98:341–356 Maloney WF, Younge BR, Moyer NJ (1980) Evaluation of the causes and accuracy of pharmacological localization in Horner’s syndrome. Am J Ophthal 90:394–402 Marx JJ, Iannetti GD, Mika-Gruettner A, Thoemke F, Fitzek S, Vucurevic G, Urban PP, Stoeter P, Cruccu G, Hopf HC (2003) Topodiagnostic investigations on the sympathoexcitatory brainstem pathway using a new method of three-dimensional brainstem m apping. J Neurol Neurosurg Psychiatry 75:250–255 Minor V (1927) Ein neues Verfahren zu der klinischen Untersuchung der Schweißabsonderung. Z Neurol 101:302–308 Mosqueda-Garcia R (1996) Central autonomic regulation. In: Robertson D, Low PA, Polinsky RJ (eds) Primer on the autonomic nervous system. Academic Press, San Diego, pp 3–12 Nagy AN, Hayman LA, Diaz-Marchan PJ, Lee AG (1997) Horner’s syndrome due to first-order neuron lesions of the oculosympathetic pathway. Am J Radiol 169:581–584 Nathan PW, Smith MC (1986) The location of descending fibres to sympathetic neurons supplying the eye and sudomotor neurons supplying the head and neck. J Neurol Neurosurg Psychiatry 49:187–194
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3.3 “Central Vestibular Disturbances” Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach KG, Ganser GL, Heide W, Büttner U, Leigh RJ (1997) A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol 41:818–825 Baier B, Bense S, Dietrich M (2008) Are signs of ocular tilt reaction in patients with cerebellar lesions mediated by the dentate nucleus? Brain 131:1445–1454 Baier B, Dieterich M (2009) Ocular tilt reaction – a clinical sign of cerebellar infarctions? Neurology 72(6):572–573 Baier B, Stoeter P, Dieterich M (2009) Anatomical correlates of ocular motor deficits in cerebellar lesions. Brain 132(8):2114–2124 Bense S, Best C, Buchholz HG, Wiener V, Schreckenberger M, Bartenstein P, Dieterich M (2006) 18F-fluorodeoxyglucose hypometabolism in cerebellar tonsil and flocculus in downbeat nystagmus. NeuroReport 17:599–603 Brandt T, Dieterich M, Strupp MV (2003) Leitsymptom Schwindel. Steinkopff, Darmstadt Brandt T, Dieterich M (1995) Central vestibular syndromes in the roll, pitch, and jaw planes. Topographic diagnosis of brainstem disorders. Neuroophthalmology 15:291–303 Brandt T, Dieterich M (1994) Vestibular syndromes in the roll plane: Topo-graphic diagnosis from brainstem to cortex. Ann Neurol 36:337–347 Brandt T, Brandt TV (1999) Its multisensory syndromes, 2nd edn. Springer, Berlin Cox TA, Corbett JJ, Thompson HS, Lennarson L (1981) Upbeat nystagmus changing to downbeat nystagmus with convergence. Neurology 31:891–892 Das VE, Orugenti P, Kramer PD, Leigh RJ (2000) Experimental tests of a neu-ral network model for ocular oscillations caused by disease of central myelin. Exp Brain Res 133:189–197 Dieterich M, Brandt T (1993c) Ocular torsion and tilt of subjective visual vertical are sensitive brainstem signs. Ann Neurol 33: 292–299 Dieterich M, Brandt T (1993d) Thalamic infarctions: Differential effects on ves-tibular function in the roll plane (35 patients). Neurology 43:1732–1740 Dieterich M, Brandt T (1992) Wallenberg’s syndrome: lateropulsion, cycloro-tation, and subjective visual vertical, indicating midbrain lesions. Neuroophthalmology 31:399–408 Dieterich M, Straube A, Brandt T, Paulus W, Büttner U (1991) The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus. J Neurol Neurosurg Psychiatry 54:627–632 Endres M, Heide W, Kömpf D (1996) See-saw nystagmus. Clinical aspects, diagnosis, pathophysiology: observations in 2 patients. Nervenarzt 67:484–489 Furman JMR, Wall C, Pang D (1986) Vestibular function in periodic alternat-ing nystagmus. Brain 113:1425–1439
3 Diagnostic Findings Glasauer S, Dieterich M, Brandt T (2001) Central positional nystagmus simu-lated by a mathematical ocular motor model of otolith-dependent modification of Listing’s plane. J Neurophysiol 86: 1546–1554 Glasauer S, Kalla R, Büttner U, Strupp M, Brandt T (2005) 4-aminopyridine restores visual ocular motor function in upbeat nystagmus. J Neurol Neurosurg Psychiatry 76:451–453 Halamgyi GM, Leigh RJ (2004) Upbeat about downbeat nystagmus. Neurology 63:606–607 Halmagyi GM, Aw ST, Dehaene I, Curthoys IS, Todd MJ (1994b) Jerk waveform see-saw nystagmus due to unilateral meso-diencephalic lesion. Brain 117:789–803 Halmagyi GM, Curthoys IS (1988) A clinical sign of canal paresis. Arch Neurol 45:737–739 Halmagyi GM, Rudge P, Gresty MA, Sander SMD (1983) Downbeating nys-tagmus. Review of 62 cases. Arch Neurol 40:777–784 Janssen JC, Larner AJ, Morris H, Bronstein AM, Farmer SF (1998) Upbeat nystagmus: clinicoanatomical correlation. J Neurol Neurosurg Psychiatry 65:380–381 Kalla R, Glasauer S, Schautzer F, Lehnen N, Büttner U, Strupp U, Brandt T (2004) 4-aminopyridine improves downbeat nystagmus, smooth pursuit, and VOR gain. Neurology 61:165–170 Leigh RJ, Burnstine TH, Ruff RL, Kasmer RJ (1991) The effect of anticholinergic agents upon acquired nystagmus: a double-blind study of trihexy-phenidyl and trihexethyl chloride. Neurology 41: 1737–1741 Leigh RJ, Zee DS. The neurology of eye movements. 4th ed. Oxford Uni-versity Press, New York 2006 Lopez LI, Bronstein AM, Gresty MA, Du Boulay EP, Rudge P (1996) Clinical and MRI correlates in 27 patients with acquired pendular nystag-mus. Brain 119:465–472 Pierrot-Deseilligny C, Milea D, Sirmai J, Papeix C, Rivaud-Pechoux S (2005) Upbeat nystagmus due to a small pontine lesion: evidence for existence of a crossing ventral tegmental tract. Eur Neurol 54:186–190 Ranalli RJ, Sharpe JA (1988) Upbeat nystagmus and the ventral tegmental pathway of the upward vestibulo-ocular reflex. Neurology 38:1329–1330 Stahl JS, Averbuch-Heller L, Leigh RJ (2000) Acquired nystagmus. Arch Ophthalmol 118:544–549 Starck M, Albrecht H, Pöllmann W, Straube A, Dieterich M (1997) Drug therapy of acquired nystagmus in multiple sclerosis. J Neurol 244:9–16 Starck M, Albrecht H, Pöllmann W, Straube A, Dieterich M (2010) Acquired pendular nystagmus in multiple sclerosis: an examinerblind cross-over study of memantine and gabapentin. J Neurol 257(3):322–337 Straube A, Leigh RJ, Bronstein A, Heide W, Riordan-Eva P, Tijssen CC, Dehaene I, Straumann D (2004) EFNS task force – therapy of nystagmus and oscillopsia. European J Neurol 11:83–89 Strupp M, Schüler O, Krafczyk S, Jahn K, Schautzer F, Büttner U, Brandt T (2003b) Treatment of downbeat nystagmus with 3.4-diaminopyridine – a placebo-controlled study. Neurology 61: 165–170 Waespe W, Cohen B, Raphan T (1985) Dynamic modification of the vestibu-loocular reflex by nodulus and uvula. Science 228: 199–202
3.4 “Tinnitus and Auditory Disturbances” Adams PF, Hendershot GE, Marano MA (1999) Current estimates from the National Health Interview Survey, 1996. National Center for Health Statistics 1999, Hyattsville, MD Andersson G, Lyttkens L, Hirvela C, Furmark T, Tillfors M, Frederikson M (2000) Regional cerebral blood flow during tinnitus: a PET case
Literature study with lidocaine and auditory stimulation. Acta Otolaryngol 120:967–972 Chen GD, Jastreboff PJ (1995) Salicylate-induced abnormal activity in the in-ferior colliculus of rats. Hear Res 82:158–178 Dobie RA (1999) A review of randomized clinical trials in tinnitus. Laryngoscope 109:1202–1211 Dobie RA (2003) Depression and tinnitus. Otolaryngol Clin North Am 36:383–388 Eggermont JJ, Kenmochi M (1998) Salicylate and quinine selectively increase spontaneous firing rates in secondary auditory cortex. Hear Res 117:149–160 Giraud AL, Chery-Croze S, Fischer C, Vighetto A, Gregoire MC, Collet L (1999) A selective imaging of tinnitus. NeuroReport 10:1–5 Häusler R, Levine RA (2000) Auditory dysfunction in stroke. Acta Otolaryngol 120:689–703 Heller AJ (2003) Classification and epdemiology of tinnitus. Otolaryngol Clin North Am 36:239–248 Jastreboff PJ, Sasaki CT (1994) An animal model of tinnitus: a decade of devel-opment. Am J Otol 15:19–27 Kaltenbach JA, Zhang J, Finlayson P (2005) Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hear Res 206:200–226 Lee H, Baloh RW (2005) Sudden deafness in vertebrobasilar ischemia: clinical features, vascular topographical patterns and long-term outcome. J Neurol Sci 228:99–104 Lenarz T (1998) Leitlinie Tinnitus der Deutschen Gesellschaft für HalsNasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie. Laryngorhinoo tologie 77:531–535 Levine RA (1999) Somatic (craniocervical) tinnitus and the dorsal cochlear nucleus hypothesis. Am J Otolaryngol 20:351–362 Lockwood AH, Salvi RJ, Burkhard RF (2002) Tinnitus. New Engl J Med 347:904–910 Lockwood AH, Salvi RJ, Coad ML, Towsley ML, Wack DS, Murphy BW (1998) The functional anatomy of tinnitus: evidence for limbic system links and neuronal plasticity. Neurology 50:114–120 Lockwood AH, Wack DS, Burkard RF, Coad ML, Reyes SA, Arnold SA, Salvi RJ (2001) The functional anatomy of gaze-evoked tinnitus and sus-tained lateral gaze. Neurology 56:472–480 Melcher JR, Sigalovsky IS, Guinan JJ Jr, Levine RA (2000) Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J Neurophysiol 83: 1058–1072 Mühlnickel W, Elbert T, Taub E, Flor H (1998) Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci USA 95: 10340–10343 Müller M, Klinke R, Arnold W, Östreicher E (2003) Auditory nerve fibre responses to salicylate revisited. Hear Res 183:37–43 Reyes SA, Salvi RJ, Burkard RF, Coad ML, Wack DS, Galantowicz PJ, Lookwood AH (2002) Brain imaging of the effects of lidocaine on tinnitus. Hear Res 171:43–50 Salvi RJ, Saunders SS, Gratton MA, Arehole S, Powers N (1990) Enhanced evoked response amplitudes in the inferior colliculus of the chinchilla following acoustic trauma. Hear Res 50:245–257 Salvi RJ, Wang J, Ding D (2000) Auditory plasticity and hyperactivity following cochlear damage. Hear Res 147:261–274 Schweri T, Geusing BG (1996) Acute vestibular deficit with initial deafness as the first manifestation of late onset multiple sclerosis. HNO 44:397–399 Weissmann JL, Hirsch BE (2000) Imaging of tinnitus. A review. Radiology 216:342–349 Zaffaroni M, Baldinin SM, Ghezzi A (2001) Cranial nerve, brainstem and cerebellar syndromes in the differential diagnosis of multiple sclerosis. Neuro Sci 22:74–78
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3.5 “Intra-axial Cranial Nerve Lesions” Achard C, Lévi L (1901) Paralysie totale et isolée du moteur oculaire commun par foyer de ramollisement pédonculaire. Rev Neurol 9:646–648 Asbury AK, Aldredge H, Hershberg R, Fisher CM (1970) Oculomotor palsy in diabetes mellitus: a clinico-pathological study. Brain 93:555–566 Benito-Léon J, Alvarez-Cermeño JC (2003) Isolated total tongue paralysis as a manifestation of bilateral medullary infarction. J Neurol Neurosurg Psychiatry 74:1698–1699 Bogousslavsky J, Maeder P, Regli F, Meuli R (1994) Pure midbrain infarction: Clinical syndromes, MRI, and etiologic patterns. Neurology 44:2032–2040 Brandt T (1999a) Miscellaneous central vestibular disorders. In: Brandt T (ed) Vertigo. Its multisensory syndromes. Springer, London, pp 241–246 Burde RM, Savino PJ, Trobe JD (1992) Incomitant ocular misalignment. In: Burde RM, Savino PJ, Trobe JD (eds) Clinical decisions in neuro-ophthalmology. Mosby Year Book, St. Louis, pp 239–281 Dreyfus PM, Hakim S, Adams RD (1957) Diabetic ophthalmoplegia: report of a case with postmortem study and comments on vascular supply of human oculomotor nerve. Arch Neurol Psychiatry 77:337–349 Duvernoy AM (1978) Human brainstem vessels. Springer, Berlin Fisher CM (1982) Lacunar strokes and infarcts: a review. Neurology 32:871–876 Francis DA, Bronstein AM, Rudge P, du Boulay EP (1992) The site of brainstem lesions causing semicircular canal paresis: an MRI study. J Neurol Neurosurg Psychiatry 55:446–449 Hassler O (1967) Arterial pattern of human brainstem. Normal appearance and deformation in expanding supratentorial conditions. Neurology 17:368–375 Hopf HC (1994a) Topodiagnostic value of brainstem reflexes. Muscle Nerve 17:475–484 Jacobs L, Kaba S, Pullicino P (1994) The lesion causing continous facial myokymia in multiple sclerosis. Arch Neurol 51: 1115–1119 Kamitani T, Kuroiwa Y, Hidaka M (2004a) Isolated hypesthesia in the right V2 and V3 dermatomes after a midpontine infarction localised at an ipsilateral principal sensory trigeminal nucleus. J Neurol Neurosurg Psychiatry 75:1508–1509 Keane JR, Ahmadi J (1998) Most diabetic third nerve palsies are peripheral. Neurology 51:1910 Krasnianski M, Neudecker S, Zierz S (2004) Klassische alternierende Syndrome der Brücke. Fortschr Neurol Psychiatry 72:460–468 Krasnianski M, Winterholler M, Neudecker S, Zierz S (2003a) Klassische alternierende medulla-oblongata-syndrome. Fortschr Neurol Psychiatry 71:397–405 Kumral E, Bayulkem G, Akyol A, Yunten N, Sirin H, Sagduyu A (2002a) Mesencephalic and associated posterior circulation infarcts. Stroke 33:2224–2231 Kumral E, Bayülkem G, Evyapa D (2002b) Clinical spectrum of pontine infarction. Clinical-MRI correlations. J Neurol 249:1659–1670 Lee H, Cho YW (2004) A case of isolated nodulus infarction presenting as a vestibular neuritis. J Neurol Sci 221:117–119 Lee H, Yi HA, Cho YW, Sohn CH, Whitman GT, Ying S, Baloh RW (2003) Nodulus infarction mimicking acute peripheral vestibulopathy. Neurology 63:1700–1702 Liu GT, Crenner CW, Logigian EL, Charness ME, Samuels MA (1992) Midbrain syndromes of Benedikt, Claude, and Nothnagel: setting the records straight. Neurology 42:1820–1822 Marx JJ, Mika-Grüttner A, Thömke F, Fitzek S, Fitzek C, Vucurevic G, Urban PP, Stoeter P, Hopf HC (2002) Electrophysiological brainstem testing in the diagnosis of reversible brainstem ischemia. J Neurol 249:1041–1047
182 Marx JJ, Thömke F, Mika-Gruettner A, Fitzek S, Vucurevic G, Urban PP, Stoeter P, Dieterich M, Hopf HC (2004) Diffusionsgewichtetes MRT bei vertebrobasilären Ischämien. Anwendung, Sensitivität und prognostischer Wert. Nervenarzt 75:341–346 Messé SR, Shin RK, Liu GT, Galetta SL, Volpe NJ (2001) Oculomotor synkinesis following a midbrain stroke. Neurology 57:1106–1107 Mohr JP (1982) Lacunes. Stroke 13:3–11 Nieuwenhuys R, Voogd J, van Huijzen C (1989) The human central nervous system. Springer, Berlin Richards BW, Jones FR, Younge BR (1992) Causes and prognosis in 4 278 cases of paralysis of the oculomotor, trochlear, and abducens cranial nerves. Am J Ophthalmol 113:489–496 Thömke F, Gutmann L, Stoeter P, Hopf HC (2002) Cerebrovascular brainstem diseases with isolated cranial nerve palsies. Cerebrovascular Diseases 13:147–155 Thömke F, Hopf HC (1999) Pontine lesions mimicking acute peripheral vestibulopathy. J Neurol Neurosurg Psychiatry 66: 340–349 Thömke F, Lensch E, Ringel K, Hopf HC (1997a) Isolated cranial nerve palsies in multiple sclerosis. J Neurol Neurosurg Psychiatry 63: 682–685 Thömke F, Tettenborn B, Hopf HC (1995) Third nerve palsy as the sole manifestation of midbrain ischemia. Neuroophthalmology 15: 327–335 Thömke F (2002) Brainstem diseases causing isolated ocular motor nerve palsies. Neuroophthalmology 28:53–67 Thömke F (1998) Isolated abducens palsies due to pontine lesions. Neuroophthalmology 20:91–100 Thömke F (1999a) Isolated cranial nerve palsies due to brainstem lesions. Muscle Nerve 22:1168–1176 Weber RB, Daroff RB, Mackey EA (1970) Pathology of oculomotor nerve palsy in diabetics. Neurology 20:835–838 Yoritaka A, Tsukamoto T, Ohta K, Kishida S (2001) Facial myokymia associated with an isolated lesion of the facial nucleus. Acta Neurol Scand 104:182–184
3.6 “Speech Disorders” Alexander MP (2001) Chronic akinetic mutism after mesencephalic– diencephalic infraction: remediated with dopaminergic medications. Neurorehabil Neural Repair 15:151–156 Esposito A, Demeurisse G, Alberti B, Fabbro F (1999) Complete mutism after midbrain periaqueductal gray lesion. NeuroReport 10: 681–685 Kammer T, Linden D, Diehl RR, Hennerici M (1993a) Paroxysmal ataxia and dysarthria with a single lesion in the cerebellar peduncle. In: Caplan LR, Hopf HC (eds) Brain-stem localization and function. Springer, Berlin, pp 75–78 Kumral E, Bayülkem G, Evyapan D (2002c) Clinical spectrum of pontine infarction. J Neurol 249:1659–1670 Matsui M, Tomimoto H, Sano K, Hashikawa K, Fukuyama H, Shibasaki H (2004a) Paroxysmal dysarthria and ataxia after midbrain infarction. Neurology 63:345–347 Orefice G, Fragassi NA, Lanzillo R, Castellano A, Grossi D (1999) Transient muteness followed by dysarthria in patients with pontomesencephalic stroke. Cerebrovasc Dis 9:124–126 Ozimek A, Richter S, Hein-Kropp C, Schoch B, Gorißen B, Kaiser O, Gizewski E, Ziegler W, Timmann D (2004) Cerebellar mutism. J Neurol 251:963–972 Schulz GM, Varga M, Jeffires K, Ludlow CL, Braun AR (2005) Functional neuroanatomy of human vocalization: an H215O PET study. Cereb Cortex 15:1835–1847
3 Diagnostic Findings Urban PP, Beer S, Hopf HC (1997a) Cortico-bulbar fibers to orofacial muscles: recordings with enoral surface electrodes. Electroenceph Clin Neurophysiol 105:8–14 Urban PP, Connemann B, Hundemer HP, Koehler J, Hopf HC (1996a) Course of the cortico-hypoglossal projections in the human brainstem. Functional testing by transcranial magnetic stimulation. Brain 119:1031–1038 Urban PP, Hopf HC, Fleischer S, Zorowka P, Müller-Forell W (1997b) Impaired cortico-bulbar tract function in dysarthria due to hemispheric stroke. Brain 120:1077–1084 Urban PP, Hopf HC, Zorowka P, Fleischer S, Andreas J (1996b) Dysarthria and lacunar stroke. Pathophysiological aspects. Neurology 47:1135–1141 Urban PP, Marx J, Hunsche S, Gawehn J, Vucurevic G, Wicht S, Massing-er C, Stoeter P, Hopf HC (2003) Cerebellar speech representation: lesion topography in dysarthria as derived from cerebellar ischemia and functional magnetic resonance imaging. Arch Neurol 60(7):965–972 Urban PP, Wicht S, Hopf HC, Fleischer S, Nickel O (1999a) Isolated dysarthria due to extracerebellar lacunar stroke – a central monoparesis of the tongue. J Neurol Neurosurg Psychiatry 66:495–501 Urban PP, Wicht S, Vukurevic G, Fitzek C, Stoeter P, Massinger C, Hopf HC (2001a) Dysarthria in ischemic stroke – Localization and etiology. Neurology 56:1021–1027 Urban PP (1999) Zur pathophysiologie der dysarthrophonie bei akuten zerebralen Ischämien. Habilitationsschrift, Mainz Weimar C, Kley C, Kraywinkel K, Schacker A, Riepe M, Wimmer MLJ, Goertler M, Diener HC (2002) Klinische Präsentation und Prognose von Hirnstamminfarkten. Nervenarzt 73:166–173 Ziegler W, Ackermann H (1994) Mutismus und Aphasie. Fortschr Neurol Psychiatry 62:366–371
3.7 “Dysphagia” Bartolome G, Buchholz DW, Hannig C, Neumann S, Prosiegel M, Schröter-Morasch H, Wuttge-Hannig A (1993) Diagnostik und therapie neurologisch bedingter Schluckstörungen. Urban & Fischer, München Chiti-Batelli S, Delap T (2001) Lateral medullary infarct presenting as acute dysphagia. Acta Otolaryngol 121:419–420 Ertekin C, Aydogdu I, Tarlaci S, Turman AB, Kiylioglu N (2000) Mechanisms of dysphagia in suprabulbar palsy with lacunar infarct. Stroke 31:1370–1376 Horner J, Buoyer FG, Alberts MJ, Helms MJ (1991) Dysphagia following brainstem stroke. Arch Neurol 48:1170–1173 Jean A (2001) Brain stem control of swallowing: neuronal network and cellular mechanisms. Physiol Rev 81:929–969 Kameda W, Kawanami T, Kurita K, Daimon M, Kayama T, Hosoya T, Kato T (2004) Lateral and medial medullary infarction: a comperative analysis of 214 patients. Stroke 35:694–699 Kim H, Chung C-S, Lee K-H, Robbins J (2000) Aspiration subsequent to a pure medullary infarction. Arch Neurol 57:478–483 Kuhlemeier KV, Rieve JE, Kirby NA, Siebens AA (1989) Clinical correlates of dysphagia in stroke patients. Arch Phys Med Rehabil 70:A56 Kwon M, Lee JH, Kim JS (2005) Dysphagia in unilateral medullary infarction. Neurology 65:714–718 Lee B-C, Hwang S-H, Chang GY (1999) Isolated dysphagia due to a medullary infarction: a new lacunar syndrome. Eur Neurol 41: 53–54 Meng N-H, Wang T-G, Lien I-N (2000) Dysphagia in patients with brainstem stroke. Am J Phys Med Rehabil 6:170–175 Prosiegel M, Heintze M, Wagner-Sonntag E, Hannig C, Wuttge-Hannig A, Yassouridis A (2002) Schluckstörungen bei neurologischen Patienten. Nervenarzt 73:364–370
Literature Prosiegel M, Holing R, Heintze M, Wagner-Sonntag E, Wiseman K (2005) The localization of central pattern generators for swallowing in humans. Acta Neurochir Suppl 93:85–88 Prosiegel M (2003) Qualitätskriterien und Standards für die Diagnostik und Therapie von Patienten mit neurologischen Schluckstörungen. Neurol Rehabil 9:157–181 The FOOD Trial Collaboration (2005) Effect of timing and method of enteral tube feeding for dysphagic stroke patients (FOOD): a multicentre randomised controlled trial. Lancet 365: 764–772 Urban PP, Zahn M, Schranz S, Glassl U, Dieterich M (2004) Abnormal patterns of swallowing in multiple sclerosis. J Neurol 251:25
3.8 “Ataxia” Arias M, Requena I, Lema C, Pereiro I, Villalba C, Iglesias C (1999) Isolated hemi-ataxia as a sign of mesencephalic lacunar infarction. Rev Neurol 29:1179–1181 Baehring JM, Phipps M, Wollmann G (2008) Rostral midbrain infarction producing isolated lateropulsion. Neurology 70:655–656 Bhidayasiri R, Hathout G, Cohen SN, Tourtellotte WW (2003) Midbrain ataxia: possible role of the pedunculopontine nucleus in human locomotion. Cerebrovasc Dis 16:95–96 Chua KS, Kong KH (1996) Functional outcome in brainstem stroke patients after rehabilitation. Arch Phys Med Rehabil 77:194–197 Duus P (2003) Neurologisch topische Diagnostik. 8. Aufl. Thieme, Stuttgart Eidelberg E, Walden JG, Nguyen LH (1981) Locomotor control in macaque monkeys. Brain 104:647–663 Fisher Miller C (1978) Ataxic hemiparesis. Arch Neurol 35:126–128 Kammer T, Linden D, Diehl RR, Hennerici M (1993) Paroxysmal ataxia and dysarthria with a single lesion in the cerebellar peduncle. In: Caplan LR, Hopf HC (eds) Brain-stem localization and function. Springer, Heidelberg, pp 75–78 Kuo S-H, Kennen C, Jankovic J (2008) Bilateral pedunculopontine nuclei strokes presenting as freezing of gait. Mov Disord 23: 616–619 Lee H, Cho YW (2003) Bilateral cerebellar ataxia as the sole manifestation of a unilateral rostral pontine tegmental infarct. J Neurol Neurosurg Psychiatry 74:1444–1446 Marx JJ, Thoemke F, Ianetti GD, Fitzek S, Urban PP, Stoeter P, Cruccu G, Hopf HC, Dieterich M (2006) MRT-basiertes HirnstammMapping zur topodiagnostischen Bedeutung der Hemiataxie. Klin Neurophysiol 37:69 Matsui M, Tomimoto H, Sano K, Hashikawa K, Fukuyama H, Shibasaki H (2004b) Paroxysmal dysarthria and ataxia after midbrain infarction. Neurology 63:345–347 Mitoma H, Hayashi R, Yanagisawa N, Tsukagoshi H (2000) Gait disturbances in patients with pontine medial tegmental lesions. Arch Neurol 57:1048–1057 Rossetti AO, Reichhart MD, Bogousslavsky J (2003a) Central Horner’s syndrome with contralateral ataxic hemiparesis. Neurology 61: 334–338 Schmahmann JD, Rosene DL, Pandya DN (2004a) Ataxia after pontine stroke: insights from pontocerebellar fibers in monkey. Ann Neurol 55:585–589 Seo SW, Heo JH, Lee KY, Shin WC, Chang DI, Kim SM, Heo K (2001) Localization of Claude’s syndrome. Neurology 57:2304–2307 Thömke F, Marx JJ, Iannetti GD, Cruccu G, Fitzek S, Urban PP, Stoeter P, Dieterich M, Hopf HC (2005) A topodiagnostic investigation on body lateropulsion in medullary infarcts. Neurology 64:716–718 Withiam-Leitch S, Pullicino P (1995) Ataxic hemiparesis with bilateral leg ataxia from pontine infarct. J Neurol Neurosurg Psychiatry 59:557–558
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3.9 “Pareses” Bauer G, Gerstenbrand F, Hengl W (1980) Involuntary motor phenomena in the locked-in syndrome. J Neurol 223:191–198 Cerrato P, Imperiale D, Bergui M, Giraudo M, Baima C, Grasso M, Len-tini A, Bergamasco B (2003) Emotional facial paresis in a patient with a lateral medullary infarction. Neurology 60:723–724 Hopf HC, Fitzek C, Marx J, Urban PP, Stoeter P (2000b) Emotional facial paresis of pontine origin. Neurology 54:1217 Hopf HC, Gutmann L (1990) Diabetic 3rd nerve palsy: evidence for a mesencephalic lesion. Neurology 40:1041–1045 Hopf HC (1994) Topodiagnostic value of brainstem reflexes. Muscle Nerve 17:475–484 Humm JL, Kozlowski DA, James DC, Gotts JE, Schallert T (1998) Use-dependent exacerbation of brain damage occurs during an early postlesion vulnerable period. Brain Res 783:286–292 Khurana D, Sreekanth VR, Prabhakar S (2002) A case of emotional facial palsy with ipsilateral anterior inferior cerebellar artery territory infarction. Neurol India 50:102–103 Kimura Y, Hashimoto H, Tagaya M, Abe Y, Etani H (2003) Ipsilateral hemiplegia in a lateral medullary infarct – Opalski’s syndrome. J Neuroimaging 13:83–84 Krasnianski M, Gaul C, Neudecker S, Behrmann C, Schluter A, Winterholler M (2003b) Yawning despite trismus in a patient with locked-in syndrome caused by a thrombosed megadolichobasilar artery. Clin Neurol Neurosurg 106:44–46 Maeder-Ingvar M, van Melle G, Bogousslavsky J (2005) Pure monoparesis: a particular stroke subtype? Arch Neurol 62: 1221–1224 Marx JJ, Iannetti GD, Thömke F, Fitzek S, Urban PP, Stoeter P, Cruccu G, Dieterich M, Hopf HC (2005) Somatotopic organization of the corticospinal tract in the human brainstem: a MRI-based mapping analysis. Ann Neurol 57:824–831 Melo TP, Bogousslavsky J, van Melle G, Rgeli F (1992) Pure motor stroke: a reappraisal. Neurology 42:789–795 Müri RM, Baumgartner RW (1995) Horner’s syndrome and contralateral trochlear nerve palsy. Neuroophthalmology 15:161–163 Paulin M, de Seze J, Wyremblewski P, Zephir H, Leys D, Vermersch P (2005) Man-in-the-barrel syndrome caused by a pontine lesion. Neurology 64:1703 Rossetti AO, Reichhart MD, Bogousslavsky J (2003) Central Horner’s syn drome with contralateral ataxic hemiparesis. Neurology 61:334–338 Ruff RL, Leigh RJ, Wiener SN, Adams NL, Newman CW, Nam KH, Thurston SE (1987) Long-term survivors of the ‘locked-in’ syndrome: patterns of recovery and potential for rehabilitation. J Neuro Rehabil 1:31–42 Scheidtmann K, Freis W, Müller F, Koenig E (2001) Effect of levodopa in combination with physiotherapy on the functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet 258:787–790 Schmahmann JD, Ko R, MacMore J (2004b) The human basis pontis: motor syndromes and topographic organization. Brain 127:1269–1291 Sherman SC, Thompson TT (2005) Pontine hemorrhage presenting as an isolated facial nerve palsy. Ann Emerg Med 46:64–66 Taub E, Miller NE, Novack TA, Cook EW, Fleming WC, Nepomuceno CS, Connell JS, Crago JE (1993) Technique to improve chronic motor deficit after stroke. Arch Phys Med Rehabil 74:347–354 Thömke F, Lensch E, Ringel K, Hopf HC (1997) Isolated cranial nerve palsies in multiple sclerosis. J Neurol Neurosurg Psychiatry 63:682–685 Thömke F (1999) Isolated cranial nerve palsies due to brainstem lesions. Muscle Nerve 22:1168–1176 Urban PP, Beer S, Hopf HC (1997c) Cortico-bulbar fibers to orofacial muscles: recordings with enoral surface electrodes. Electroenceph Clin Neurophysiol 105:8–14
184 Urban PP, Connemann B, Hundemer HP, Koehler J, Hopf HC (1996c) Course of the cortico-hypoglossal projections in the human brain stem. Functional testing by transcranial magnetic stimulation. Brain 119:1031–1038 Urban PP, Wicht S, Fitzek S, Marx J, Thomke F, Fitzek C, Hopf HC (1999b) Ipsilateral facial weakness in upper medullary infarction – supranuclear or infranuclear origin? J Neurol 246: 798–801 Urban PP, Wicht S, Marx J, Mitrovic S, Fitzek C, Hopf HC (1998) Isolated facial paresis due to pontine ischemia. Neurology 50:1859–1862 Urban PP, Wicht S, Vucurevic G, Fitzek S, Marx J, Thömke F, MikaGrüttner A, Fitzek C, Stoeter P, Hopf HC (2001b) The course of cortico-facial projections in the human brainstem. Brain 124: 1866–1876 Urban PP, Wicht S, Vukurevic G, Fitzek C, Stoeter P, Massinger C, Hopf HC (2001c) Dysarthria in ischemic stroke – localization and etiology. Neurology 56:1021–1027 Zakaria T, Flaherty MC (2006) Locked-in syndrome resulting from bilateral cerebral peduncle infarctions. Neurology 67:1889 Zickler P, Seitz RJ, Hartung HP, Hefter H (2005) Bilateral medullary pyramid infarction. Neurology 64:1801
3.10 “Sensory Disturbances” Cerrato P, Imperiale D, Bergui M, Giraudo M, Baima C, Grasso M, Lo-piano L, Bergamasco B (2000) Restricted dissociated sensory loss in a patient with a lateral medullary syndrome. Stroke 31: 3064–3066 Combarros O, Berciano J, Oterino A (1996) Pure sensory deficit with crossed orocrural topography after pontine haemorrhage. J Neurol Neurosurg Psychiatry 61:534–535 Cruccu G, Pennisi E, Truini A, Ianetti GD, Romaniello A, Le Pera D, De Armas L, Leandri M, Manfredi M, Valeriani M (2003) Unmyelinated trigeminal pathways as assessed by laser stimuli in humans. Brain 126:2246–2256 Fitzek S, Baumgärtner U, Fitzek C, Magerl W, Urban P, Thömke F, Marx J, Treede RD, Stoeter P, Hopf HC (2001) Mechanisms and predictors of chronic facial pain in lateral medullary infarction. Ann Neurol 49:493–500 Frese A, Husstedt I, Wingelstein EB, Evers S (2006) Pharmacologic treatment of central post-stroke pain. Clin J Pain 22:252–260 Graham SH, Sharp FR, Dillon W (1988) Intraoral sensation in patients with brainstem lesions: role of the rostral spinal trigeminal nuclei in pons. Neurology 38:1529–1533 Iizuka O, Hosokai Y, Mori E (2006) Trigeminal neuralgia due to pontine infarction. Neurology 66:48 Ikeda K, Iwasaki Y, Kishi H, Imai K, Kinoshita M (1995) Brain stem cheirooral syndrome: neurological signs for brain stem lesions. Clin Neurol Neurosurg 97:192–194 Julkunen L, Tenovuo O, Jääskeläinen SK, Hämäläinen H (2005) Recovery of somatosensory deficits in acute stroke. Acta Neurol Scand 111:366–372 Kamitani T, Kuroiwa Y, Hidaka M (2004) Isolated hypesthesia in the right V2 and V3 dermatomes after a midpontine infarction localised at an ipsilateral principal sensory trigeminal nucleus. J Neurol Neurosurg Psychiatry 75:1508–1589 Kim JS, Jo KD (1992) Pure lemniscal sensory deficit caused by pontine hemorrhage. Stroke 23:300–301 Kim JS, Lee JH, Lee MC (1997) Patterns of sensory dysfunction in lateral medullary infarction. Neurology 49:1557–1563 Kim JS (1993) Trigeminal sensory symptoms due to midbrain lesions. Eur Neurol 33:218–220
3 Diagnostic Findings Lee S-H, Kim D-E, Song E-C, Roh J-K (2001) Sensory dermatomal representation in the medial lemniscus. Arch Neurol 58: 649–651 MacGowan DJL, Janal MN, Clark WC, Wharton RN, Lazar RM, Sacco RL, Mohr JP (1997) Central poststroke pain and Wallenberg’s lateral medullary infarction. Neurology 49:120–125 Minagar A, Sheremata WA (2000) Glossopharyngeal neuralgia and MS. Neurology 54:1368–1370 Nakamura K, Yamamoto T, Yamashita M (1996) Small medullary infarction presenting as painful trigeminal sensory neuropathy. J Neurol Neurosurg Psychiatry 61:138 Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Lavenne F, Veyre L, Froment JC, Maugiere F, Michel D (1998) Laurent. Allodynia after lateralmedullary (Wallenberg) infarct. Brain 121:345–356 Schommer M, Weiß J, Kiehl P, Kapp A, Prawitz RH, Brodersen JP (2000) Trigeminotrophe Ulzeration des Nasenflügels bei Wallenberg-Syndrom. Hautarzt 51:434–438 Shiga K, Miyagawa M, Yamada K, Nakajima K (2003a) Pontine pseudoathetosis: lemniscal involvement visualized by axonal tracking method with diffusion tensor imaging. J Neurol 250:511–512 Stöhr M, Petruch F, Scheglmann K (1981) Somatosensory evoked potentials following trigeminal nerve stimulation in trigeminal neuralgia. Ann Neurol 9:63–66 Treede RD, Lorenz J, Baumgärtner U (2003) Clinical usefulness of laser-evoked potentials. Neurophysiol Clin 33:303–314 Urban PP, Hansen C, Baumgärtner U, Fitzek S, Marx J, Fitzek C, Treede RD, Hopf HC (1999c) Abolished laser-evoked potentials and normal blink reflex in midlateral medullary infarction. J Neurol 246:347–352 Valls-Solé J (2005) Neurophysiological assessment of trigeminal nerve reflexes in disorders of central and peripheral nervous system. Clin Neurophysiol 116:2255–2265 Vuadens P, Bogousslavsky J (1998) Face-arm-trunk-leg sensory loss limited to the contralateral side in lateral medullary infarction: a new variant. J Neurol Neurosurg Psychiatry 65:255–257 Yasuda Y, Akiguchi I, Ishikawa M, Kakeyama M (1988) Bilateral cheirooral syndrome following pontine hemorrhage. J Neurol 235: 489–490 Yasuda Y, Watanabe T, Tanaka H, Ogura A (1998) Localizing value of bilateral cheiro-oral sensory impairment. Intern Med 37:982–985 Yekutiel M, Guttman E (1993) A controlled trial of the retraining of the sensory function of the hand in stroke patients. J Neurol Neurosurg Psychiatry 56:241–244
3.11 “Bladder Disturbances” Athwal BS, Berkley KJ, Hussain I, Brennan A, Craggs M, Sakakibara R, Frackowiak RSJ, Fowler CJ (2001) Brain responses to changes in bladder volume and urge to void in healthy men. Brain 124:369–377 Barrington FJF (1925) The effect of lesions of hind and midbrain on micturation in the cat. Q J Exp Physiol 127:958–963 Blok BF, Holstege G (1994) Direct projections from the periaqueductal gray to the pontine micturation center (M-region). An anterograde and retrograde tracing study in the cat. Neurosci Lett 166: 93–96 Blok BFM, Willemsen ATM, Holstege G (1997) A PET study on brain control of micturation in humans. Brain 120:111–121 Deleu D, El Siddij A, Kamran S, Hamad A, Salim K (2004) Urinary retention associated with mild rhombencephalitis. J Neurol Neurosurg Psychiatry 75:1504–1509
Literature Grifiths D, Holstege G, Dalm E, de Wall H (1990) Control and coordination of bladder and urethral function in the brainstem of the cat. Neurourol Urodyn 9:63–82 Komiyama A, Kubota A, Hidai H (1998) Urinary retention with a unilateral lesion in the dorsolateral tegmentum of the rostral pons. J Neurol Neurosurg Psychiatry 65:953–954 Naganuma M, Inatomi Y, Yonehara T, Hashimoto Y, Hirano T, Uchino M (2005) Urinary retention associated with unilateral medullary infarction. Rinsho Shinkeigaku 45:431–436 Nour S, Svarer C, Kristensen JKI, Paulson OB, Law I (2000) Cerebral activation during micturation in normal men. Brain 123:781–789 Vanderhorst VG, Mouton LJ, Blok BF, Holstege G (1996) Distinct cell groups in the lumbosacral cord in the cat project to different areas in the periaqueductal gray. J Comp Neurol 376:361–385 Yaguchi H, Soma H, Miyazaki Y, Tashiro J, Yabe I, Kikuchi S, Sasaki H (2004) A case of urinary retention caused by periaqueductal grey lesion. J Neurol Neurosurg Psychiatry 75:1200–1207
3.12 “Drop Attacks” Baloh RW, Jacobson K, Winter T (1990) Drop attacks with Meniere’s syndrome. Ann Neurol 28:384–387 Brantberg K, Ishiyama A, Baloh RW (2005) Drop attacks secondary to superior canal dehiscence syndrome. Neurology 64:2126–2128 Brust JCM, Plank CR, Healton EB, Sanchez GF (1979) The pathology of drop attacks: a case report. Neurology 29:786–790 Gerstner E, Liberato B, Wright CB (2005) Bi-hemispheric anterior cerebral artery with drop attacks and limb shaking TIAs. Neurology 65:174 Grunwald T, Mothersill I, Krämer G (2005) Stürze. In: Schmitz B, Tettenborn B (eds) Paroxysmale Störungen in der Neurologie. Springer, Heidelberg, pp 27–49 Kubala M, Milikan C (1964) Diagnosis, pathogenesis and treatment of drop attacks. Arch Neurol 11:107–113 Lee MS, Choi YC, Heo JH, Choi IS (1994) Drop attacks with stiffening of the right leg associated with posterior fossa arachnoid cyst. Mov Disord 9:377–378 Meisner I, Wiebers DO, Swanson JW, O’Fallon WM (1986) The natural history of drop attacks. Neurology 36:1029–1034 Mumenthaler M (ed) (1984) Synkopen und Sturzanfälle. Thieme, Stuttgart, p 55 Schelosky L (2005) Paroxysmale Bewegungsstörungen. In: Schmitz B, Tettenborn B (eds) Paroxysmale Störungen in der Neurologie. Springer, Heidelberg, pp 156–175 Stevens DL, Mathews WB (1973) Cryptogenetic drop attacks: an affliction of women. Br Med J I:439–442 Tinuper P, Cerullo A, Marini C, Avoni P, Rosati A, Riva R, Baruzzi A, Lugaresi E (1998) Epileptic drop attacks in partial epilepsy: clinical features, evolution, and prognosis. J Neurol Neurosurg Psychiatry 64:231–237
3.13 “Respiratory Disturbances” Holstege G (1991) Descending motor pathways and the spinal motor system: limbic and non-limbic components. Prog Brain Res 87:307–421 Hui SHL, Wing YK, Poon W, Chan YL, Bukley TA (2000) Alveolar hypoventilation syndrome in brainstem glioma with improvement after surgical resection. Chest 118:266–268
185 Lanczik O, Szabo K, Lecei O, Binder J, Thiel S, Gass A, Hennerici M (2006) Central respiratory dysfunction following vertebral artery dissection. Neurology 66:944 Lassman AB, Mayer SA (2005) Paroxysmal apnea and vasomotor instability following medullary infarction. Arch Neurol 62:1286–1288 Munschauer FE, Mador MJ, Ahuja A, Jacobs L (1991) Selective paralysis of voluntary but not limbically influenced automatic respiration. Arch Neurol 48:1190–1192 Oya S, Tsutsumi K, Yonekura I, Inoue T (2001) Delayed central respiratory dysfunction after Wallenberg’s syndrome. Neurol Med Chir Tokyo 41:502–504 Plum F, Posner JB (1982) The diagnosis of stupor and coma. Davis, Philadelphia Rao GSU, Ramesh VJ, Lalla RK (2005) Ventilatory management and weaning in a patient with central hypoventilation caused by a brainstem cavernoma. Acta Anaesthesiol Scand 49:1214–1217 Schäfer D, Bianchi O, Greulich W, Schäfer C, Schäfer T, Schläfke ME (1996) Störungen von Schlaf und Atmung bei Patienten mit Hirnstammläsionen. Wien Med Wschr 146:296–298 Schestatsky P, Fernandes LNT (2004) Acquired ondine’s curse. Arq Neuropsiquiatr 62:523–527 Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL (1991) Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254:726–729 Urban PP, Morgenstern M, Brause K, Wicht S, Vucurevic G, Kessler S, Stoeter P (2002) Distribution of cortico-respiratory projections for voluntary activation in man. J Neurol 249:735–744 Whit DP, Zwillich CW, Pickett CR (1982) Central sleep apnea. Improvement with acetazolamide therapy. Ann Intern Med 142:1816–1819
3.14 “Disturbances of Consciousness” Markowitsch HJ (1999) Funktionelle anatomie von Bewusstsein und Bewusstseinsstörungen. In: Hopf HC, Deuschl G, Diener HC, Reich-mann H (eds) Neurologie in Praxis und Klinik. Thieme, Stuttgart, pp 61–65 Parvizi J, Damasio AR (2003) Neuroanatomical correlates of brainstem coma. Brain 126:1524–1536 Posner JB, Saper CB, Schiff ND, Plum F (2007) Plum and posner’s diagnosis of stupor and coma. Oxford University Press, New York Moruzzi G, Magoun HW (1949) Brainstem reticular formation and activation of the EEG. Electroenecphalogr Clin Neurophysiol 1:455–473 Thömke F (2001c) Augenbewegungsstörungen im Koma. In: Thömke F (ed) Augenbewegungsstörungen. Thieme, Stuttgart, pp 229–234
3.15 “Brain Death Diagnosis in Primary Brainstem Injury” Besser R (1994) EEG-Diagnostik beim Hirntod. EEG Labor 16:64–74 Bonetti MG, Ciritella P, Valle G, Perrone E (1995) 99mTc-HMPAO brain perfusion SPECT in brain death. Neuroradiology 37:365–369 Buchner H, Schuchardt V (1990) Reliability of electroencephalogram in the diagnosis of brain death. Eur Neurol 30:138–141 Deutsche Gesellschaft für Klinische Neurophysiologie (1994) Empfehlungen der Deutschen Gesellschaft für Klinische
186 Neurophysiologie (Deutsche EEG-Gesellschaft) zur Bestimmung des Hirntodes. Z EEG EMG 25:163–166 George MS (1991) Establishing brain death: the potential role of nuclear medicine in the search for reliable confirmatory test. Eur J Nucl Med 12:707–713 Goodman JM, Heck LL, Moore BD (1985) Confirmation of brain death with portable isotope angiography: a review of 204 consecutive patients. Neurosurgery 16:492–497 Grigg MM, Kelly MA, Celesia GG, Ghobrial MW, Ross ER (1987) Electroencephalographic activity after brain death. Arch Neurol 44:948–954 Hassler W, Steinmetz H, Gawlowski J (1988) Trancranial Doppler ultrasonography in raised intracranial pressure and intracranial circulatory arrest. J Neurosurg 68:745–751 Lemmon GW, Franz RW, Roy N, McCarthy MC, Peoples JB (1995) Determination of brain death with use of color duplex scanning in the intensive care unit setting. Arch Surg 130:517–522 Pallis C (1995) Brainstem death. In: Braakman R (ed) Handbook of clinical neurology, vol 57 (volume 13 revised series). Elsevier, Amsterdam, pp 441–496 Payen DM, Lamer C, Pilorget A, Moreau T, Beloucif S, Echter E (1990) Evaluation of pulsed doppler common carotid blood flow as a noninvasive method for brain death diagnosis: a prospective study. Anesthesiology 72:222–226 Petty GW, Mohr JP, Pedley TA, Tatemichi TK, Lennihan L, Duterte DI, Sacco RL (1990) The role of transcranial Doppler in confirming brain death: Sensitivity, specificity, and suggestions for performance and interpretation. Neurology 40:300–303 Powers AD, Graeber MC, Smith RR (1989) Transcranial Doppler ultrasonography in the determination of brain death. Neurosurgery 24:884–889 Schlake H-P, Böttger IG, Grotemeyer K-H, Husstedt IW, Brandau W, Schober O (1992) Determination of cerebral perfusion by means of planar scintigraphy and 99mTc-HMPAO in brain death, persistent vegetative state and severe coma. Intensive Care Med 18:76–81 Wijdicks EFM (1995) Determining brain death in adults. Neurology 45:1003–1011 Wissenschaftlicher Beirat der Bundesärztekammer. Richtlinien zur Feststellung des Hirntodes. Dritte Fortschreibung 1997 mit Ergänzung gemäß Transplantationsgesetz (TPG) (1998). Dtsch Ärztebl 95: B1509–1516
3.16 “Clinical Brainstem Reflexes” Addington WR, Stephens RE, Widdicombe JG, Rekab K (2005) Effect of stroke location on the laryngeal cough reflex and pneumonia risk. Cough 4:1–4 Davies AE, Kidd D, Stone SP, MacMahon J (1995) Pharyngeal sensation and gag reflex in healthy subjects. Lancet 345:487–488 Duus P (1983) Neurologisch-topische Diagnostik. Thieme, Stuttgart Hughes TAT, Wiles CM (1996) Palatal and pharyngeal reflexes in health and in motor neuron disease. J Neurol Neurosurg Psychiatry 61:96–98 Ongerboer de Visser BW (1980) The corneal reflex: electrophysiological and anatomical data in man. Progr Neurobiol 15:71–83 Pantaleo T, Bongianni F, Mutolo D (2002) Central nervous mechanisms of cough. Pulm Pharmacol Ther 15:227–233
3.17 “Rare Findings/Symptoms” Al Deeb SM, Sharif H, Al Moutaery K, Biary N (1991) Intractable hiccup induced by brainstem lesion. J Neurol Sci 103:144–150
3 Diagnostic Findings Arif H, Mohr JP, Elkind MSV (2005) Stimulus-induced pathologic laughter due to basilar artery dissection. Neurology 64: 2154–2155 Arita H, Oshima T, Kita I, Sakamoto M (1994) Generation of hiccup by electrical stimulation in medulla of cats. Neurosci Lett 175:67–70 Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic parkinson’s disease. Neurobiol Aging 24:197–211 Brandt T, Dieterich M, Strupp M (2004) Vertigo. Steinkopff, Darmstadt, S. 54 Brandt T (1999b) Vertigo: its multisensory syndromes, 2nd edn. Springer, Heidelberg Cascino GD, Adams RD (1986) Brainstem auditory hallucinosis. Neurology 36:1042–1047 Cattaneo L, Cucurachi L, Chierici E, Pavesi G (2006) Pathological yawning as a presenting symptom of brain stem ischaemia in two patients. J Neurol Neurosurg Psychiatry 77:98–100 Cerrato P, Lentini A, Baima C, Grasso M, Azzaro C, Bosco G, Destefanis E, Benna P, Bergui M, Bergamasco B (2005) Hypogeusia and hearing loss in a patient with an inferior collicular infarction. Neurology 65:1840–1841 Dabby R, Watemberg N, Lampl Y, Eilam A, Rapaport A, Sadeh M (2004) Pathological laughter as a symptom of midbrain infarction. Behav Neurol 15:73–76 Esteban Munoz J, Tolosa E, Saoz A, Vila N, Marti MJ, Blesa R (1996) Upperlimb dystonia secondary to a midbrain hemorrhage. Mov Disord 11:96–99 Fink JN (2001) Localization of the sneeze center. Neurology 56:138 Hersch M (2000) Loss of ability to sneeze in lateral medullary syndrome. Neurology 54:520–521 Hornby PJ (2001) Central neurocircuitry associated with emesis. Am J Med 111:106S–112S Jacome DE (1997) Gaze-evoked orbicularis oculi myokymia. J Neuroophthalmol 17:95–100 Kamalakannan D, Ravi S, Moudgil SS (2004) Peduncular hallucinosis: unusual complication of cardiac catheterization. S Med J 97: 99–1000 Kataoka S, Hori A, Shirakawa T, Hirose G (1997) Paramedian pontine infarction. Stroke 28:809–815 Kaufman DK, Brown RD, Karnes WE (1994) Involuntary tonic spasms of a limb due to a brainstem lacunar infarction. Stroke 25: 217–219 Kellett MW, Young GR, Fletcher NA (1997) Painful tonic spasms and pure motor hemiparesis due to lacunar pontine infarct. Mov Disord 12:1094–1096 Kim BS, Kim YI, Lee KS (1995) Contralateral hyperhidrosis after cerebral infarction. Stroke 26:896–899 Kim JS (1997) Pathologic laughter after unilateral stroke. J Neurol Sci 148:121–125 Korpelainen JT, Huikuri HV, Sotaniemi KA, Myllylä VV (1996) Abnormal heart rate variability reflecting autonomic dysfunction in brainstem infarction. Acta Neurol Scand 94:337–342 Korpelainen JT, Sotaniemi KA, Myllylä VV (1993) Ipsilateral hypohidrosis in brainstem infarction. Stroke 24:100–104 LeDoux MS, Brady KA (2003) Secondary cervical dystonia associated with structural lesions of the central nervous system. Mov Disord 18:60–69 Lee B-C, Hwang SH, Rison R, Chang GY (1998) Central pathway of taste: clinical and MRI study. Eur Neurol 39:200–203 Manford M, Andermann F (1998) Complex visual hallucinations. Brain 121:1819–1840 Marx JJ, Iannetti GD, Mika-Gruettner A, Thoemke F, Fitzek S, Vu-curevic G, Urban PP, Stoeter P, Cruccu G, Hopf HC (2004b) Topodiagnostic investigations on the sympathoexcitatory brainstem pathway using a new method of three dimensional brainstem mapping. J Neurol Neurosurg Psychiatry 75:250–255 Marx JJ, Thömke F, Birklein F (2004c) Das Horner-Syndrom – ein update zur Neuroanatomie, topographischen Differentialdiagnostik und Ätiologie. Fortschr Neurol Psychiat 72:1–7
Literature Meglic B, Kobal J, Osredkar J, Pogacnik T (2001) Autonomic nervous system function in patients with acute brainstem stroke. Cerebrovasc Dis 11:2–8 Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y (2005) Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica. Neurology 65:1479–1482 Morgan JC, Sethi KD (2003) Midbrain infarct with parkinsonism. Neurology 60:E10 Mumentahler M, Altermatt M (1967) Zur Klinik der tonischen Hirnstammanfälle. Schweiz Arch Neurol Neurochir Psychiatr 100: 70–87 Nikkah G, Prokop T, Hellwig B, Lücking CH, Ostertag CB (2004) Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions. J Neurosurg 100:1079–1083 Okuda DT, Chyung ASC, Chin CT, Waubant E (2005) Acute pathological laughter. Mov Disord 20:1389–1390 Orima S, Amino T, Tanaka H, Mitani K, Ishiwata K, Ishii K (2004) A case of hemiparkinsonism following ischemic lesion of the contralateral substantia nigra: a PET study. Eur Neurol 51: 175–177 Parisis D, Poulis I, Karkavelas G, Drevelengas A, Artemis N, Karacostas D (2003) Peduncular hallucinosis secondary to brainstem compression by cerebellar metastases. Eur Neurol 50:107–109 Park MH, Kim BJ, Koh SB, Park MK, Park KW, Lee DH (2005) Lesional location of lateral medullary infarction presenting hiccups (singultus). J Neurol Neurosurg Psychiatry 76:95–98 Patzner J, Pfister R, Pfadenhauer K (2004) Paradoxe Innervation der Kaumuskulatur bei ipsilateraler Hirnstammläsion. Akt Neurol 31:200–202 Pellecchia MT, Crisuolo C, Joanna G, D’Amico A, Santor L, Barone P (2003) Pure unilateral hyperhidrosis after pontine infarct. Neurology 61:1305 Phillips AM, Jardine DL, Parkin PJ, Hughes T, Ikram H (2000) Brain stem stroke causing baroreflex failure and paroxysmal hypertension. Stroke 31:1997–2001 Saglitz SA, Gaab MR (2002) Investigations using magnetic resonance imaging: is neurovascular compression present in patients with essential hypertension? J Neurosurg 96:1006–1012 Sawaii S, Sakakibara R, Kanai K, Kawaguchi N, Uchiyama T, Yamamoto T, Ito T, Liu Z, Haltori T (2006) Isolated vomiting due to a unilateral dorsal vagal complex lesion. Eur Neurol 56: 246–248
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4
Diseases
Contents 4.1 Vascular Brainstem Diseases . . . . . . . . . . . . . . . . . . . . 4.1.1 Brainstem Infarctions . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Local Atherothrombosis . . . . . . . . . . . . . . . . . . . . . . . . . Microangiopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dissections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Altered Hemodynamics . . . . . . . . . . . . . . . . . . . . . . . . . Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aneurysms and Megadolichobasilaris . . . . . . . . . . . . . . Vertebral Artery Compression on Head Rotation . . . . . . Mitochondrial Disorders . . . . . . . . . . . . . . . . . . . . . . . . . Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebral Vein Thrombosis . . . . . . . . . . . . . . . . . . . . . . . Arterial Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medulla Oblongata Infarctions . . . . . . . . . . . . . . . . . . . . Pontine Infarctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Midbrain Infarctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thalamic Infarctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Infarctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basilar Artery Occlusion . . . . . . . . . . . . . . . . . . . . . . . . Dissection of Vertebral Arteries . . . . . . . . . . . . . . . . . . . Subclavian Steal Syndrome . . . . . . . . . . . . . . . . . . . . . . Classic Brainstem Syndromes . . . . . . . . . . . . . . . . . . . . 4.1.1.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parenchymal Imaging Diagnostics . . . . . . . . . . . . . . . . . Vascular Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1.5 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1.6 Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1.7 Prognosis and Course of Disease . . . . . . . . . . . . . . . . . . 4.1.2 Intraparenchymatous Brainstem Hemorrhage . . . . . . . . 4.1.2.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.7 Conservative Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.8 Operative Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2.9 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3 Perimesencephalic Subarachnoid Hemorrhage and Cerebral Superficial Siderosis . . . . . . . . . . . . . . . . . 4.1.3.1 Perimesencephalic Subarachnoid Hemorrhage . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
193 193 193 193 193 194 194 195 195 196 196 196 197 197 197 197 197 198 199 200 201 201 202 203 203 204 204 204 208 209 210 210 211 211 212 212 214 214 214 215 215 215 216 216 216 216 217
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3.2 Cerebral Superficial Siderosis . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4 Vascular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4.1 Cavernomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4.2 Capillary Telangiectasias . . . . . . . . . . . . . . . . . . . . . . . . Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Developmental Venous Anomalies . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4.3 Pial Arteriovenous Malformations . . . . . . . . . . . . . . . . . Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4.4 Dural Arteriovenous Malformations . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5 Basilar Migraine/Vestibular Migraine . . . . . . . . . . . . . . Marianne Dieterich and Sandra Bense . . . . . . . . . . . . . . 4.1.5.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5.6 Therapy and Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5.7 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
217 218 218 218 219 219 219 219 219 220 220 220 220 220 221 221 222 222 222 222 223 223 223 223 223 223 224 224 224 225 225 225 225 225 225 225 225 226 226 227 227 227 228
4.2 Inflammatory Brainstem Diseases . . . . . . . . . . . . . . . . 4.2.1 General Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.5 Laboratory Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.6 Diagnostic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
228 228 228 229 229 230 230 232
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4.2.1.7 Electrophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.8 Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.9 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.10 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.11 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Specialized Part . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.1 Viral Encephalitides . . . . . . . . . . . . . . . . . . . . . . . . . . . . Herpes Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . Enterovirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . Myxovirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . Arboviral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infections with Other Viruses . . . . . . . . . . . . . . . . . . . . . 4.2.2.2 Bacterial Encephalitides . . . . . . . . . . . . . . . . . . . . . . . . . Meningoencephalitis, Focal Encephalitis, Cerebral Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Borreliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Listeriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lues (Syphilis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Whipple’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Legionellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Encephalitides Caused by Atypical Bacterial Causative Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.3 Parasitic Encephalitides . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.4 Fungal Encephalitides . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.5 Encephalitides in Immunosuppressed and HIV/AIDS Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.6 Non-causative Agent-Specific Encephalitides . . . . . . . . 4.2.2.7 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.8 Behçet’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.9 Systemic Lupus Erythematosis . . . . . . . . . . . . . . . . . . . .
233 233 233 233 234 235 235 235 236 236 237 237 238
238 238 239 239 239 240 240
240 241 241 242 242
4.3 Brainstem Involvement in Demyelinating Diseases . . 4.3.1 Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.2 Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.4 Oculomotor Disturbances . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.5 Cranial Nerve Deficits . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.6 Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.7 Auditory Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.8 Vertigo, Balance, and Gait . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.9 Lesions of the Pyramidal Tract . . . . . . . . . . . . . . . . . . . . 4.3.1.10 Emotional Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.11 Paroxysmal Phenomena . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.12 Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.13 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.14 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.15 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1.16 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2 Multiple Sclerosis Subtypes . . . . . . . . . . . . . . . . . . . . . . 4.3.2.1 Acute Disseminated Encephalomyelitis . . . . . . . . . . . . . 4.3.2.2 Baló’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2.3 Marburg-Type Multiple Sclerosis . . . . . . . . . . . . . . . . . . 4.3.3 Progressive Multifocal Leukoencephalopathy . . . . . . . .
243 243 243 243 244 244 245 246 246 246 246 247 247 247 247 249 249 249 249 249 250 250 250
4.4 Paraneoplastic Brainstem Syndromes . . . . . . . . . . . . 4.4.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.7 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
251 251 251 252 253 254 254 255 255
240 240 240
4.5 Brainstem Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 4.5.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 4.5.1.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
4.5.1.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.1.3 Clinical Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.1.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic Resonance Imaging and Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MR Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Positron Emission Tomography . . . . . . . . . . . . . . . . . . . Cerebrospinal Fluid Examination . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2 Intrinsic Brainstem Tumors . . . . . . . . . . . . . . . . . . . . . . 4.5.2.1 Brainstem Gliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition and Epidemiology . . . . . . . . . . . . . . . . . . . . . 4.5.2.2 Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Gliomas in Adults . . . . . . . . . . . . . . . . . . . . . Pediatric Brainstem Gliomas . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.7 Ependymomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology and Classification . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostics and Differential Diagnosis . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.8 Medulloblastomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostics and Differential Diagnosis . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.9 Gangliogliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2.10 Tumors of the Choroid Plexus . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.3 Extrinsic Brainstem Tumors . . . . . . . . . . . . . . . . . . . . . . 4.5.3.1 Metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.3.2 Schwannomas of the Cerebellopontine Angle . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.3.3 Meningiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology and Classification . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
256 256 257 257 257 258 258 258 258 259 259 259 260 260 260 261 261 261 261 262 262 262 263 263 263 263 264 264 264 264 264 264 264 265 265 265 265 265 265 265 265 265 266 266 266 266 266 266 266 266 267 267 267 267 268 268 268 268 268 269 269 269 270 270 270 270 270
4 Diseases
191
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.3.4 Hemangioblastomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology and Etiopathogenesis . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis and Differential Diagnosis . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
270 270 270 271 271 271 271 271 271 272
4.6 Traumatic Brainstem Lesions . . . . . . . . . . . . . . . . . . . 4.6.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.4 Diagnosis and Differential Diagnosis . . . . . . . . . . . . . . . 4.6.5 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.6 Prevention of a Secondary Brainstem Lesion . . . . . . . . . 4.6.7 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
272 272 272 273 275 277 277 278 278
4.7 Degenerative Brainstem Diseases . . . . . . . . . . . . . . . . Andres Ceballos-Baumann . . . . . . . . . . . . . . . . . . . . . . 4.7.1 Syndrome-Orientated Classification . . . . . . . . . . . . . . . . 4.7.2 Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2.3 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.2.7 Course and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3 Parkinsonism with Early Onset of Dementia . . . . . . . . . 4.7.3.1 Lewy Body Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3.2 Subcortical Vascular Encephalopathy, Vascular Parkinsonism and Normal Pressure Hydrocephalus . . . . 4.7.3.3 Parkinsonism in Alzheimer’s Dementia . . . . . . . . . . . . . 4.7.3.4 Frontotemporal Lobar Degeneration . . . . . . . . . . . . . . . 4.7.3.5 Progressive Supranuclear Gaze Palsy . . . . . . . . . . . . . . . 4.7.3.6 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3.7 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3.8 Clinical Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3.9 Diagnosis and Differential Diagnosis . . . . . . . . . . . . . . . 4.7.3.10 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3.11 Corticobasal Degeneration . . . . . . . . . . . . . . . . . . . . . . . 4.7.3.12 Rare Parkinsonian Syndromes with Dementia . . . . . . . . 4.7.4 Multiple System Atrophy . . . . . . . . . . . . . . . . . . . . . . . . 4.7.4.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.4.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.4.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.4.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.4.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.4.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.4.7 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.5 Tremors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.5.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.5.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.5.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.5.4 Diagnosis and Differential Diagnosis . . . . . . . . . . . . . . . 4.7.5.5 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
279 279 279 280 280 280 282 284 284 284 285 285 285
4.8 Abnormalities of Brainstem Development . . . . . . . . . 4.8.1 Chiari Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.1 Chiari Malformation Type I . . . . . . . . . . . . . . . . . . . . . . 4.8.1.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.3 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.4 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.5 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.6 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . .
297 297 298 298 298 298 298 298
286 288 288 288 289 289 289 290 290 291 292 292 292 292 293 293 294 294 295 295 295 295 295 297 297
4.8.1.7 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.8 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.9 Chiari Malformation Type II . . . . . . . . . . . . . . . . . . . . . . 4.8.1.10 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.11 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.12 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.13 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.14 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.15 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1.16 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2 Dandy-Walker Malformation . . . . . . . . . . . . . . . . . . . . . 4.8.2.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.2.7 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3 Aqueductal Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3.6 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.3.7 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.4 Rare Disturbances in Brainstem Development . . . . . . . 4.8.5 Brainstem Impairment due to Pathologic Neighboring Structures . . . . . . . . . . . . . . . . . . . . . . . . . .
299 299 299 299 299 299 299 300 300 300 300 300 300 300 301 301 301 301 302 302 302 302 302 302 302 302 303
303
4.9 Metabolic Brainstem Diseases . . . . . . . . . . . . . . . . . . . 4.9.1 Central Pontine Myelinolysis . . . . . . . . . . . . . . . . . . . . . 4.9.1.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1.2 Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1.3 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1.5 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1.6 Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1.7 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.1.8 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2 Vitamin Deficiency Diseases . . . . . . . . . . . . . . . . . . . . . 4.9.2.1 Vitamin B1 Hypovitaminosis . . . . . . . . . . . . . . . . . . . . . 4.9.2.2 Beriberi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.3 Strachan’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.4 Wernicke’s Encephalopathy . . . . . . . . . . . . . . . . . . . . . . Epidemiology and Etiopathogenesis . . . . . . . . . . . . . . . . Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.5 Course and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.6 Vitamin B12 Hypovitaminosis . . . . . . . . . . . . . . . . . . . . . 4.9.2.7 Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.8 Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.9 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.10 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.11 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.12 Course and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2.13 Other Vitamin Deficiency Diseases . . . . . . . . . . . . . . . . 4.9.3 Hereditary Metabolic Diseases . . . . . . . . . . . . . . . . . . . . 4.9.3.1 Wilson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.2 Pantothenate Kinase-Associated Neurodegeneration . . .
303 304 304 304 305 305 306 306 306 307 307 307 308 308 308 308 308 309 309 309 310 310 310 310 310 311 311 311 311 312 312 312 312 312 313 313 314 314
192 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.3 Aceruloplasminemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.4 Lysosomal Metabolic Diseases . . . . . . . . . . . . . . . . . . . . 4.9.3.5 Gaucher’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.6 Fabry’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.7 Niemann-Pick Type C Disease . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.8 GM2 Gangliosidoses . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.9 Chediak-Higashi Syndrome . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.10 Other Lysosomal Metabolic Diseases . . . . . . . . . . . . . . . 4.9.3.11 Cerebrotendinous Xanthomatosis . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.12 Leukodystrophies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.13 Metachromatic Leukodystrophy . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.14 Other Leukodystrophies . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.15 Neurotransmitter Defects . . . . . . . . . . . . . . . . . . . . . . . .
4 Diseases 314 314 314 314 314 314 314 314 315 315 315 315 315 315 315 315 315 315 316 316 316 316 316 316 316 316 316 316 316 316 317 317 317 317 317 317 317 317 317 317 317 317 318 318 318 318 318 318 318 318 318 318 318 319 319 319 319 319
4.9.3.16 Segawa Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.17 Tyrosine Hydroxylase Defects . . . . . . . . . . . . . . . . . . . . 4.9.3.18 Neuronal Ceroid Lipofuscinoses . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3.19 Urea Cycle Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.4 Mitochondrial Encephalomyopathies . . . . . . . . . . . . . . . 4.9.4.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.4.2 MELAS Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.4.3 Leigh’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.4.4 Kearns-Sayre Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10 Vascular Cranial Nerve and Brainstem Compressions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.10.1 Vascular Compression of Cranial Nerves . . . . . . . . . . . . 4.10.1.1 Oculomotor Nerve Compression . . . . . . . . . . . . . . . . . . 4.10.1.2 Trochlear Nerve Compression . . . . . . . . . . . . . . . . . . . . 4.10.1.3 Trigeminal Nerve Compression . . . . . . . . . . . . . . . . . . . 4.10.1.4 Abducens Nerve Compression . . . . . . . . . . . . . . . . . . . . 4.10.1.5 Facial Nerve Compression . . . . . . . . . . . . . . . . . . . . . . . 4.10.1.6 Vestibulocochlear Nerve Compression . . . . . . . . . . . . . . 4.10.1.7 Glossopharyngeal Nerve Compression . . . . . . . . . . . . . . 4.10.2 Arterial Hypertension Secondary to Brainstem Compression . . . . . . . . . . . . . . . . . . . . . . .
320 320 320 320 320 320 320 320 320 320 320 321 321 321 321 321 321 321 321 321 321 322 322 322 322 323 324 324 324 324 324 325 325 325 325 325 325 325 325 326 326 326 326 326 326 326 327 327 328 328 329 329
330
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
4.1 Vascular Brainstem Diseases
4.1 Vascular Brainstem Diseases Jürgen Marx, Peter P. Urban, Frank Thömke, Wibke Müller-Forell, Sandra Bense, and Marianne Dieterich
4.1.1 Brainstem Infarctions Cerebral circulatory disturbances represent the third most frequent cause of death in Western industrialized countries after cardiovascular diseases and neoplasms. With the advent of new diagnostic and therapeutic procedures as, e.g. thrombolysis therapy, cerebral ischemias have become a topic of central importance in clinical neurology. In particular due to the increasing number of available interventional therapies in the carotid artery territory, significantly less attention has been given to the posterior circulation and therefore to vertebrobasilar infarctions. In many instances the described vascular system continues to be only insufficiently evaluated. The great morphologic and clinical variability of the findings further contributes to the difficulty of viewing brainstem infarctions as a nosologic unit.
4.1.1.1 Epidemiology The annual incidence of cerebral ischemia ranges from 190– 350 per 100,000 population (Häussler 1996). Approximately 20% of cerebral perfusion is supplied by the vertebral arteries, and a similar percentage (15–20%) of all cerebral ischemias occurs in the posterior circulation (Caplan et al. 2004). The results of large epidemiologic studies (Heinemann et al. 1998; Fitzek and Fitzek 2005) indicate that males are more often affected by vertebrobasilar ischemia, accounting for 65–70% of all cases. Different studies have reported a median age from 60–65 years for patients with brainstem ischemia, which shows this group of patients to be approximately 5 years younger on average than patients with supratentorial infarctions. Patients with brainstem infarctions were further characterized by a higher rate of vascular risk factors: compared with the risk profile of patients with anterior circulation infarctions, patients with brainstem infarctions had a higher incidence of arterial hypertension (54–72%) and diabetes mellitus (33–42%) (Weimar et al. 2002; Fitzek and Fitzek 2005). Additional vascular risk factors, including lipometabolic disturbances and nicotine consumption had a distribution similar to that of other infarction localizations. Atrial fibrillation was detected significantly less often in patients with brainstem ischemia (9–12%) than in those with anterior circulation infarctions (approx. 20%). Different infarction topographies with varying incidence rates can be identified depending on the brainstem vascular architecture (see Table 4.1).
193 Table 4.1 Distribution of the infarction topography in prospectively recruited patients with brainstem ischemias identified on magnetic resonance imaging (according to Marx 2005) Infarction localization Incidence (in %) Mesencephalon
10
Pontomesencephalic
14
Pons
35
Pontomedullary
16
Medullary
18
4.1.1.2 Etiology Until recently it was assumed based on necropsy findings that the majority of vertebrobasilar infarctions were sequelae of an in-situ thrombosis predominantly associated with a microangiopathy (Bamford et al. 1991). The widely-used term vertebrobasilar insufficiency further implies that vertebrobasilar ischemia due to hypoperfusion as a result of local thrombotic or hemodynamic complications represents the major important causal factor. Cardiac-origin embolism was previously generally regarded as a rare cause of vertebro basilar infarctions. This view may be accounted for by the relatively recent availability of magnetic resonance imaging techniques, which today enable a more adequate depiction and classification of brainstem ischemias. The advent of echocardiography and cardiac rhythm monitoring that defined better cardiac function and identified more potential cardiac and aortic sources of embolism, was also important. Results reported in the available literature permit the assumption that most of the causal mechanisms of cerebral ischemias in the anterior circulation are also responsible for vertebrobasilar infarctions (Bogousslavsky et al. 1993). These include: • Embolism (up to 40%, portion of cardiac-embolic events (10–15%) • Local atherothrombosis (up to 30%) • Microangiopathy (up to 30%) • Dissection • Altered hemodynamics • Migraine • Aneurysms and dolichoectasia (dilatative arteriopathy) • Vertebral artery compression on head rotation (rarely) • Mitochondrial disorders • Vasculitis • Cerebral vein thrombosis • Arterial hypertension Embolism A basic prerequisite for the diagnosis of an embolic infarction is the identification of the source and the site of the
194
embolus. The incidence rate cited for embolic brainstem infarctions ranges at approximately 40% (Caplan and Tettenborn 1992). There are a number of predilection sites for the occurrence of emboli that are also sites for vascular occlusion. These include the V4 segments (see Sect. 2.2, p. 18) of the vertebral arteries near the origin of the posterior inferior cerebellar artery, the confluence of the vertebral arteries, and the region of the basilar tip at the bifurcation into the posterior cerebellar arteries. Approximately 10–15% of the respective emboli are from cardiac sources. About 20% of all cardiac embolisms manifest in the posterior circulation. While the most prevalent among the known sources of embolism with a high risk for ischemia is atrial fibrillation, left ventricular aneurysms, different types of endocarditis, valvular diseases, and rarer causes such as atrial myxoma are also frequently identified. The role of the persistent foramen ovale (PFO) found in 20–25% of individuals in the general population is currently only incompletely known. An association with an increased risk for cardiac embolism has been hypothesized for the combined occurrence of a PFO and an atrial septal aneurysm (Mas et al. 2001). Similarly inconclusive is the current understanding of isolated mitral valve disease processes as, e.g. mitral valve prolapse, mitral annular calcification, and mitral valve strands. In these settings, other artery-to-artery embolic or microangiopathic mechanisms of infarct development should always be discussed. In particular simultaneously occurring infarctions of the anterior and posterior circulation suggest cardiac-origin embolism. Cerebellar infarctions with hemorrhagic transformation are known to be almost exclusively the result of a cardiac embolism (Chaves et al. 1996). Primary recipient sites for cardiac embolism may, in turn, function as a source for embolism. This is particularly relevant for an embolus of the basilar tip (top of the basilar syndrome; Caplan 1980). In addition to producing local midbrain and thalamus infarctions, ischemia can extend in these cases via the posterior cerebral arteries and induce mesiotemporal and occipital infarctions. An embolic origin of ischemia can be assumed in particular in patients with concurrent visual field defects and brainstem symptoms.
4 Diseases
debatable if – analogous to the situation in the anterior circulation – a medullary infarction with the concurrent occurrence of an ipsilateral vertebral artery stenosis is directly attributable to the stenosis, and thus represents an indication for an only insufficiently validated endovascular therapy. In solitary pontine or, mesencephalic infarctions, clinical or imaging morphologic features that permit an accurate differentiation between an embolic origin and a macroangiopathic or microangiopathic genesis are often absent. The favored sites of local macroangiopathic and thrombotic vascular occlusion in the posterior circulation are in the region of the extracranial vertebral artery segments, chiefly the V0 and V4 segments, as well as in the entire basilar artery region. Other occlusion sites are relatively uncommon. It is known that people of African or Asian descent are more susceptible to intracranial atheromatous vascular changes in the posterior circulation, while Caucasians have a predilection to extracranial local thrombosis (Caplan et al. 1986). In addition to producing an insitu thrombosis with subsequent infarction in distal arterial vascular territories, intrinsic plaques may also be the source of artery-to-artery embolism. Stenoses resulting from atherosclerotic vascular changes may further serve as recipient sites of cardiac emboli. Definite distinguishing features of macroangiopathic and microangiopathic infarctions have not been established. Ischemias of macroangiopathic origin often represent territorial infarctions characterized by a usually wedge-shaped ischemic area extending to the brainstem surface, whereas circular/oval and partially confluent infarct areas at the center of the pontine base are mostly of microangiopathic origin. Paramedian pontine infarctions extending to the surface may further be caused by “growing” basilar artery plaques if these occlude the ostium of a perforating or a circumferential artery. Recently, the presence of stereotyped fluctuating symptoms with a patent basilar artery, was assigned as ‘pontine warning syndrome’ indicating approaching occlusion of the proximal portion or the ostium of a single basilar branch (Saposnik et al. 2008).
Microangiopathies Local Atherothrombosis The subdivision into microvascular and macrovascular etiologies has not been conclusively established for the vertebrobasilar circulation. In contrast to ischemias in the anterior circulation, where a high-grade stenosis of upstream large vessels is regarded as risk for artery-to-artery embolic events, in the posterior circulation this may presumably apply to medullary infarctions in pathologic processes of the vertebral artery. In up to 50% of all patients, occlusion of the vertebral or posterior inferior cerebellar artery was reported as being responsible for these infarctions (Kim 2003). It remains nevertheless
The occlusion of small, only 200 mm thick perforating arteries may be due to lipohyalinosis; although local perforating arteries can also be occluded by microatheromas. An occlusion of the origin of penetrating branches is significantly more often the result of macroangiopathic changes of the larger intracranial vessels (Fisher and Caplan 1971; Fisher 1977; Caplan 1989). The major risk factors for these changes are arterial hypertonia and diabetes mellitus (Bamford and Warlow 1988). Imaging confirmation of the infarction, which is also confined to the territory of a perforating vascular branch, is mandatory for the diagnosis of respective
4.1 Vascular Brainstem Diseases
microangiopathic ischemias. The most common mechanisms of small lacunar ischemias in the posterior circulation constitute occlusions of the paramedian pontine, mesencephalic, thalamogeniculate and thalamostriate branches. The presence of multiple, concurrent acute infarctions largely excludes a microangiopathic genesis.
Dissections The incidence of dissections as the cause of vertebrobasilar ischemia is lower than in the anterior circulation and has been reported to range from 1–1.5 cases per 100,000 population (Schievink et al. 1994a). Dissections nevertheless represent an important disease entity in younger patients. Because the history often only yields a preceding trivial trauma as a possible cause, in many instances a definite decision between a traumatic and a spontaneous dissection is impossible. It is well known that specific connective tissue disorders as, e.g. Ehlers-Danlos syndrome type IV, or fibromuscular dysplasia frequently predispose to multiple dissections. Dissections also occur more commonly after chiropractic maneuvers of the cervical spine and therefore constitute an independent risk factor (Reuter et al. 2006). Dissections in the vertebrobasilar vascular system manifest primarily extracranially, but may also occur intracranially. Similarly, extracranial dissections may extend to intracranial. The most common localizations are the region of the extracranial vertebral artery between its origin and entry into the intervertebral segment of the sixth cervical vertebra, as well as the segment between the arch of the atlas and entry into the dura, which both correspond to the mobile segments of the vertebral artery. The intracranial segment of the vertebral artery is substantially less often involved. Dissections of the basilar artery and the posterior cerebral arteries are rare (Yoshimoto et al. 2005).
Fig. 4.1 Vertebral artery dissection right. PICA infarction (posterior inferior cerebellar artery) right after dissection of the right vertebral artery; (a) DWI, (b) MR angiography and (c) T1-sequence with demonstration of the intramural hematoma
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An early diagnosis is crucial, because distal embolisms can be prevented with the use of appropriate therapeutic procedures. In contrast to the situation described for the carotid artery, extracranial dissections of the vertebral artery more commonly extend to intracranial. The results of current, although non-randomized studies, indicate that the therapy with acetylsalicylic acid alone may have a similar effect on the overall low risk of a further ischemic event (<5% in the first quarter) (Georgiadis et al. 2009). Intracranial dissections may represent the origin of vertebral and basilar artery aneurysms that cause subarachnoid hemorrhage. The described intracranial dissections occur chiefly in children and young adults. The number of diagnosed dissections has increased significantly in recent years with the availability of non-invasive magnetic resonance imaging and MRangiographic modalities. The fact that MR angiography only permits the demonstration of vascular stenosis or occlusion renders it unsuitable for the conclusive differentiation between an atherothrombotic occlusion and a dissection. T1- or proton density-weighted sequences are required to demonstrate the characteristic intramural hematoma in transverse plane slices (Auer et al. 1998; Fig. 4.1). Color coded duplex sonography is particularly useful in the demonstration of a dissection membrane, although it provides primarily unspecific findings which should be validated using magnetic resonance imaging.
Altered Hemodynamics Hemodynamically induced ischemias are poorly characterized in the posterior circulation, while classic ischemia areas of watersheds have not been established by imaging studies. The diagnosis of a hemodynamic infarction origin appears to be justified only in patients with high-grade bilateral vertebral artery stenosis or bilateral occlusions. Upstream vascular stenoses of at least 50% are found in up to 35% of all patients
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with brainstem ischemia (Caplan et al. 2004). The causal attribution of the described moderate-grade stenoses to brainstem infarctions is problematic, because the extensive collateral supply in the brainstem facilitates the hemodynamic compensation of the respective occlusions. In many patients, transitory vertigo symptoms are further considered to be the result of “vertebrobasilar insufficiency”, although they are, in fact, chiefly due to peripheral vestibular lesions. Although individual patients with location-dependent compression of the vertebral arteries in spondylarthrosis have been described in the literature, this diagnosis is rarely established. In only extremely rare cases does cerebral ischemia manifest in the form of isolated unconsciousness, which may be interpreted as bilateral marked hypoperfusion or localized focal ischemia of the ascending reticular system. In the absence of additional brainstem symptoms, this is, however, extremely unlikely to be a transitory lesion. The subclavian steal phenomenon represents a special case and may also in only extremely rare cases be responsible for posterior circulation infarction.
Migraine The incidence of migrainous infarctions is assumed to be significantly lower than described in the older literature. Migrainous infarctions are typically found in the posterior cerebral artery territory (Shuabib 1991). The CAMERA study (Kruit et al. 2005) confirmed this finding and described the cerebellum as the primary site for the occurrence of ischemia, although in one case a pontine localization was also identified. The approach to the diagnosis recommended by the authors is the establishment of a respective migraine history. A further prerequisite is to ensure that the neurological deficits are consistent with the clinical symptoms of individually experienced auras. In contrast to neurologic deficits, the duration of at least 7 days is to be confirmed for the described clinical symptoms. Migrainous infarctions commonly develop slowly – often over 48 h – and are characterized by a tendency to fluctuate. The concurrent headache symptoms further need to correspond to the known migraine headache symptoms. Headaches – in particular retroorbital headaches – with concurrent brainstem symptoms can in no case serve as evidence of a migrainous infarction etiology. This is accounted for by the finding that various headache syndromes may also develop in cases of trigeminal nuclear region involvement, which is responsible for the sensory supply of the meninges of the posterior cranial fossa. Since other symptoms typically associated with migraine, including nausea and emesis, are also characteristic symptoms of vertebrobasilar ischemia, their conclusive assignment is often impossible. Individual case reports have described a higher rate of migrainous infarctions in young women with vascular risk factors, in particular smoking and the intake of oral contraceptives (Tzourio and Bousser 1997; Fig. 4.2).
Fig. 4.2 Medullary migrainous infarction. (a) Diffusion weighted MRI (DWI) on day 1, showing patch-like signal increases bilateral in the ventral medulla oblongata. The patient described a 6-year history of migraine with aura. Brainstem symptoms with direction-changing spontaneous horizontal nystagmus, dysarthria, dysphagia, central tetraparesis, more pronounced on the right, with inexhaustible foot clonus, and bilateral limb ataxia were diagnosed on admission. Repeat MRI after 3 days demonstrated increased signal intensity (b) on DWI and (c) initial manifestation of signal increases in the FLAIR sequence; (d) MR angiography without pathologic findings
Aneurysms and Megadolichobasilaris In younger patients, large fusiform basilar and vertebral artery aneurysms have been described as the source of local thrombosis and subsequent embolism (Pessin et al. 1989). This also applies to a dolichoectasia (dilatative arteriopathy) as the source of emboli in older patients, in particular in patients with concomitant hypertension (Kumral et al. 2005; Savitz and Caplan, 2008). An elongated basilar or vertebral artery can also be a causal factor of direct ventrolateral brainstem segment compression, although only a weak correlation between the clinical symptoms and the degree of the compression has been described in these cases (Savitz et al. 2006). Vertebral Artery Compression on Head Rotation In patients with unilateral high-grade stenosis, hypoplasia, or vertebral artery occlusion, rapid rotation of the head to one side can in rare cases cause compression of the contralateral vertebral artery in the region of the arch of the atlas, leading
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to head position-dependent transitory rotational vertebral artery syndrome (Choi et al. 2005). In some patients with rheumatoid arthritis involving the atlanto-axial region, vertebral artery compression and thrombosis may develop in relation to head and neck motions.
Mitochondrial Disorders Disorders such as MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) frequently manifest with posterior cerebral artery territory dysfunction (Jackson et al. 1995).
Vasculitis Different types of vasculitides can manifest in the form of vertebrobasilar ischemia. Especially in Takayasu’s disease, an occlusion or stenosis in the vicinity of the origin of the vertebral artery is less prevalent than a stenosis of vessels near the aorta in the anterior circulation (Subramanyan et al. 1989). The large arteries are also involved in temporal arteritis. Pathoanatomic studies have shown a similar involvement for the superficial temporal artery and the vertebral artery in 75–100% of cases (Wilkinson and Russell 1972). The described involvement is clinically significantly less often manifest. Isolated cerebral angiitis is a further common cause of cerebral ischemia due to the dominant involvement of medium sized intracranial arteries; this is again, however, without a confirmed predilection for the posterior circulation. In other types of medium sized vessel vasculitis as, e.g. polyarteritis nodosa, ischemic infarctions occur chiefly in the later course of the disease and less commonly involve the posterior circulation (Provenzale and Allen 1996). Intracerebral vascular occlusions associated with vasculitis are extremely rare in Churg-Strauss syndrome or Wegener’s granulomatosis. Behcets disease can be associated with brainstem inflammatory and ischemic abnormalities in a perivenous distribution (Kumral 2008). The rheumatic diseases with cerebral involvement, in particular lupus erythematodes, Sjogren’s syndrome, progressive scleroderma, and various, only insufficiently characterized forms of paraneoplastic vasculitides, may in 10% of cases be associated with cerebral ischemias, primarily of the small vessels. The vascular territories preferentially targeted by these disorders have not yet been sufficiently investigated.
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the infarction areas are typically viewed as differently configured congestive infarctions, whose extension is not confined to arterial vascular territories (Bousser and Ross Russell 1997). Cerebral vein thromboses with a confirmed lesion to the brainstem are very rare (Krespi et al. 2001), which may be accounted for by the large number of venous drainages that are interconnected via collateral circulations (Hassler 1967a). The occlusion of individual vessels is therefore unlikely to produce flow impairment. Deficits of isolated cranial nerves due to thrombosis of the transverse sinus have nevertheless been described (Kuehnen et al. 1998). Arterial Hypertension Hypertensive brainstem encephalopathy constitutes an essentially rare MRI diagnosis, as it is clinically generally asymptomatic or exhibits uncharacteristic symptoms and symptoms with a nonspecific localization, including disturbance of consciousness or delirium (Cruz-Flores et al. 2004; Fig. 4.3). The findings of imaging studies suggest the most likely disease mechanism to be an edema mediated by a lesion to the blood brain barrier, which may occur in the presence of pre-existing and acute uncontrolled hypertension. In rare cases, the MRI changes may be confined to the brainstem, i.e. they may not be associated with supratentorial hypertensive cerebral encephalopathy and are partially reversible with antihypertensive therapy (Fujiwara et al. 2005; McCarron and McKinstry 2008). Clinical Symptoms Due to the generally poor representation of vertebrobasilar symptoms on current stroke scales, the prevalence of different brainstem symptoms is underestimated in large epidemiologic stroke studies, and the respective figures are of limited value. The leading symptom of vertebrobasilar ischemia is gait disturbance, which is found in up to 80% of all patients (Marx
Cerebral Vein Thrombosis Sinus thrombosis is an important differential diagnosis of basilar artery thrombosis with progressive disturbance of consciousness, headache, and brain infarctions. On neuroimaging,
Fig. 4.3 Asymptomatic hypertensive brainstem encephalopathy with diffuse signal increases in the pons. MRI-FLAIR – (a) transverse and (b) sagittal
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et al. 2002). This symptom is, however, not included in any of the established stroke scales as, e.g. the NIHSS (National Institute of Health Stroke Scale). Furthermore, up to 60% of all patients have poorly characterized dizziness or vertigo. In addition to trunk, postural and gait ataxia, eye movement abnormalities (30–50%), limb ataxia (20–30%), and trigeminal sensory disturbances are the principal symptoms of vertebrobasilar ischemia. Dysarthria and dysphagia are more frequently described with posterior circulation infarctions than in supratentorial localizations, although these symptoms are not exclusively attributable to the posterior circulation. The incidence of motor hemiparesis observed in 40–60% cases was lower overall than in supratentorial infarctions and is unusual for infarct localizations in the posterior circulation other than the pons (Weimar et al. 2002; Table 4.2). It is consistently reported that patients with brainstem infarctions appear to be generally less compromised on admission to hospital than patients with supratentorial infarctions (Weimar et al. 2002). Due to the poor representation of function deficits on available stroke scales, this statement is of limited use only. A validated function scale with special emphasis on injury to the posterior circulation does not exist. The proportion of patients with consciousness disturbance is, however, larger in this group than in patients with supratentorial infarctions, which may be primarily accounted for by
Table 4.2 The most common clinical neurologic deficits in prospectively recruited patients with MRI confirmation of brainstem ischemia (According to Marx 2005) Symptoms Incidence (in %) Postural and gait ataxia
61
Dysarthria
28
Cranial nerve lesions
24
N. III
8
N. V
12
Motor hemiparesis
22
Pathologic nystagmus
19
Limb kinetic ataxia
18
Dissociated disturbance of sensitivity
17
Internuclear ophthalmoplegia
11
Skew deviation
10
Fig. 4.4 (a–c) Different lateral medulla oblongata infarctions in patients with clinical Wallenberg’s syndrome on T2-weighted MRI
the subgroup of patients with thrombotic processes of the basilar artery.
Medulla Oblongata Infarctions Infarctions of the lateral medulla oblongata were long regarded as being due solely to an occlusion of the posterior inferior cerebellar artery. This may, however, apply at most to 10% of the described ischemias (Vuilleumier et al. 1995). In the majority of cases, the vertebral artery occlusion is localized in an intradural region and causes an obstruction of the perforating arteries to the lateral medulla oblongata. With an incidence rate of 25%, the resulting lateral or dorsolateral medulla oblongata syndrome constitutes the most prevalent entity of all brainstem infarctions (Marx et al. 2004; Fig. 4.4). This has given rise to the definition of the classic complex of symptoms by the German internist and neurologist Adolf Wallenberg, which is, nevertheless, not in all aspects as complete as the list of neurologic deficits shown in Table 4.3. Minor variants with individual absent symptoms are often described that are due to pial anastomoses between branches of the anterior and posterior inferior cerebellar arteries, as well as to the concurrent supply of the medulla oblongata by perforating arteries of the basilar artery. In these conditions, motor deficits are generally absent, since the lesion does not extend to the ventral region of the pyramidal pathway. Diagnostic imaging commonly shows a diamond-shaped or triangular infarction area slightly dorsal to the olivary nucleus. In cases where the posterior spinal artery, which also supplies the dorsal medulla oblongata, does not originate directly from the posterior inferior cerebellar artery (PICA), vertebral artery and PICA infarctions can further be associated with symptoms of a dorsolateral medulla oblongata lesion. Infarctions of the medial medulla oblongata are comparatively rare; they are attributable to an occlusion of the distal vertebral arteries immediately before their confluence into the basilar artery, which is due to an obstruction near the origin of the ventral branches. Typically affected are the pyramidal pathway, the medial lemniscus and – less frequently – the emerging hypoglossal fibers. Clinically manifest is a contralateral hemiparesis sparing the face, a contralateral disturbance of proprioception, as well as an ipsilateral tongue paresis. In rare cases cardiac arrhythmias,
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Table 4.3 Classic symptoms of the Wallenberg syndrome and causal functional lesion (According to Norrving and Cronqvist 1991; Marx et al. 2004) Symptom Functional lesion Ipsilateral Horner’s syndrome
Sympathoexcitatory fibers and integration centers
Vertigo and nystagmus
Vestibular neurons
Ipsilateral limb kinetic ataxia
Anterior/posterior spinocerebellar tract
Gait ataxia
Anterior/posterior spinocerebellar tact, lateral vestibulospinal tract
Contralateral dissociated disturbance of sensitivity
Spinothalamic tract
Dysarthria/dysphagia
Nucleus ambiguus, solitary tract nucleus
Ipsilateral hypesthesia of the face
Nucleus of spinal tract of trigeminal nerve
disturbances of blood pressure regulation, or even apnea (Undine’s curse) may occur and represent a vital threat for the patient. Furthermore, PICA infarctions with ischemia typically involving two thirds of the ipsilateral cerebellar hemisphere may also lead to infarctions in the region of the medial medulla oblongata.
Pontine Infarctions Pontine ischemias are commonly sequelae of artery-toartery-arterial embolic processes from the vertebral arteries or basilar artery, or local thrombotic occlusions of the median, paramedian or lateral perforators (Bassetti et al. 1996; Figs. 4.5 and 4.6). Ischemias resulting from atherothrombotic occlusion of the origin of perforating arteries branching off the basilar artery are generally responsible for larger infarctions than lacunes that are due to a microangiopathic occlusion of the distal perforating arteries, or an arterio-arterial embolism from an ostial plaque (Fig. 4.7a). Conversely, ischemias mediated by proximal perforator occlusions frequently extend to the ventral surface of the pons (Fig. 4.7b). Clinical evidence of a lesion to the corticospinal, corticopontine and corticonuclear projections, as well as to pontine nuclei comprises symptoms of a pure motor hemiparesis, ataxic hemiparesis, or a dysarthria-clumsy hand syndrome. Lesions with a more lateral location can involve the spinothalamic tract and be responsible for contralateral disturbances of pain and temperature sensitivity. Large population studies (Kumral et al. 2002) have described various typical infarct localizations in the pons. Most ischemias were found in the anteromedial zone, chiefly
Fig. 4.5 (a) Brainstem vascularization with representation of the long perforating arteries (from Hassler 1967b). (b) Distal artery occlusion due to lipohyalinosis resulting in central infarction localized in the pontine base (MRI axial-T2)
Fig. 4.6 (a) Basilar artery macroangiopathy with occlusion of the ostia of different perforating arteries (from Schulte-Altedorneburg and Brückmann 2006). (b) Resulting paramedian pontine infarction extending to the surface (MRI axial DWI)
in the lower pons, and rarely extended beyond the fourth ventricle. The typical clinical symptoms identified included a pure contralateral hemiparesis with variable, primarily facio-crural expansion, as well as limb kinetic ataxia. Dysarthria was also found in approximately 50% of patients. In this region, a
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a
b
c
Fig. 4.7 (a) Medial pontomedullary infarction on T1-weighted MRI; (b–c) different pontine infarctions associated with lateral perforating artery occlusions on T2-weighted MRI
responsible for a contralateral disturbance of the spinothalamic tract. Large cerebellar infarcts in the territory of the superior cerebellar artery can cause occlusive hydrocephalus. These occlusions are chiefly observed in patients with embolism in the superior cerebellar artery territory (Amarenco and Hauw 1990). Bilateral pontine infarctions are uncommon. The most common symptoms include pseudobulbar paralysis and (in extreme cases) the locked-in syndrome. The majority of patients develop acute tetraparesis resulting from infarctions occurring primarily in the region of the lower and middle ventral pons and are frequently associated with basilar artery thrombosis due to occlusion of the exiting perforating artery branches. Occasional patients develop sequential hemiparesis, first on one side of the body and then on the other side. These are due to blockage of basilar artery penetrating branches at different pontine levels (Fisher 1977).
Midbrain Infarctions sensorimotor paresis or dysarthria-clumsy hand syndrome is typically associated with smaller areas of infarction. Although there is a marked similarity between the clinical symptoms of capsular ischemias and the described infarctions, these can be differentiated from capsular ischemia by the presence of concomitant limb kinetic ataxia and vertigo. In addition, pontine ischemias more often appear to be a causal factor of motor pareses in the distal arm than in the leg, because the fibers supplying the arm course in the region of the ventrotegmental junction while axons supplying the leg travel more ventrally. The second most common infarction syndrome is based on ischemias of the anterolateral pons, which is generally attributable to occlusions of the small lateral pontine arteries. These ischemias manifest primarily with contralateral motor syndromes with varying degrees of severity, in addition to ataxic hemiparesis. Tegmental pontine infarctions are very rare and the symptoms are often rapidly reversible. This is most likely accounted for by the extensive collateral supply from the short and long pontine circumferential arteries. Typical clinical signs comprise vertigo, double vision in eye movement disturbances like ipsilateral abducens paresis, conjugate gaze paresis, or internuclear ophthalmoplegia. Other frequently observed signs are contralateral dissociated sensory deficits and, occasionally, hypesthesia with a cheiro-oral distribution. Motor symptoms of the long pathways are rare overall and almost never occur with lesions to the lateral pontine tegmentum. Depending on the individual supply territory of the superior cerebellar artery, an occlusion may not only lead to ischemia in the characteristic supply territory of the upper portions of the cerebellar hemispheres and the superior vermis, but also to ischemias in portions of the pontine tegmentum. These are primarily
Eye movement abnormalities represent the most frequent symptoms of midbrain infarction with high localizational significance (Bogousslavsky et al. 1994). In patients with lateral infarction localizations, a contralateral motor hemiparesis and a contralateral hemiataxia may further be found, as well as a contralateral sensory disturbance. The infarcts often involve both anteromedial and anterolateral locations (Fig. 4.8). Infarctions with a median location typically manifest with ipsilateral nuclear or fascicular oculomotor pareses, as well as with an accompanying contralateral hemiparesis, hemiataxia, or large amplitude tremor. Lateral ischemias are more likely to be associated with contralateral sensory disturbances, in particular superficial sensation. Mesencephalic infarctions with an extremely rostral location that involve the rostral interstitial nucleus of the medial longitudinal fasciculus (ri MLF) can induce vertical a
b
Fig. 4.8 (a, b) Diffusion-weighted MRI showing thalamic infarction right in a patient with acute onset skew deviation, rotatory vertigo and gait ataxia
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associated with extrapyramidal motor disturbances like dystonia or choreatiform disturbances due to damage to the thalamic and subthalamic nuclear regions.
Multiple Infarctions Fig. 4.9 Extended pontomesencephalic infarction left with thrombosis of the upper basilar artery segment on T2-weighted MRI. The 72-yearold patient was comatose, showed an oculomotor paresis left, as well as a high-grade motor hemiparesis right
gaze pareses. Lesions in the region of the periaqueductal gray often produce mutism. Patients with bilateral lesions frequently have severe disturbances of consciousness due to involvement of the reticular system. Isolated midbrain infarctions are relatively rare; smaller medial lesions are mediated by the occlusion of penetrating branches near their origin from the basilar artery. Lateral lesions are more likely caused by occlusions of the exit points from the posterior cerebral artery (Bogousslavsky et al. 1994). Mesencephalic ischemias more commonly occur combined with infarctions in other vertebrobasilar territories. Large ischemic areas extending into the pons are often associated with basilar artery thrombosis (Fig. 4.9), while a combination with supratentorial ischemias – in particular occipital and thalamic infarcts – suggest an embolic etiology.
Thalamic Infarctions Although the thalamus is not part of the brainstem, vertebrobasilar ischemia, chiefly of embolic origin, is often found here. After the pons, the thalamus is the structure most susceptible to lacunar infarctions in the posterior circulation. A prevalent etiology is an occlusion of the perforating arteries originating from the posterior cerebral artery (thalamogeniculate artery, thalamoperforating artery) (Hommel et al. 1990; Fig. 4.8). Clinically this often leads to sensory deficits of the contralateral half of the body, extending from the face via the trunk to the arm and the leg, which is uncharacteristic of cortical ischemias. In cases of a cranial ischemic lesion area extending to the posterior limb of the internal capsule, additional motor deficits with varying degrees of severity may occur. A postischemic pain syndrome produced by an injury to the spinothalamic fibers represents a common complication in ischemia of the lateral thalamus (Nasreddine and Saver 1997). Thalamic infarctions may further lead to the development of memory impairment. Bilateral thalamic lesions, e.g. in basilar thrombosis or by occlusion of the artery of Percheron (Krampla et al. 2008), can be a cause of deep unconsciousness. The respective ischemias are rarely
Reports in the literature show the presence of multiple areas of infarction in at least 10% of all vertebrobasilar territory infarcts (Bernasconi et al. 1996). This is usually accounted for by an embolic origin, although in some instances, e.g. in bilateral infarctions of the posterior inferior cerebellar artery (PICA), vascular variants as, e.g. a common artery giving rise to both PICA branches, may be responsible for the occurrence of multiple infarcts (Kang et al. 2000). With an incidence rate of 8%, combined medulla oblongata and cerebellar infarctions represent the largest group of multiple infarctions. An occlusion of the PICA leads to a combined medullary and cerebellar ischemia when the anterior spinal artery does not originate directly from the vertebral artery, but from the PICA. In cases where the PICA does not only supply caudal aspects of the cerebellum, but also portions of the anterior inferior cerebellar artery (AICA) territory, an occlusion is associated with a high risk for a malignant cerebellar artery infarction with subsequent hydrocephalus. The maximum swelling generally takes place after 3–4 days and is associated with high lethality if left untreated. Indications for the identification of patients at risk are an increasing loss of vigilance and neuroradiologic signs such as effacement of the basal cisterns, as well as displacement and compression of the fourth ventricle. Because the AICA typically supplies both rostral hemispheric cerebellar regions and rostral portions of the medulla oblongata in addition to the pontine base, occlusions of the origins from the basilar artery lead to cerebellar and pontine signs like nystagmus, ipsilateral hemiataxia and horizontal gaze paresis, or symptoms of pyramidal pathway lesions. Present in up to 75% of the overall rare superior cerebellar artery (SCA) infarctions are concurrent infarctions of neighboring rostral brainstem structures like the midbrain and thalamus (Amarenco and Hauw 1990). While occlusions of the distal posterior cerebral artery can in isolated cases lead to quadrantanopsia or hemianopsia, additional symptoms may be present in proximal occlusions. Several small paramedian arteries, which also contribute to the supply of portions of the rostral mesencephalon and thalamus, often originate in particular from one side of the lower segment of the posterior cerebral artery up to the junction with the posterior communicating branch. Occlusions can therefore lead to additional symptoms, including oculomotor paresis or disturbance of consciousness. The clinical diagnosis of multiple vertebrobasilar infarctions is not always possible, because symptoms, e.g. eye movement disturbances, may be masked by a
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Fig. 4.10 (a–c) Digital subtraction angiography in an initially unconscious patient with complete occlusion of the middle basilar artery segment. In the course, reopening after local lysis therapy. The only persisting symptom after basilar thrombosis was oculomotor paresis left with lacunar midbrain infarction
disturbance of consciousness mediated by a lesion with a different localization. In this setting, the most common causes are cardiac embolisms, although artery-to-artery -arterial embolism may also be identified.
Basilar Artery Occlusion The basilar artery is the central vessel for the blood supply to the brainstem. the branches arising from the basilar artery are responsible for the supply not only to centers of vital importance for respiratory and circulatory regulation, but also to the reticular formation. Complete occlusions of the basilar artery therefore generally lead to life-threatening situations. A mortality rate from 85–90% has been reported for patients without treatment. The prognosis depends on the individually highly variable anatomic basis of the collateral circulation, the cause of occlusion (embolic vs. thrombotic), the extent of ischemic lesions on MRI (DWI sequences), the time interval from the onset of lysis therapy to the manifestation of initial clinical symptoms, as well as on the success of basilar artery recanalization (Eckert et al. 2002; Arnold et al. 2004; Lindsberg and Mattle 2006). An occlusion can be compensated intracranially primarily by collateralization via pial vessels and the long circumferential arteries. The onset of symptoms may, also depending upon the collateralization situation, be marked by an immediate loss of consciousness. The development of symptoms is, however, slower in some patients continuing over several days with fluctuating eye movement disturbances and initially nonspecific symptoms like nausea and vertigo. The increasing number of thrombi formed by apposition or additional artery-to-artery embolisms from the local thrombosis eventually leads to vascular occlusion with disturbance of consciousness. Different syndromes are described depending on the extension and localization of the thrombosis with consecutive occlusion of the originating perforating branches of the vertebral artery (Ferbert et al. 1990). In the caudal vertebral artery syndrome primarily medullary structures and portions of the pontine base are affected, a phenomenon which may also be observed in bilateral vertebral artery occlusion. Clinical manifestations include caudal cranial nerve deficits with dysarthria and
Fig. 4.11 MR angiography in a patient basilar artery thrombosis in the middle and distal segment. The patient died on the day of the event from central respiratory paralysis and circulatory dysregulation
dysphagia, gait ataxia, limb kinetic ataxia, and hemiparesis or tetraparesis. The most prominent symptoms of the middle basilar artery syndrome consist of an ischemia in ventral pontine segments with motor hemiparesis or tetraparesis, as well as dysarthria. In the overall rare occurrence of a thrombosis limited to the middle segment of the basilar artery, blood flow through larger vessels like the SCA and AICA is not interrupted, so that the supply to medullary areas and parts of the pontine base is undiminished. In these conditions, disturbance of consciousness occurs only if a distal extension of the thrombosis with additional occlusions of the perforating arteries manifests in the later course (Figs. 4.10 and 4.11). In 1980 Caplan introduced the term “top of the basilar” syndrome which describes ischemia in the territory of the rostral basilar artery, the posterior cerebral artery, and the branches originating from these vessels. Included are primarily combined infarctions of the midbrain, and thalamus as well as mesiotemporal and occipital regions (Fig. 4.12). The prominent clinical symptoms include vertical eye movement disturbances combined with disturbances of consciousness. The described ischemia can also occur in isolation, accompanied by neuropsychological deficits like amnestic and perception disturbances, and may in rare cases also be associated with symptoms of delirium, agitation, confusion, and chiefly visual hallucinations. If the mesodiencephalic perforating arteries are also involved in the circulatory disturbance, ophthalmoplegia and akinetic mutism may further be present.
4.1 Vascular Brainstem Diseases
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Fig. 4.12 Basilar tip occlusion in a patient with atrial fibrillation. At the time of imaging within the 3-h window, the patient was somnolent and showed an oculomotor paresis of the left eye as well as left hemiparesis. (a) CT angiography with evidence of distal basilar artery occlusion (with hypoplasia of the left vertebral artery at color duplex). (b) Complete recanalization and complete regression of the clinical symptoms after systemic rt-PA thrombolysis
High-grade motor dysfunctions are generally absent. In almost all cases the “top of the basilar” syndrome is due to an embolus (Mehler 1989). The term locked-in syndrome refers to a neurological condition due to the bilateral destruction of the pontine base, produced by a basilar thrombosis and in some instances also by brainstem hemorrhage or a brainstem contusion (Smith and Delargy 2005). Portions of the pontine tegmentum together with the posterior longitudinal bundle and the reticular formation remain intact, so that the patient is awake and aware; the sensory functions are in most cases also unimpaired. The patient is not capable of voluntary motor control due to bilateral lesions in the corticospinal and corticobulbar projections. Control of voluntary vertical eye movements is generally the only exception and enables the patient to communicate with others.
Dissection of Vertebral Arteries Dissection of the vertebral arteries is frequently associated with severe neck pain and occipital headache with subsequent larger territorial infarction due to occlusion of the affected artery, or a distal embolus from the affected vessel. Although in most patients, clinical symptoms and signs are observed during the acute phase, there are reports of patients with cerebral ischemia occurring up to several weeks after the dissection event.
Subclavian Steal Syndrome The so-called subclavian steal syndrome can be associated with stenoses in the subclavian artery territory or the brachiocephalic trunk proximal to the origin of the vertebral
artery. It arises from retrograde blood flow in the vertebral artery of the side with the pathology that ensures perfusion of the ipsilateral arm. Subclavian steal syndrome typically occurs during muscular activity of the affected arm, especially during activities requiring raising the arm above the head, and produces brachialgia comparable to a claudication symptom. A difference in the systolic blood pressure of both arms of at least 25 mmHg is observed in most patients, and the pulse is invariably smaller and delayed on the side of the ischemic arm. In patients with high-grade stenoses, a stenosis bruit is audible on supraclavicular auscultation. The diagnosis of a subclavian steal syndrome with retrograde flow in the vertebral artery is readily accomplished using duplex sonography, as it permits the conclusive determination of the flow direction in the intervertebral segment. If the application of Doppler sonography as the only modality does not enable a definite diagnosis, an upper arm compression test can be carried out for validation purposes. Compression of the upper arm is applied over a period of 20 s before the cuff is deflated as rapidly as possible under close observation of the blood flow reaction in the vertebral artery. The resulting ischemia causes distension of the vessels in the arm and leads to an increased blood requirement in the extremity at the end of compression. The pathologic steal phenomena are subsequently increased, and a deceleration phenomenon or reversal of blood flow may be detectable for the first time. The Doppler sonographic findings permits the differentiation between an initially incomplete Grade I steal phenomenon with systolic deceleration of the blood flow velocity, and steal phenomena Grade II with retrograde flow in diastole (pendular flow), and Grade III with complete retrograde flow (Fig. 4.13). Brainstem syndromes with hemodynamic causes, including transient vertigo, double vision or trigeminal hypesthesia
204 Fig. 4.13 Subclavian steal syndrome. Proximal subclavian artery occlusion left (a) on MR-angiography with (b) highorthograde flow (transcranial Doppler) in the right vertebral artery and (c) retrograde flow in the left vertebral artery
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a
b
c
are extremely rare. The occurrence of brainstem infarction is a rarity, even in pronounced steal syndromes with retrograde flow into the basilar artery (Hennerici et al. 1988).
Classic Brainstem Syndromes During the past century, multiple brainstem syndromes, chiefly those associated with lacunar ischemia, were defined and are generally named after the first scientist to describe the respective syndrome. The characteristic feature of these brainstem syndromes may be seen in the frequent concurrent occurrence of a cranial nerve paresis with ipsilesional localization and an injury to the long pathways. Out of the multiple symptom complexes shown in Table 4.4, Wallenberg’s syndrome is the only clinical picture associated with brain ischemia that is frequently observed in clinical practice (Marx and Thoemke 2009). This may be explained by the vascular brainstem anatomy making typical lateral medulla oblongata infarctions a frequent form of brainstem ischemia (for a detailed overview see Wolf 1971; Liu et al. 1992; Silverman et al. 1995; Schmidt 2000; Krasnianski et al. 2003, 2004, 2006).
4.1.1.4 Diagnosis Parenchymal Imaging Diagnostics The introduction of magnetic resonance imaging (MRI) first enabled the adequate neuroradiologic depiction of brainstem ischemia. In addition to its initially limited availability, the
long measurement times of MRI posed a problem, since these were often intolerable for patients in the acute phase of stroke. A highly sensitive rapid emergency diagnosis with the specific demonstration of a cytotoxic cerebral edema has become possible with the development of diffusion-weighted MR imaging (Marx et al. 2004) (Figs. 4.14 and 4.15). The respective changes were apparent in animal models already within a few minutes after the onset of ischemia (Li et al. 2000). While the examination period of only a few minutes is comparable to that of cranial computer tomography (CCT), the sensitivity of diffusion-weighted MRI is significantly higher. Depending upon the technique used and the length of the time interval, brainstem infarctions can be successfully demonstrated in 73–100% of clinically suspected infarctions (Linfante et al. 2001; Marx et al. 2004; Fig. 4.16). Furthermore, the detection of isolated cases of reversible diffusion disturbances in transient ischemia has been described (Fig. 4.17). CT is of use in the diagnosis of large infarction areas after their complete demarcation only, due to the beam-hardening artefacts and poor resolution in the posterior cranial fossa characteristic of this modality. The successful application of CT is generally possible solely in cerebellar ischemia or larger pontine infarctions. Even extended isolated brainstem infarctions can frequently not be differentiated from healthy brainstem parenchyma. The maximal sensitivity ranges from 30–40%, so that CT is suitable only for the exclusion of hemorrhage. Due to its immediate availability, short measurement times, and the possibility of close patient observation during the measurement period, CT continues to be of importance in the follow-up of intensive care patients, e.g. patients with space-occupying cerebellar
4.1 Vascular Brainstem Diseases Table 4.4 Classic brainstem syndromes Syndrome
205
Ipsilesional symptoms
Contralesional symptoms
Midbrain Parinaud’s syndrome
Gaze paresis upward Gaze paresis downward Convergence paresis Light-near dissociation
Chiray-Foix-Nicolesco syndrome (upper nucleus ruber syndrome)
Hemiataxia Hemiparesis (?) Hyperkinesia
Benedict’s syndrome (upper nucleus ruber syndrome)
Oculomotor paresis
Hemiataxia Hyperkinesia Rigor
Claude’s syndrome (lower nucleus ruber syndrome)
Oculomotor paresis
Hemiataxia
Weber’s syndrome
Oculomotor paresis
Hemiparesis
Nothnagel’s syndrome
Oculomotor paresis
Hemiataxia Hemichoreoathetosis (?) Vertical gaze paresis (?)
Pons Grenet’s syndrome
Trigeminal lesion
Hemihypalgesia Hemithermohypesthesia
Gasperini’s syndrome
Trigeminal lesion
Hemihypesthesia
Facial paresis Gaze paresis Raymond-Céstan syndrome
Gaze paresis
Hemiataxia Hemiparesis Hemihypesthesia
Raymond’s Syndrome
Abducens paresis
Hemiparesis
Millard-Gubler syndrome
Abducens paresis Facial paresis
Hemiparesis
Brissaud-Sicard syndrome
Facial myokymia
Hemiparesis
Abducens paresis
Hemiparesis
Foville’s syndrome Upper
Hemihypesthesia Lower
Pierre-Marie-Foix and Alajouanine syndrome
Abducens paresis
Hemiparesis
Facial paresis
Hemihypesthesia
Abducens paresis
Hemiparesis
Facial paresis
Hemihypesthesia
Horner’s syndrome Gellé’s syndrome
Hypacusia/tinnitus
Hemiparesis
Vertigo (continued)
206 Table 4.4 (continued) Syndrome
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Ipsilesional symptoms
Contralesional symptoms
Horner’s syndrome
Hemiparesis
Hemiataxia
Hemihypesthesia
Trigeminal lesion (?)
Hemihypalgesia
Soft palate paresis (?)
Hemithermohypesthesia
Medulla oblongata Babinski-Nageotte syndrome
Posterior pharyngeal wall paresis(?) Vocal cord paresis (?) Wallenberg’s syndrome
Trigeminal lesion
Hemihypalgesia
Horner’s syndrome
Hemithermohypesthesia
Hemiataxia Soft palate paresis Posterior pharyngeal wall paresis Vocal cord paresis Céstan-Chenais syndrome
Horner’s syndrome
Hemiparesis Hemihypesthesia
Soft palate paresis Posterior pharyngeal wall paresis Vocal cord paresis Reinhold’s syndrome
Trigeminal lesion
Hemiparesis
Horner’s syndrome
Hemihypesthesia
Hemiataxia
Hemihypalgesia
Soft palate paresis
Hemithermohypesthesia
Posterior pharyngeal wall paresis Vocal cord paresis Tongue paresis Avellis’ syndrome
Soft palate paresis
Hemiparesis
Posterior pharyngeal wall paresis
Hemihypesthesia
Vocal cord paresis
Hemihypalgesia (?) Hemithermohypesthesia (?)
Schmidt’s syndrome
Soft palate paresis
Hemiparesis (?)
Posterior pharyngeal wall paresis
Hemihypesthesia (?)
Vocal cord paresis Sternocleidomastoid paresis Trapezius paresis Tongue paresis (?) Tapia’s syndrome
Soft palate paresis Posterior pharyngeal wall paresis Vocal cord paresis Tongue paresis
Hemiparesis
4.1 Vascular Brainstem Diseases Table 4.4 (continued) Syndrome Vernet’s syndrome
207
Ipsilesional symptoms
Contralesional symptoms
Soft palate paresis
Hemiparesis
Posterior pharyngeal wall paresis Sternocleidomastoid paresis Hemiageusia Pharyngeal hemihypesthesia Jackson’s syndrome
Soft palate paresis
Hemiparesis
Posterior pharyngeal wall paresis (?) Tongue paresis (?) Vocal cord paresis (?) Déjérine’s syndrome
Tongue paresis
Hemiparesis
Spiller’s syndrome
Tongue paresis
Hemiparesis Hemihypesthesia
Opalski’s syndrome
Hemiparesis (sparing the face)
Hypothermalgesia
The (?) after different clinical findings serves as an indication of a divergence between the initial description and subsequent publications, or of the absence of reliable evidence in the initial reports.
Fig. 4.14 Pontomesencephalic infarction right in a patient with oculomotor paresis right and gait ataxia. Corresponding lesion (a) on DWI after 3.5 h and (b) on high-resolution T2-weighted MRI after 5 days
Fig. 4.15 Pontine infarction left in a patient with dysarthria and brachiofacial hemiparesis right. Corresponding lesion (a) on DWI after 6 h and (b) on high-resolution T2-weighted MRI after 5 days
Fig. 4.16 Lacunar pontine infarction right in a patient with internuclear ophthalmoplegia left as well as gait and postural ataxia. (a) No demonstration of ischemia on DWI 5 hours after onset of symptoms; (b) small infarction area on T2-weighted MRI after 7 days without corresponding lesion of the tegmentum (medical longitudinal fasciculus)
Fig. 4.17 Lacunar mesencephalic infarction left in a patient with oculomotor paresis left and gait ataxia. Acute ischemic diffusion disturbance on DWI 7 h after onset of symptoms (a) without corresponding lesion on high-resolution follow-up MRI after 6 days (b)
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infarctions or after basilar artery thrombosis. In addition to diffusion-weighted imaging, axial and sagittal T2-weighted images are of special value in the demonstration of ischemic brainstem lesions, in particular since they permit the often difficult differentiation between acute and older ischemic lesions in the posterior cranial fossa. Although a definite diagnosis of ischemia can also be established using perfusion-weighted MRI, the small volumes in the brainstem place some restrictions on the suitability of this technique for diagnostic purposes. Imaging studies have found that areas with disturbed perfusion are typically larger during the first hours of ischemia than the region with reduced diffusion, which is assumed to be an early manifestation of necrotic ischemic areas. The mismatch between tissue with perfusion and diffusion disturbances is therefore also referred to as “tissue at risk”, or penumbra. Potential deficits may be reversed on prompt sufficient reperfusion of the penumbra (Neumann-Haefelin et al. 1999), while an expansion of the infarction area with restricted diffusion developing at increasing duration of ischemia exerts a negative effect on the penumbra. Follow-up studies in the anterior circulation have shown that the maximum extension of restricted diffusion with respect to the infarction volume is to be expected on approximately the third day (Schwamm et al. 1998). In contrast, maximum infarction volumes have been observed as early as after 24 h in patients with brainstem infarctions (Fitzek et al. 2001). Because the overall incidence of territorial infarctions is lower while that of lacunar lesions is higher in the vertebrobasilar than in the anterior circulation, the penumbra concept is of only limited value in the region of hypoperfused tissue at risk surrounding an infarction core here. Volume increases in the early course have been observed only in individual patients. This may be accounted for by the difference in the vascular anatomy, since the supplying vessels in the posterior circulation consist predominantly of perforating end arteries. A potential penumbra, provided this even exists in brainstem infarctions, may therefore be assumed to be small and of short duration. Due to the tightly packed important structures in the brainstem, even small areas of ischemia without noteworthy penumbra can produce substantial functional deficits. In this setting, there is a strong correlation between the size of the infarction volume and functional deficits on neurologic scales (Fitzek et al. 2001). In up to 60% of patients with rapidly reversible deficits, magnetic resonance imaging does not demonstrate a lesion in the posterior circulation (Marx et al. 2004). This rate and therefore the clinically often difficult allocation of transient function disturbances, including vertigo or gait ataxia, to a central ischemic lesion can be significantly improved if electrophysiologic brainstem testing is performed in addition to diagnostic imaging. Especially suitable for the demonstration of a brainstem lesion are diagnostic techniques that
4 Diseases
enable an examination of long pathways. These include the masseter and the blink reflex, as well as electrooculographic procedures characterized by a high sensitivity based on the wide distribution of the structures in the brainstem responsible for eye movements. The described topographic mapping can, for example, be crucial in the decision regarding the commencement of secondary prophylaxis following the diagnosis of a central ischemic lesion.
Vascular Imaging Extracranial and intracranial Doppler and duplex sono graphy represent non-invasive techniques for the evaluation of vertebrobasilar vessels. The extracranial segment of the vertebral artery, in particular the V0 segment and the prevertebral and intervertebral segments, are accessible for duplex sonographic diagnosis. In addition to an assessment of the flow velocities, information on the vascular wall morphology can be obtained from the described segments. This is of particular importance in the differentiation between vertebral artery hypoplasia and stenosis or occlusion, and offers an advantage over angiography techniques that are capable of depicting blood flow, but do not provide information on the wall morphology. Furthermore, in the presence of a dissection with a typical intervertebral localization, sonomorphology can provide information of diagnostic significance with the demonstration of a dissection membrane, false lumina, or intramural hematoma. With the use of transnuchal insonation of the V4 segments of the vertebral arteries and the basilar artery through the foramen magnum, intracranial Doppler and duplex sonography can demonstrate circumscribed flow accelerations, high flow resistance profiles, or absent flow in the respective segments. In contrast to the situation in the anterior circulation, no uniform vertebrobasilar stenosis criteria exist and the findings are therefore strongly investigator-dependent. A supplementary transcranial examination of the posterior cerebral artery can be performed, e.g. in patients with suspected basilar artery thrombosis, which can be excluded if abnormal findings are absent in either branch of the artery. The depiction of the distal basilar artery is generally difficult with this technique; particularly in cases of slow basilar thrombosis progression, when only normal findings may be detected in the accessible segments (Schulte-Altedorneburg et al. 2000). A complementary examination using transtemporal insonation of the proximal segments of the posterior cerebral arteries – also with the administration of contrast enhancers – may prove to be helpful in some instances. Its non-invasiveness and good resolution in the posterior circulation have made MR angiography without contrast agents in the time of flight (TOF) technique the currently most widely used neuroradiologic modality for
4.1 Vascular Brainstem Diseases
visualization of the vertebrobasilar vascular system. Moreover, the development of faster gradient systems has led to the increased application of contrast-enhanced 3D-gradient echo-MRA (CE-MRA), which is characterized by low susceptibility to swallowing and movement artefacts. These techniques permit the reliable identification of stenoses in the large vessels up to the proximal segments of the superior cerebellar artery. The visualization of stenoses in vessels with a thin lumen caliber like the PICA or the AICA is, however, significantly less readily achieved. Digital subtraction angiography therefore continues to be the standard technique for use in the distal intracranial vessels (Korogi et al. 1997). Special problems are encountered in the depiction, e.g. of tandem stenoses, because reduced intracranial flow velocity can produce artificial signal intensity decreases or losses and thus render grading of a stenosis impossible. In particular the use of the multislice technique with multislice spiral CT has proven reliable in the identification of vertebrobasilar occlusive lesions (Graf et al. 2000). This applies especially to the quantification of stenoses at the origin of the vertebral arteries. The advantage of CTA consists of the wide availability and short examination times of the technique; a disadvantage are the required large volumes of contrast agents. Since MR angiography frequently overestimates the stenosis grade, the use of CTA for flow measurements through the remaining lumen can provide supplementary information. Despite significant advances in the field of non-invasive diagnostic techniques made in recent years, digital subtraction angiography remains the gold standard for a variety of clinical problems, in particular with regard to pathologic processes of the basilar artery. This is of special significance in the discussion of the indication for endovascular treatments.
4.1.1.5 Therapy Recanalization procedures are of crucial importance in basilar artery occlusions. Until the introduction of the first fibrinoloytic treatments in the early 1980s, heparinization of the basilar artery with a mortality rate of up to 90% was the only therapeutic intervention in the acute phase. Early lysis studies using the fibrinoloytic agents streptokinase or urokinase led to a significant decrease in the mortality rate of the patients undergoing treatment with the described method from 80% to 30% or 40% (Freitag 1993) (Fig. 4.10 ). The introduction of the thrombolytic agent rt-PA in the mid1990s enabled a further improvement of the recanalization rate at an overall lower complication rate (Hacke et al. 1988). The successful recanalization with intravenous (IV) thrombolysis using rt-PA has been described in smaller
209
patient populations, although with reports of varying, comparatively high mortality rates (Hennerici et al. 1991; Huemer et al. 1995). The results of a meta-analysis showed that IV and intraarterial thrombolysis represent options of equal value in regard to both the recanalization and mortality rates (Lindsberg and Mattle 2006). There are, however, a number of factors that limit the significance of the findings of this meta-analysis: Only 20% of the included patients had IV therapy; no differentiation was made between an embolic and thrombotic basilar artery occlusion; different dosages were used for intraarterial lysis; the results of smaller studies on the use of mechanical recanalization were excluded from consideration. Furthermore, in a prospective analysis of more than 600 patients (BASICS) no significant difference was found between the two therapeutic modalities (Schonewille et al. 2009). A definite answer to the question of the optimal therapeutic procedure therefore awaits further research, especially since no findings of prospective, randomized comparative studies on the difference between systemic and intraarterial lysis have been published thus far. If both procedures are available in close temporal proximity, intraarterial lysis should always be given preference in clinical practice, as it offers the possibility of mechanical recanalization and stent-protected angioplasty in patients with residual basilar artery stenosis. This is an aspect of particular importance, since thrombosis is frequently associated with a pre-existing stenosis, which accounts for the high rate of reocclusions in the clinical course (Brückmann et al. 1986). When a patient needs to be transferred to a neuroradiologic center, the immediate administration of a GP-IIb/IIIa antagonist (e.g. abciximab) may be expedient for bridging the interval. Only if such a referral center is not available, or in patients with the rare finding of a conclusively embolic etiology, systemic thrombolysis should be promptly commenced. Alternatively to intraarterial thrombolysis as the only therapeutic measure, the FAST study investigated the low dose intraarterial therapy with rt-PA (mean 20 mg) followed by the intravenous application of GP –IIb/IIIa antagonist abciximab at approved dosages (previously for cardiologic indications only) (Eckert et al. 2005). Additional percutaneous transluminal angioplasty with stent application was carried out in patients with residual severe arterial stenosis. The results were compared with those of a retrospective study in patients with intraarterial rt-PA lysis alone. The mortality rate in the group receiving the combination therapy (38% vs. 68%) was significantly lower, at a better outcome. Current developments of methods for mechanical recanalization have led to the availability of suction systems, systems using snares for disruption or retrieval of the thrombus, or for the local obliteration of thrombi with ultrasound and saline jets. The validity of these methods has thus far been investigated in only small series of patients.
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In cases with fluctuating onset, an intervention may be expedient up to 12 h after symptom onset. A favorable course is not expected after coma lasting longer than 4 h (Freitag 1993). In contrast to studies on conditions in the anterior circulation – apart from the exceptional situation of basilar thrombosis – data on the effectiveness of systemic thrombolysis therapy in brainstem and cerebellar infarctions are scarce. Respective subgroup analyses from the large thrombolysis studies are still lacking. A study including 223 patients undergoing IV rt-PA lysis therapy compared the outcome in patients with infarctions in the anterior and the posterior circulation (Dimitrijeski et al. 2006). An isolated brainstem infarction was found in ten of these patients. Due to the limited applicability on account of the small random sample, no difference in the mortality rate and functional outcome was found by the 3-month analysis. Even though prospective randomized studies are lacking, in patients with dissections initial anticoagulation therapy with heparin, directly followed by Vitamin K antagonists such as warfarin given over a period from 3–6 months is widely accepted as the standard of therapy for symptomatic dissections (Schievink et al. 1994b). Intracranial dissecting aneurysms in the vertebrobasilar circulation are associated with a particularly high risk for re-hemorrhage and should be treated surgically or with endovascular procedures. In view of the frequent finding of spontaneous remission described by imaging studies (Mizutani et al. 1995), initial conservative therapy is indicated in the absence of a preceding hemorrhage. Regarding all other aspects of acute therapy, there is no difference between the recommendations for the treatment of brainstem infarctions and infarctions in the anterior circulation. Further recommended is the application of rehabilitative measures of neurophysiologically oriented physiotherapy, occupational and speech therapy, with special emphasis on the rehabilitation of the symptoms frequently associated with ataxia and dysarthria/dysphagia.
4.1.1.6 Prophylaxis There are currently no published results of studies on the question as to whether secondary prophylaxis generally established in cerebral ischemias are of greater or lesser effectiveness here in the posterior circulation than in infarctions in other regions of the brain. For this reason the etiologic classification alone is of relevance in the decision on the administration of platelet aggregation inhibitors or anticoagulants. Against the background of the overall over-represented portion of microangiopathic ischemias in the posterior circulation, adequate monitoring of risk factors such as arterial hypertension, hypercholesterinemia and diabetes mellitus may have a more important role in prophylaxis. Epidemiologic studies in answer to this question are again lacking.
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Significantly fewer valid data on the therapeutic consequences of different vascular stenoses are available for the posterior than the anterior circulation. Stenoses in the region of the subclavian artery and the brachiocephalic trunk can cause a steal phenomenon, although they are extremely rare causes of brainstem ischemia. This can occasionally be observed in bilateral stenoses. Therapy with stent application appears to be safe and effective in these patients (Du et al. 2009). While antiproliferative drug-eluting stents represent a promising therapeutic option, its usefulness cannot yet be conclusively determined (Edgell et al. 2008). Vertebral artery stenoses commonly exert a hemodynamic effect and require treatment only in cases of bilateral involvement or contralateral hypoplasia. The risk for recurrence of artery-to-artery embolic ischemia in high-grade stenoses may, however, be higher in the posterior circulation than in the carotid artery territory (Marquardt et al. 2009). While balloon angioplasty is the safer procedure under these conditions, it is nevertheless characterized by a high stenosis rate in the further course, so that a combination therapy with stent placement appears to be a more expedient procedure (Nahser et al. 2000). Larger studies in support of this assumption are not available to date. Intracranial stenoses can elicit hemodynamic TIA symptoms, although they are more often a causal factor of infarctions due to an occlusion of the exiting perforating branches. They are further known to be a frequent contributor to the development of basilar thrombosis. Stent angioplasty represents a very promising but not yet widely established therapeutic option.
4.1.1.7 Prognosis and Course of Disease The majority of previous, generally older publications describe brainstem ischemia as a nosologic unity, which does not appear to be justified on the basis of the described heterogeneous etiologic mechanisms and topographies. Further problems of classification arise from the allocation of patients with multiple vertebrobasilar ischemias involving the thalamus and the cerebellum to the same group. Despite the presence of substantial impairments, patients with brainstem symptoms often have very low scores already early in the course on disease assessment scales typically used by epidemiologic stroke studies. The reason for this is that a large number of vertebrobasilar symptoms such as eye movement disturbances, vertigo, or gait ataxia are not represented on these scales. Widely used scales specifically designed for the assessment of the described brainstem syndromes do not currently exist. The early recurrence rate of vertebrobasilar ischemias ranges from 3.5% to 7.1% for the first 10 days and is therefore comparable to the situation in the anterior circulation (Fitzek and Fitzek 2005; Weimar et al. 2002). There is also
4.1 Vascular Brainstem Diseases
211
wide divergence between the reported hospital mortality rates, depending upon whether only isolated brainstem infarctions (0.8%) or cerebellar infarctions and basilar thromboses (19%) were included in the evaluation. Compared with a mortality rate of approximately 32% on inclusion of all cerebral infarctions, a markedly lower rate ranging from 10–20% was reported for brainstem infarctions (Indredavik et al. 1999). An overall low mortality rate from 1–3% p.a. has been consistently reported for isolated brainstem infarctions (Kim 2003; Fitzek and Fitzek 2005). Gait ataxia, dysarthria and dysphagia, as well as primarily motor hemiparesis in pontine infarctions are the most common symptoms associated with functional impairment in patients with vertebrobasilar ischemia. The analysis of stroke registry data as well as the results obtained by one study showed an overall favorable outcome in isolated brainstem infarctions, with almost 50% of patients being able to walk freely after 3 months, while even 80% of all survivors were functionally independent after 5 years (Weimar et al. 2002; Fitzek and Fitzek 2005). A number of different studies reported complete functional independence after 3 months in 35% of all surviving patients with brainstem ischemia, compared to only 22% in patients with supratentorial infarctions (Turney et al. 1984). Poor outcomes with death or severe disability were found in only 21% of patients with isolated brainstem infarctions after 30 days (Glass et al. 2002). Sensory disturbances and ataxias, chiefly of the trunk, were associated with only limited improvement in the course of disease (Fitzek and Fitzek 2005). A completely different situation presents itself in the group with combined brainstem infarctions, which also includes patients with basilar artery thrombosis. A 3-month mortality rate of up to 43.5% has been reported for brainstem infarctions occurring in combination with cerebellar or posterior circulation infarctions (Chambers et al. 1987; Weimar et al. 2002). The mortality rate does, however, not increase significantly in the course of disease up to 1 year after the event. Initial unconsciousness is the most important risk factor for an unfavorable prognosis. Up to 82% of all patients with an initial loss of consciousness die in the course of 1 year.
4.1.2 Intraparenchymatous Brainstem Hemorrhage Peter P. Urban 4.1.2.1 Epidemiology Intracerebral hemorrhages (ICH) are associated with approximately 10–19% of all cerebral insults and represent the second most common cause of stroke after ischemic cerebral infarction (Table 4.5). The worldwide intracerebral hemorrhage incidence ranges from 10–20 cases per 100,000 population (Qureshi et al. 2001). Primary brainstem hemorrhages account for only about 2–6% of all spontaneous intracerebral hemorrhages. Primary brainstem hemorrhage is therefore significantly less often the causal factor of acute brainstem symptoms than infarctions (1.5–11.6%). A study of 44 consecutive patients with pontine ICH found a primary (hypertensive) ICH in 24 and a cavernoma in 20 patients (Rabinstein et al. 2004). Patients with a cavernoma as the cause of bleeding were significantly younger (45 vs. 71 years) and had a lower incidence of arterial hypertension (30% vs. 67%). Different localizations provide useful information on the etiology. Cavernous hemorrhages had a significantly higher prevalence than hypertensive hemorrhages with a unilateral tegmental localization (cavernoma: 18 of 20 vs. primary ICH: 11 of 24). An analysis of bleeding localizations in the brainstem showed that pontine hemorrhages have the highest incidence, followed by mesencephalic hemorrhage (Nakajima 1983). Hemorrhages limited to the medulla oblongata are very rare. Necropsy findings in 24 patients showed the middle of the pontine base or the border to the tegmentum, respectively, to be the most common localizations of pontine ICHs. An extension of the hemorrhage into the fourth ventricle (21 of 24), and pontine hemorrhages extending to the mesencephalic region were frequently found (13 of 24). An extension into the medulla oblongata represented a very rare finding (1 of 24) (Nakajima 1983).
Table 4.5 Incidence of intracerebral bleeding (ICB) and brainstem hemorrhage in European stroke registries Registry ICB Author Patient no. ICB (in % of all Brainstem (in % strokes) of all ICBs)
Brainstem syndromes (in % of all ICBs)
Barcelona Stroke Registry
Marti-Vilalta (1999)
3,577
19.1
4.7
10.8
Ege Stroke Registry
Kumral (1998)
2,000
19.0
6.0
11.6
Besancon Stroke Registry
Moulin (1997)
2,500
14.2
1.9
1.5
Lausanne Stroke Registry
Bogousslavsky (1988)
1,000
10.9
6.5
6.2
212
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4.1.2.2 Etiology A differentiation between primary (= spontaneously occurring) and secondary (bleeding into other lesions) ICHs is generally made, even though in clinical practice a conclusive etiologic clarification is not always possible in vivo. Hypertension is the most common cause of primary intracerebral bleeding (ICB). Patients with a history of persistent hypertension may develop lipohyalinosis (microangiopathy), which promotes the rupture of arterial vessels under conditions of increased blood pressure. The penetrating pontine arteries with a diameter from 50–200 mm are primarily affected in the brainstem. There may be a marked increase in the severity of bleeding over the initial 5–6 h, as coagulation does not start until activation of tissue factor, and tissue resistance rises in response to the increased mass produced by the blood. The space-occupying effect of the hemorrhage is often enhanced by surrounding vasogenic edema. The risk for primary ICH rises with increasing age. In addition to arterial hypertension as the most significant risk factor, the risk for intracerebral bleeding is further augmented by diabetes mellitus, as well as alcohol and nicotine consumption. The increasing use of T2*-weighted sequences in MRI also permits the demonstration of asymptomatic brainstem microhemorrhages in 24–78% of older patients with chronic arterial hypertension and preceding trauma or ICB (Lee et al. 2004). The described microbleeds have an nonspecific etiology and may be associated with other causes, including cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) and cerebral amyloid angiopathy (CAA). Secondary intracerebral bleeds may be due to vascular malformations (arteriovenous malformations, cavernomas) (see Sect. 4.1.4, p. 32). Non-hypertensive causes of brainstem hemorrhage as the result of microangiopathy may be cerebral amyloid angiopathy or CADASIL. According to the so-called Boston criteria, the presence of CAA may be assumed in an older patient (>55 years) without arterial hypertension but preceding recurrent subcortical hemorrhages, or if multiple subcortical bleeds can be demonstrated with T2*-weighted sequences (Knudsen et al. 2001; Fig. 4.18). Yet, histopathologic studies have shown that CAA represents an extremely rare cause of brainstem hemorrhage. Indications of the presence of CADASIL are a history of recurrent ischemic events and vascular dementia with an autosomal dominant heredity. Brainstem hemorrhage may also be the result of iatrogenic coagulation disturbances (warfarin therapy, intake of platelet aggregation inhibitors, intravenous or intraarterial thrombolysis), genetic or hereditary hemophilic diseases (e.g. idiopathic thrombocytopathy, von Willebrand disease, hemophilia A and B), as well as of acquired hemophilic diseases (e.g. in leukemia, lymphoma, hepatic diseases, disseminated coagulation disturbance). Rare causes of secondary brainstem
Fig. 4.18 Cerebral amyloid angiopathy (probable CAA acc. to Boston criteria) with multiple cortical and subcortical hemorrhages and slight brainstem involvement. MRI – T2-weighting
hemorrhage include drug consumption (chiefly sympathomimetic drugs, e.g. amphetamines, cocaine, crack), bleedings in tumors (e.g. chondromas, astrocytomas), or vasculitis (e.g. Behçet’s disease). Craniocerebral trauma can lead to secondary contusions with bleeding into the brainstem.
4.1.2.3 Clinical Findings The symptoms are generally manifest in the acute phase, i.e. in a time window from minutes up to 2 h. In only 13% of patients, the symptoms develop over a period of more than 12 h (Dziewas et al. 2003). A course similar to TIA has been described in individual patients. In the majority of patients the hematoma gradually enlarges causing progression of neurological deficits within the initial hours (Fig. 4.19). Life-threatening conditions arise due to local space-occupying effect, resulting in compression of vital medullary respiratory and circulatory centers, or compression of conduits conveying cerebrospinal fluids (cerebral aqueduct). Blood flow into the fourth ventricle poses an additional, although less common vital threat to the patient.
Fig. 4.19 Massive pontine hemorrhage in arterial hypertension. Fiftythree-year-old female patient with initial dysarthrophonia. Tetraparesis and respiratory insufficiency developed over a period of 3 h. The patient died after 10 days. (a) Day 1; (b) day 2
4.1 Vascular Brainstem Diseases
In view of the variety of symptoms, prognosis and the causes of the hemorrhage, a differentiation is generally made in pontine hemorrhage between bleedings of the pontine base (= paramedian bleeding, massive pontine bleeding, Fig. 4.19), basotegmental bleedings on the border between the pontine base and the tegmentum (Fig. 4.20), and pure tegmental hemorrhage (Figs. 4.21 and 4.22), (Caplan and Goodwin 1982; Chung and Park 1992; Dziewas et al. 2003).
Fig. 4.20 Basotegmental pontine hemorrhage in arterial hypertension. Fifty-five-year-old patient with initial headache and subsequent acute tetraparesis as well as complete ophthalmoplegia; initially spontaneous breathing followed by respiratory insufficiency and bilateral extension synergisms
Fig. 4.21 Acute pontine tegmental hemorrhage due to a cavernoma. (a) Visualized already on CCT in addition to pontine bleeding are multiple hyperdense areas (calcifications) temporal and cerebellar; (b) demonstration of multiple hemosiderin depositions on MRI (T2-weighting)
Fig. 4.22 Finding after pontine tegmental hemorrhage mediated by a cavernoma (a), with secondary ipsilateral olivary hypertrophy (b, c). Forty-nine-year-old patient with acute rotatory vertigo and visual disturbances. Clinical manifestations: downbeat nystagmus, pendular nystagmus, dysarthrophonia, limb kinetic ataxia, and left hemihypesthesia
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• Massive pontine hemorrhage involving the base of the pons, which may also involve the tegmentum, is often associated with disturbance of consciousness as the primary symptom. An initial tetraparesis is a frequent finding and often accompanied by flexion and extension synergisms, as well as different forms of central eye movement and pupillary disturbances, commonly occurring in the form of bilateral miosis. Respiratory insufficiency requiring ventilation, as well as vegetative symptoms (hyperthermia, tachycardia, bradycardia, arrhythmias) are frequently found in the course of disease. A locked-in syndrome as the sequela of extended pontine bleeding has also been described. • Localized, unilateral hemorrhage limited to the tegmentum can lead to isolated cranial nerve deficits (e.g. peripheral facial paresis, trigeminal sensory disturbance, trigeminal motor disturbance with masticatory muscle paresis, unilateral gustatory disturbance, unilateral or bilateral hearing loss), or produce crossed brainstem syndromes (e.g. hemihypesthesia in the region of trigeminal innervation and contralateral dissociated sensory disturbance, Foville’s syndrome, Raymond’s syndrome). Lesions in the pontine tegmentum are often accompanied by eye movement disturbances (e.g. internuclear ophthalmoplegia, skew deviation, one-and-a-half syndrome, horizontal gaze paresis, ocular bobbing) or Horner’s syndrome. There have been isolated reports of hypersomina, and in some cases patients may describe lively, complex and objective visual hallucinations. • Pontine tegmental hemorrhage is often due to a cavernoma. An especially typical sequela of a unilateral pontine tegmental hemorrhage is the development of ipsilateral olivary hypertrophy, which can be clearly shown on MRI by an increase in signal intensity in the T2-weighted sequences (Fig. 4.22). As early as approximately 1 month after the pontine lesion, serial MR-images depict a signal increase in the T2-weighted sequences, olivary hypertrophy is visualized after 6 months. The causal factor is a lesion involving the dentato-rubro-olivary projections (Guillain-Mollaret triangle). In pontine tegmental bleeding, the central tegmental tract is affected between the red nucleus and the inferior olive. A lesion to the inhibitory neurons mediates
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disinhibition with enhanced excitatory input followed by pseudohypertrophy, that is characterized histologically by vacuolary degeneration of the neurons, astrocytic hypertrophy and gliosis. Clinically there may develop different tremor-myoclonus syndromes. These comprise isolated soft palate tremor, soft palate tremor in combination with intention tremor or pendular nystagmus (oculopalatal tremor), isolated pendular nystagmus and Holmes tremor (combination of intention tremor and 3.5–4-Hz resting tremor). The spectrum of neurologic deficits in mesencephalic ICHs is extremely varied, ranging from isolated cranial nerve paresis to crossed brainstem syndromes and complex combinations thereof. Frequent findings include a lesion in the oculomotor and the trochlear nerve, as well as central eye movement disturbances (Parinaud syndrome, vertical gaze paresis, skew deviation, upbeat nystagmus, bilateral ptosis, internuclear ophthalmoplegia). Additional findings in mesencephalic ICHs are Horner’s syndrome, ipsilateral Horner’s syndrome and contralateral trochlear paresis, initial coma, hemihypesthesia, symptomatic hemiparkinson syndrome, focal dystonia of the arm, pseudoathetosis of one arm, and hypothermia in mesodiencephalic hemorrhage. Extensive hemorrhages into the medulla oblongata are in almost all cases associated with initial coma and tetraparesis. Very small bleedings may also cause isolated symptoms and findings as, e.g. vertigo and gaze direction nystagmus, upbeat and downbeat nystagmus, dysphagia, singultus, recurrent and hypoglossal nerve paresis, as well as respiratory insufficiency. 4.1.2.4 Diagnosis Cranial computed tomography (CCT) is an imaging method of vital importance in the demonstration of primary hemorrhages, which are visualized as hyperdense areas on the scan. It further provides information on the degree of the space-occupying effect of the lesion, on the presence of blood entering into the ventricle, and thus on the possibility of an extension of the hemorrhage in the further course of disease with secondary stasis of cerebrospinal fluid. In addition, information on blood absorption in the further course is provided. The breakdown of hemoglobin leads to a decrease in the density values, so that the CT scan shows diminished central hyperdense areas surrounded by a hypodense margin at the end of the first week of disease progression. After 3–6 weeks, the hemorrhage becomes hypodense and a remaining parenchymal defect is observed. The conclusive identification of ICH using magnetic resonance imaging (MRI) is achieved chiefly with the application of T2*-sequences. MRI is of significance in the non-invasive detection of the possible cause of bleeding, e.g. arteriovenous malformations, an aneurysm or cavernoma.
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Clinically silent microhemorrhages can also be shown using T2*-weighted sequences. Cerebral catheter digital angiography is indicated if the causes of hemorrhage are unclear. MRI findings are generally sufficient for the diagnosis of an arteriovenous malformation. In the early phase, angiography is avoided in the majority of unstable patients if the findings are of no immediate therapeutic consequences. Electrophysiologic diagnostics (chiefly auditory and somatosensory evoked potentials) do not have an important role in the primary diagnosis, although evoked potentials can make a valuable contribution in establishing the diagnosis (Ferbert et al. 1990). Lumbar puncture should be avoided in ICH in view of the frequently observed initial increase in intracranial pressure. Of particular importance in brainstem hemorrhage is the performance of a laboratory test for the diagnosis of thrombophilia. The molecular genetic proof of CADASIL can be obtained with a blood test demonstrating a Notch3 gene mutation.
4.1.2.5 Differential Diagnosis Of interest is mainly the differential diagnosis of hemorrhagic brainstem infarctions. In contrast to hemispheric infarctions, these represent extremely rare events (Jung et al. 2000; Kimura et al. 2001). None of the 97 Besancon Stroke Registry patients with brainstem infarctions had a secondary hemorrhage (Moulin et al. 2000). An evaluation of the German stroke data bank showed secondary hemorrhage in three of 340 (0.9%) patients with brainstem infarctions (Weimar et al. 2002). Additional differential diagnoses refer primarily to the different causes of hemorrhage.
4.1.2.6 Therapy The initial therapeutic measures consist of the establishment of a venous access, oxygen administration via nasogastric tube (e.g. 2 L/min), ECG monitoring, pulse oximetry and blood pressure measurements. In the presence of decreasing O2-saturation or decreased level of consciousness, the patient is immediately intubated and rapidly transferred to a clinic for CCT. Patients showing decreased level of consciousness on admission to the hospital should always be admitted to an intensive care unit. Patients who are awake and cooperative can undergo initial treatment in a stroke unit. All patients with the threat of herniations and the indication for surgical intervention should receive primary neurosurgical therapy.
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A placebo-controlled randomized multicenter study including 399 patients with ICH showed that the intravenous use of recombinant activated factor VII within 4 h after the bleeding event leads to a significant reduction in the volume increase of bleeding after 24 h (Mayer et al. 2005). The 90-day mortality rate was reduced from 29% (placebo) to 18% (factor VII), although thromboembolic events occurred significantly more often in the group with factor VII treatment. However, this study included only 16 patients with brainstem hemorrhage and a subgroup analysis was not carried out. It is hoped that advances in hemostatic approaches will prevent the progression of existing bleeding (as shown in Fig. 4.19, p. 24) in the future. 4.1.2.7 Conservative Therapy Conservative therapy strategies in brainstem hemorrhage are in accord with the general recommendations for the treatment of intracerebral bleeding (Broderick et al. 1999; Qureshi et al. 2001). Of prime importance are the protection of the respiratory tract and the provision of adequate ventilation and oxygenation. Early intubation is indicated in patients with rapid progression of impaired consciousness. The indication for intubation generally exists in the presence of pO2-levels below 70 mmHg, or pCO2 levels above 50(−55) mmHg. With regard to blood pressure readings, elevated blood pressure levels (>180 mmHg systolic) should be prevented due to the risk for secondary bleeding. Antihypertensive therapy with urapidil and clonidine is recommended with a view to the known related reduction in intracranial pressure provided by these agents. In patients with invasive monitoring of intracranial pressure, cerebral perfusion – not exceeding 60–70 mmHg – should further be measured. Perihematomal edema often develops during the first few days and can add significantly to the space-occupying effect of the hemorrhage. A randomized study of patients with supratentorial ICH has not shown a positive effect for the use of steroids (Poungvarin et al. 1987). Similarly, the efficacy of osmotherapeutics for the prophylaxis or therapy of a developing perihematomal edema has not been conclusively shown (Bereczki et al. 2001). Patients with oral anticoagulant use (warfarin) receive vitamin K and prothrombin complex concentrate concurrently, depending on the INR values. No conclusive data on thrombosis prophylaxis with subcutaneous heparin or heparinoids are currently available. Low-dose heparinization is generally applied. 4.1.2.8 Operative Therapy The establishment of ventricular drainage is required in patients with impaired cerebrospinal fluid drainage.
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A pronounced space-occupying effect with secondary brainstem compression may develop in hemorrhages involving primarily the cerebellum and less often also parts of the brainstem. In this setting, surgical removal of the hematoma is required, usually in combination with establishment of ventricular drainage. Intraparenchymatous bleeds limited to the brainstem do not generally represent a primary indication for surgery (Komiyama et al. 1989). Surgical removal of the hematoma is indicated only in isolated cases with massive and progressive symptoms (Haines and Mollman 1993). A better functional outcome over conservative therapy has, however, been reported for CT-guided stereotactic hematoma aspiration (Takahama et al. 1989). Due to the lack of results reported by comparative therapy analyses, no general recommendations can be made on the therapeutic approach in patients with the first occurrence of hemorrhage from cavernomas. Recommendations range from early surgical removal (Sandalcioglu et al. (2002) to stereotactic irradiation (Liu et al. 2005) to a conservative approach (Kupersmith et al. 2001). Treatment is therefore contraindicated on principle in cavernomas without neurologic deficits.
4.1.2.9 Prognosis The prognosis in ICH is generally markedly poorer compared to the outcome in ischemic infarctions. The crucial prognostic factor for survival are the first hours to days, as extended pontine hemorrhages may extend to rostral-caudal areas and damage centers of vital importance. The 30-day mortality rate ranges from 20% to 56% and depends, in addition to blood flow volume, hemorrhage extending into the ventricle, initial severity of the clinical picture (coma), and patient age, on bleeding localization and causes (Chung and Park 1992; Dziewas et al. 2003; Wessels et al. 2004). The following findings within the first 2 h after symptom onset are known to be associated with a very unfavorable prognosis: coma, bilateral miosis, anisocoria, and diameter of pontine bleeding ³20 mm (Chung and Park 1992; Dziewas et al. 2003). An analysis of patients with pontine hemorrhage who underwent conservative therapy only, showed the combination of coma, pontine base hemorrhage and hemorrhage diameter of ³20 mm to be the highest positive predictive value (100%) – at 74.1% sensitivity and 100% specificity – with regard to a lethal outcome (Dziewas et al. 2003). Almost all patients with a small, unilateral tegmental hemorrhage survive (94% or 100%, respectively). Among patients with bleedings on the border between the pontine base and the tegmentum 26–87% will survive. Massive bleedings in the region of the pontine base, which generally also involve the tegmentum, are associated with a very low survival rate of 0–9%. In addition to clinical and imaging diagnostics, evoked potentials (AEP, SEP) provide useful prognostic
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information as to outcome (Ferbert et al. 1990). It has been shown that a bilateral loss as of wave II of AEPs and a bilateral loss of N20 of SEPs is always associated with a lethal outcome. Reliable data on the long-term prognosis are not available at present, due to the fact that the data collected for the small subgroup of patients with the rare occurrence of primary brainstem lesions are not considered separately in the large stroke databanks. Yet, recent MRI studies using chiefly T2*-weighted sequences have documented a large proportion of clinically unapparent microangiopathic brainstem bleedings. These findings suggest that smaller hemorrhages may have a more favorable prognosis, also with regard to functional outcome. A comparison between patients with primary ICH and cavernoma showed the functional deficits in the survivors of the latter group to be significantly less severe (modified Rankin Scale £2%; Rabinstein et al. 2004). At an annual hemorrhage recurrence rate from 5% (Kupersmith et al. 2001) to 30% (Porter et al. 1999) reported for cavernomas, every additional hemorrhage may be expected to lead to an increase in the residual functional deficit.
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Fig. 4.23 Prepontine subarachnoid hemorrhage without demonstration of an aneurysm on angiography
4.1.3 Perimesencephalic Subarachnoid Hemorrhage and Cerebral Superficial Siderosis Peter P. Urban and Wibke Müller-Forell 4.1.3.1 Perimesencephalic Subarachnoid Hemorrhage
Fig. 4.24 Perimesencephalic subarachnoid hemorrhage, also localized dorsal to the brainstem. No angiographic demonstration of an aneurysm
Etiology Epidemiology Subarachnoid hemorrhages (SAH) are the third most common cause of stroke, occurring in 3% of cases. Perimesencephalic subarachnoid hemorrhage was first described as a clinical entity in 1985 and constitutes approximately 10% of all SAHs (van Gijn et al. 1985). Comparable to other SAHs, the greatest incidence is observed in the fifth and sixth decades of life. While the hemorrhage is generally localized immediately ventral to the mesencephalic brainstem, it can also occur ventral to the pons (prepontine). For this reason the term pretruncal hemorrhage has been suggested to describe the condition (Schievink and Wijdicks 1997; Fig. 4.23). In rare cases localized bleeding may be found dorsal to the brainstem in the ambient cistern anterior to the lamina quadrigemina, which represent about 3.4% of all perimesencephalic hemorrhages (Rinkel and van Gijn 1995; Fig. 4.24).
Most patients with perimesencephalic SAH have normal panangiographic findings, and an aneurysm as the source of bleeding is usually also excluded on control angiographic examination. The cause of perimesencephalic SAH is usually not identifiable, and in the presence of negative angiography it is therefore also referred to as idiopathic perimesencephalic SAH. Due to the generally favorable prognosis there are currently no results of autopsy studies. However, in the majority of cases the cause of hemorrhage is attributed to venous sources (van der Schaaf et al. 2004) or to bleeding from capillary telangiectasies of the brainstem (Wijdicks and Schievink 1997), which are undetected on angiography. No reliable data on the incidence of capillary telangiectasies in perimesencephalic SAH are available, since MRI in addition to CT and angiography has only been performed in exceptional cases. Anatomic variants of venous drainage from the brainstem may be a predisposing
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factor to perimesencephalic SAH, because in these patients the venous blood drains more often into the intradural sinus instead of into the large cerebral vein (vein of Galen) compared to the control group (van der Schaaf et al. 2004). Arterial hypertension has been identified as an independent risk factor for the occurrence of idiopathic perimesencephalic SAH (Canhao et al. 1999). Rare causes of perimesencephalic hemorrhage include an aneurysm in the posterior cranial fossa (Rinkel et al. 1991b; van Calenbergh et al. 1993), basilar artery dissection, and spinal dural arteriovenous fistula located in the high cervical region (C1).
Diagnosis Computed cranial tomography (CCT) has a crucial role in the demonstration of primary bleeding. Within the first 24 h, the sensitivity of CCT in the demonstration of (aneurysmal) SAH ranges from 92–98%. The described sensitivity decreases with every subsequent day to approx. 50% on day 5. A further advantage offered by CCT is the demonstration of concomitant intracerebral bleeding, which is frequently observed in aneurysms of the middle cerebral and anterior communicating arteries, of accompanying brain edema, hydrocephalus, or a large aneurysm. A cerebrospinal fluid analysis must be performed when no hemorrhage can be identified on CCT, but SAH is nevertheless suspected,
Clinic There is no significant difference between the clinical symptoms of idiopathic perimesencephalic SAH and aneurysmal hemorrhage. The principal sign is a severe headache with sudden onset, which, in contrast to the ‘thunderclap headache’ in aneurysmal hemorrhage, increases in intensity over just a few minutes; the predictive value of this criterion is, nevertheless, very low (Linn et al. 1998). Nuchal rigidity is observed in 70% of cases. The following symptoms are found in only a small number of patients: nausea and vomiting, disturbance of consciousness (up to 31% (Linn et al. 1998; Ildan et al. 2002)), transient amnesia (up to 30% (Hop et al. 1998)), acute hydrocephalus (up to 20% (Ildan et al. 2002)); clinically symptomatic vasospasm (6.8% (Ildan et al. 2002)). In extremely rare cases focal neurologic deficits have been identified (in one out of 65 patients: Rinkel et al. 1991a). The incidence of autonomic complications (arrhythmia, ECG changes), and hyponatremia is comparable to that in aneurysmal SAHs (Rinkel et al. 1991a). The severity of SAH is assessed with the Hunt and Hess scale (Table 4.6). Table 4.6 Hunt and Hess classification of subarachnoid hemorrhage Grade Findings I
Asymptomatic or mild headaches and meningism
II
Moderate-severe headache, meningism, no neurologic deficits besides cranial nerve symptoms (due to compression by the aneurysm)
III
Lethargy, confusion or mild neurologic deficits
IV
Stupor, mild-severe hemiparesis, vegetative disturbances
V
Coma, signs of decerebration, moribund patient
CCT is mandatory prior to lumbar puncture, since SAH can produce an increase in intracranial pressure with the associated risk for herniation. Clear and colorless cerebral spinal fluid excludes the presence of (aneurysmal) SAH. There have thus far, however, been no studies to determine whether the cerebrospinal fluid drawn by spinal tap always contains red blood cells in patients with perimesencephalic SAH. If the sample of cerebrospinal fluid contains red blood cells, differentiation from an artificial admixture of blood (“traumatic tap”) has to be made. This may be done with the three-vial test, or preferably by immediate centrifugation of the cerebrospinal fluid. Xanthochromic cerebrospinal fluid after centrifugation confirms the presence of SAH. Xanthochromia can be present up to 2 weeks after SAH, siderophages are identifiable for 3–4 weeks. In perimesencephalic SAH, cerebral panangiography using digital subtraction technique should on principle be performed to exclude an aneurysm. The recommendation to limit the examination to CT angiography has not yet been widely accepted (Ruigrok et al. 2000), and it remains in dispute if, in the presence of a normal angiogram, a control angiography should be performed after 14 days, i.e. on completion of a possible vasospasm phase. While van Gijn and Rinkel (2001) are opposed to the performance of a second angiography in view of both the low probability that an aneurysm is detected and the risk associated with the examination, other authors argue strongly in its favor, based on the finding that vasospasm, which may mask an aneurysm, occurs in 10% of patients. MRI enables the demonstration of intraparenchymatous malformations as, e.g. capillary telangiectasies, which are being discussed as possible causes of bleedings in perimesencephalic SAH (Wijdicks and Schievink 1997). Daily transcranial Doppler sonographic (TCD-) examinations should be performed later in the course to detect the presence of a vasospasm. TCD permits early detection
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of vasospasm with a high sensitivity and specificity (Sloan et al. 2004). However, clinically apparent vasospasm is only rarely observed in idiopathic perimesencephalic SAH.
Differential Diagnosis Since hemorrhage can be definitively differentiated from other causes of a hyperdensity on CCT or in cerebrospinal fluid, differential diagnostic considerations are essentially focussed on the clarification of the cause of the hemorrhage. Subarachnoid hemorrhages are often due to a ruptured aneurysm usually a saccular aneurysm. Rarer causes of an aneurysmal vascular expansion comprise mycosis, primarily in endocarditis, dissection, trauma, and malignant aneurysms in chorionic carcinoma. Further causes of hemorrhage are arteriovenous malformations and dural fistulae, vascular disorders including vasculitis, sinus thrombosis, moyamoya disease, tumors (primary CNS tumors and metastases), drug abuse (primarily cocaine, amphetamines and ecstasy), craniocerebral trauma, hematologic disorders (coagulation anomalies, acute leukemia, platelet function abnormalities, infections (abscess, herpes encephalitis, bacterial meningitis) and spinal SAH (van Gijn and Rinkel 2001).
Therapy Initial medical care consists of the establishment of venous access, oxygen administration via nasal tube (e.g. 2 L/min), and monitoring with ECG, pulse oximetry, and blood pressure readings (lowering of increased blood pressure at values of >170/90 mmHg). Decreasing O2-saturation or cognitive impairment are indications for early intubation, followed by immediate transfer to a clinic for CCT. Although patients with SAH should on principle be admitted to a neurologic or neurosurgical intensive care unit, patients with perimesencephalic SAH can also undergo treatment in a stroke unit. Conservative therapy comprises • • • •
Bed rest Avoidance of straining (laxatives) Adequate fluid intake Regulation of systolic blood pressure to systolic values from 120 to 150 mmHg • Analgesia with opioids in patients with severe headache (avoid analgesics with platelet aggregation inhibiting action)
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Low-dose heparinization for the prophylaxis of deep vein thrombosis should be applied during immobilization of the patient. In intracerebral hemorrhage under oral anticoagulants (warfarin) vitamin K and prothrombin complex concentrate are given simultaneously, depending on the INR values. Because vasospasm is shown in up to 10% of patients with perimesencephalic SAH, prophylactic therapy with calcium antagonists (nimodipine) should be considered in all patients. According to the German Society of Neurology guidelines, vasospasm prophylaxis is, however, not indicated in all patients, and should be used only in the presence of an increase in flow velocity on transcranial Doppler (mean value >120 m/s). The recommended dose is 60 mg p.o. every 4 h. In patients with swallowing difficulty, nimodipine 1 mg/h (5 mL/h) i.v. is given over the first 6 h; depending on blood pressure readings, the dose is increased over another 6 h to a maintenance dose of 2 mg/h (10 mL/h). Nimodipine prophylaxis should be continued over a period of 3 weeks. During this time the maintenance of systolic blood pressure readings from 130 to 160 mmHg should be given priority over nimodipine therapy, which can have a blood pressure-lowering effect. The indication for interventional or surgical therapy in perimesencephalic SAH is given only in exceptional cases. These include an angiographic demonstration of a vertebral aneurysm, or the rare case of an occlusive hydrocephalus, which requires placement of a ventricular drain. Aneurysms of the vertebrobasilar circulation are commonly occluded by endovascular placement of platinum coils of varying length (Wanke et al. 2004). The earliest possible occlusion of the aneurysm is generally attempted.
Prognosis Perimesencephalic SAH is associated with a very favorable prognosis compared to aneurysmal bleeding. Long-term follow-up studies have reported conflicting results on the psychosocial outcome. While nearly all patients of one study had fully recovered and returned to their previous activities (Brilstra et al. 1997), 62% of patients from another study reported persistent complaints, including headache, depression, forgetfulness, and reduced mental and physical fitness, so that 53% had taken early retirement or were unemployed (Marquardt et al. 2000). Conversely, the prognosis is significantly less favorable in perimesencephalic hemorrhage due to a vertebrobasilar aneurysm. Vertebrobasilar dissections are also associated with a high mortality rate from 19–83%, and early recurrent hemorrhages have been observed in 24–58% of patients (Ramgren et al. 2005).
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4.1.3.2 Cerebral Superficial Siderosis Epidemiology Superficial siderosis is a very rare condition and has been described in only 150 patients.
Etiology Chronic recurrent subarachnoid hemorrhage is associated with hemosiderin depositions on the surfaces (leptomeningeal, subpial, subependymal) of cerebrospinal fluid-surrounded structures of the cerebrum, the brainstem, the spinal cord, and the nerve roots. Histopathology shows the occurrence of gliosis, nerve cell apoptosis, and demyelination at the sites of hemosiderin accumulation (Koeppen et al. 1993). A potential source of hemorrhage is identified in about 50% of patients. The main sources of hemorrhage are dural lesions, spinal root processes (e.g. posttraumatic root avulsion, slipped disk, meningeomas), tumors (chiefly ependy momas), and vascular malformations (primarily cavernomas) (Fearnley et al. 1995). The occurrence of arachnoid pathologies or defects as, e.g. (pseudo-) meningoceles, encephaloceles, posttraumatic or postoperative arachnoid adhesions, and epidural cysts are found in up to 50% of patients (Fearnley et al. 1995; Leussink et al. 2003; Kumar et al. 2006). Systemic hemochromatosis secondary to cerebral vasculitis has been described in isolated cases.
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primarily with the use of T2*-weighted sequences, enabled the highly sensitive and specific demonstration of hemosiderin depositions. A uniform pattern can be identified (Fig. 4.25): in addition to pronounced superior vermis cerebellar atrophy, T2-weighted (T2*w, respectively) images depict a marked hypointense rim around the cerebellar sulci and the brainstem comprising the surface structure of the cerebral parenchyma. The described subpial hemosiderin depositions can also be differentiated in the vertebral canal as a pronounced hypointense peripheral structure around the spinal cord and/or the cauda equine fibers (Urban et al. 1999). The presence of hemorrhage is demonstrated by analysis of the cerebrospinal fluid, which always contains erythrocytes, although siderophages, free hemoglobin, and xanthochromia are also identified, and thus enable definitive differentiation from artificial blood admixture. A careful search for the potential source of hemorrhage must be performed. Required for this purpose is the performance of spinal MRI imaging, cerebral panangiography and, in the
Clinical Findings The variety of clinical symptoms associated with superficial siderosis is very wide. Typical is a combination of • A slowly progressive, bilateral retrocochlear hearing loss sometimes severe (95%) • Cerebellar ataxia (88%) • Pyramidal tract signs (76%) • Dementia (24%) • Anosmia (17%) • Anisocoria (10%) • Sensory disturbances (13%) • Bladder voiding disturbances (13%), low back pain and • Polyradicular symptoms of the lower extremities (5–10%) (Fearnley et al. 1995).
Diagnosis Diagnosis of superficial siderosis was until recently usually established at post-mortem. The introduction of MRI,
Fig. 4.25 Myxopapillary ependymoma of the vertebral canal (with extended subarachnoid filamentation, also to intracranial). Twentythree-year-old male with progressive paraparesis for several years, followed by tetraparesis, gait ataxia, and onset of hearing loss. (a) Axial T2w-image shows expansion of the inner and outer infratentorial and supratentorial cerebrospinal fluid spaces in addition to signal extinction affecting all cerebellar sulci, the classic picture of cerebral superficial siderosis. (b) Sagittal T2w-image demonstrating hemosiderosis of the brain and brainstem surfaces and the extent of cerebellar atrophy, as well as the cervical spinal cord edema, produced by the more caudally localized tumor. The irregular expansion of the ependymal/periventricular brain tissue is due to ubiquitous tumor seeding. (c) Axial T2wimage at the level of C2. (d) Sagittal T1w-image, contrast-enhanced depiction of the solid part of the tumor at Th1 level
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presence of a normal finding, spinal angiography. In view of the limited number of possible conservative treatment measures, thorough clarification of the cause of hemorrhage is of particular importance for subsequent treatment.
Therapy A therapeutic approach that emphasizes the cause with the earliest possible elimination of the source of hemorrhage is in the foreground. Because in about half of the patients no source of hemorrhage can be identified, theoretical considerations suggest the application of chelating agents (trientine) and antioxidative substances (vitamin C and E) (River et al. 1994; Leussink et al. 2003), although conclusive evidence of their efficacy is still lacking. A case report describes the successful administration of corticosteroids in a man who also had positive anti-Ri-antibodies (Angstwurm et al. 2002).
Prognosis The prognosis is unfavorable for patients without a demonstrable source of hemorrhage, which precludes the possibility of its surgical or interventional-radiologic elimination. With the exception of a small number of patients, slowly progressive worsening of symptoms to complete loss of hearing is observed despite conservative therapy. Approximately 27% of patients are confined to bed within a median period of 11 years, due to severe cerebellar ataxia and/or myelopathy (Fearnley et al. 1995).
4.1.4 Vascular Malformations Wibke Müller-Forell Although vascular malformations can be localized in all regions of the central nervous system (CNS), primarily cavernomas, capillary telangiectasias, and developmental venous anomalies (DVA) (Mull et al. 1995) are found in the brainstem. Pial/dural arteriovenous malformations (AVM) represent rare brainstem findings.
4.1.4.1 Cavernomas Histopathology Up to 35% of all cerebral cavernous malformations (cavernomas) are found in the region of the brainstem. Cavernomas
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are the only venous vascular malformations of the brain (Okazaki 1989). Macroscopically they appear as low contrast, reddish lesions with a raspberry-like structure, consisting of a compact agglomeration of many different-sized communicating cystic vascular spaces that have no actual capsule, but are characterized by vascular walls of varying thickness. These vascular spaces are irregularly thrombosed with a secondary organization, so that in the presence of a normal vascular structure the walls exhibit secondary alterations such as calcifications and fibroses. The characteristic feature that differentiates cavernomas from capillary telangiectasias is the absence of neuronal brain tissue inside of the lesion. The gliotic cerebral parenchyma of the vicinity almost always shows signs of old hemorrhages, due to the presence of hemosiderin-loaded macrophages. In many cavernomas small satellites can be identified in the periphery of the malformation, which cause a slight blurring of the characteristic feature of cavernomas, namely the absence of neuronal tissue between the individual vascular spaces (Russel and Rubinstein 1977; Okazaki 1989). The histology of the two vascular changes, telangiectasia and cavernoma, gave rise to the description “cerebellar capillary malformation” for both entities, a nomenclature that did not prove useful in routine clinical practice (Rigamonti et al. 1991; Küker and Forsting 2004). Cavernomas can change their size and configuration, which is not due to invasive growth, but is always the result of osmotic alterations (Küker and Forsting 2004). The characteristic low compression system enabling cavernomas to produce spontaneous, often clinically silent (micro-) hemorrhages cannot be fully explained based on the etiology alone. Neither does the histologic demonstration of rarefaction of endothelial tight junctions with gaps of different sizes (Wong et al. 2000) provide a satisfactory explanation, but their frequent vicinity to DVAs and/or capillary telangiectasias is conspicuous (Küker and Forsting 2004). Cavernomas are characterized by significant variability in size and extension, as well as by a mostly primary origin. Secondary cavernomas can form after radiation therapy. Although the genesis of cavernomas is not clear, different endothelial and subendothelial properties, e.g. angiogenic and proliferative markers like proliferative cell nuclear antigen (PCNA) and/or vascular endothelial growth factor (VEGF) are discussed as having a role in their development (Bertalanffy et al. 2002). The preferred localization of infratentorial cavernomas is the pons (26%), followed by the cerebellum (17%), the midbrain (12%), and the medulla oblongata (8%). Symptomatic cavernomas usually have a diameter greater than 1 cm. Multiple cavernomas are rare, their detection is suggestive of a hereditary etiology; several members of a family (up to 93%) are commonly affected (Bertalanffy et al. 2002).
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Clinical Findings
Diagnosis
The clinical symptoms in patients with cavernomas vary widely. They mainly present with seizures, spontaneous hemorrhage, or focal neurologic deficits (Bertalanffy et al. 2002). There are conflicting reports in the literature as to the risk for hemorrhage in cavernomas (independent of their localization): the prospective probability of hemorrhage ranges from 1.6% to 3.1% per patient and year (Porter et al. 1997; Moriarity et al. 1999), while infratentorial and brainstem cavernomas are associated with a significantly higher frequency rate of hemorrhage than supratentorial cavernomas (Bertalanffy et al. 2002). Spontaneous hemorrhages from cavernomas (Fig. 4.26a) have a more benign course than those from arteriovenous malformations. In the brainstem this usually benign course becomes particularly apparent on comparison with the etiology of other spontaneous hemorrhages (Rabinstein et al. 2004). Although clinical improvement in individual patients, mostly after surgical intervention, is difficult to predict, most patients, including those with severe neurologic deficits, show complete recovery or only minor impairments (Bertalanffy et al. 2002).
The preferred imaging technique for imaging cavernomas is MRI. The different old blood remnants from previous, usually clinically silent microhemorrhages (which contain deoxyhemoglobin and/or hemosiderin) are responsible for the characteristic hypointense, low signal in T2-weighted, and particularly in T2*-weighted gradient-echo sequences, which form the hypointense rim around the mulberry-shaped larger part of the cavernoma. T2*-weighted sequences are therefore obligatory in the examination protocol of patients with a positive family history or a history of radiation therapy of the brain, to enable the definitive demonstration or exclusion of multiple or newly developed cavernomas (Fig. 4.26b, c). In particular the methemoglobin content in the differently old thrombi seen in native T2-weighted images, combined with the associated increase in signal intensity and the lesion morphology provides evidence for a cavernoma. The administration of contrast agent is not obligatory, especially since the slow flow velocity may lead to a delay in demonstrable contrast enhancement (Küker and Forsting 2004). Due to the blood slow flow velocities cerebral angiography almost never demonstrates cavernomas, rendering the
Fig. 4.26 Image obtained in a 17-year-old girl with multiple cavernomas and clinical evidence of nystagmus and right-sided hemihypesthesia. The symptoms resolved completely after surgery. (a) Native CT examination with paramedian left localized acute pontine hemorrhage. (b) Corresponding native T1-weighted MRI showing, in addition to a mixed signal increase (deoxyhemoglobin and methemoglobin), two smaller partly hyperintense and partly hypointense alterations (arrows) in the right cerebellum (not definitively identifiable on CT). (c) Corresponding T2*-weighted image does not only confirm these lesions as additional cavernomas (signal extinction due to the high susceptibility of hemosiderin), but also demonstrates a further (fourth) cavernoma left temporal (arrow)
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indication for digital subtraction angiography questionable. CT often detects cavernomas only if the lesions are large. They are visualized as delicate, small but pronounced calcifications (which should not be mistaken for hemorrhages) with low contrast enhancement; smaller cavernomas may be missed.
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Therapy Despite the extremely challenging localization in the brainstem region, surgical removal of cavernoma should always be considered after a first hemorrhage. This is based on both the continued improvement of preoperative imaging techniques, which enables differentiated therapeutic strategy, and the resulting possibility of planning an approach tailored to the individual finding. This, together with the continuous refinement of microneurosurgical techniques (e.g. neuronavigation), intraoperative monitoring, and differentiated anesthesiologic care (brain protection), has led to a significant decrease in perioperative morbidity (Bertalanffy et al. 2002; Ferroli et al. 2005). The alternative of radiation (Liscák et al. 2005) or conservative therapy (Kupersmith et al. 2001) should always be individually considered. In contrast, incidental brainstem cavernomas without neurologic deficits are always left untreated.
4.1.4.2 Capillary Telangiectasias Histopathology These lesions consist of a network of thin-walled expanded capillaries without smooth musculature or elastic fibers, nonuniformly surrounded by partially gliotically altered brain parenchyma. They have most often been detected incidentally at autopsy and were described as spongy, pale red areas (Russel and Rubinstein 1977). Saccular convoluted dilatations (no increase) of capillary vessels are always found surrounded by normal neuronal parenchyma reminiscent of cavernomas (Okazaki 1989). The preferred localizations are chiefly near the midline of the pontine base (Fig. 4.27), less commonly the cerebral cortex and white matter (Okazaki 1989). The clinical relevance of the described vascular alterations is questionable, because they almost always represent incidental findings and are not diagnosed based on relevant neurologic symptoms. They should not be mistaken for hereditary hemorrhagic telangiectasia (Rendu-Osler syndrome), which is an independent clinical entity, characterized by cerebral vascular malformations, but not associated with cerebral capillary telangiectasias (Krings et al. 2005).
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Fig. 4.27 MRI obtained in a 43-year-old woman with telangiectasia. The examination was performed due to the presence of tinnitus. (a) T2-weighted image without distinctive features; (b) corresponding contrast-enhanced image, showing a delicate signal increase paramedian in the mid-pontine segment; (c) corresponding coronal demonstration of telangiectasia (white arrow)
Magnetic resonance imaging is the only modality capable of an intra vitam diagnosis of these brainstem lesions (Fig. 4.27), in particular since only in isolated cases these alterations can be reconciled with clinical neurologic abnormalities (Huddle et al. 1999). In contrast-enhanced T1-weighted images, capillary telangiectasias are imaged as a delicate but distinct increase in signal intensity. In some cases (dependent also on the slice thickness and individual appearance) a small collecting vein is visualized, a finding suggestive of a special form of DVA (Küker and Forsting 2004). On T2-weighted, but particularly T2*-weighted sequences they appear as only mildly hypointense, which is explained by the presence of deoxyhemoglobin in the slowflowing blood (Auffray-Calvier et al. 1999). Neither followup examinations nor a biopsy are required in view of the benign clinical course, lacking pathognomonic importance, and the absence of a respective therapeutic option (Forsting and Wanke 2004).
Developmental Venous Anomalies For many years the nature of developmental venous anomalies (DVAs) was not recognized (they were considered to be a vascular malformation, a so-called venous angioma). This alteration in cerebral veins is now increasingly
4.1 Vascular Brainstem Diseases
diagnosed with modern imaging modalities; it is neither an “angioma” (with a certain risk for hemorrhage) nor a dynamic tumor-like process, but a variant of the venous drainage; it does therefore not represent a pathology, but an anomaly without clinical significance. Daily clinical experience shows that this lack of understanding is the reason why patients continue to be advised to submit to surgical “care” for their “venous malformations”.
Etiology The genesis of this anomaly is still not fully understood. The hypothesis of intrauterine events during the development of the medullary veins has been advanced (Saito and Kabayashi 1981), and was corroborated by the finding of an absent normal collecting vein in the vicinity of a DVA. Their association with cavernomas is striking (Rigamonti and Spetzler 1988) and possible common genetic factors may be responsible for this phenomenon (Plummer et al. 2004). Physiologically, the major part of the venous drainage from the brain parenchyma (white matter, central gray) to the ependymal, and thus to the inner veins, occurs via deep medullary veins. The cortex and a small part of the subcortical white matter are chiefly drained via superficial medullary (cortical) veins. Both, the superficial and the deep medullary venous system are connected by transcerebral veins (Huang and Wolf 1964). The characteristic appearance of DVA, the so-called “caput medusa” (syn. spider vein configuration) appearance to DVAs are formed by these dilated medullary veins, histologically proven with normal wall architecture. Only the drainage is a variant of the usual pathway, which implies that DVAs drain normal brain tissue via an anatomically normal fashion but in an unusual direction. Corresponding to the main and collecting vein, a differentiation is made between superficial and deep DVAs: superficial DVAs drain normal (deep) medullary areas of the brain into cortical, superficial veins and vice versa (Lasjaunias 1997).
Clinical Findings The clinical symptoms of DVAs are vague. It is questionable in how far nonspecific symptoms such as headache, or more specific symptoms like epileptic seizures can be attributed to the presence of a DVA (McLaughlin et al. 1998). The diagnosis of an atypical DVA is based on the coexistence of a DVA, a perifocal edema, and non-AVM typical arteriovenous
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shunts with premature venous drainage (Berlis et al. 2004). If clinical symptoms are present, they are most commonly determined by their coexistence with clinically asymptomatic cavernomas.
Diagnosis Due to the association with cavernomas, MRI examination should not only include T2-weighted, but also T2*-weighted sequences to enable the demonstration or exclusion of a small cavernoma in the vicinity of a DVA (Forsting and Wanke 2004). A DVA may be missed in native T2-weighted images. Due to the slow venous flow, the dilated medullary, transcerebral veins with the medusa head appearance (Fig. 4.28) are visualized only on contrast-enhanced images. Also detectable in contrast-enhanced images is the markedly dilated collecting vein, which drains either into the cortical or the deep venous system (Forsting and Wanke 2004). The collecting vein is identifiable in T2-weighted images due to the flow void with the characteristic signal extinction (Fig. 4.28a). Angiography reveals the typical spider vein configuration of the transcerebral enlarged medullary veins converging towards the collecting vein. There is absolutely no indication for cerebral angiography if magnetic resonance imaging has confirmed the suspected diagnosis of a DVA (Forsting and Wanke 2004).
Therapy Logically consistent, there are no therapeutic options for a DVA, as its presence does not represent a pathologic substrate. Earlier experiences of a disastrous course after surgical removal of a “venous angioma” with significant swelling of the brain produced by venous congestion and venous infarction associated with subsequent high morbidity and mortality rates due to occlusion of the normal drainage from healthy brain tissue should be relegated to neurosurgical history.
4.1.4.3 Pial Arteriovenous Malformations Histopathology The histological examination of these complex vascular anomalies shows an irregular wall structure with areas of knob-like, thickened smooth musculature extending into the vascular lumen, in addition to hyaline and calcifying or amyloid-like alterations of the vascular wall (McCormick et al. 1968; Okazaki 1989). The so-called nidus consists of a net-like glomerule of convoluted abnormal vascular canals of different extensions and size whose wall structure can be assigned to neither the arterial nor the venous site. The
224 Fig. 4.28 Image obtained in an 11-year-old boy with mesencephalic DVA. Since early childhood, the patient had hydrocephalus treated by ventriculo-peritoneal shunt; MRI was performed for suspected shunt insufficiency. (a) T2-weighted paramedian sagittal depiction of an atypical vessel (flow void) arising from the interpeduncular cistern (arrow). The adjacent slices demonstrate the course to the vein of Galen. (b) Axial contrast-enhanced T1-weighted image showing the collecting vein in the left cerebral crus (arrow). (c) A slice further to apical visualizes the dilated, supplying deep medullary veins (arrows) of both thalami (more pronounced left than right). (d) Venous phase of a DSA (left vertebral artery) with depiction of the classic caput medusa appearance (arrows) of the supplying veins and drainage into the vein of Galen (star)
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vascular channels are without detectable capillaries, while marked vascular proliferation is often observed in adjacent brain tissue (Okazaki 1989). Clinical Findings Spontaneous hemorrhage is the most frequent symptom of arteriovenous malformations (AVM), followed by seizures, chronic headache, and focal neurologic deficits. The proportion of infratentorial AVMs supplied by branches from the posterior circulation is small, comprising up to 12% of all intracranial AVMs (Khaw et al. 2004). The majority of these lesions (up to 75%) are found in the cerebellum, the localization of the remaining lesions is evenly distributed in the brainstem (pons, midbrain, medulla oblongata), or in a combination of both localizations, respectively (Sinclair et al. 2006). Although spontaneous hemorrhage is commonly the initial symptom, the risk for hemorrhage in infratentorial AVMs is not significantly different from that in AVMs with a supratentorial localization (multivariate analysis, Khaw et al. 2004). The risk for hemorrhage is chiefly determined by the angioarchitecture (most important in this context are a deep venous drainage and associated aneurysms) and the age of the patient (>40 years) (Cognard et al. 2004; Hashimoto et al. 2004; Khaw et al. 2004).
Diagnosis Although CT can visualize the hemorrhage, it fails to clearly show the size and exact location of the nidus. MRI enables precise morphological depiction of the nidus and possible reactions in the surrounding tissue (gliosis, old hemorrhage) with the use of T1- and T2-(T2*-) weighted (including FLAIR) sequences. The performance of MR-angiography does not represent a substitute for digital subtraction angiography, which also serves as a preparatory procedure for interventional therapy (Cognard et al. 2004). Therapy The therapy of pial AVM is individually different and diversified, since the indication for therapy, which should be reached by an interdisciplinary team of experts, depends on multiple factors. The most notable ones are the clinical findings at the time of diagnosis, the localization, and the angioarchitecture of the arteriovenous malformation. Therapeutic options range from emergency or elective neurosurgical operations, to neuroradiologic interventions such as embolizations, to radiation therapy, but they may also include the decision to forego any therapeutic intervention (Cognard et al. 2004; Stapf 2006).
4.1 Vascular Brainstem Diseases
4.1.4.4 Dural Arteriovenous Malformations Definition Dural arteriovenous malformations (DAVM) are abnormal dural shunts between arterial and venous vessels, with arterial supply from meningeal branches (Aminoff 1973). The classification of DAVMs is grouped into three to five types (depending on the author) based on their characteristic venous drainage (Szikora 2004).
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congestion. Since this cannot be achieved in all cases, the conversion of a high-risk DAVM into a type associated with a lower risk, or the improvement of clinical symptoms (here chiefly pulse-synchronous tinnitus) should be the therapeutic goal (Szikora 2004).
4.1.5 Basilar Migraine/Vestibular Migraine Marianne Dieterich and Sandra Bense
Clinical Findings
4.1.5.1 Epidemiology
Although the preferred localization of DAVMs is the region of the posterior cranial fossa (transverse/sigmoid sinus 25%, tentorial incisura 26%; Lucas et al. 1997), the patients usually do not present with brainstem symptoms, but have specific symptoms such as pulse-synchronous tinnitus, exophthalmos, or rather nonspecific symptoms of chronic venous congestion, including headache, nausea, vomiting, and spontaneous cerebral hemorrhage (Szikora 2004). Intrinsic alterations as, e.g. venous congestion of the pons mediated by a dural arteriovenous fistula, have been described in isolated cases only (Takahashi et al. 1994; Crum and Link 2004; Iwasaki et al. 2006).
Basilar migraine was first described by Bickerstaff (1961) as a typical disorder of adolescence, affecting women significantly more often than men. However, retrospective studies in patients with “basilar migraine with vertigo” or monosymptomatic “vestibular migraine”, whose symptoms were markedly improved or who became symptom-free under prophylactic treatment, showed that migraine can manifest at any time throughout life, most often between the third and fifth decade, and affects women and men at a ratio of 1.5–5: 1 (Dieterich and Brandt 1999; Neuhauser et al. 2001). The median age at the onset of vestibular migraine is approximately 38 years in women and 42 years in men, which is substantially later than in patients with migraine without aura. The prevalence of basilar migraine is not known. An incidence rate for vestibular migraine of 7–10% has been reported in selected patient collectives of specialized vertigo outpatient clinics (Dieterich and Brandt 1999; Neuhauser et al. 2001; Brandt and Strupp 2006). An epidemiologic study of the German general population revealed a lifetime prevalence of approximately 1% and a 1-year prevalence of approximately 0.9% (Neuhauser et al. 2006). The latter ranges are markedly below the 1-year prevalence of migraine with aura after puberty, which has been reported between 12% and 14% in women, respectively 7% and 8% in men (Rasmussen 1993; Silberstein and Lipton 1993). The classification of the International Headache Society (IHS) requires for the diagnosis of basilar migraine an aura with two or more symptoms that originate concurrently from the brainstem and/or both occipital lobes, develop over 5–20 min, and last no longer than 60 min (Headache classification subcommittee 2004). This definition is currently controversially discussed, because monosymptomatic aura attacks of shorter or longer duration, that frequently occur particularly in monosymptomatic audiovestibular forms, cannot be classified as basilar migraine (Baier et al. 2009; Neuhauser and Lempert 2004; Olesen 2005; Brandt and Strupp 2006; Strupp et al. 2010). Several authors have called for the introduction of a new category into the migraine classification named
Diagnosis Non-invasive diagnosis of DAVMs with computed tomography and magnetic resonance imaging (MRI) shows primarily secondary alterations such as hydrocephalus, atrophy, or hemorrhage (which can involve all intracranial spaces, and may be subarachnoid, subdural, intraparenchymal, or intraventricular). MRI can also show merely indirect signs, including dilated veins, or atypical ischemias that cannot be allocated to an arterial supply territory; this is in contrast to a pial AVM, where the nidus can be defined. Digital subtraction angiography (DSA) is therefore the method of choice for demonstration, classification, and treatment planning/management in patients with suspected DVAMs (Szikora 2004).
Therapy The choice of therapy depends upon the type of DAVM; the decision should, however, not be influenced by the diagnosis, but by the expected outcome. A conservative approach with careful observation is thus justified in benign DAVMs (low shunt volume, no cortical drainage), while the primary goal of an interventional therapy with combined arterial and/or venous embolization is occlusion of the shunts, aiming to eliminate/reduce the high risk for hemorrhage due to venous
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“vestibular migraine” or “migraine with vestibular aura” for auras with clearly rotatory or directed vertigo, excluding nonspecific dizziness sensations, analogous to hemiplegic or ophthalmoplegic migraine. The “vertigo experts” have agreed to the diagnostic criteria proposed by Neuhauser and co-workers (2001), which are based on a combination of migraine symptoms and associated vertigo attacks: 1. Recurrent attacks with vestibular vertigo 2. Migraine without aura according to the IHS classification 3. Migraine symptoms during at least two vertigo attacks (migraine headache, phonophobia, photophobia, aura symptoms) 4. Exclusion of other causes of vertigo When all of the above criteria are fulfilled, the term “certain vestibular migraine” is applied, while the term “probable vestibular migraine” is used if three of these criteria are met. Furthermore, successful migraine prophylaxis or attack arrest can be helpful for diagnosis.
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with sumatriptan, but not in the pain-free interval (Weiller et al. 1995). These studies support the assumption of a causal relationship between activation of the described brainstem regions and migraine attacks. The findings of recent functional imaging studies underline the importance of “cortical spreading depression” as an additional pathophysiologic mechanism in human migraine aura. The vestibular symptoms may be caused either by stimulation of the temporo-parietal vestibular cortex or be classified as a brainstem aura in the sense of a non-cortical “spreading depression” (Furman et al. 2003). This is supported by the results of an animal study in rats, which, showed a “spreading depression” in the brainstem associated with alterations in the local brain perfusion as well as in the systemic blood pressure (Richter et al. 2008). Migraine induced ischemia of the brainstem and labyrinth may be attributable to vasospasm. On the other hand, recurrent transient labyrinthine ischemia may explain the occurrence of an endolymphatic hydrops and thus Menière-like symptoms, as well as benign paroxymal positioning vertigo, both of which frequently occur in association with vestibular migraine (Ishiyama et al. 2000; Lee et al. 2000; Radke et al. 2002).
4.1.5.2 Etiology The precise mechanisms involved in the development of pain in migraine are still incompletely understood. At the center of different pathophysiologic processes involved is an activation of the trigeminovascular system with activation of peripheral trigeminal branches, the release of vasoactive neuropeptides with meningeal reaction (neurogenic inflammation), as well as impulse transmission from the caudal nuclear regions to the thalamus and from descending pain-modulating systems. These neurovascular mechanisms are possibly based on a genetic defect – an ion-channel gene defect. It should be mentioned in this context that the rare episodic ataxia type-2 with mutation in the calcium channel gene on chromosome 19p can occur in some families in combination with a hemiplegic migraine also found to be localized on chromosome 19 (Ophoff et al. 1996). Furthermore, in patients with basilar migraine/vestibular migraine, central oculomotor disturbances in the interval similar to those observed in patients with ataxia type-2 are suggestive of congenital neuronal dysfunctions in brainstem and/or cerebellar nuclei, comparable to the mechanisms discussed in other forms of migraine. In experimental animal studies, stimulation of the pontine noradrenergic nucleus coeruleus leads to a frequency-dependent reduction in blood flow, whereas stimulation of the predominantly serotonergic dorsal raphe nucleus produced a rise in blood flow (Goadsby 2000). Consistent with this finding, positron emission tomography during migraine attacks in humans showed brainstem activation in the region of the periaqueductal gray, which was evident even immediately after successful therapy
4.1.5.3 Clinical Findings Basilar Migraine is characterized by recurrent attacks with different combinations of neurologic symptoms that can be assigned to the brainstem and/or both cerebral hemispheres (e.g. vertigo, stance and gait ataxia, double vision, sensory, vision, auditory or speech disturbances, paraparesis), head congestion or headache pronounced in the occipital region, and autonomic/gastrointestinal symptoms such as nausea and vomiting. Less commonly noted are disturbances of consciousness, psychomotor deficits and personality changes. If monosymptomatic rotatory/to- and-fro vertigo is the only aura symptom, some authors use the term “vestibular migraine” or “migrainous vertigo”. This diagnosis may be established when concurrent headaches occur frequently or regularly, and a positive family or individual history of migraine exists (approx. 50%) (Dieterich and Brandt 1999). The diagnosis is further facilitated by the presence of sensitivity to light or noise, need of rest, fatigue after the attack, and hyperdiuresis. The diagnosis becomes more difficult if the headache is completely missing (approx. 30%), or monosymptomatic attacks are predominant, as observed in more than 70% of all audiovestibular attacks. The duration of vertigo attacks can vary significantly between patients with vestibular migraine – from seconds or minutes to several days (Cutrer and Baloh 1992; Dieterich and Brandt 1999; Neuhauser et al. 2001). In more than 60% of patients with
4.1 Vascular Brainstem Diseases
the vestibular form of migraine also in the symptom-free interval mild central oculomotor disturbances are evident, such as age-inappropriate saccades, internuclear ophthalmoplegia or nystagmus (gaze-evoked, spontaneous, or central nystagmus) as signs of a discrete persisting neuronal brainstem or cerebellar dysfunction. This finding can be helpful in establishing the diagnosis. These patients are frequently sensitive to motions and motion sickness (Cutrer and Baloh 1992) not only during the attack, but, in a milder form, also in the symptom-free interval. In analogy to phonophobia and photophobia during migraine attacks this may be attributable to neuronal sensory overexcitability, probably of the inner ear receptors.
4.1.5.4 Diagnosis The diagnosis of basilar migraine/vestibular migraine essentially draws on a detailed description of the case history and the clinical-neurologic and neurootologic examination including an assessment of oculomotor function. The individual concomitant brainstem symptoms should be explicitly discussed in taking the history (e.g. perioral numbness), because they frequently take second place to the main symptom and may not be spontaneously reported. Particular attention should be given to the individual history regarding other forms of migraine and the family history of migraine. There is no diagnostic marker that enables definitive diagnosis of basilar migraine/vestibular migraine. In cases of an undetermined diagnosis a careful exclusion of conditions within the differential diagnosis should be made.
4.1.5.5 Differential Diagnosis Due to the variable clinical picture of basilar migraine, the differential diagnosis comprises a variety of episodic neurologic disorders. Important differential diagnoses in emergency cases, comprise ischemias in the basilar circulation, basilar thrombosis and/or brainstem/cerebellar hemorrhage. These conditions require immediate diagnostic clarification (computer tomography, magnetic resonance imaging, ultrasound), as they pose a grave threat to life and require specific therapy. Vertebral artery dissection should be considered in patients with back head or neck pain in combination with brainstem symptoms following a chiropractic maneuver or (trivial) trauma. It requires a selective search. The differentiation of vestibular migraine from recurrent transient ischemic attacks, and recurrent attacks due to a labyrinthine hydrops (Menière’s disease) or vestibular paroxysmia (neurovascular cross-compression of the vestibulocochlear nerve) may be difficult in individual patients, so
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that the diagnosis needs to be established based on the result of treatment. In these cases, a stepwise prophylactic regimen often results in a positive response to a specific therapeutic measure, e.g. migraine prophylaxis, and thus provides diagnostic information. The differential diagnosis of monosymptomatic audiovestibular attacks is further complicated by transitional and mixed forms between Menière’s disease and migraine for which a common pathophysiology is being discussed (Radke et al. 2002). Neurootologic examinations (including electrooculography with caloric testing, audiogram, acoustic evoked potentials and vestibulocollic reflex) can provide helpful additional findings in this setting. Patients with Menière’s disease commonly have progressive hearing loss up to deafness in the affected ear after several attacks, while in migraine patients hypacusia often fluctuates, generally stabilizes under therapy, and deafness is rare.. It is striking that nausea and vomiting during caloric testing occur at a fourfold higher frequency in patients with vestibular migraine compared to other patients with vestibular diseases (Vitkovic et al. 2008), a phenomenon that may be comparable to the susceptibility of migraine patients to kinetosis. In vestibular migraine, a central positional nystagmus/vertigo can in some instances also mimic the clinical picture of a peripheral benign paroxysmal positional vertigo (Von Brevern et al. 2004). The rare episodic ataxia type 2 is associated with episodic vertigo attacks with central oculomotor disturbances also in the symptom-free interval (Griggs and Nutt 1995). In these patients, treatment with potassium channel blocker 4-aminopyridine or the prophylactic therapy of attacks with acetazolamide has produced successful (Jen et al. 2007; Strupp et al. 2004; Strupp et al. 2007). The different neurologic symptoms may in rare cases also represent a partial symptom of an epileptic attack; EEG and MRI are valuable diagnostic tools in these conditions.
4.1.5.6 Therapy and Prophylaxis The substances used in the pharmacotherapy of migraine target different pathophysiologic mechanisms of migraine. The same therapeutic principles apply to basilar migraine as those valid in migraine with aura, both with regard to the arrest of attacks and migraine prophylaxis. Therapy of migraine attacks is expedient if the symptoms persist for 45 min or longer or are characterized as extremely unpleasant, e.g. are associated with severe vegetative symptoms. Recommended in these conditions is the early intake of an antiemetic agent (e.g. metoclopramide, domperidone) in combination with a non-steroidal antiphlogistic agent (e.g. ibuprofen, diclofenac), or an analgesic (acetylsalicylic acid or paracetamol, also as a suppository). Although 5-HT 1B/1D-receptor agonists (triptan) have been
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shown to be very effective in the therapy of migraine with and without aura, they are currently not recommended for the management of basilar/vestibular migraine, as controlled studies are still lacking. A small placebo-controlled pilot study showed a non-significant trend in favor of zolmitriptan over placebo (Neuhauser et al. 2003). Individual patients have reported a comparable efficacy of triptan agents in the therapy of vestibular migraine to that known for other forms of migraine. In patients with nausea, oral forms should be avoided in favor of rectal (e.g. sumatriptan), nasal (e.g. zolmitriptan), or lingual (e.g. rizatriptan) ones. Migraine prophylaxis should be considered in the following clinical circumstances: • Two or more migraine attacks per month • Migraine attacks lasting 48 h or longer • Unsatisfactory outcome of attacks with agents for symptomatic treatment or • The persistence of neurologic symptoms longer than 7 days in complicated forms of migraine The drugs of first choice in migraine prophylaxis according to the revised guidelines of the German Neurological Society (2005) comprise the beta-receptor blockers metoprolol (50– 200 mg/day) and propranolol (40–240 mg/day), the calcium antagonist flunarizine (5–10 mg evenings), and the antiepilectic drug valproic acid (500–600 mg/day, off-label use). The authors of a small observational study described the positive effect of lamotrigine (lamictal 100 mg/day) in vestibular migraine (Bisdorff 2004). A recently recommended alternative for the prophylaxis of migraine without aura is the administration of topiramate (Topamax® 25–100 mg/day). Positive effects following the use of this agent in patients with basilar migraine/vestibular migraine have been reported by specialized outpatient clinics. However, it must be emphasized that none of these drug approval studies included an evaluation of the special subgroup of patients with vestibular migraine. A retrospective study of patients with vestibular migraine reported a significant reduction in the frequency of attacks (80% of patients), intensity (68%), duration (65%), as well as of concomitant migraine symptoms treated with migraine prophylaxis (Baier et al. 2009), findings that appear to justify an approach to prophylaxis based on the outcome of treatment. Long-term follow-up studies are required to evaluate the individual tolerance and efficacy of all medications used in the prophylaxis of migraine. Depending on the frequency of the attacks, prophylactic treatment for a minimum period from 6 months, with the patients keeping a headache and/or vertigo diary, has proved useful in assessing the individual success or failure of the therapy. Substances and procedures without demonstrated efficacy in controlled studies should not be used, including the anticonvulsives carbamazepine, diphenylhydantoin and primidone.
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Obsolete in the therapy of basilar migraine are in particular chiropractic manipulations in the region of the cervical spine and injections of migraine prophylaxis medications into the cervical muscles. Recommendations for the nonpharmacologic therapy in patients with migraine with/without aura (e.g. endurance sport, cognitive-behavioral therapy, or biofeedback techniques) also apply to patients with basilar/vestibular migraine, not least because in a large number of patients different types of migraine attacks can occur in parallel. 4.1.5.7 Prognosis The frequency and the intensity of the attacks, as well as the spontaneous course of vestibular migraine vary significantly between patients. The results of different studies have shown migraine with aura to be a risk factor for clinically silent ischemic infarctions. The authors found subclinical cerebellar infarctions in approximately 8% of patients with migraine with aura, while especially young women with severe and frequent migraine attacks appear to be at a particular risk for white matter lesions (Bousser and Welch 2005; Kruit et al. 2005). Furthermore, an increased risk exists for developing a secondary somatoform, chiefly phobic postural vertigo, due to the presence of a significant association with anxiety disorders (Best et al. 2009a; Eckhardt-Henn et al. 2008), which may lead to a sensation of persistent vertigo or dizziness although migraine prophylaxis is successful. The prognosis of vestibular migraine can nevertheless be described as good, taking into consideration the variable disease activity with longer phases of a significant reduction in attacks or symptom-free periods throughout the individual’s life, the very rarely life-threatening sequelae, and the available valid therapeutic options. An individual prognostic assessment is often not possible.
4.2 Inflammatory Brainstem Diseases Uta Meyding-Lamadé and André Grabowski
4.2.1 General Part 4.2.1.1 Epidemiology Viruses are the leading cause of meningoencephalitis worldwide. The estimated annual incidence rate ranges from 10–20:100,000 population (Rotbart 2000). In most viral encephalitides the course is usually mild and the condition is therefore frequently not detected or diagnosed. In addition to the clinically significant and treatable herpes simplex virus type 1, the most common causative agents of meningoencephalitides
4.2 Inflammatory Brainstem Diseases
comprise varicella-zoster viruses, enteroviruses, and influenza viruses (Koskiniemi et al. 2001). A number of causative agents or diseases are endemic. Early summer meningoencephalitis (ESME) has an important role in the European Region, with the highest incidence rates reported for Central Europe (e.g. Southern Germany, Austria, Hungary, the Czech Republic, Slovak Republic, Baltic States). With 546 cases reported in Germany (incidence 0.5:100,000) in 2006 (2005:432 cases), ESME represents a rather rare, but increasingly frequent infectious disease. A drop in the infection rate in 2008 (288 cases) maybe explained by a better vaccination rate and environmental factors (Robert-Koch Institute, February 2010). Other, significantly less common causes of viral encephalitis are, e.g. the West Nile virus (epidemic USA 2002/2003), the Nipah virus (among farmers in Malaysia 1998) and the enterovirus 71 (among children in Taiwan 1998). Japanese B encephalitis is endemic chiefly in Southeast Asia and northern Australia, where it is responsible for an estimated number of 30,000–50,000 of encephalitis cases annually (Solomon 2004). Other viral diseases, e.g. rabies and poliomyelitis play an important role particularly in developing countries. The estimated annual incidence rate of acute bacterial meningitis ranges from 1–3:100,000, and is regionally even as high as 5–10:100,000 population. Common causative organisms in adults are not only meningococci and pneumococci, but also staphylococci, listeria and enterobacteria. The incidence rate for focal encephalitides or brain abscesses is significantly lower (0.3–1.3:100,000 annually). Behçet’s disease is characterized by a distinctive epidemiologic feature among the non-viral encephalitides, in that it occurs primarily in Mediterranean, Near Eastern and Asian countries at an incidence rate of up to 300:100,000, although it is found as well in Germany among immigrants from these countries. Since all causative organisms of encephalitis can, on prin ciple, also involve the brainstem, the conclusive differentiation of individual causative agents is difficult. A precise description cannot be made given the lack of epidemiologic data due to the low prevalence of isolated brainstem encephalitides. Frequent involvement of the brainstem is observed in the rare cerebral listeriosis; Bickerstaff’s encephalitis typically involves the brainstem. 4.2.1.2 Etiology Inflammatory alterations in the brain parenchyma can essentially be categorized into viral and non-viral encephalitides. Responsible causative agents include viruses, bacteria, fungi and rare parasites, able to cause meningitis and/or encephalitis, which often develop after or at the same time as a general infection. To be differentiated from these are “aseptic” inflammations, e.g. post lumbar puncture meningitis, or inflammations in systemic diseases
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(e.g. sarcoidosis, Behçet’s disease), as well as para- and postinfectious inflammatory reactions, comparable to those found in Bickerstaff’s encephalitis. In humans, more than 30 out of the large number of viruses are known to attack the CNS and can cause meningoencephalitis. The incidence of meningitis is higher than that of parenchymatous inflammation. Common causal organisms of encephalitis include herpes simplex virus type 1, cytomegaly virus, EpsteinBarr virus, influenza virus, FSME and HI-viruses. Bacterial inflammations often spread contiguously, e.g. from the paranasal sinus or the middle ear, and are a common cause of meningitis. Other portals of entry for bacterial infections may be trauma or surgical interventions in the region of the cranium or the vertebral column. Shunt or drainage infections also need to be considered in neurological or neurosurgical patients. An important differentiation has to be made between the described conditions and both, bacterial abscesses and bacterial focal encephalitides, with a view to possible hematogenous and cerebral dissemination of bacteria (chiefly Staphylococcus aureus, Streptococcus viridans, enterobacteria, anaerobes, Hemophilus spp.), and the development of unifocal or multifocal encephalitis in patients with septic clinical pictures. Special attention needs to be given to immunocompromised and immunosuppressed patients. These patients may develop opportunistic infections that frequently affect the CNS with involvement of brainstem structures. 4.2.1.3 Clinical Findings The clinical symptoms and course primarily depend on the underlying etiopathogenesis. In isolated viral encephalitides of the brainstem general symptoms such as fever, headache, neck stiffness, photosensitivity, myalgia and fatigue may be absent. It is therefore important to pay careful attention to non-neurologic concomitant symptoms such as skin alterations, pulmonary involvement, local inflammations (e.g. otitis media, sinusitis) and preexisting infections (e.g. soft tissue infections), as well as to accompanying or primary disorders (e.g. HIV, immunosuppression). In this context it is also essential to take an expanded case history, including questions on foreign travel in recent months, diseases of close persons and relatives, contact with animals, and tick bites. The localization and extension of the inflammatory brainstem lesion determine the degree of the clinical symptoms and neurologic deficits. Because inflammatory alterations are generally not limited to a specific region, the deficit pattern is very heterogeneous and depends on the course of the disease. The clinical picture can range from mild symptoms with involvement of
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individual cranial nerves to injury to all brainstem structures with complex neurologic deficit patterns and impairment of circulatory and respiratory regulation. An in-depth discussion of the clinical findings in brainstem diseases is presented in Chap. 3. Detailed information on the clinical symptoms associated with the individual causative organisms or diseases is provided in Sect. 4.2.2 (p. 224 47.) The course of disease is crucial for both the differential diagnostic approach and prognostic assessment in inflammatory brainstem diseases. A number of different courses of disease have been described:
4 Diseases Table 4.7 Diagnosis of suspected inflammatory brainstem disease History • Concomitant, primary and preexisting diseases • Family history • Foreign travel • Drug history • Have similar symptoms occurred in the past? Clinical investigation • Whole body status • Neurologic examination
• Acute course (hours to several days): herpes simplex encephalitis, bacterial meningoencephalitis, CNS listeriosis, amebic meningoencephalitis • Subacute course (days to weeks): tuberculous meningitis, septic focal encephalitis, neuroborreliosis, neurolues, cryptococcal meningitis, CNS toxoplasmosis, CNS aspergillosis, HIV encephalitis • Chronic course (weeks to several months): HIV encephalitis, progressive multifocal leukoencephalopathy, CNS Whipple’s disease, tuberculous meningitis, neuroborreliosis, neuro-Behçet’s disease, neurosarcoidosis
• Fever?
There is a smooth transition between subacute and chronic courses. Particular mention is to be made of bacterial abscesses, bacterial focal encephalitides and CNS tuberculosis, which often become symptomatic with marked latency to the primary infection.
• Poss. angiography
• Are autonomous disturbances demonstrable? Laboratory diagnostics • Blood count • Inflammatory markers • Serology • Immunoparameters, poss. blood culture • Cerebral spinal fluid analysis (incl. cytology, cerebral spinal fluid culture, immunology) Diagnostic imaging • MRI plus contrast agent (poss. computer tomography) Emergency diagnostics In patients with suspected acute inflammatory disease, the investigation should initially be limited to essential diagnostic measures required for the initiation of a therapy : • Cranial CT scan: exclusion of increase in intracranial pressure
4.2.1.4 Diagnosis The most important diagnostic steps in patients with a suspected inflammatory brainstem disease are summarized in Table 4.7. In cases of possible bacterial inflammation, primary identification of the focus should be carried out depending on the history and the clinical finding (paranasal sinuses, tympanum, mastoid air cells, teeth). If there is suspicion of a septic focal encephalitis, other infectious foci have to be identified (pulmonary and abdominal inflammations, endocarditis, soft tissue infections). In patients with bacterial infections, isolation of the causative agent should be attempted as early as possible for initiation of targeted antibiotic therapy. Isolation of the causative agent in bacterial meningoencephalitides can be accomplished either from the primary focus or the cerebral spinal fluid. This is more difficult to achieve in cerebral abscesses, because mixed infections may be present that do not reflect the causative agent of the cerebral focus on the one hand, or the primary source of infection may already have received therapy before the cerebral focus became symptomatic and was diagnosed. It is important to note that cerebral spinal fluid analysis may be unremarkable in cerebral abscesses and that it may not be possible to isolate the causative agent, as long as the abscess does not extend to the subarachnoid space.
• Blood sampling: leucocytosis, CRP, in patients with fever → blood culture! • Cerebral spinal fluid collection + CST culture – Cell count >1,000/mL, lactate ↑ and glucose ↓: bacterial infection likely – Cell count <1,000/mL lactate and glucose normal: viral infection likely
Aspiration or excision/evacuation of the abscess (which can serve concurrently as a therapeutic or curative measure) may be required in some cases to isolate the causative agent and confirm the diagnosis. Verified foci of disseminated infection should be treated with early medical and/or surgical therapy (identification of the causative agent must be considered in this setting!). Viral CNS infections often arise from a systemic viral infection. The respective symptoms are to be identified.
4.2.1.5 Laboratory Diagnostics The recommended laboratory diagnostic procedures for the respective causative organisms are shown in Table 4.8.
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Table 4.8 Recommended laboratory tests in dependence on the encephalitic causative agent Causative agent Diagnosis Viruses Herpes viruses
Mycobacterium tuberculosis
PCR, culture tuberculin test
Toxoplasma gondii
PCR, AB, micro
Treponema pallidum
TPHA, AB, AI VDRL
Tropheryma whipplei
PCR, micro Bacterium-specific: micro, AB, PCR
Epstein-Barr virus (EBV)
AB, PCR
Herpes simplex virus 1 and 2 (HSV 1/2)
AB, PCR
Atypical bacteria: rickettsias, plasmodia, microplasms, Coxiella burnetii, Bartonella spec., Ehrlichia
Human herpes virus (HHV) type 6 and 7
AB, PCR
Fungi
Varicella zoster virus (VZV)
AB, PCR
Cytomegaly virus (CMV)
AB, PCR
Enteroviruses Coxsackie virus A and B, echo virus
AB, PCR
Enterovirus 71
PCR, cell cultures
Poliomyelitis virus
AB, (PCR)
Aspergillus
PCR, micro, AB
Candida albigans
Micro, culture, AB
Cryptococcus neoformans
PCR, India ink
Micro = microscopy; culture = cerebrospinal fluid culture with demonstration of causative agent; AB = demonstration of antibodies in cerebrospinal fluid; AI = antibody specific index in cerebrospinal fluid; PCR = polymerase chain reaction (antigen/DNA-demonstration of pathogenic organism from the cerebrospinal fluid.
Myxoviruses Influenza virus A and B
AB
Measles virus
AB
Mumps virus
AB
Nipah virus
PCR, AB
Parainfluenza virus
AB
Arboviruses Flaviviridae virus Dengue virus
PCR, AB
ESME virus
AB, AI
Japan B encephalitis virus
AB, PCR
St. Louis encephalitis virus, West Nile virus Togaviridae Rubella virus
AB
California virus, Eastern equine encephalitis virus, Western equine encephalitis virus
AB
Other viruses Hanta virus
AB (PCR)
HIV 1 and 2
PCR, AB
JC virus
PCR
Lymphocytic choriomeningitis (LCM) virus
AB
Rabies (lissa) virus
AB, PCR Cerebral tissue Mucosa Cornea
Toscana virus
AB, PCR
Bacteria Borrelia burgdorferi
AB, AI, PCR
Legionella pneumophila
AB, culture
Listeria monocytogenes
Micro, culture
Meningococci, pneumococci,
Micro, culture
Hemophilus influenzae, staphylococci
PCR
Routine blood and serum analysis should comprise: • Complete blood count (leucocytosis versus leucocytopenia? anemia? thrombocytopenia?) • Determination of electrolytes, renal retention values, and liver enzymes (kidney/liver involvement?) • Determination of C-reactive protein (sensitive inflammation marker) and blood sedimentation rate • Determination of coagulation parameters (PTT, INR, fibrinogen) • In suspected autoimmune disease: determination of ANCA, ANA, rheumatoid factor To further distinguish the spectrum of causative agents or enable isolation of pathogenic organisms, a blood culture should be performed prior to initiation of therapy (demonstration of causative agent in 60–70% of cases). If isolation of the causative agent remains unsuccessful and/or no clinical improvement is noted under empirical therapy, additional blood cultures have to be taken in the further course of disease. The majority of causative organisms can be shown indirectly with serologic markers (antibodies) or directly by using immunologic methods (demonstration of antigens using PCR). Serologically demonstrated pathogenic organisms are not unconditionally responsible for CNS infection, and an etiopathogenic classification is difficult/ not possible in mixed infections. In patients with suspected inflammatory or infectious CNS diseases, cerebrospinal fluid analysis (cytologic, chemical, bacteriologic and immunologic) constitutes one of the most important steps in the confirmation of a diagnosis, since cerebrospinal fluid represents a dynamic and metabolically active substance characterized by multiple metabolic and immunologic functions.
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Table 4.9 Typical cerebrospinal fluid constellations: normal findings versus inflammatory diseases Normal finding Bacterial Viral inflammation inflammation
Other inflammation
Total protein (in mg/L)
200–500
↑ ↑ (↑)
Normal to ↑
Normal to ↑
Glucose ratio (cerebrospinal fluid/serum)
>0.7
↓
Normal
Normal
Lactate (in mmol/L)
<3.5
>3.5
Normal
Normal
Cell count per mL
<5
>1,000
10–1,000
Normal to mild
Granulocytic
Lymphocytic
Pleocytosis Cell picture
The use of the appropriate analytical method usually enables confirmation of the diagnosis. Cerebrospinal fluid analysis is also a valuable tool in monitoring the course of disease and the efficacy of therapy. Normal cerebrospinal fluid findings are contrasted with findings in inflammatory and infectious diseases in Table 4.9. Cytologic evaluation of cerebrospinal fluid enables differentiation of cells after staining. Neutrophilic granulocytosis is an indication of acute bacterial inflammation (although it may also occur in the initial phase of a viral infection). A lymphocytic cell picture (lymphocytes and plasma cells) is commonly found in viral inflammations. A mononuclear transformation (monocytes and macrophages) usually occurs in the postacute phase. In a suspected acute bacterial infection (meningococci, pneumococci, staphylococci), a gram stain standard or bacterial quick-test (for meningococci, pneumococci and Haemophilus influenzae) should be attempted. While eosinophilic granulocytes are normally not found in cerebrospinal fluid, they are frequently identified in parasitic infections. Although the use of Ziehl-Neelsen staining is expedient in the demonstration of tuberculous meningitis, it is nevertheless strongly dependent on the total number of pathogenic organisms and therefore often has only a low sensitivity. If opportunistic infections are suspected, the possibility of mycotic infection has to be considered. Cryptococci are readily confirmed by using the India ink method (sensitivity 80–90%). The microscopic detection of candidiasis and aspergillosis can usually be accomplished with methylene blue staining. Confirmation of the diagnosis is, however, frequently achieved only by culture of the organisms. With regard to differential diagnosis, the cerebrospinal fluid sample should always be tested for the presence of malignant cells (tumor cells, lymphoma cells; detection rate 50–70% at the initial examination). In analogy to blood cultures in infectious diseases, a cerebrospinal fluid culture (approx. 5 mL in aerobic blood culture bottle) should routinely be performed in conditions involving the CNS. Today, the majority of pathogenic organisms can be shown based on the formation of specific antibodies (IgM and IgG)
(immunological detection of causative organisms). The so-called Reiber’s graph shows the cerebrospinal fluidserum-ratio and reflects the relationship between the bloodbrain barrier disturbance and intrathecal antibody synthesis (IgG, IgM, IgA). The diagnosis of a CNS infection can only be established based on demonstration of specific intrathecal antibody production. The antibody specific index (AI) according to Reiber has become widely used in cerebrospinal fluid analysis. Concurrent serum sampling is required to determine the AI. The antibody index is a mathematical value calculated – in the presence of a normal cerebrospinal fluid-serum IgG ratio – from the cerebrospinal fluid-serum ratio of specific antibodies and the cerebrospinal fluid-serum ratio of the total IgG. Pathogen-specific intrathecal antibody production is demonstrable at an AI > 1.5. Antigen detection using polymerase chain reaction (PCR) represents a rapid, reliable (sensitivity 75–95%), and relatively cost-effective method, that is particularly useful in viral CNS diseases. The humoral antibody response may be inadequate in the acute phase of a viral disease, so that only the direct DNA or RNA finding enables establishment of the diagnosis. PCR is indicated without exception when • Microscopy, culture and serology are imprecise or inadequate • The results of the culture are incompatible with the clinical symptoms and do not match the expected spectrum of causative agents • Immunosuppressed patients are affected by viral disease Table 4.10 contains information on the practical application of cerebrospinal fluid analysis.
4.2.1.6 Diagnostic Imaging Brain imaging represents the second most important diagnostic tool after cerebrospinal fluid analysis in patients with inflammatory brainstem processes. The method of choice in
4.2 Inflammatory Brainstem Diseases Table 4.10 Information on the practical application of cerebrospinal fluid (CSF) analysis • CSF sampling prior to onset of therapy; ensure aseptic sampling conditions (to avoid contamination). • Sufficiently large sample should be taken for CSF chemistry + cytology + serology + culture (poss. consultation with laboratory!) • No “untargeted” centrifugation → cell destruction! • CSF analysis as close as possible to sampling (<1 h, due to risk of cell destruction) • Concurrent gram stain in bacterial infections • Cell count, protein, lactate and glucose may be without significant alterations in the acute phase of an inflammatory disease → follow-up requisite!
this setting is cranial magnetic resonance imaging (MRI). The advantage of this modality consists of good soft tissue visualization and spatial resolution. The different T2-weighted sequences permit particularly good depiction of inflammatory alterations (commonly as blurred delimited hyperintense lesions). Disadvantage are the relatively long examination times and the requirement of patient compliance. Cranial computer tomography (CCT), possibly with the addition of contrast agent for the “orientating” diagnosis of edematous alterations and space occupying lesions, can be used as an alternative technique. In particular with regard to the clarification of hemorrhagic processes or signs of intracranial pressure, CT is of nearly equal value to MRI. Detailed information on brain imaging is provided in Sect. 2.1, p. 3.
4.2.1.7 Electrophysiology The special domain of electrophysiological diagnostics is identification of damage to different functional systems. While it represents an important building block in the understanding of injuries to the brainstem, it is of prime importance in monitoring the course of disease and efficacy of therapy, as well as in prognostic assessment of the lesions (for details see Sect. 2.3, p. 25).
4.2.1.8 Biopsy Despite currently available extensive diagnostic possibilities, including laboratory diagnostics and modern cerebral MRI, in some cases an etiopathogenetic classification may not be possible. In these circumstances a tissue biopsy may be considered if it is of demonstrable therapeutic relevance and a favorable risk-benefit relationship is assumed. Most notably a biopsy can provide an answer to the question as to whether a process is malignant or benign.
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4.2.1.9 Differential Diagnosis The differential diagnosis of suspected inflammatory brainstem disease should include primarily vascular lesions, autoimmune diseases, metabolic disturbances, toxic lesions (including medications and drugs), malignant processes, and paraneoplastic phenomena. The relevant differential diagnoses including diagnostic considerations are listed in Table 4.11. 4.2.1.10 Therapy The decision on therapeutic measures is contingent on the disease course, the severity of the inflammatory alterations, and the respective functional deficits. Patients with acute symptoms, impaired level of consciousness, and complex cranial nerve deficits should be admitted to an intensive care unit. Since changes in the clinical picture can be rapid – for example in edematous swelling of the brainstem with signs of increased intracranial pressure – respiratory insufficiency or cardiocirculatory disturbances, admission to an intermediate or intensive care unit is justified. Depending on the course of disease, therapeutic measures can span a spectrum from single antibiotic and/or antiviral medication to anti-edematous therapy and intensive care procedures, including controlled ventilation and cardiocirculatory support. Due to the high risk for symptomatic seizures, anticonvulsant therapy should be initiated after the first seizure. Symptomatic therapy encompasses adequate and continuous pain therapy, fever reduction, adequate fluid replacement, and thrombosis prophylaxis with low molecular weight heparin. Medical therapy of viral encephalitides is primarily dependent upon the causative agent (see Sect. 4.2.2, p. 47). Conclusive etiologic classification or isolation of the pathogenic organism is frequently not possible in the initial phase, so that choice of medication in acute conditions has to be made empirically, with consideration of the clinical course, results of the laboratory and cerebrospinal fluid diagnoses, and the expected spectrum of causative organisms. In the presence of inconclusive findings (e.g. in the early phase of a bacterial disease), combination therapy consisting of a virustatic and an antibiotic should be administered. Priority should always be given to selective use of antibiotics or virustatics. The choice of medication is determined by the findings of blood and cerebrospinal fluid cultures (request antibiotic sensitivity testing!) and the serologic or immunologic results. Considering the clinical condition of patients with subacute or chronic diseases, a target-specific diagnosis – if possible with isolation of the causative organism – should be established and, where appropriate, a differential diagnostic evaluation may be attempted.
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Table 4.11 Differential diagnosis of encephalitis Disease Diagnostic information Vascular diseases (see Sect. 4.1, p. 5) Ischemias
• Acute symptoms • DWI lesion • Vascular alterations
Hemorrhages Subarachnoidal hemorrhage
• Hyperdense focus • Acute symptoms • Three-tube method and ferritin
Vascular malformations
• Angiography
Aneurysms
• Angiography
Vascular compression syndromes
• MRI + angiography
Vasculitides
• Inflammation parameters (e.g. CRP, ESR) • AB-determination (e.g. ANA, ANCA) • Angiography
Ependymomas
• MRI: T1 hypointense, T2 hyperintense, calcifications
Lymphomas
• MRI : strong contrastenhancement ; probatory cortison administration
Metastases
• MRI : multiple foci ? • “B-symptoms” • Primary tumor identification : CT-thorax, CT-abdomen, tumor markers, poss. biopsy
Paraneoplastic phenomena (see Sect. 4.4, p. 63) Bronchial carcinoma
• Anti-hu/anti-ri-AB, Ma-1-AB, CV-2-AB, CYFRA • “B-symptoms” • CT-Thorax
Breast carcinoma
• Anti-ri-AB, CA 13-3
Testicular carcinoma
• Ma-2-AB, AFP, hCG
Ovarian carcinoma
• Anti-Yo-AB, AFP
Autoimmune diseases (see Section 4.3)
Rare diseases
Multiple sclerosis
Subacute angioencephalopathy
• Very rare, edematous, necrotising disease with unclear etiology and progressive course
Subacute scleroting panencephalitis
• Chiefly in children/adolescents after measles infection • Cerebrospinal fluid: measlesIgG-AB, measles AI
Necrotising encephalopathy (Leigh’s disease)
• Chiefly in children • MRI: hyperintense symmetrically bilateral foci, partly necroses • Cerebrospinal fluid and serum: lactate and pyruvate increased
Rasmussen’s encephalitis
• Very rare chronic focal inflammation of the cerebral parenchyma, onset commonly in childhood
Acute hemorrhagic leucoencephalitis (Hurst’s encephalitis)
• Fulminant parainfectious disease with multiple petechial bleedings + cerebral edema • Laboratory: leucocytosis
Acute disseminated encephalomyelitis (ADEM)
• MRI : multiple lesions, “old and new” • Cerebrospinal fluid: mild pleocytosis, IgG increase, positive oligoclonal bands • Acute course • Frequently post-infectious or post-vaccination • MRI: multiple contrast-enhanced foci → florid inflammation
Metabolic disturbances (see Section 4.9) Wilson’s disease
• Serum copper increased • Ceruloplasmin level decreased
Wernicke’s encephalopathy
• Malnutrition • Triad: ataxia + oculomotor disturbances + personality changes • MRI: T2 hyperintense foci
Central pontine myelinolysis
• Hyponatremia + rapid compensation • MRI: central demyelinization
Hypoxic/anoxic encephalopathy
• Case history! • MRI: diffuse edemas, ischemias, necroses
Toxic lesions Drug and medication-induced • (Medication) history and clinic (NSAR, IVIG) • MRI • Laboratory incl. cerebrospinal fluid frequently without pathologic findings • Toxicological screening! Toxic substances
• Chronic exposition (occupational history) • Description of accident, etc.
In addition to antibiotic therapy for patients with bacterial abscesses, focal encephalitides, tuberculomas, etc., the (neuro)surgical removal of the focus (anatomic and functional conditions permitting) may be expedient and has to be considered individually. Detailed recommendations on therapy are presented in the discussion of the individual pathogenic organisms (see Sect. 4.2.2).
Malignant processes (see Sect. 4.5, p. 67) Gliomas
• Space-occupying lesion + poss. perifocal edema, contrastenhancement
4.2.1.11 Prognosis
Medulloblastomas
• Chiefly in children, cerebellar symptoms, often cystic tumor
Prognosis is chiefly dependent on the origin (causative organism) of the inflammation, the clinical course, therapeutic options
4.2 Inflammatory Brainstem Diseases
and the concomitant diseases. Complicated or fulminant courses are observed primarily in children, older adults, and immunosuppressed patients. Crucial for prognosis determination are the available diagnostic and therapeutic options. Early isolation of the causative agent and subsequent targeted therapy can prevent progression of the inflammation and further damage to the tissue. The availability of supportive measures (e.g. intensive care therapy, early rehabilitation) further determines the clinical course. Additional information on the course and prognosis of individual diseases is provided in the Sect. 4.2.2.
4.2.2 Specialized Part 4.2.2.1 Viral Encephalitides Herpes Virus Infections Epstein-Barr Virus (EBV) Epstein-Barr virus infection is commonly clinically manifest as “Pfeiffer’s glandular fever” (infectious mononucleosis) and is associated with influenza-like complaints, fever, pharyngitis, lymphadenopathy, as well as splenomegaly. It is usually characterized by a mild course and CNS involvement occurs only rarely (approx. 5%) and is often mild. Complicated clinical courses with encephalitides have been observed primarily in infants and immunosuppressed patients. The diagnosis can be made based on the detection of EBV-specific antibodies or virus DNA using the PCR assay. The treatment for EBV virus consists of ganciclovir (2 × 5 mg/kg BW i.v.) for 10–14 days (cave: renal insufficiency).
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The diagnosis should be rapidly established based on the clinical picture, cerebrospinal fluid findings and supplementary imaging (cMRI). In the acute phase of infection (first week); serologic and immunologic methods to identify the causative agent in cerebrospinal fluid are frequently not serviceable (HSV-AB-increase generally as of the end of the second week). The use of PCR often enables confirmation of the diagnosis in the early phase (within the first or second day). However, HSV-PCR will again be negative in the further course, also in patients without treatment. In addition to patient age and level of consciousness, the early onset of antiviral therapy is a factor determining outcome. Administered is acyclovir (3 × 10 mg/kg BW/day) for a period from 10–14 days (cave: dose adjustment in renal insufficiency). Alternatives are foscarnet (3 × 40 mg/kg BW, cave: renal function disturbance) or brivudine (1 × 0.125 mg/ day p.o.). Human Herpes Virus Type 6 and 7 (HHV-6/7) Symptomatic infections with HHV occur primarily in children and immunosuppressed patients. Predominantly HHV-6 associated encephalitides were observed in these patient groups. Possible additional symptoms comprise fever attacks (children), myelitides and demyelinizing processes (acute disseminated encephalomyelitis = ADEM). Infections with the HHV-7 are observed significantly less frequently. Typical clinical manifestations are absent, although the presence of encephalitis has been described (Dewhurst 2004). The diagnosis is established by demonstration of antibodies or causative organisms using PCR. The therapy consists of ganciclovir or cidofovir (dosage see “Cytomegaly Virus”).
Varicella Zoster Virus (VZV) Herpes Simplex Virus Type 1 and 2 (HSV-1/2) HSV-1 is the most common cause of herpes simplex encephalitis (>90%); HSV-2 is more often responsible for the occurrence of benign lymphocytic meningitis (e.g. Mollaret’s meningitis). CNS infection with HSV-1 involves primarily the temporobasal and frontobasal cerebral parenchyma and causes focal encephalitis. Isolated HSV-associated brainstem encephalitides are rare. Clinical symptoms depend chiefly on the location of the inflammation. The most prevalent anamnestic and clinical primary symptoms include fever, headache, and an impaired level of consciousness. The classic temporal HSV encephalitides are frequently associated with personality changes. Various focal neurologic deficits, cranial nerve deficits, seizures, and increased cranial pressure may be present. Hemorrhagic parenchymal necrosis can be observed.
Primary varicella zoster virus infection can occur in the form of a systemic infection (chickenpox, or herpes zoster), or manifest as a secondary infection due to reactivation of the virus. Immunosuppressed and chronically ill individuals, as well as children are at a particular risk for infection. The clinical picture and the course of the encephalitis are similar to that observed in other encephalitides. In addition to focal neurologic deficits and disturbances of consciousness, an acute cerebellar ataxia may be present in cerebellitis, as well as signs of myelitis and zoster radiculopathies and zoster neuralgias. Of importance from a differential diagnostic point of view is the VZV-associated unifocal vasculopathy (large-vessel granulomatous arteritis), which may clinically mimic an encephalitis, but is commonly characterized by a more subacute course.
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The diagnosis of VZV infection is made using PCR and the specific Antibody Index. The therapy is similar to that of HSV encephalitis.
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The diagnosis is established based on the clinical picture with vesicular skin alterations and mucosal ulcerations, and demonstration of antibodies or DNA in the cerebrospinal fluid using PCR assays.
Cytomegaly Virus (CMV) In addition to severe prenatal and perinatal encephalitides, CMV infection represents one of the most common opportunistic infections (after organ transplants and, most importantly, in advanced HIV disease) in immunosuppressed patients. The disease is characterized by an acute to subacute course. Neurologic complications manifest predominantly as severe encephalitis with a lethal outcome, or chorioretinitis, myelitis, and polyradiculitis. Focal neurologic deficits and signs of isolated brainstem inflammations are rare, more frequently observed are psychiatric complaints (DD: AIDS dementia complex), including confusion, apathy, and slowing of mental processing (Griffiths 2004). The diagnosis is established by means of antibody antigen identification (PCR) from cerebrospinal fluid. For the treatment of CMV, ganciclovir (2 × 5 mg/kg BW i.v.) can be used, alternatively or in combination also foscarnet (initially 2 × 90 mg/kg BW/day i.v., maintenance therapy 90–120 mg/kg BW/day i.v.) or cidofovir (5 mg/kg BW i.v. 1 × per week).
Poliomyelitis Virus Although the infection does not now play a major role in European countries, where it was brought under control with the use of effective vaccines, an emerging vaccine fatigue gives rise to fear of a possible resurgence of the disease. The incidence of poliomyelitis is particularly high in children and young adults in developing countries. More than 90% of the infections have an asymptomatic clinical course, or are associated with only minor gastrointestinal or respiratory symptoms. CNS involvement can manifest as aseptic meningitis, encephalitis or rapidly progressing myelitis or radiculitis. Most infected individuals develop flaccid paralysis of the extremities (legs > arms). Complicated clinical courses may be associated with respiratory insufficiency and involvement of the cranial nerve motor nuclei, so that approximately 10% of patients require intensive care management. The diagnosis of acute anterior poliomyelitis is supported by the typical course of disease and a fourfold increase in anti-polio antibodies. The direct culture of virus from cerebrospinal fluid is expensive and time-consuming, and therefore represents a diagnostic method of second choice.
Enterovirus Infections Myxovirus Infections Coxsackie and ECHO virus Clinically, these infections frequently manifest as an “influenzal infection”. In Central Europe the Coxsackie and ECHO viruses are the most common causative organisms of meningitis with a mild course (“cold of the brain”, herpangina, gastroenteritis, meningeal irritation). A polio-like clinical course is occasionally observed. Meningoencephalitides or isolated encephalitides are rare. The diagnosis can be made following the detection of specific antibodies or virus DNA (PCR) in cerebrospinal fluid. The therapy with pleconaril still lacks regulatory approval. Enterovirus 71 In 1998, this virus last caused endemic hand, foot and mouth disease in several thousand children in Taiwan. Neurologic involvement, primarily in the form of brainstem or rhombic encephalitides, was reported and described as being associated with a poor prognosis and a mortality rate of approximately 15% (Huang et al. 1999).
easles Virus, Mumps Virus, Influenza A and B Virus, M Parainfluenza Virus These viruses frequently cause parainfectious encephalitis with a benign clinical course and generally very good prognosis. Measles encephalitis may, however, have a severe course with coma and extended parenchymal defects (in up to 50% of patients), and be associated with a mortality rate from 10–20% in patients with a fulminant clinical course. In the discussion of measles infections consideration has to be given to the very rare condition of subacute scleroting panencephalitis (SSPE; synonym: Van Bogaert’s leucoencephalitis; incidence 1: 1,000,000). Affected are primarily children and adolescents after measles infection. SSPE has a progressive clinical course leading to death. The diagnosis is established based on the positive measles antibody index in the cerebrospinal fluid. Serologic diagnostic methods are available for all described myxoviruses (IgM and IgG antibodies, including the antibody-specific index). Definitive diagnosis can be made using PCR with demonstration of the virus DNA.
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Nipah Virus
Togaviridae Virus
The Nipah virus was discovered in 1999 during the investigation of a severe encephalitis epidemic among pig farmers in Malaysia and Singapore. The infection is caused by contact with the affected animals. It usually manifests with general symptoms (fever, headache, vomiting); patients with CNS involvement also show disturbance of consciousness, myoclonas, areflexia, cranial nerve deficits, while circulatory dysregulation (hypotension, hypertension, tachycardia) occurs in patients with brainstem involvement. The detection of antibody in cerebrospinal fluid can be used to make the diagnosis. The mortality rate is about 30% in patients with a complicated clinical course (Goh et al. 2000).
The West Nile virus is mosquito-borne; the encephalitis caused by the virus is mostly endemic (USA, Africa, Europe). The St. Louis encephalitis virus is found primarily in regions of North, Central and South America; it is spread through mosquitoes, and affects mainly older adults. The Japanese encephalitis virus is responsible for several thousand encephalitides in children from different Asian countries every year. Clinically, nonspecific general symptoms are initially observed in the three viral infections. Encephalitis with brainstem involvement occurs in approximately 60–70% of patients. The CNS disturbance can be associated with disturbances of consciousness, seizures, poliomyelitis-like paralyses, and parkinsonoid motor disturbances. Diagnosis is based on demonstration of virus-specific antibodies (IgM using ELISA) and detection of the virus in the cerebrospinal fluid by using PCR. The prognosis is significantly dependent on the localization of the lesion. Courses with a fatal outcome have been described in 10–30% of patients. Rubella virus encephalitis frequently manifests as a parainfectious disease and is usually characterized by a mild course. Comparable to measles encephalitis, complicated clinical courses may be accompanied by parenchymal defects and severe neurologic deficits (coma, cranial nerve deficits, seizures). The diagnosis of rubella virus encephalitis is established with the demonstration of antibodies in cerebrospinal fluid. A specific therapy is lacking. The reported mortality rate ranges at approximately 10%. The California virus is endemic in the USA. The infections affect mostly children and are frequently associated with seizures, although the prognosis is generally good. The Eastern equine encephalitis virus is endemic in East and Central American regions and is mosquito-borne. The disease is characterized by a mortality rate from 30–80%. The Western equine encephalitis virus occurs in Western Pacific regions, and is also spread through mosquitoes. At a mortality rate of <4%, the infection has a relatively mild course. The diagnosis in all three viruses is supported by demonstration of virus-specific antibodies. A specific therapy is again lacking.
Arboviral Infections Flaviviridae The early summer meningoencephalitis (ESME) virus is endemic primarily in Central and Southeast Europe and is spread through tick bites. The general vaccine fatigue has led to a current increase in the number of new cases in Germany (from 2001: 255 cases to 2006: 546 cases). Actually the infection rate dropped to 288 cases in 2008. Older adults are at a particular risk with a 15-fold increased mortality rate compared to younger individuals. The vaccination rate in patients older than 70 years ranges below 3–4%. The clinical course of infection is mild in most patients (approx. 70% of cases). In the presence of a neurologic manifestation it may, however, be associated with a biphasic clinical picture. The initial manifestation is a catarrhal infection which may, after a short phase of improvement, lead to meningitis, meningoencephalitis and radiculitis, or myelitis. The main areas involved are the brainstem, the diencephalon, the cerebellum, the cortex, and the anterior horns of the upper cervical spinal cord. The spectrum of clinical symptoms range from cranial nerve deficits and vegetative disturbances to cerebellar signs and flaccid or spastic paralyses. ESME virus infection can further manifest as an acute poliomyelitis or Guillain-Barré syndrome. The diagnosis is established based on demonstration of virus-specific antibodies and a positive antibody index. The mortality rate may be as high as 20%. Neurologic and long-term neuropsychologic deficits have been observed in almost 50% of patients (Haglund and Gunther 2003). The Dengue virus is chiefly endemic in the tropics and subtropics and causes feverish infections, arthralgia, or exanthema; in secondary infection it may have a hemorrhagic course with CNS involvement.
Infections with Other Viruses Rabies (Lissa) Virus Rabies infection is usually transmitted by a bite from an infected animal (overview in Hemachudha et al. 2002) and manifests after an nonspecific prodromal phase, and in the second stage of the disease in a paralytic (1/3) or
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encephalitic (2/3) form. The latter form is associated with phobic spasms, primarily of the pharyngeal, but also of the musculature of the extremities (e.g. hydrophobia, optic/ acoustic stimulation), disturbances of consciousness, as well as psychiatric conditions (panic, depression, rage). The paralytic form involves the spinal cord, the peripheral nerves and particularly the cranial nerves, so that clinically a Guillain-Barré syndrome may be mimicked initially. The disease course is always (with few exceptions) progressive and fulminant, leading to coma, respiratory paralysis, and death, usually within 1–2 weeks from the onset of the initial neurologic symptoms. The diagnosis is based on the history, typical symptoms, and possibly with the demonstration of antigens in the saliva, cerebrospinal fluid, and the corneal impression. Lymphocytic Choriomeningitis (LCM) Virus Lymphocytic choriomeningitis is a rare rodent-borne CNS infection that usually presents protracted over weeks and months as meningoencephalitis. It rarely manifests in the form of fulminant encephalitis, whose occurrence has, e.g., been described after organ transplants (Fischer et al. 2006). Other viral causative agents of encephalitis comprise the Hanta and the Toscana viruses. The Hanta virus occurs worldwide. The infection leads to fever, myalgia, hemorrhagic nephropathy and pneumonia, but rarely to encephalitis. The Toscana virus is endemic in the Mediterranean region; it is associated with influenza-like complaints and, in rare cases, with meningitis/encephalitis; the infection has a good prognosis.
4.2.2.2 Bacterial Encephalitides Meningoencephalitis, Focal Encephalitis, Cerebral Abscess Meningococci, pneumococci, Listeria monocytogenes and Haemophilus influenzae are common causative agents of bacterial meningitis. Focal encephalitis results from embolic (hematogenous) spreading of bacteria. Endocarditis has been identified as a frequent causal factor. Brain abscesses can arise from an intracranial, but also, via a hematogenous route, from an extracranial focus; they may also be caused by injuries or surgical interventions (e.g. drainage/shunt infections). Common causative organisms include streptococci, anaerobes, enterobacteria, Pseudomonas spp., staphylococci and Haemophilus spp. The diagnosis of a bacterial CNS infection is established by cerebrospinal fluid analysis (pleocytosis, increased lactate, decreased glucose levels), gram staining and cerebrospinal fluid culture. Cranial MRI can be performed to detect the focus.
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Suitable for empirical parenteral therapy of bacterial meningoencephalitis of unknown origin are cefotaxim (6–12 g/day, divided into three doses), or ceftriaxon (4 g/day, divided into 1–2 doses), possibly plus ampicillin (12–15 g/ day, divided into in 3–4 doses), and dexamethasone 10 mg i.v. prior to antibiotic infusion, followed by 4 × 10 mg/day i.v. administered over a period of 4 days. Further antibiotic therapy is carried out depending on the antibiotic susceptibilities of the causative organisms! Therapy of bacterial focal encephalitis/of the bacterial cerebral abscess consists of focal attack on the foci of infection by means of excision, evacuation or puncture of the abscess. In addition, isolation of the causative agent and an antibiogram should be attempted as part of targeted antibiotic therapy. Suitable agents for empirical therapy are, e.g. third generation cephalosporins plus metronidazole (due to anaerobes), possibly also fosfomycin or flucloxacillin in cases of suspected staphylococci infection (e.g. postoperative shunt infection). Also Meropenem is known to have good penetration into inflamed cerebrospinal tissue.
Borreliosis The tick-borne infection with Borrelia burgdorferi can lead to CNS involvement in up to 20% of affected patients in the phase of early dissemination (stage II). General symptoms of a Borrelia infection (stage I) comprise influenza-like complaints, headache, arthralgia, myalgia, and erythema migrans. In the early stage of the disease, clinical signs of neuroborreliosis include painful mono- and polyradiculitides as well as cranial nerve neuritides (Bannwarth’s syndrome). Less frequently observed are myelitis, aseptic meningitis, encephalitis and cerebral vasculitis (primarily in the brainstem region). Chronic encephalomyelitis, polyneuropathy and myositis can develop in stage III of the infection. The diagnosis of neuroborreliosis is made based on the clinical course and a positive Borrelia antibody index (AI), concurrent pleocytosis. Where applicable Borrelia PCR test has a low sensitivity of 20% ; since the AI may remain positive for years, it is not sufficient as the sole diagnostic test for follow-up. Signs of reinfection include cerebrospinal fluid pleocytosis and increased AI. The diagnosis of neuroborreliosis cannot be established based on serology testing alone. Effective therapy in acute neuroborreliosis is provided by ceftriaxon (2–4 g/day i.v.) or cefotaxim (3 × 2 g/day i.v.) for 2 weeks, in chronic neuroborreliosis for 2–3 weeks (ideal length of therapy is currently not known). A dosage of doxycycline from 200–300 mg/day can also be given alternatively.
4.2 Inflammatory Brainstem Diseases
Listeriosis Listeria monocytogenes is a gram-positive, facultatively anaerobic bacterium. The infection is usually transmitted through contaminated food and affects primarily immunosuppressed, older and chronically ill individuals, as well as pregnant women. A frequent manifestation is a generalized infection, often with a septic course. CNS involvement (incidence of neurolisteriosis 28–79%) may manifest as meningitis, meningoencephalitis, rhombencephalitis (frequent!), cerebritis and cranial abscess. Clinical signs of infection comprise headache, disturbances of vigilance and consciousness and, depending on the localization, focal neurologic deficits, including cranial nerve deficits. Epileptic seizures may also be observed. The diagnosis is supported by demonstration of the causative organism in blood, cerebrospinal fluid, pus, and biopsy tissue material. Therapy consists of ampicillin 10 g/day (in 3–4 doses) or minocycline (0.2 g/day) plus gentamicin (5 mg/kg BW) i.v.
Tuberculosis Neurotuberculosis (causative organism: Mycobacterium tuberculosis) commonly manifests as tuberculous meningitis, preferentially in the basal subarachnoidal space, and can thus lead to brainstem involvement (Fig. 4.29). Cerebral tuberculomas are localized primarily supratentorially, but are, in rare cases, also found in the brainstem and adjacent structures (Mancusi et al. 2005). Multifocal foci may be present in immunosuppressed patients.
Fig. 4.29 Tuberculous meningitis. (a) Axial T1w-image after contrast agent administration. In addition to meningeal enhancement, visualized in the right cerebellar hemisphere is a nodular contrast-enhanced lesion, representing a tuberculous granuloma. (b) T1w image after contrast agent administration. Typical of meninges at the base of the brain is a sugar coating-like contrast-enhancement of the meninges covering the surface of the pons and the cerebellar vermis. (Image courtesy of Professor Dr. Kress, Institute for Neurology, Krankenhaus Nordwest, Frankfurt/Main)
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Due to the usually low density levels of pathogenic organisms in cerebrospinal fluid, the demonstration of the causative agent can be difficult, in particular in the presence of cerebral tuberculomas (sensitivity of microscopy and culture approx. 10–20%). PCR confirmation of the diagnosis (demonstration of causative agent) from cerebrospinal fluid is achieved in only approximately 30–50% of patients, so that the clinical suspicion and the typical cerebrospinal fluid constellation (moderate lymphocytic pleocytosis, severe barrier disturbance, increased total protein, decreased glucose quotient and increased lactate) serve as an indication for antituberculostatic therapy. A strongly positive tuberculin skin test may also be an indication of acute tuberculosis. Therapeutic measures consist of antibiotic combination therapy (rifampicin, ethambutol, isoniazide, pyrazinamide), which may be supplemented by local removal of the septic focus when applicable.
Lues (Syphilis) In view of the increasing number of new lues infections (causative agent: Treponema pallidum), the presence of neurolues has to be considered, especially in patients with subacute and chronic symptoms and a respective history or exposure. The manifestation of symptoms is categorized with reference to the primary infection into primary, secondary and tertiary, or late symptoms. Primary syphilitic lesions include regional lymphadenopathy and a firm ulceration (ulcus durum) localized at the portal of entry of the causative agent. In the secondary and tertiary stages syphilitic meningitis with cranial nerve lesions, polyradiculitides and, rarely, brainstem syndromes may be present, in addition to general symptoms (fever, fatigue, myalgia). Neurologic symptoms in the late stage may manifest in the form of the meningovascular symptoms described above, or as “tabes dorsalis”, paralytic neurosyphilis in terms of chronic progressive encephalitis, and as local syphilitic gumma. The definite diagnosis of neurolues is established by the demonstration of intrathecal antibody expression (Treponema pallidum hemagglutination assay) and calculation of the ITpA (intrathecal Treponema pallidum antibody) index, or the Treponema-specific AI (using ELISA), and the reactive VDRL (Venereal Disease Research Laboratory) test in cerebrospinal fluid. The VDRL test reflects disease activity and will be negative after therapy. The treatment for neurolues consists of penicillin G (25–30 mio. I.U./day, 3–5 × daily i.v.), or ceftriaxone 2–4 g/ day i.v. The length of therapy depends on the stage of the disease.
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Whipple’s Disease In more than 80% of patients an infection with Tropheryma whipplei is associated with general symptoms such as gastrointestinal complaints, weight loss, fever, and arthralgias. Neurologic symptoms (dementia, oculomotor disturbances, myoclonia, hypothalamic function disturbances) can occur in 40% of patients and are usually sequelae of granulomatous encephalitis (cMRI: hypointense lesions) persisting for many years. The diagnosis is made by biopsy (e.g. small intestine, brain) and the demonstration of PAS-positive inclusions. Specific DNA sequences are frequently identified in cerebrospinal fluid using PCR. Treatment is with penicillin G (30 mio. I.U./day i.v.) and streptomycin (1 g/day i.m.) for 2 weeks, thereafter with trimethoprim/sulfamethoxazole (3 × 160/800 mg/day) or third generation cephalosporins.
Legionellosis Infection with Legionella pneumophilia is a primarily pulmonary, often severe atypical pneumonia, which may involve the nervous system in up to 50% of infected individuals. Neurologic manifestations encompass encephalitides, myelitides and polyneuropathies with the respective neurologic deficits. The diagnosis can be established by means of bacterial culture and demonstration of antibodies. The therapy is with macrolid antibiotics (e.g. erythromycin 2 g/day; plus rifampicin in the first week as required). E ncephalitides Caused by Atypical Bacterial Causative Agents The following atypical bacterial diseases should be considered in immunosuppressed patients and individuals with the respective exposure (e.g. livestock in cases of brucellosis), or positive travel history: • • • • • •
CNS rickettsioses Cerebral brucellosis Cerebral malaria Mycoplasma infections of the CNS Cerebral Coxiella burnetii infection (Q fever) CNS bartonelloses and ehrlichioses.
The symptoms in all of the above infectious diseases are often nonspecific (e.g. headache, fever, myalgias, disturbances of consciousness, neurologic deficits, meningeal irritations). The diagnosis can in some instances be reached serologically with the demonstration of antibodies, or be based on bacteriologic/microscopic evidence.
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The decision on the therapy depends on the causative organism and should be made after isolation of the respective causative bacterium. 4.2.2.3 Parasitic Encephalitides In rare cases – individuals with exposure to the respective organism and/or travel history – local CNS involvement may be caused by protozoa and worms. Examples to be noted in particular include: Entamoeba histolytica, Trypanosoma cruzi and T. brucei rhodensiensis, Schistosoma spp., Echinococcus spp., Taenia solium and Paragonimus spp.
4.2.2.4 Fungal Encephalitides Cerebral mycotic infections occur mainly in patients with primary or secondary immunodeficits. To be named in particular are cerebral cryptococcosis, candidoses, and aspergillosis. The diagnosis is made based on demonstration of causative antigens, fungal culture, and a biopsy if applicable. Mycotic infections do not have an important role in the general population. The therapy is with amphotericin B (0.5–1 mg/kg/BW/ day i.v.) and flucytosine (100 mg/kg/BW/day i.v) and, when indicated, plus fluconazole (400–800 mg/day i.v.) Ampho tericin B may also be administered intrathecally.
4.2.2.5 Encephalitides in Immunosuppressed and HIV/AIDS Patients Infection with the human immunodeficiency-(HI) virus per se represents an increased risk for neurologic complications. In HIV patients, an incidence rate of up to 15% has been reported for HIV-1 associated encephalopathy, despite the successful use of antiviral therapy (HAART) (McArthur et al. 2005). Opportunistic infections constitute a significant problem in HIV/AIDS patients. In this setting, the number of CD4 cells is a particularly important marker, whose decrease to <150– 200 mL represents a critical value associated with an increased risk for opportunistic infections (Maschke et al. 2000). In addition to HIV patients, immunosuppressed patients are at an increased risk for opportunistic infections after organ, bone marrow and stem cell transplants, at a reported cumulative incidence rate of approximately 5% (Padovan et al. 2000). Also at risk for opportunistic infections are oncologic/hematologic patients with a neutropenia level <0.5 G/L (Maschmeyer and Kern 2004), as well as alcoholics, patients with diabetes mellitus and patients with longterm medical immunosuppression (e.g. in rheumatoid diseases, vasculitides, myasthenia gravis).
4.2 Inflammatory Brainstem Diseases
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The most common infections manifest in the CNS of immunosuppressed patients include: • • • • • • • • • • •
Cerebral toxoplasmosis Cryptococcal encephalitis, meningoencephalitis Progressive multifocal leukoencephalopathy (JC virus) CMV encephalitis EBV encephalitis Human herpes virus 6 encephalitis Aspergillosis Nocardia infections CNS tuberculosis Herpes simplex encephalitis CNS listeriosis
In Europe, cerebral toxoplasmosis is found primarily in HIV/AIDS patients (most often opportunistic CNS infections with an incidence of approx. 30% in untreated HIV patients), although it may also occur in immunosuppressed patients, e.g. after organ or bone marrow transplants. In approximately 10% of patients it may be the initial symptom of an HIV infection. It is frequently clinically manifest in the form of multiple brain abscesses and/or diffuse foci of encephalitis with focal neurologic deficits. The clinical course ranges from subacute to chronic. The definitive diagnosis is based on the histologic findings or PCR detection of the respective organism in cerebrospinal fluid (cave: low sensitivity, approx. 50%). The characteristic finding of brain imaging and demonstration of Toxoplasma gondii-specific antibodies are usually sufficient indication for therapy. When demonstration of the causative agent is not possible (approx. 30% of cases), various differential diagnoses (primarily CNS lymphoma [!], bacterial brain abscess, tuberculosis) have to be considered. A biopsy should be requested in patients with inconclusive findings. Therapy for toxoplasmosis consists of antibiotic combination treatment (e.g. spiramycin, pyrimethamine, sulfadiazine, clindamycin) (Robert Koch-Institute, Epidemiologic Bulletin 40/2007).
Fig. 4.30 Bickerstaff’s encephalitis. Image obtained in a 71-year-old female; 4 weeks after severe pneumonia the patient developed over several days complete progressive external ophthalmoplegia, limb ataxia, dysarthria to transitory anarthria, as well as central tetraparesis, more pronounced on the right, with somnolence. MRI visualizes diffuse signal intensity increases without contrast-enhancement in the region of the pons, midbrain and both thalami. (Image courtesy Institute of Neuroradiology, University of Mainz)
The diagnosis is dependent on the clinical picture, MRI findings (see Fig. 4.30), cerebrospinal fluid analysis (cytoalbuminal dissociation), and the demonstration of ganglioside antibodies. Bickerstaff’s encephalitis has a good prognosis in more than two thirds of patients (Odaka et al. 2003).
4.2.2.6 Non-causative Agent-Specific Encephalitides
4.2.2.7 Sarcoidosis
Bickerstaff’s encephalitis commonly presents as a (parainfectious or) postinfectious brainstem inflammation. The classic clinical picture is characterized by
Sarcoidosis (Boeck’s disease) is a systemic granulomatous disease that most often affects the lungs, mediastinal lymph nodes, liver, skin, or the eyes, and less often also involves the kidneys, bones (joints) and the heart. In approximately 5–10% of patients (in autopsies 25–60%) CNS involvement may be present and, in the form of neurosarcoidosis, preferentially affects the basal leptomeninx (granulomatous meningoencephalitis), frequently with involvement of the cranial nerves (including the optic nerve) and the vessels at the base of the brain (Kellinghaus et al. 2004). The definitive diagnosis is based on the histologic examination (e.g. extracranial granulomas). Indirect diagnostic indicators include pulmonary granulomas (CT-thorax) and,
• Ophthalmoplegia • Ataxia and • Disturbance of consciousness Additional signs of brainstem involvement, e.g. facial pareses and disturbances of pupillary motor function, as well as paralyses and sensory function disturbances may be observed. Overlapping with Guillain-Barré and Miller-Fisher syndrome exists both with a view to the clinical findings and the regular demonstration of anti-GQ1b antibodies.
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to some extent, an increase in ACE, lysozyme, and interleukin-2 receptor in serum. Nonspecific alterations are frequently found in the cerebrospinal fluid (pleocytosis + increased protein + blood-brain barrier disturbance, and possibly increased ACE). Cranial MRI may show leptomeningeal thickening and contrast enhancement. Differentiation from a brain tumor is not always possible, so that a biopsy is indicated in cases of diagnostic uncertainty. 4.2.2.8 Behçet’s Disease Behçet’s disease is an inflammatory, vasculitic systemic disorder with an unclear etiology, which occurs predominantly in Mediterranean regions as well as in countries of the Near East and Far East, and frequently affects young men (aged 20–40 years). General symptoms are recurrent oral and genital ulcers. Skin and eye involvement as well as arthritic, gastrointestinal and pulmonary manifestations have also been described. Neurologic symptoms are present in 10–50% of cases. CNS involvement can manifest as meningoencephalitis, but characteristically also as sinus/cranial venous thrombosis. Parenchymal involvement of the brainstem is found in up to 50% of patients (Kidd et al. 1999). Frequently observed symptoms include brainstem deficits (e.g. internuclear ophthalmoplegia), pyramidal tract signs, hemiparesis, and bladder/rectal disturbances. The disease course may be characterized by episodic attacks over many years, or be chronic progressive. The diagnosis can be established based on typical clinical features, a positive pathergy test (induction of a vasculitic papule after intracutaneous NaCl injection), cranial MRI findings (T2 lesions) and cerebrospinal fluid analysis (mixed pleocytosis plus increased total protein) (Diagnostic Criteria of the International Study Group for Behçet’s Disease).
4.2.2.9 Systemic Lupus Erythematosis From differential diagnostic viewpoints, consideration should also be given to systemic lupus erythematosis (SLE). The disease can manifest in 50–70% of affected patients in the form of “neurolupus”. It is typically associated with cranial vessel vasculopathy (including venous structures) and may cause inflammatory lesions with associated neurologic deficits, as well as psychiatric complaints, in addition to thromboses and infarctions (see Fig. 4.31). The diagnosis is made on the basis of clinical criteria (e.g. dermatologic alterations, arthritis) and supplementary immunologic testing (anti-dsDNA-AB, ANA, anti-Sm-AB, antiphospholipid-AB).
Fig. 4.31 Image obtained in a 23-year-old woman with systemic lupus erythematodes with CNS involvement. The initial diagnosis was made based on clinical signs (butterfly erythema, photosensitivity, arthritides, serositis) as well as on the neurologic findings of bilateral abducens paresis and transient psychiatric symptoms. cMRI revealed diffuse hyperintense lesions bilateral medial temporal, diencephal, and in the brainstem (above T2-sequence, below FLAIR sequence (Images courtesy Institute of Neuroradiology, Krankenhaus Nordwest, Frankfurt/Main)
In the acute phase, cortisone is used for the therapy of non-causative agent-specific encephalitides (neurosarcoidosis and neuro-Behçet). The recommended dosage consists of 0.5–1.5 mg prednisolone/kg/BW for approximately 1–3 months (with subsequent slow dose reduction). In patients with a severe clinical course or acute exacerbations, an initial high-dose therapy with, e.g. 500–1,000 mg methylprednisolone i.v. for 5 days may be expedient. Depending on the response to steroid therapy and the further course, a single agent or a combination long-term immunosuppressive therapy with methotrexate, azathioprine, cyclosporin, or hydrochloroquine has to be considered. Cyclophosphamide therapy may be required in patients with a severe course of Behçet’s disease. Evidence-based recommendations for the therapy of Bickerstaff encephalitis do not exist. In analogy to the therapy for Guillain-Barré syndrome or Miller-Fisher syndrome, positive therapeutic results have been reported in individual patients (case reports) following administration of cortisone, intravenous immunoglobulins, plasmapheresis or immunoadsorption plasmapheresis.
4.3 Brainstem Involvement in Demyelinating Diseases
4.3 Brainstem Involvement in Demyelinating Diseases Oliver Kastrup Demyelinating diseases of the central nervous system can be categorized pathophysiologically into conditions of autoimmune, infectious, toxic, metabolic, and vascular origin. This chapter focuses on multiple sclerosis (disseminated encephalomyelitis) and its clinical subtypes – acute disseminated encephalomyelitis (ADEM), Balo’s sclerosis and the Marburg type – as autoimmune inflammatory demyelinating diseases, as well as on the progressive multifocal leukoencephalopathy (PML) as an infectious demyelinating disease.
4.3.1 Multiple Sclerosis 4.3.1.1 Epidemiology Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the CNS. The mean age at disease onset is 23.5 years, with women being affected more frequently and on average 5 years earlier (women:men = 1.8:1) than men. The purely relapsing-remitting course of MS is usually associated with an earlier onset, while the chronic progressive form occurs later, on average between 35 and 39 years. Although an initial manifestation in the seventh decade of life has been described, this represents a rare finding. There is no dominant age group in patients with brainstem symptoms. The risk for developing MS is related to the geographic region. Regions with the highest prevalence rate of 60:100,000 include Europe, Russia, Canada, the northern United States, New Zealand, and South East Australia. Regions with a median prevalence rate are located in the remaining parts of Australia, the southern United States, Mediterranean regions outside of Italy, Asia, South America, and areas of South Africa with a large Caucasian population. The regions with a low risk for MS comprise large parts of South America, Mexico, Asia, Africa and Japan. It is assumed that the determinant factor for this phenomenon is racial distribution of genetic risk, with the Caucasian population with a northern European gene pool being at the highest risk. Individuals of Asian, Black African, or Native American descent are at the lowest risk for developing MS. 4.3.1.2 Etiopathogenesis Typical histopathologic findings include demyelination, with initially relative axonal sparing, loss of oligodendroglia and
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astrogial scarring. Zones of demyelination are described as MS plaques. In addition to demyelination, a number of studies have emphasized the role of axonal damage and loss as an important component of the demyelination process. This assumption was supported not only by the findings of pathology studies, but also by the results of MRI investigations (Trapp et al. 1998). Axonal loss also represents the pathophysiologic basis for cerebral atrophy and ventricular enlargement frequently found in MS patients. The plaques develop around the brain vessels, in particular around the brain ventricles and veins. Plaques are also often found in the brainstem and the spinal cord. These lesions or plaques in the CNS serve as the pathophysiologic explanation for the acute and chronic symptoms of MS. Under normal conditions, myelinated axons conduct impulses rapidly by means of the so-called saltatoric propagation of excitation. A lesion extending across two or three nodes of Ranvier causes an interruption of stimulus conduction. This causes a conduction block in some of the nerve fibers in the demyelinated region as well as a pronounced conduction delay of up to approximately 10% of the normal value. In addition, the refractory period of the demyelinated axons is prolonged. Persistent neurological deficits are due to demyelinated regions with a prolonged conduction block and axonal damage. Fluctuating function deficits may occur in partially demyelinated axons, mediated by the temporary decrease in conductivity below the safety margin of its normal value. This may serve as an explanation for the exacerbation of symptoms during periods of increased body temperature seen in Uthoff’s phenomenon. Histology shows a blood-brain barrier abnormality already early in the developmental phase of an acute MS plaque. This disturbance constitutes the critical primary step in lesion development, as it is not only a causative factor for the formation of potential edema surrounding the zone of inflammation, but also triggers active transport processes enabling antibodies and cytokines (as well as contrast agents/gadolinium) to enter into the brain. This leads to the perivascular infiltration, primarily of T-lymphocytes, but also of macrophages and plasma cells. Macrophages have an important role in the demyelinization reaction and are usually found at the center of the plaques. The result is the occurrence of reactive astrocytosis. Activated T-cells and macrophages can release a variety of cytokines, including Interleukin 2, interferon-gamma, tumor necrosis factor-b (TNF-b), which further perpetuate the inflammatory process. This leads to a shift in the direction of Th1 cells, which express the above mentioned cytokines, with a reactive decrease in Th2 cells expressing IL-4, IL-5, IL-10 and IL-13. Macrophages release TNF-a, leukotrienes, thromboxane, proteases and complement. Specific B-cell associated antibodies have not yet been identified. An additional process consists of the upregulation of adhesion molecules, which further exacerbates the
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pathologic process due to the migration of lymphocytes and macrophages. The specific target of the immunomediated inflammatory reaction is only incompletely known, although it has been suggested that the primary attack may be targeted against an antigen in oligodendroglial cells or myelin. Genetic studies have shown that, in the sense of a polygenic inheritance, the susceptibility for MS is passed on in the family. Studies of families and twins have shown a potential 3–5% risk for siblings of MS patients to acquire MS. This rate also applies to dizygotic twins, while the risk is increased to approximately 25–40% in monozygotic twins. The risk for children of MS patients, in particular of MS-mothers, is increased up to 3.8% (Sadovnik and Baird 1988).
4.3.1.3 Clinical Findings The clinical symptoms of function disturbances are highly variable. Multifocal demyelinization in the brainstem that usually occurs as the disease advances, leads to a cumulative deficit and incomplete regression of symptoms. Localization and clinical correlation of new lesions becomes increasingly difficult due to the manifold remaining residues accumulating over time. The clinical findings in nearly all patients with longstanding definite multiple sclerosis comprise multiple disturbances of brainstem function. These consist primarily of ocular motor disturbances, which are often not observed by the patient. Due to the often multiple foci in the brainstem, ocular motor disturbances frequently consist of a combination of residual unilateral or bilateral internuclear ophthalmoplegia, pontocerebellar ocular motor abnormalities with rapid pendular eye movements, abnormal fixation suppression of the vestibuloocular reflex, and saccadic disturbances. Also observed especially at the onset of the disease, are circumscribed brainstem function abnormalities mediated by isolated demyelinization foci. These will be discussed in the following sections.
4.3.1.4 Oculomotor Disturbances The most common abnormalities found are suggestive of a lesion in the region of the nuclear or the vestibuloocular network. Nystagmus occurs frequently in patients with multiple sclerosis. In addition to horizontal, vertical or omnidirectional gaze-evoked nystagmus, an acquired pendular nystagmus is typically found. Pendular nystagmus is a rapid and small amplitude pendular oscillation of the eye in straightahead gaze. The patients often have oscillopsia, although this type of nystagmus is often also associated with significant vision loss. The isolated occurrence of typical downbeat
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nystagmus has only rarely been reported. In these patients a demyelinization focus was identified at the midline of the caudal medulla. Upbeat nystagmus is found in patients with demyelinization foci in the region of the mesencephalic interstitial nucleus of Cajal, as well as in the caudal medulla oblongata with attribution to the intercalate nucleus. Periodic alternating nystagmus has been found in individual patients (Matsumoto et al. 2001). The occurrence of ocular flutter has also been described. This is defined as a rare eye movement disturbance characterized by rapid horizontal saccadic oscillations in patients with isolated localized lesions in the paramedian pontine reticular formation (PPRF). The proposed pathophysiologic hypothesis consists of a loss of neuronal inhibition related to dysfunction of the so-called burst neurons in the PPRF. Internuclear ophthalmoplegia (INO) is defined as a pathologic horizontal eye movement with delayed or incomplete adduction and dissociated horizontal nystagmus of the abducing eye, mediated by a lesion of the medial longitudinal fascicle on the side of impaired adduction. The convergence is unimpaired. INO may also occur bilaterally, in which case it is commonly associated with vertical nystagmus on upgaze. Although this gives rise to a reasonable suspicion of MS, it may also be observed in the presence of vascular lesions, neoplasms of the brainstem, Chiari malformations, and Wernicke’s encephalopathy. MRI imaging, preferably with the use of proton-weighted sequences, enables imaging of the usually discrete lesions (Frohman et al. 2001). In a study that included 65 patients with INO, this was unilateral in 55.4%, and bilateral in 23.8% of patients. A one-and-a-half syndrome was found in 10.8%. In 49.2% of patients complete resolution occurred during the first 3 months, while the INO persisted in 50.8% sometimes even after more than 12 months (Bolanos et al. 2004). Different combination variants of INO with other oculomotor function abnormalities have been described in individual patients (Frohman et al. 2004) as, e.g. the combined occurrence with a nuclear abducens paresis as a horizontal mononuclear saccadic impairment (Frohman and Frohman 2003). In patients with abduction paresis, which may be unilateral or bilateral and associated with slowed saccades without dissociated nystagmus, the existence of a supranuclear gaze paresis is presumed in the presence of rostral pontine and/or mesencephalic lesions (Thömke and Hopf 2001). In addition to a typical Parinaud’s syndrome with vertical gaze paresis and convergence retraction nystagmus in upgaze, complex oculomotor abnormalities have been described in individual patients that have been attributed to demyelination foci from the midbrain to the medulla oblongata worsening over several days. This includes a patient with mononuclear convergence-retraction nystagmus on the right, combined with a divergence-retraction nystagmus on
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the left on upgaze, combined with skew deviation on the left and left-sided impaired abduction. In parallel to the brainstem function disturbances described above, in most patients signs of cerebellar function disturbances, saccadic dysmetria at the end of saccades, chiefly hypermetric saccades, and, occasionally, saccadic intrusions (so-called square wave jerks) are observed. The one-and-a-half syndrome is characterized by a gaze paresis with gaze toward the side of the lesion, combined with an INO with gaze away from the side of the lesion. Clinically this represents in most cases an INO, associated with mononuclear adduction impairment and an additional abducens disturbance. The patients frequently report double vision, oscillopsia and blurred vision. Combinations with skew deviation and gaze direction nystagmus, in a horizontal or vertical, less often downward direction may be present. In the acute phase, exotropia may occur in straight-ahead gaze, usually concurrently with a convergence paresis. The syndrome is suggestive of a lesion in the vicinity of the PPRF and the abducens nucleus, with extension to the internuclear fiber tracts (medial longitudinal fasciculus) crossing to the contralateral oculomotor nucleus. 4.3.1.5 Cranial Nerve Deficits Although individual cranial nerve deficits are observed in MS, they represent isolated and rare occurrences. In the order of decreasing frequency these include involvement of the abducens nerve, the oculomotor and, rarely, the trochlear nerve. A bilateral isolated nuclear oculomotor paresis triggered by an MS relapse has also been described in a patient with secondary progressive multiple sclerosis (MarcelViallet et al. 2005). MRI disclosed a large T2- hyperintense lesion in the mesencephalon. • Oculomotor paresis: The clinical signs comprise double vision, less frequently also ptosis. Weakness of the medial and superior rectus muscles as well as of the inferior oblique muscle is commonly found on the side of the lesion. Bilateral weakness of upgaze may be present, due to the bilateral representation of both the superior rectus and the superior eyelid levator muscle. Because the nuclear portion of the medial rectus muscle is located in the rostral portion of the ventral part of the nucleus, and axons from the dorsal nuclear portions travel through it, a discrete bilateral involvement of the medial rectus muscle is often noted. In some cases, the superior eyelid levator muscle may be spared, since the respective neurons are located in the nucleus at the dorsocaudal periphery. After localization of the demyelinization focus, bilateral ptosis with dilated pupils, and a sluggish pupillary response to light may be observed in isolated cases, which is
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a ttributable to the bilateral representation of both the nuclear portion of the superior eyelid levator muscle and the Edinger-Westphal nucleus. Oculomotor paresis may be very painful in some patients with MS. A reported rarity in multiple sclerosis is the plus-minus-lid syndrome, which is characterized by an ipsilateral ptosis with contralateral retraction of the upper eyelid. The lesion is found in lesions in a paramedian mesencephalic location (Gaymard 1992). • Trigeminal involvement: This occurs in multiple sclerosis in the form of a symptomatic trigeminal neuralgia or painless paresthesia and dysesthesias. The results of MRI studies have shown that trigeminal structures are also involved in patients without clinical complaints owing to the inflammatory process. Detected among others were signal abnormalities without gadolinium uptake in the pontine trigeminal root entry zone, or gadolinium enhancement in the cisternal portion of the nerve (Da Silva et al. 2005). Sensory deficits are often clinically silent and the patients are unaware of their presence. In contrast, trigeminal neuralgia is associated with excruciating pain, in particular in patients with bilateral manifestations. In addition to trigeminal neuralgia with the classic tic douloureux, individual patients may develop chronic painful trigeminal neuropathies. • Abducens paresis: The neurons of the abducens motor nucleus terminate on the ipsilateral lateral rectus muscle. Interneurons cross at the level of the abducens nucleus, course with the medial longitudinal fascicle and terminate on the nuclear portion of the medial rectus muscle of the oculomotor nerve. A lesion to the abducens nucleus therefore mediates an ipsilateral horizontal gaze paresis. The patients are typically unaware of the isolated horizontal gaze paresis, because they only have subjective difficulties on looking to the side. An impressive clinical finding is a conjugate horizontal gaze paresis which responds neither to caloric stimulation with water or the vestibuloocular reflex. As a rule, concomittant discrete facial pareses may be expected in multiple sclerosis, due to the anatomic vicinity of the knee of the facial nerve. • Facial paresis: Unilateral or bilateral facial pareses rarely occur during an acute MS relapse with an isolated brainstem focus in the region of the facial nerve or in the course of the facial nerve (Jonsson 2001). The patients are frequently unaware of the paresis. A clinically highgrade paresis is rare. In the further course (after years) discrete bilateral facial paresis, reminiscent of weakened mimic muscles, is often observed. These lend a hypomimic expression to the face of the patient; facial diplegia is a rare clinical finding. A combination with a
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nuclear abducens paresis is commonly found during an acute relapse. • Caudal cranial nerve injury: A lesion involving the corticolingual projections coursing through the ventral brainstem may be the cause of dysarthrophonia or tongue motility impairment as a result of disturbed supranuclear control of the tongue. These may occur either during an acute relapse or pursue a chronic course. Dysarthrophonia can be very pronounced in advanced stages of MS and mimic the clinical picture of pseudobulbar paralysis. Swallowing function may be compromised in patients with advanced MS (Urban et al. 2004). • Studies of patients with primary and secondary progressive MS undergoing videoendoscopic and videofluoroscopic examinations reported the presence of dysphagia in 34% of cases. The degree of dysphagia was clearly correlated with both the lesion load in the brainstem detected on MRI and the severity of the disease status. Surprisingly, compensation strategies like voluntary swallowing and swallowing training were sufficient in 93% of patients to achieve adequate swallowing function. With a view to the high risk for aspiration and malnutrition as well as the good success of swallowing training, thorough swallowing function testing is recommended in all patients with advanced MS, in particular in individuals with brainstem involvement and a high level of physical disability (Calcagno et al. 2002). Patients with advanced MS often have bilaterally reduced shoulder function, resulting from supranuclear lesions to segments of the pyramidal tract projecting to the accessory nerve nucleus. This is, however, apparent only in patients with a concomitant highgrade tetraparesis/tetraplegia. The isolated loss of shoulder or sternocleidomastoid muscle function due to accessory nucleus involvement is rare.
4.3.1.6 Headache The results of recent studies show an association of midbrain lesions with an increased incidence of migraine headache in patients with MS (Gee et al. 2005).
4.3.1.7 Auditory Abnormalities Although overall, auditory abnormalities are rare in patients with multiple sclerosis, unilateral or bilateral auditory disturbances with involvement of the central auditory pathways have repeatedly been reported. These include reports of individual patients with intramedullary lesions, who had an abrupt unilateral hearing loss and showed no acoustic evoked potentials after wave I (Ozunlu et al. 1998). The so-called central hyperacusis with phonophobia represents a rare phenomenon. This
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condition is associated with unpleasant and partly painful paresthesias provoked by acoustic stimuli. The patients described shooting pain in the trigeminal nerve caused by ringing of the telephone, hearing actually non-existent noise induced by acoustic stimuli, and hearing multiple echoes. All patients had a clinical brainstem syndrome. MRI visualized foci of demyelinization in the ipsilateral pons. The pathophysiologic assumption is the presence of abnormal impulse conduction from the lateral lemniscus to the central trigeminal pathway.
4.3.1.8 Vertigo, Balance, and Gait Disorders of balance represent the most common symptoms of multiple sclerosis. Rotatory vertigo is a frequently reported symptom, in addition to multifactorial disturbances of balance and gait or multisensory vertigo. Rotatory vertigo is mediated by demyelinating foci in the region of the vestibular nuclei (Papathanasiou et al. 2005). In patients with a single focus of demyelinization in the lateral medulla oblongata in the entry zone of the vestibulocochlear nerve, multiple sclerosis may manifest with the clinical picture of vestibular neuritis with positional rotatory vertigo, spontaneous nystagmus, ataxia with falling to one side and nausea (Bruzzone et al. 2004) (Fig. 4.32). In this setting the condition is defined as ‘vestibular pseudoneuritis’, based on the MRI demonstration of the lesion and/or additional supratentorial demyelinating lesions and later progression to multiple sclerosis.
4.3.1.9 Lesions of the Pyramidal Tract In the early phase of an acute relapse, as well as in the long-term course of MS with involvement of single or multiple cranial nerves, findings that include pyramidal tract signs are increasingly observed. These typically include unilateral or bilateral paresis, often spastic tetraparesis with significantly less impaired upper extremity motor function (Fig. 4.33). Sensory deficits are frequently observed early in the course of MS. These patients often have demyelinating lesions in the region of the spinothalamic tract, the posterior white columns, or the dorsal root entry zone. In addition to negative symptoms such as a “pins and needles” feeling and impaired temperature perception, the patients commonly describe burning, electrical or pin-prick sensations, cold-induced paresthesia, or feelings of tightness or swelling. A very small number of MS patients may develop a “dysarthria-clumsy-hand syndrome”, which is associated with a significantly limited use of the hands, due to proprioceptive deficits without pure motor paresis. Lesions of the root entry zone or the posterior white columns in combination with a brainstem focus have been posited in these cases.
4.3 Brainstem Involvement in Demyelinating Diseases
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4.3.1.10 Emotional Incontinence The findings of various case reports support the assumption that emotional incontinence with pathologic laughing and crying may be triggered by brainstem plaques. MRI demonstrated a reduction in the number of these lesions following steroid pulse therapy with a concurrent improvement of emotionalism (Takado et al. 2002). 4.3.1.11 Paroxysmal Phenomena Paroxysmal phenomena mediated by demyelinating brainstem lesions are common in MS. However, many patients only report these on being asked. The phenomena include paroxysmal diplopia, facial paresthesias, trigeminal neuralgia, as well as ataxia and dysarthria. Painful tonic contractions in one half of the body, or an arm or leg (socalled tonic brainstem attacks) have been reported in patients with brainstem and pyramidal tract involvement. Another proxysmal phenomenon is intermittent facial myokymia with undulating waves of muscle contractions in one side of the face, which may, in some cases, persist for hours or days. Fig. 4.32 MRI obtained in a 29-year-old woman with relapsingremitting multiple sclerosis and definite diagnosis in the course. During the first day of the initial relapse, worsening of rotatory vertigo, nausea, hearing loss left, rotatory spontaneous nystagmus to the right, and falling tendency to the left occurred. MRI disclosed a new lesion in the left medial cerebellar peduncle with involvement of the vestibulocochlear nerve. (Image courtesy Institute of Neuroradiology, University Essen)
4.3.1.12 Tremor Although intention tremor is generally defined as a cerebellar tremor, the results of different studies indicate that intention tremor amplitude is related to the lesion load in the brainstem, but not to the lesion load in the cerebellum. Patients with severe tremor in the arms consistently showed a greater lesion load in the bilateral pons, while the tremor amplitude correlated with the lesion load in the contralateral pons (Feys et al. 2005). These findings support the hypothesis that tremor represents the expression of a dysfunction of the pontocerebellar inflow and/or outflow pathways in patients with MS. 4.3.1.13 Diagnosis
Fig. 4.33 MRI obtained in a 46-year-old woman with definite diagnosis of MS. Primary relapsing-remitting, secondary chronic progressive course; new lesion in the right ventral medulla oblongata formed during the current attack, and pronounced increase in the tetraparesis with right predominance. (Image courtesy Institute of Neuroradiology, University Mainz)
The diagnosis of MS is usually established clinically, based on the symptoms observed after an attack that can be ascribed to demyelinization of the white matter in the central nervous system, and are corroborated by their dissemination in space and time. The diagnosis of MS was facilitated by the introduction of evoked potentials for the detection of preceding occult attacks, in particular of previous retrobulbar neuritis, which can be demonstrated by visual evoked potentials. A further important diagnostic finding is an immunoreactive cerebrospinal fluid syndrome with intrathecal IgG synthesis and oligoclonal bands. This abnormality is present in 95% of patients in classic MS.
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A pivotal milestone in the diagnosis of MS was the introduction of magnetic resonance imaging, enabling the visualization of the findings characteristic for the disease. These comprise multiple, usually transverse oval, periventricular signal hyperintensities found on FLAIR and T2-weighted images, seen as partly hypointense lesions on T1-weighted images; these hypointensities are referred to as “black holes”. The blood-brain barrier breakdown is responsible for gadolinium-enhancement of acute MS lesions. Callosal involvement is typically detected on sagittal T2-weighted sequences. Frequently identified – and associated with a relatively good specificity – is infratentorial involvement with foci in the brainstem and the cerebellum, as well as in the spinal cord. The currently applied diagnostic criteria for the diagnosis of MS are the so-called McDonald criteria (Polman et al. 2005, see Table 4.12). Table 4.12 McDonald criteria – clinical presentation and required additional findings for the diagnosis of MS Clinical presentation Required additional findings Two or more attacks, objective clinical evidence of two or more lesions
None
Two or more attacks, objective clinical evidence of one lesion
Dissemination in space, demonstrated by MRI, or two or more MRI-detected lesions consistent with MS plus positive CSF, or await further clinical attack implicating a different site of inflammation
One attack, objective clinical evidence of two or more lesions
Dissemination in time demonstrated by typical MRI or second clinical attack
One attack, objective clinical evidence of one lesion with monosymptomatic presentation, clinically isolated syndrome
Dissemination in space, demonstrated by typical MRI or two or more MRI –detected lesions consistent with MS plus positive CSF, and dissemination in time demonstrated with MRI or by second attack
Insidious neurological progression suggestive of MS
Positive CSF and dissemination in space determined by: • Nine or more T2-lesions in the brain or • Two or more lesions in the spinal cord or • Four to 8 brain lesions plus 1 spinal lesion or • Abnormal visual evoked potentials plus 4 – 8 brain lesions or • With fewer than four brain lesions plus 1 spinal cord lesion demonstrated by MRI and dissemination in time demonstrated by MRI or • One year of continuous disease progression
The currently used specific MRI criteria have been integrated into the above criteria. According to Barkhof et al. (1997) they include, in addition to periventricular lesions also juxtacortical, infratentorial and gadolinium-enhancing foci. Demonstration of infratentorial lesions is therefore of particular importance for the diagnostic specificity of the revised criteria. The previously, as well as currently, still widely used criteria published by Fazekas et al. in 1988, calling for a minimum of three foci >5 mm periventricular or infratentorial, were characterized by a slightly lower specificity for the diagnosis of MS. Approximately 60% of patients with progressive and advanced MS have infratentorial lesions in the brainstem and the cerebellum, in addition to multiple supratentorial foci (Yousry et al. 2000). Although diagnostic categorization does not present a problem (Fig. 4.34), the classification of a clinically isolated syndrome (CIS) with cranial nerve deficits is less readily achieved (Fig. 4.35). While the presence of an internuclear ophthalmoplegia is virtually pathognomonic for MS in young adults, other deficits have a wider differential diagnosis. In addition to the demonstration of oligoclonal bands in cerebrospinal fluid, the detection of multiple, also supratentorial lesions on magnetic resonance imaging serves to both confirm the diagnosis
Fig. 4.34 MRI in chronic MS with purely infratentorial foci. Neurologic findings: internuclear ophthalmoplegia bilateral and mild spastic tetraparesis. (Image courtesy Institute of Neuroradiology, University Essen)
Fig. 4.35 MRI in clinically isolated syndrome (CIS). Image obtained in 30-year-old patient with vertigo and discrete double vision. Oligoclonal bands positive. Symptom remission with steroid therapy. (Image courtesy Institute of Neuroradiology, University Essen)
4.3 Brainstem Involvement in Demyelinating Diseases
and provide prognostic indicators. In more than 80% of young adults with MS the onset is characterized by the subacute development of a CIS that is attributable to an optic nerve, the brainstem, or the spinal cord (Miller et al. 2005). However, in only 30–70% of these patients multiple sclerosis will become manifest at a later time. The demonstration of clinically silent multiple lesions on MRI is associated with a high probability of subsequent development of MS. More recent studies have shown that MRI findings of positive Barkhof criteria with a sensitivity of 78% and a specificity of 61% are predictors of the subsequent conversion to MS (Sastre-Garriga et al. 2003, 2004).
4.3.1.14 Differential Diagnosis The clinical assessment often conforms to neuroradiological isolated brainstem syndromes and brainstem lesions. This makes the initial differential diagnostic evaluation difficult (Zaffaroni et al. 2001). The neuroradiological differential diagnoses of isolated brainstem foci includes: neoplastic lesions such as brainstem gliomas and lymphomas, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, listeria rhombencephalitis, neurosarcoidosis, Whipple’s disease, Behçet’s disease and neuroborreliosis. In atypical cases, MRI changes in central pontine myelinolysis can also be suggestive of an MS plaque. In this setting, only a detailed clinical and neuroradiological correlation and synthesis are the right way to the diagnosis (Falini et al. 2001).
4.3.1.15 Therapy The primary aim of therapy during acute attacks is the administration of high doses of steroids. Symptomatic therapy is, however, often indicated in patients with persistent symptoms. This is tailored to the presenting symptom. The management of pendular nystagmus is extremely difficult. In individual patients the administration of gabapentin and memantine were shown to be effective (Fabre et al. 2001). In other patients, the administration of gabapentin combined with a vertical Kestenbaum procedure for nystagmus with muscle recession was beneficial (Jain et al. 2002). Botulinum toxin for the generation of an external ophthalmoplegia represents a therapeutic alternative (Menon and Thaller 2002). In patients with ocular flutter, a dramatic improvement was found clinically and on imaging after steroid therapy (Schon et al. 2001). The standard therapy for trigeminal neuralgia or chronic painful trigeminal neuropathies consists of the
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administration of antiepileptics (carbamazepine, oxcarbazepine, lamotrigin, gabapentin, pregabalin), tricyclic antidepressants (amitriptylin), baclofen, as well as supportive opioids. The therapeutic failure rate is higher than in nonMS patients (De Simone et al. 2005). In patients with MS refractory to conservative therapy, a Jannetta procedure or gamma knife surgery was shown to be effective (Cheng et al. 2005). Paroxysmal attacks are usually reliably resolved on low doses of membrane stabilizers (carbamazepine 200–600 mg/ day) and remit spontaneously after weeks to months. A recurrence is rare. The management of tremor with pharmacologic therapy is difficult in patients with MS. Individual therapeutic attempts with beta-receptor blockers, primidone and pregabalin can be helpful. In analogy to Parkinson’s disease, deep brain stimulation (VIM) may be used in patients with an unsatisfactory response to conservative therapeutic measures (Nandi and Aziz 2004), while vagal nerve stimulation may also be helpful in individual patients (Marrosu et al. 2005). Improvement of bilateral cerebellar arm tremor was reported for patients who received an intrathecal baclofen pump for management of lower extremity spasms (Weiss et al. 2003).
4.3.1.16 Prognosis A low lesion load demonstrated on MRI at the onset of the disease, a long time interval to the secondary manifestation, and the absence of clinically relevant impairment at the end of the fifth year after disease onset are indicators of a favorable prognosis.
4.3.2 Multiple Sclerosis Subtypes Several disease subtypes can be differentiated in addition to benign, relapsing-remitting and primary and secondary progressive forms of multiple sclerosis. These include acute disseminated encephalomyelitis (ADEM), Baló’s disease, as well as the Marburg type MS (Menge et al. 2005).
4.3.2.1 Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis (ADEM) is a monophasic demyelinating autoimmune disease that affects the brain and the spinal cord (Wegner 2005). It is usually preceded by an inflammatory condition, infection, or vaccination; disease onset is frequently in childhood. Although a myriad of viral and bacterial pathogens as
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well as different vaccinations have been described in association with ADEM, no single causative organism has been identified. The results of several experimental studies are suggestive of a secondary autoimmune inflammatory reaction with demyelinization triggered primarily by a causative organism. MRI visualizes the development of extensive, multifocal, subcortical T2-hyperintensities, which are partly confluent or present as contrast-enhanced areas. As opposed to MS, ADEM is characterized by a more pronounced lymphocytic pleocytosis as well as elevated protein in cerebral spinal fluid. Oligoclonal bands are significantly less often positive than in MS and may only be transient (Dale et al. 2000). In rare cases, the antibodies to aquaporins which are otherwise typical for optic neuromyelitis (Devic’s syndrome) may be positive, in particular in the absence of MRI gadolinium enhancement. Although the large demyelinating lesions are generally found in the hemispheres, individual cases with ADEM confined to the brainstem are known (Tateishi et al. 2002) Reported patients often had clouded consciousness to the point of coma and focal brainstem signs in combination with tetraparesis (Firat et al. 2004). The therapy of ADEM consists of steroids in adults and immunoglobulins in children. Plasmapheresis is indicated as a second-line treatment. Some patients have a good prognosis, because the disease appears to be self-limiting. This applies in particular to ADEM with onset in childhood. In half of the patients, however, a primary acute form of ADEM is diagnosed in the course and the disease will be reclassified as MS. Both an initially elevated ADC value on diffusion-weighted MRI, and rapid recovery of signal intensity to baseline are viewed as positive prognostic markers (Axer et al. 2005).
4.3.2.2 Baló’s Disease Baló’s disease (syn. concentric sclerosis) is a subtype of MS characterized by concentric layers of partial demyelinization alternating with completely demyelinated circles. MRI commonly shows target-like lesions in the hemispheres. Brainstem involvement is rarely observed in the generally mild clinical course of the disease.
4.3.2.3 Marburg-Type Multiple Sclerosis Marburg-type multiple sclerosis is also known as encephalitic multiple sclerosis. It manifests with large tumor-like, demyelinating plaques (Fig. 4.36). Brainstem involvement has been reported in individual patients (Capello and Mancardi 2004).
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Fig. 4.36 MRI in Marburg-type MS with tumor-like plaque formation in the pons. Images obtained in a 33-year-old woman with subacute tetraparesis, dysarthria, dysphagia, horizontal gaze paresis, and upbeat nystagmus with rapid progression to locked-in syndrome. No response to therapy with cortisone (i.v.), plasmapheresis and cyclophosphamide (i.v.). Stabilization and clinical improvement of the symptoms only with rituximab. (Image courtesy Institute of Neuroradiology, University Mainz)
4.3.3 Progressive Multifocal Leukoencephalopathy The differential diagnosis of MS subtypes has to include consideration of an isolated infratentorial manifestation of viral inflammatory demyelinating diseases: progressive multifocal leukoencephalopathy (PML). This is a subacute encephalitis, caused by the polyomavirus of the JC genotype. The disease usually occurs in patients with severe cellular immunodeficiency. Earlier reports frequently describe the occurrence of this complication in immunodeficient patients with hematologic tumors, or after chemotherapy. In the past 2 decades it was reported as a complication of AIDS or noted MS-therapy with natalizumab. Definitive diagnosis is made based on the findings of stereotactic biopsy; laboratory tests can also include detection of JC virus DNA in cerebrospinal fluid by PCR. T2-weighted MRI typically discloses extensive confluent signal hyperintensities, generally without contrast agent uptake (Fig. 4.37). There have been reports of individual cases with the histologic confirmation of PML confined to the brainstem. In this setting, the imaging aspect and depiction of the lesions can be similar to that of foci typically observed in MS. In patients with an atypical presentation of brainstem encephalitis with demyelinating lesions, PML should be included in the differential diagnostic considerations. Patients with space-occupying disease generally have a poor prognosis with an almost always fatal outcome. The survival time of patients with AIDS was significantly improved with high-dose combined antiretroviral therapy (HAART). Even though an aggravation may occur initially, a potent antiretroviral therapy with the hope for
4.4 Paraneoplastic Brainstem Syndromes
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to the tumor diagnosis, e.g. of small-cell lung cancer (SCLC), 1–3% of patients have PNS. Paraneoplastic brainstem syndromes are a subgroup of paraneoplastic conditions that may constitute the clinically leading symptom or occur in combination with other findings as part of a syndrome. The diagnosis of a PNS is of crucial importance for the individual patient, because the a priori probability that a particular neurologic symptom is caused by a tumor may be very high (e.g. Lambert-Eaton myasthenic syndrome [LEMS] 60%, subacute cerebellar degeneration 50%, opsoclonusmyoclonus 50% in children or 20% in adults, limbic encephalitis 20%).
4.4.2 Etiology
Fig. 4.37 T2-weighted MRI with isolated brainstem PML (progressive multifocal leukoencephalopathy). Signal alterations in the brainstem and cerebellum (arrows). Image obtained in a 27-year-old patient with subacute clouded consciousness, double images, swallowing disturbances and tetraparesis. No supratentorial lesions demonstrable, oligoclonal bands negative, HIV and JC virus PCR positive. (Image courtesy Institute of Neuroradiology, University Essen)
immune reconstitution is currently recommended. Clinical studies did not prove therapy with cidofovir to be of relevant benefit. In patients with MS and natalizumab induced PML, immediate plasmapheresis is mandatory. Adjunct therapy with mefloquine and mirtazapine has been recommended.
4.4 Paraneoplastic Brainstem Syndromes Heidrun Golla and Raymond Voltz
4.4.1 Epidemiology Paraneoplastic neurologic syndromes (PNS) are complications of neoplastic diseases that are not due to the tumor itself, its metastases, or vascular, infectious, metabolic and therapy-associated causes. PNS are rare. They constitute approximately 10% of all non-metastatic neurologic complications in tumor patients (Posner 1995). Corresponding
Metabolic alterations or viral infections were long suggested as possible pathomechanisms of a PNS. Although there are case reports describing the coincidence of a viral and a paraneoplastic disease (Sharshar et al. 2000; Kararizou et al. 2005), since the first description of the Hu-antibody (Graus et al. 2001) and subsequent characterization of numerous, highly specific neuronal antibody reactivities in the serum and cerebrospinal fluid of affected patients, autoimmunopathogenesis appears to be the most likely pathomechanism. The neuronal antibodies (Ab) are directed against proteins constitutively expressed in neurons and other immunoprivileged tissues (eye, testis) (Darnell 1996). In the presence of PNS, the associated tumors express these so-called onconeuronal proteins “ectopically”, and may thereby initiate the immunoreaction, which is then directed not only against the tumor itself, but also attacks the neurons that express the respective antigen physiologically. When the target antigen is initially unknown, neuronal antibodies are named according to the initials of the index patient, e.g. “Hull” in Hu-Ab, and “Margret” in Ma-Ab. Their number is continuously increasing. The clinically relevant antibodies found in association with paraneoplastic brainstem syndromes include Hu-, Ri-, Ma/Ta, amphiphysin and CRMP5/CV2-Ab; Yo-Ab may also be identified when paraneoplastic cerebellar degeneration is the main finding. The pathogenicity of the majority of paraneoplastic antibodies continues to be debated. A direct pathogenetic role of the antibody itself has thus far been conclusively demonstrated for one paraneoplastic Ab-reactivity alone, the antirecoverin-Ab. Conflicting results have been reported for sera of other paraneoplastic antibodies with regard to cytotoxic effects of the IgG-fraction (Verschuuren et al. 1997; Schafer et al. 2000). Various attempts to fulfil the modified Koch’s postulate to elicit an autoimmune reaction with the use of active or passive immunization in an animal model have
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failed (Sillevis Smitt et al. 1995; Tanaka et al. 1995; Auf et al. 2002). Thus far a neurologic syndrome triggered by means of passive IgG transfer has been reported in only one patient: Described was the induction of a stiff-person syndrome in the rat after transfer of immunoglobulins from an amphiphysin-Ab positive patient; this was, however, achieved only after opening the blood-brain barrier with autoaggressive T-cells (Sommer et al. 2005). The findings of different studies published since then suggest that cytotoxic T-cells have an important role in primary injury to neurons. Cellular infiltrates have been described for some time, in particular in the early phase of the disease (Rosenblum 1993; Sutton et al. 2001). Histopathologic studies showed destruction of neurons combined with typical inflammatory infiltrates; perivascular infiltrates are primarily composed of T-helper-cells (CD4-positive) and B-cells, while chiefly cytotoxic T-cells (CD8 positive) are localized interstitially (Aye et al. 2009; Vigliani et al. 2009). Analysis of T cell receptors from the brains of Hu-Ab positive patients showed an oligoclonal expansion of cytotoxic T-cells, an observation that gives rises to the assumption of a primary reaction against an antigen, in this case presumably Hu (Voltz et al. 1998). Furthermore, there are indications of antigen specific TH1 and cytotoxic T-cells in the blood and cerebrospinal fluid of Hu-Ab and Yo-Ab positive patients, respectively (Benyahia et al. 1999). The initial attempt to establish an animal model via DNA vaccination of Hu-specific T-cells showed, in addition to the induction of high Ab-titers in serum, a marked inhibition of tumor growth in the respective animals. However, neither clinical nor histologic signs of neurologic damage were detected (Carpentier et al. 1998). The successful induction of subclinical encephalomyelitis with the transfer of highly specific CD4-positive T-cells directed against the Ma1 protein in a rat model has also been reported; this observation is in support of the hypothesis of an autoimmunopathogenesis of paraneoplastic diseases (Pellkofer et al. 2004). The animal model showed, among other findings, mesencephalon and diencephalon involvement in encephalitis, areas of the brain typically characterized by inflammatory alterations in patients with Ma/Ta-Ab associated brainstem encephalitis (Dalmau et al. 1999; Voltz et al. 1999; Rosenfeld et al. 2001).
4.4.3 Clinical Findings The brainstem consists of three anatomic segments: mesencephalon, pons and medulla oblongata. The segment chiefly affected by paraneoplastic changes determines the clinical symptoms, which typically have a subacute course and usually manifest a considerable time before the tumor is diagnosed (up to 3–4 years). The various characteristic
4 Diseases Table 4.13 Overview of the neuronal antibodies which are most frequently associated with paraneoplastic brainstem syndromes and the respective associated tumors Localization Paraneoplastic Typically antibody associated tumors Mesencephalon, pons, cerebellar peduncles
Ta(Ma2)-Ab
Germ cell tumor (testicular tumor)
Ma-(Ma1- and Ma2-) Ab
SCLC, adenocarcinoma of the lung, breast cancer, lymphoma
Pons, cerebellum
Ri-Ab
Breast cancer, lung cancer
Medulla oblongata, pons
Hu-Ab
SCLC, adenocarcinoma of the lung (rarer), prostate cancer, neuroblastoma, thymoma
p araneoplastic antibodies are associated with pathologies characterized by different patterns of localization within the brainstem (see Table 4.13). Most patients with Ma/Ta-Ab present with clinical symptoms of the upper brainstem. Typically found are oculomotor symptoms such as gaze and ocular muscle pareses, nystagmus (e.g. rotatory nystagmus with or without a downbeat component) and skew deviation, or – in cases with additional cerebellar peduncle involvement – cerebellar ataxia and/ or dysarthria. The greater number of patients with Ta(Ma2)-Ab are men who have germ cell (testicular) tumors, while those with an additional Ma1-Ab usually have different tumors, mainly lung and breast cancer, or, more rarely, lymphoma (Voltz et al. 1999; Rosenfeld et al. 2001; Dalmau et al. 2004). Ri-Ab typically cause an opsoclonus-myoclonus syndrome (OMS), but may in some instances also be associated with ataxia (POMA: paraneoplastic opsoclonus-myoclonus ataxia). The described symptoms constitute the only “classical” paraneoplastic brainstem syndromes, and can therefore be of crucial importance for the definite diagnosis of PNS (Graus et al. 2004). The question as to which brainstem structures are injured remains in dispute: both involvement of “omnipause” neurons in the middle brainstem (Zee and Robinson 1979) and cerebellar lesions (Ellenberger et al. 1968), in particular a lesion of the cerebellar nuclei, have been described. These patients have rapid conjugate ocular oscillations without intersaccadic intervals of varying directions, frequency and amplitude, myoclonia of the trunk and limb musculature, and frequently also ataxia of the trunk and limbs (here: POMA). In adults, the most frequently associated tumors are found in the breasts and the lungs (Bataller et al. 2001). In children this PNS is most commonly associated with a neuroblastoma; thus far definitely associated antibodies have not been reliably identified in this group of patients (Pranzatelli et al. 2002).
4.4 Paraneoplastic Brainstem Syndromes
Patients with Hu-Ab, who frequently have a lung tumor (SCLC more commonly than adenocarcinoma), exhibit chiefly lower brainstem symptoms. These comprise, e.g. dysphagia, dysarthria, facial paresis, facial myokymias, impaired auditory acuity, or a central paraneoplastic dysautonomia with coma and respiratory depression (Crino et al. 1996; Al-Shekhlee et al. 2003; Saiz et al. 2009). Oculomotor symptoms, such as slowed saccades and gaze pareses (Crino et al. 1996) have further been described, which indicates that more cranial brainstem regions may as well be affected, and that deviations from the typical regions of involvement may be encountered. Brainstem paraneoplasias may also occur in patients without identifiable classical paraneoplastic antibodies (Baloh et al. 1993; Corato et al. 2004). Depending on the brainstem structures involved, they may further be responsible for very isolated clinical symptoms, e.g. in cases of strategically located cranial nerve (nuclei) involvement. In this setting, a paraneoplastic bilateral vestibulopathy (Rinne et al. 1998), an isolated lesion of the oculomotor cranial nerve nuclei (Pillay et al. 1984) or complex syndromes with an early lethal outcome (e.g. central pontine myelinolysis (Hardjasudarma et al. 1992)) may be observed.
4.4.4 Diagnosis The diagnosis of a PNS rests on three pillars: • Typical clinical neurologic symptoms • Identification of neuronal antibodies • Tumor diagnosis The diagnosis of definite PNS in the region of the brainstem can be made based on one of the following criteria (Graus et al.): • Concomitant occurrence of an otherwise etiologically non-classifiable neurologic brainstem syndrome and the detection of typical neuronal antibodies (tumor diagnosis not compulsory) • A clinically classical PNS (brainstem region OMS/ POMA) with typical tumor developing (e.g. breast cancer) within 5 years of the diagnosis; the demonstration of neuronal antibodies is not required in this setting • A non-classical neurologic brainstem syndrome (all with the exception of OMS/POMA) of unclear etiology with tumor development within 2 years of diagnosis, and concurrent improvement of the neurologic disorder after tumor therapy The assumption that a neurologic symptom is associated with an underlying tumor is corroborated by 100% with the demonstration of highly specific Ab reactivities in serum found in approximately two thirds of patients with PNS. The
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search for an occult primary tumor is facilitated by the close association between certain types of malignant tumors and so often enables its early diagnosis. In a suspected paraneoplastic brainstem syndrome, testing in the serum, possibly also in the cerebrospinal fluid of the patient is indicated for the following antibodies: Hu-, Ri-, Ma/Ta-, amphiphysin-, CV2/CRMP5-Ab, additionally Yo-Ab in patients with primarily cerebellar symptoms. The aim of autoantibody diagnostics is the optimum diagnostic specificity and sensitivity from an economic point of view. According to the German Society of Neurology (DGN) (Voltz et al. 2008) guidelines, initial screening is to be carried out with the combined use of immunohistochemistry and Western blot (neuronal extract or recombinant proteins) in cases of suspected malignancy. The safety of this methodologic approach is imperative with regard to the high clinical relevance of the Ab results. Testing in cerebrospinal fluid can detect an intrathecal synthesis of specific antibodies in the great majority of all Ab-positive paraneoplastic patients with central symptoms. The cerebrospinal fluid should also be examined for cell counts, protein and oligoclonal bands; often – although not mandatory – pathologic changes with mild pleocytosis, slightly elevated protein levels and/or the presence of oligoclonal bands can be found in the cerebrospinal fluid of patients with PNS. For the exclusion of CNS tumor invasion, a cytologic examination of the cerebrospinal fluid as well as a cranial MRI should be performed. The latter is more specifically indicated for the exclusion of a differential diagnosis, as it is not always very meaningful in regard to the suspected brainstem paraneoplasias. These are – in contrast to paraneoplastic limbic encephalitides – often without pathologic findings on MRI, despite the frequent presence of pronounced brainstem symptoms (Saiz et al. 2009). In the presence of possible alterations that are, as a rule, found in T2- and/or contrast enhanced sequences; these correlate well with clinically suspected areas of the brain with pathologic alterations. Pathologic MRI changes are more often identified in Ta(Ma2)-Ab positive patients than in other antibody carriers. Essential first measures in patients with suspected PNS and unknown underlying neoplasia are a physical or, depending on the clinically suspected site of malignancy, gynecological examination. These should be followed by a chest x-ray and CT of the thorax, mammography, as well as tumor marker identification, and a whole-body FDG-PET (whole-body 18-fluoro-2-deoxyglucose positron emission tomography) where applicable (Linke et al. 2004). If a PNS event is identified based on the antibody constellation, an aggressive search for the tumor, i.e. including whole-body FDG-PET, is indicated. PNS associated tumors can remain small for an extended period of time due to an apparent biologically effective immune response. Screening examinations should be carried out at short intervals (e.g. every 2–3 months) in patients with
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Table 4.14 Recommended tumor diagnostic measures in dependence on the suspected underlying tumor Suspected tumor (Tumor-)marker Additional diagnostic measures SCLC
NSE, Pro-GRP
Chest x-ray, thorax-CT, FDGPET, poss. bronchoscopy, mediastinoscopy, thoracotomy
NSCLC
CYFRA, CEA, SCC
Thorax-CT, poss. FDG-PET, poss. bronchoscopy, mediastinoscopy, thoracotomy
Neuroblastoma
Catecholamines and metabolites in urine
Thorax- and abdomen-CT, MIBG scintigraphy, octreotide scintigraphy, poss. FDG-PET
Prostate cancer
(free) PSA prior (!) to palpation
Palpation, sonography
Germ cell tumor (testicular)
b-HCG, AFP
Palpation, sonography, abdomen CT
Breast cancer
CEA, CA15-3
Palpation, mammography, sonography, MRI, poss. FDG-PET
Ovarian cancer
CA125, 72-4
Clinical examination, sonography, CT, poss. FDG-PET
Cervical-/uterine cancer
Table 4.15 Important differential diagnoses of paraneoplastic brain stem encephalitides Paraneoplastic syndrome Differential diagnoses Brainstem encephalitis
• Infectious (e.g. listerias, toxoplasmosis, tropheryma whipplei, viruses, e.g. in Bickerstaff’s encephalitis), parainfectious, autoimmune brainstem encephalitis (e.g. lupus erythematodes, multiple sclerosis) • Brain tumor or metastases • Basilar meningitis, e.g. in granulomatous diseases (e.g. sarcoidosis, tuberculosis) • Central pontine myelinolysis • Miller-Fisher syndrome • Myasthenia gravis
Opsoclonus-myoclonus syndrome
• Opsoclonus: viral, toxic • Myoclonus: physiologic, toxic, medicinal, hereditary, infectious (e.g. priones), sporadic, epilepsy syndromes, encephalopathies of different etiology, degenerative diseases (e.g. spinocerebellar degenerations)
Paraneoplastic encephalomyelitis with brainstem involvement
• Infectious, parainfectious, autoimmune, metabolic encephalitis (see also brainstem encephalitis) • Brain tumor/metastases • Brain abscess
Clinical examination, pelvic-CT, poss. FDG-PET
a negative finding. The screening examinations are based on the suspected underlying tumor (see Table 4.14). In an undirected tumor search, e.g. in patients with clinical suspicion of a PNS but lacking demonstration of specific paraneoplastic Ab, screening in women should be for breast cancer and SCLC, and for testicular and prostate cancer, as well as for SCLC in men.
4.4.5 Differential Diagnosis The most important differential diagnoses in paraneoplastic (brainstem) encephalitides are summarized in Table 4.15.
4.4.6 Therapy Treatment of most patients with PNS, especially patients with involvement of the central nervous system – is difficult and should be started immediately after the diagnosis, since
an early onset of therapy is crucial for its success. The main pillar in the treatment of neurologic symptoms is sufficient tumor therapy. Against the backdrop of autoimmunopathogenesis as the presumptive cause of PNS, immunomodulatory therapies are used, although they are not equally promising for all paraneoplastic symptoms. Consideration should further be given to possible fluctuations in the natural course of PNS (Voltz et al. 1999; Rosenfeld et al. 2001), as well as to reports of isolated cases of spontaneous improvement of neurologic symptoms (Byrne et al. 1997) or tumor regression (Darnell and DeAngelis 1993). Even though the treatment of PNS in the central nervous system is especially difficult, it should nevertheless be attempted, because individual patients are known to respond favorably to therapy. The earlier the therapy is begun, the higher is the probability of symptom improvement (Keime-Guibert et al. 2000). The concern over the possibility of tumor progression under immunosuppressive therapy has thus far been unwarranted (Keime-Guibert et al. 1999), although it cannot be excluded if the respective immunosuppressive regimen is too high. The most widely used immunotherapies include: medical treatment with steroids, immunoglobulins, cyclophosphamide,
4.5 Brainstem Tumors
plasmapheresis and immunoabsorption. In some patients a combination of these options may be used. Good evidencebased data regarding therapy are lacking, so that a definite, widely recognized treatment scheme is currently not available. Recommended is initial treatment with a cycle of high-dose steroids (5 × 500 mg methylprednisolone i.v. for 5 days). On improvement or stabilization of the neurologic symptoms, this treatment can be repeated every 6–8 weeks. However, in the absence of a therapeutic result 1–2 weeks after steroid administration, a cycle with immunoglobulins i.v. (2 g/kg BW distributed over 5 days) should be given. After further observation period of 1–2 weeks without a favorable clinical result, an additional plasmapheresis or therapy with cyclophosphamide (750 mg i.v./m2 body surface area every 4 weeks) may be given in individual cases. If the therapy continues to be ineffective, i.e. symptoms cannot even be stabilized, a long-term immunotherapy is not advisable. Clinical improvement of PNS is not in all patients associated with a decrease in Ab-titers (Voltz et al. 2008). After tumor therapy alone or in combination with immunomodulatory therapy, clinical stabilization of the neurologic symptoms is observed more often in Ta(Ma2)-Ab positive patients than in those with other antibody-associated PNS, e.g. Hu-, Ri-, Yo-associated (Graus et al. 2001; Peterson et al. 1992; Sutton et al. 2002; Weizmannn and Leong 2004) or Ma-Ab-associated (in addition to Ma2- also Ma1-Ab) PNS (Voltz et al. 1999; Rosenfeld et al. 2001; Dalmau et al. 2004). A possible explanation may be that the associated tumors in pure Ta(Ma2)-Ab positive patients are generally germ cell tumors which can relatively often be successfully treated with combined surgical and adjuvant therapy compared to other tumor diseases (e.g. SCLC, ovarian cancer, breast cancer) (Kraker 2009). In addition to immunomodulatory therapeutic options, supplementary symptomatic medical treatment options are available for individual PNS, e.g. clonazepam (3 × 0.5–2 mg/day) or propranolol (3 × 40–80 mg/day) for opsoclonus, trihexyphenidyl (3 × 1–35 mg/day), benzatropine (3 × 1–3 mg/day), clonazepam (3 × 0.5–2 mg/day) or valproine acid (2 × 300–3 × 1,200 mg/day) for myoclonus, 3.4-diaminopyridine (up to 60 mg/day) or pyridostigmine (up to 600 mg/day) for Lambert-Eaton myasthenic syndrome, gabapentin (100–3,600 mg/day), pregabalin (75–600 mg/day) or amitriptyline (up to 75 mg/day) for sensory neuropathy, as well as antiepileptics and antidepressants for limbic encephalitis (Voltz et al. 2008).
4.4.7 Prognosis The neurologic symptoms of PNS are usually severe and frequently irreversible; in rare cases they may have a relapsing-remitting course. This explains the need for an
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early onset of the therapeutic attempt. The prognosis of the tumor itself often improves with the occurrence of a PNS, in particular in Hu-Ab positive SCLC patients. In these cases the PNS is commonly the life-limiting factor.
4.4.8 Summary Although brainstem syndromes with a paraneoplastic etiology are comparatively rare, they are relatively often missed. This is despite an increasing number of currently available readily identifiable Ab-reactivities, which enable the definite diagnosis. If this is established rapidly, the patient is provided with the prospect of a positive influence on the disease process.
4.5 Brainstem Tumors Thomas Hundsberger and Dorothee Wiewrodt
4.5.1 General 4.5.1.1 Epidemiology In the central nervous system (CNS) primary and secondary brainstem tumors are differentiated. Primary brainstem tumors derive from neuronal structures, the glia as well as vessels of the brain, and the choroid plexus. Secondary brain tumors are primarily extraneuronally growing space-occupying masses which displace or invade the CNS. The incidence of all primary brain tumors is 12:100,000 population; according to the WHO classification approximately one half of these tumors is malignant (Wrensch et al. 2002). The incidence of brain tumors in the region of the brainstem (2.2%) and the cerebellum (3.9%) is very low compared to supratentorial tumors (http://www.cbtrus.org). The annual incidence is therefore 0.35:100,000 population. The most common malignant space-occupying lesions of the CNS are metastases of various carcinomas (DeAngelis 2001). Out of these tumors, breast and small-cell/non-smallcell lung cancers, melanomas, as well as gastrointestinal tumors show a marked cerebral tropism. According to physical factors the distribution of metastases occurs in the proportion of blood flow. Therefore, 80% of metastases are found in the cerebral hemispheres, 15% in the cerebellum and only 5% in the brain stem (Norden et al. 2005). Brainstem symptoms in oncologic patients require particular attention. Differential diagnoses are solid metastases, leptomeningeal tumor spread or paraneoplastic brainstem symptoms.
256 Table 4.16 The most prevalent brainstem and brainstem-associated tumors • Neuroepithelial tumors – Gliomas (astrocytic, oligodendroglial) – Ependymomas • Embryonic tumors – Medulloblastomas • Glioneuronal tumors – Gangliogliomas • Tumors of the choroid plexus • Extrinsic brainstem tumors – Metastases – Meningeomas
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4.5.1.2 Etiology As with almost all tumor diseases, the occurrence of benign and malignant brain tumors rests on a multifactorial genesis. In addition to the overall rare hereditary syndromes, e.g. the Li-Fraumeni syndrome, Hippel-Lindau disease or neurofibromatosis Type I and II (NF-1, -2), initiation of tumor growth is attributed to molecular aberrations (i.e. p53 mutation) as the initial event with subsequent failure of the cellular regulatory mechanisms (e.g. apoptosis) in the so called cancer initiating cell. The production of immunosuppressive factors further inhibits immunologic tumor control. The extent to which environmental factors contribute to tumor genesis is largely unknown.
– Neurinomas/schwannomas • Tumors with unclear histology – Hemangioblastomas
A characteristic difference exists between children and adults with regard to the incidence of brainstem tumors. While 20–30% of all primary brain tumors in children manifest in the brainstem and the cerebellum (Donaldson et al. 2006), this applies to only 2% of all brain tumors in adults. The median age of onset in children is around the sixth year of life. In contrast brainstem gliomas occur only rarely in older adults. In addition to the definition of primary and secondary brainstem tumors of the CNS, intrinsic tumors of the brainstem that arise from central nervous tissue and infiltrate this structure are differentiated from extrinsic tumors originating from tissues outside the brainstem (Table 4.16). The intrinsic brainstem tumors include • Neuroepithelial gliomas and ependymomas • Medulloblastomas • Tumors of the choroid plexus (papillomas and carcinomas) • Gangliogliomas deriving from neuroglial precursor cells The extrinsic brainstem tumors comprise • • • •
Metastases Hemangioblastomas Meningiomas and Vestibular nerve schwannomas
Excepting metastases, extrinsic tumors are more accessible to surgical therapy due to their outward growth pattern. The divergent growth patterns of intrinsic and extrinsic brainstem tumors further lead to diagnostic, therapeutic and prognostic differences that are discussed in detail in the following part.
4.5.1.3 Clinical Symptoms The clinical symptoms of intrinsic and extrinsic brainstem tumors are determined by the location, size and growth rate of the tumor. Rapidly growing space-occupying masses, such as metastases, which further induce a large perifocal edema, generally lead to rapid development of neurologic symptoms and the respective diagnosis. More slowly growing tumors as, e.g. meningiomas and low-grade malignant brainstem gliomas, can reach a substantial size and expansion before becoming symptomatic. Mesencephalic tumors growing in the tegmentum, mediate central oculomotor disturbances and lesions to the oculomotor and the trochlear nerve. In the case of damage to the pyramidal tract, crossed brainstem syndromes may also be observed. Tumors in the vicinity of the mesencephalic aqueduct can result in occlusive hydrocephalus. Apart from the common occurrence of an occlusion hydrocephalus, tectal gliomas may be asymptomatic for many years. In addition to the frequent presence of aqueductal compression due to alterations in the lamina quadrigemina, tumors of the mesencephalic tectum can also lead to visual and auditory disturbances. Tumors growing in the ventral pontine brainstem cause lesions to the long pathways, which are clinically manifest as contralateral sensory disturbances and central pareses. Tumors taking their growth in the direction of the rhomboid fossa are associated with cranial nerve symptoms of the abducens nerve (horizontal double vision), the trigeminal nerve (sensory disturbances over the facial region, masticatory muscle paresis), nuclear and near nuclear paresis, as well as functional disturbances of the facial nerve (facial hemispasm), lesions to the vestibulocochlear nerve (auditory and balance disturbances) and the vagus nerve (disturbances of swallowing, hoarseness). Such clinical phenomena as facial hemispasm and facial myokymias should therefore always be an indication for cranial imaging to exclude a brainstem tumor.
4.5 Brainstem Tumors
In addition to symptoms due to damage of the long pathways, caudal cranial nerve deficits with disturbances of swallowing and speech functions may develop in the region of the medulla oblongata. Medulloblastomas, ependymomas, and cerebellar astrocytomas cause cerebellar symptoms with ataxia of posture and gait, as well as disturbances of the cerebrospinal fluid circulation. 4.5.1.4 Diagnosis agnetic Resonance Imaging and Computed M Tomography Cranial magnetic resonance imaging (cMRI) is an important prerequisite for the non-invasive differential diagnosis of a brainstem tumor, in particular because histologic material for a definitive tumor diagnosis is often unavailable in the brainstem region. In addition to the physical examination, imaging provides the essential information required for the diagnostic classification and additional therapeutic measures. cMRI enables an accurate identification of the anatomic localization and expansion of a space-occupying mass in the brainstem. Compared to cMRI, cranial computed tomography (CCT) is of significantly less diagnostic value in the brainstem region, not only due to the radiation exposure and low soft tissue contrast, but also with regard to possible artefacts caused by the dense bones in the base of the skull. An indication for the CCT examination is its wide availability in emergency situations, where a rapid assessment of mass effects, bleeding, and cerebrospinal fluid disturbances is essential. Used as a supplementary examination to MRI, CT offers very good visualization of calcifications. CT is also used in patients with a general contraindication against an MRI examination as, e.g. the presence of MR-incompatible electronic implants. Slice thicknesses from 3–5 mm are recommended for the posterior cranial fossa. With a view to radiation exposure, the indication for CCT has to be particularly strict in infants and young children, due to potential actinic damage with an influence on brain development and the increased risk for later development of malignancies. The axial slice direction in cMRI is the standard plane. For efficient scheduling of surgical neuronavigation procedures can be carried out in all spatial planes (axial, sagittal, coronary), as well as with a three dimensional data set. The T2-weighted slices are obtained as spin echo sequences prior to and after contrast agent administration. In patients with suspected brainstem tumor, a strong T2-weighted sequence can be supplemented with a proton density weighted or FLAIR sequence (Jacobs et al. 2005). With consideration of pulsation artefacts in the posterior
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c ranial fossa, a proton density weighted sequence should be given preference over the FLAIR sequence. The selected slice thickness should not be greater than 6 mm. In brainstem malignancies, particularly those associated with spinal drop metastases or meningeal spread, spinal imaging has to be added to cMRI. This applies especially to brain metastases, medulloblastomas, germ cell tumors, ependymomas, lymphomas and plexus carcinomas. New cMRI modalities as, e.g. diffusion tensor imag ing sequences can depict altered anatomic conditions in space-occupying processes by visualization of pathways coursing in transverse and longitudinal directions through the brainstem (Phillips et al. 2005). This method can provide useful information in assessing the benefits and risks of surgical intervention. Particular attention needs to be given to postoperative and follow-up imaging examinations, as their results influence therapeutic decisions. It is also important to ensure that the slice thicknesses and sequences are identical to those used in the initial examination and that the same device is used whenever possible. Substantial variations in interpretation of response rates have been reported for the follow-up evaluation of CT and MRI images of gliomas after chemotherapy, so that the results of imaging alone are not sufficient for assessing the therapeutic response or tumor recurrence (Vos et al. 2003). This is especially true in the era of antiangiogenic drugs, agents for which validated guidelines of response or progression are still in discussion (Wen et al. 2010). In addition to regular neurologic examinations, the amount of steroids required and daily life assessments (e.g. Karnofsky-Index, ECOG performance status) represent necessary follow-up parameters. For supratentorial gliomas the extent of tumor resection is ideally determined within a 48-h interval using MRI in T1- and T2-weighting prior to and after contrast agent administration (Wen et al. 2010). This time window can, with reservations, also be applied to tumors in the posterior cranial fossa. Despite the fact that the extent of resection in the anatomically precarious region of the brainstem is a priori limited, the assessment of residual tumor disease is of prognostic importance in individual tumor entities like medulloblastomas and ependymomas. A T1-weighted sequence before contrast agent infusion is required to avoid the confusion of hyperintense methemoglobin in the operative field with a pathologic contrast agent uptake.
MR Spectroscopy (1)H-MR spectroscopy is an additional diagnostic tool for grading and differentiating intracranial tumors (Lanfermann
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et al. 2004). N-acetyl aspartate represents a neuronal marker that is found to be reduced in tumors. The peak creatinine level is usually unchanged or reduced in tumors, while choline as a marker of membrane metabolism is typically increased. MR spectroscopy has been successfully used in differentiating between brainstem gliomas and nonneoplastic enlargement of the brainstem in patients with NF-1 (Broniscer et al. 1997). The results of recent studies support the value of MR spectroscopy as an adjunct to cMRI in the assessment of response to chemotherapy in brainstem gliomas (Balmaceda et al. 2006).
Positron Emission Tomography Positron emission tomography (PET) is an imaging modality that enables the non-invasive diagnosis of metabolic processes in the brain. The spatial resolution is, however, limited to a minimum of 2–6 mm. The diagnostic value of PET has been evaluated for gliomas and other tumor entities of the brain (Jacobs et al. 2005). PET with different tracers can provide important information in gliomas regarding differentiating radiation necrosis from tumor recurrence, although in individual patients only the joint use of several diagnostic procedures can provide a conclusive result. The glucose metabolism of a glioma can be demonstrated with the radioactive tracer 2-(18F-) fluor-2-deoxy-D-glucose ([18F]FDG). This tracer correlates with tumor grade, tumor cell density, biologic aggressiveness and survival (Jacobs et al. 2005). Yet, a differentiation between neoplastic and inflammatory tissue is not possible with 18F-FDG-PET. By comparison, radioactive marked methyl-(11C-)L-methionine ([11C] MET) is significantly better suited to determine extension of a glioma, since the relatively low uptake of this substance in the normal brain – in contrast to the use of glucose – also enables a more accurate differentiation from infiltrating tumor tissue. This tracer also permits the differentiation of inflammatory processes from malignomas. Against the high differential diagnostic value of cMRI and PET used alone or in combination in supratentorial tumors these techniques are limited in brainstem tumors (Massager et al. 2000).
Cerebrospinal Fluid Examination The indication for a diagnostic lumbar puncture in spaceoccupying processes in the region of the brainstem and the cerebellum has to be carefully weighted and cannot be considered without prior imaging, due to the risk of herniation into the foramen magnum. Recall that the diagnostic sensitivity increases with the number of lumbar punctures (minimum of two) and the volume of the cerebrospinal fluid (minimum
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10 mL) sampled for the assessment of neoplastic meningitis (Glantz et al. 1998). In addition to the usual parameters such as cell counts, total protein, glucose and lactose, a cytospin preparation is advised to detect malignant cells. Sufficient additional cerebrospinal fluid has to be available in the presence of a low total cell count to enable a representative assessment of an adequate number of cells. At a typical constellation of the respective parameters, an elevated lactate level serves as an indicator of the presence of malignant cells and represents a useful follow-up parameter. A reactive pleocytosis developing under therapy due to the toxic effect of cytostatics may lead to misinterpretations. With the exception of b-HCG and alpha fetoprotein no other diagnostic biochemical markers have thus far been established.
Differential Diagnosis Differential diagnostic considerations are of paramount importance in space-occupying lesions of the brainstem, since biopsy confirmation, in particular in cases of diffuse intrinsic processes, is only rarely possible as a result of the close proximity of important anatomic structures in a very small area (Guillamo et al. 2001). In view of the frequently lacking therapeutic options, the risk of a persistent neurologic deficit resulting from surgical intervention has to be very carefully weighed against the benefit derived from the information gained. But on account of the diversity of the underlying pathology and the low mortality and morbidity associated with a stereotactic brainstem biopsy, a number of authors advocate a histologic confirmation under all circumstances (Leach et al. 2008; Samadani and Judy 2003). Demyelinating and inflammatory diseases of the brainstem such as multiple sclerosis, vasculitis, neurosarcoidosis (Gizzi et al. 1993) and focal infectious or non-infectious brainstem encephalitis, as well as vascular malformations and central pontine myelinolysis rarely mimic a brainstem tumor. Hypertensive brainstem encephalopathy can also be confused with a diffuse brainstem glioma (Jurcic et al. 2004). Brainstem tumors that manifest at an atypical patient age and exhibit particular radiologic characteristics have to be included into the differential diagnosis of rare entities as, e.g. teratomas, rhabdoid tumors, lymphomas (Campbell et al. 2005) and germinomas (Ben Amor et al. 2004). Gangliogliomas and hemangioblastomas of the brainstem are additionally rare tumor entities in this region of the brain (Lagares et al. 2001).
Therapy Three major therapeutic modalities are available to treat brainstem tumors: neurosurgical intervention, irradiation and chemotherapy. These can be applied individually, in combination, or
4.5 Brainstem Tumors
sequentially, depending on the tumor entity. The importance of surgical resection is different for tumors with well-defined borders, such as acoustic neurinomas, meningiomas, cerebellar metastases, hemangioblastomas or pilocytic astrocytomas, than for diffuse infiltrating pontine brainstem gliomas. In addition to removal of the space-occupying mass, surgical intervention enables histologic confirmation and thereby tumor-specific therapy. Surgical resection of a cerebellar metastasis can also eliminate a cerebrospinal fluid disturbance resulting from fourth ventricular compression and therefore serves as an excellent palliative measure. In inoperable tumors such as diffuse brainstem gliomas, the establishment of a shunt system or a ventriculocisternostomy are therapeutic measures for the treatment of occlusive hydrocephalus. This condition may be found at time of the diagnosis or in the further course, especially in cases of lesions with mesencephalic localizations. Surgical measures, in particular in patients with diffuse processes, have to be limited to a biopsy or the treatment of complications. In contrast, postoperative radiation therapy and chemotherapy has led to significant improvement in the therapeutic outcome of various tumor entities, specifically of pediatric tumors.
4.5.2 Intrinsic Brainstem Tumors 4.5.2.1 Brainstem Gliomas Definition and Epidemiology The name brainstem glioma is an imprecise description of neuroepithelial tumors infiltrating the brainstem tissue and causing alterations in the brainstem structures. The term brainstem glioma generally does not correspond to the clinical situation, with a view to significant differences in the histologic classification, biologic behaviour and the prognosis on the one hand, and the localization in the brainstem, radiologic characteristics and the therapeutic procedure on the other hand. A more suitable sub-classification divides the brainstem gliomas into three groups (Fisher et al. 2000): • According to localization: mesencephalic, tectal and pontine glioma, focal medullary or cervicomedullary glioma • According to radiographic appearance: focal versus diffuse, intrinsic, cystic, dorsal exophytic, pencil glioma • According to histologic type: WHO Grade I to IV With an incidence rate of 80%, diffuse gliomas are the most common intrinsic brainstem tumors in children (Donaldson et al. 2006). Histologically they correspond to high-grade anaplastic gliomas (WHO Grade III) or glioblastomas (WHO
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Fig. 4.38 Infiltrative brainstem glioma. Images obtained in a 6-yearold boy with an extensive space-occupying lesion in the brainstem region. Inhomogeneous depiction in all sequences without contrast agent uptake. The finding is so typical that a biopsy was dispensed with and radiotherapy was commenced. T2-weighted sagittal MRI (a), axial FLAIR sequence (b)
Grade IV). More rarely observed are differentiated astrocytomas WHO Grade II. The preferential location of diffuse brainstem gliomas is the pontine tegmentum (Fig. 4.38), with frequent involvement of the basilar artery into the disease process (Fisher et al. 2000). Due to the malignant histologic phenotype, diffuse gliomas disseminate along the neuroaxis in the diencephalon, the thalamus, or into the cervical part of the medulla oblongata. In contrast to the pontine gliomas, diffuse neuroepithelial tumors of the mesencephalon are more commonly of lowgrade malignancy. Due to the anatomic conditions in the mesencephalic tegmentum and the tectum, the pressure exerted by the expanding space-occupying lesion frequently compresses the mesencephalic aqueduct, causing an occlusive hydrocephalus. In contrast to childhood brainstem tumors, diffuse pontine gliomas in adults correspond in 80% of cases to lowgrade gliomas of WHO Grade II (Guillamo et al. 2001). To enable differentiation from the childhood entities, the term “diffuse intrinsic low-grade brainstem gliomas” has been suggested for this subgroup, despite the fact that high-grade malignant gliomas may also be detected (Fig. 4.39). In view of the more favourable long-term prognosis, diffuse brainstem gliomas in adults therefore vary significantly in their biologic phenotype and growth pattern from childhood brainstem gliomas, although conclusive findings of histologic or molecular genetic investigations on this topic are currently lacking. Focal, dorsal exophytic and cervicomedullary brainstem gliomas are chiefly low-grade pilocytic WHO Grade I astrocytomas (Fig. 4.40). More rarely found are gangliogliomas from the group of glioneural tumors or WHO Grade II astrocytomas (Donaldson et al. 2006). Oligo dendrogliomas and primary cerebral lymphomas of the brainstem are rarely seen.
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4 Diseases Table 4.17 Neurologic symptoms and their incidence in adult patients with brainstem gliomas (according to Guillamo et al. 2001) Symptom Incidence (in %)
Fig. 4.39 Mesencephalic glioblastoma in an adult. Images obtained in a 52-year-old male with hemihypesthesia and central facial paresis left. Rapidly progressing tumor growth and lethal outcome after 5 months. Partly homogeneous contrast-enhancing, partly cystic lesion in the mesencephalic tegmentum. T1-weighted MRI after enhancement with paramagnetic contrast media: (a) coronary; (b) axial
Gait disturbances
61
Headaches
44
Hemiparesis
42
Double vision
40
Dysphagia
15
growth. Analogous to supratentorial tumors, pilocytic astrocytomas (WHO Grade I), diffuse astrocytomas (WHO Grade II), as well as anaplastic astrocytomas and glioblastomas are also found in the brainstem region. The molecular analysis of only a small number of brainstem gliomas showed the known glioma-associated genetic alterations, including p53 aberrations and epidermal growth factor receptor (EGFR) overexpression (Louis et al. 1993; Gilbertson et al. 2003). However, the more common occurrence of brainstem gliomas in children and adolescents than in adults serves as an indication of a different molecular pathology and a particular predisposition to genesis of gliomas at a younger age. 4.5.2.3 Clinical Findings
Fig. 4.40 Pilocytic astrocytoma. Images obtained in a 26-month-old boy with torticollis and elevated right shoulder. Extended tumor with contrast-enhanced borders in the region of the inferior cerebellar vermis, pons, medulla oblongata and the upper cervical spinal cord. T1-weighted MRI with contrast agent; (a) sagittal; (b) axial
A special group comprises patients with neurofibromatosis type 1 (NF-1) with an inherited tendency toward the development of (bilateral) optic gliomas, as well as pilocytic and diffuse astrocytomas, in addition to dermal and plexiform neurofibromas of the skin. In contrast to NF-2 patients, whose bilateral acoustic neurinomas are pathognomonic, NF-1 patients have a higher probability for the development of brainstem gliomas (Laigle-Donadey et al.2008). Histologic studies have shown that fibrillary (WHO Grade II) or anaplastic astrocytomas (WHO Grade III) have a predilection for medullary growth. With the knowledge of a markedly better prognosis NF-1 associated brainstem tumors appear to be a distinct clinical entity. 4.5.2.2 Etiopathogenesis There are, on principle, no indications of a different molecular etiology in tumors with supratentorial or infratentorial
Brainstem gliomas become clinically manifest consistent with their localization (mesencephalic, pontine, medullary see Sect. 4.5.1). The most common clinical symptoms are listed in Table 4.17. An analysis of the data obtained in 48 adult patients with brainstem gliomas showed a median Karnofsky Index of 80%. The average time from the onset of initial symptoms to the diagnosis was 4 months. Five of the 48 patients had sudden onset of symptoms accompanied by intratumoral hemorrhage. The number of patients with slow (>3 months) or rapid (<3 months) tumor progression was evenly distributed (Guillamo et al. 2001). In addition to other clinical symptoms, cranial nerve involvement was present in 87% of patients.
4.5.2.4 Diagnosis cMRI enables differentiation between focal and diffuse brainstem gliomas. Focal brainstem gliomas typically have well-defined borders, frequently undergo contrast enhancement, and occupy less than 50% of the axial diameter of the midbrain or the medulla oblongata. Conversely, diffuse gliomas with a frequent pontine location are poorly defined and as a rule occupy more than 50% of the axial brainstem diameter (Fig. 4.38). In diffuse brainstem gliomas, the basilar artery is often involved in the process. The extent of
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brainstem gliomas is particularly well delineated on T2-weighted MRI sequences, and the mass usually appears with a hyperintense signal, in contrast to T1-weighted sequences where it is often visualized as a hypointense lesion. After paramagnetic contrast agent infusion, focal brainstem gliomas usually undergo contrast enhancement. They are characterized by partially exophytic and cystic growth. Hemorrhages are rare. Compared to normal brain tissue, brainstem gliomas are viewed as hypodense to isodense on CCT without contrast medium. A pathologic contrast-enhancement as an indicator of a blood-brain barrier disturbance is frequently detected in high-grade malignant gliomas (WHO Grade III-IV). However, in 25% of patients contrast enhancement is also found in lower-grade gliomas, so that this imaging characteristic is not suitable for definitive determination of the tumor grading. Cerebellar astrocytomas typically occur in children and young adults with a peak incidence from 8–15 years. 50% arise in the cerebellar vermis (Fig. 4.40). They correspond histologically to pilocytic astrocytomas WHO Grade I. A portion of these tumors often has several centimetre large sized cysts, while the smaller contrast-enhanced tumor nodules may only be a few millimeters in size. Calcifications and hemorrhages may be found.
4.5.2.5 Differential Diagnosis A differential diagnosis has to be made between benign and malignant lesions of the brainstem. Multiple sclerosis which frequently occurs in young adults may manifest alone or additionally to spinal and supratentorial foci in the brainstem. It can be differentiated by means of imaging, electrophysiologic (VEP) and laboratory tests and – when possible – cerebrospinal fluid analysis. Infectious, non-infectious and paraneoplastic brainstem encephalitides should also be considered in the differential diagnosis, especially in patients with prior extracerebral tumor disease, or in immunosuppressed individuals. Patient age, dynamics of the disease course (acute vs. subacute/chronic), and accompanying symptoms such as fever can serve as significant indicators.
4.5.2.6 Therapy Brainstem Gliomas in Adults Microsurgical resection of adult brainstem gliomas is associated with substantial risk of postoperative irreversible damage (Mursch et al. 2005). With a view to the limited therapeutic possibilities, it is therefore open to question if the information gained on histology justifies diminishment in the patient’s quality of life.
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Due to the potential risk of a surgical intervention, today many treating physicians are willing to commence tumorspecific therapy in the absence of a biopsy, provided the clinical, imaging and laboratory findings are indicative of, e.g. a diffuse infiltrating brainstem glioma. In cases of doubt as, e.g. in contrast-enhancing processes in adults where the differential diagnosis of an inflammatory disease cannot always be excluded, the option of a biopsy has to be carefully weighed after exhaustion of all possible non-invasive measures (cerebrospinal fluid analysis, MR-spectroscopy, PET). On the other hand, when performed at specialized centers, the risk of morbidity and mortality can, at least in adult patients, be as low as the risk involved in the biopsy of a supratentorial lesion (Samadani and Judy 2003). Despite possible adverse side effects and an only moderate probability of response, radiation therapy represents the treatment of first choice. A partial remission was observed in 20% of patients after radiotherapy, while a temporary stabilization of the disease course was observed in 60% (Guillamo et al. 2001). The recommended treatment modality is fractionated conformal stereotactic radiotherapy with a total dose of 54 Gy (Schulz-Ertner et al. 2000). As in supratentorial glioma, local recurrence is the cause of death in the majority of patients. The most important prognostic factors are the clinical and radiologic response 6 weeks after radiotherapy. Published findings on the validity of chemotherapy for adult brainstem glioma are sparse and non-uniform due to the use of widely varying drug regimens (Guillamo et al. 2001). In view of the inadequacy of available data and despite a lack of alternatives, the use of chemotherapy appears justified only in selected patients with tumor recurrence or progression. The question as to whether combined radiochemotherapy with temozolomide (Stupp et al. 2005) holds promise of improved survival for patients with malignant brainstem gliomas as well will have to remain open, since the frequently lacking histologic confirmation and the low incidence do not give rise to the expectation of data obtained by future studies. Analogous to the superior results of combined radiochemotherapy in supratentorial glioblastomas, the use of the described therapeutic escalation in patients with good prognoses has to be carefully considered. A study of children with brainstem gliomas did report an increase in toxicity as a result of adjuvant cisplatin as a radiosensitizer in hyperfractionated radiotherapy at a dose of 70 Gy (Freeman et al. 2000).
Pediatric Brainstem Gliomas The therapy of pediatric brainstem gliomas essentially depends on whether the respective tumor is a diffuse or a non-diffuse
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entity. Diffuse brainstem gliomas have a very poor prognosis with a mean survival time of less than 1 year (Donaldson et al. 2006). The therapy of choice in these patients consists of external focal radiotherapy at a total dose of 54–60 Gy administered over 6 weeks. Radiotherapy can accomplish temporary clinical improvement and prolonged survival. An increase in the radiation dosage or hyperfractionated radiotherapy were not found to be of advantage over the standard dosage, but caused severe side effects as a result of vascular complications and hormonal and auditory disturbances (Packer et al. 1994). In view of the high diagnostic value of imaging modalities, neither a biopsy nor surgical dissection plays an important role in the therapy of the typical diffuse brainstem gliomas (Hargrave et al.2006), in particular since the histologic results are without any influence on the therapy. Furthermore, currently there is no evidence of a beneficial effect of additional chemotherapy on survival. Non-diffuse brainstem gliomas have a significantly more favourable prognosis with a median survival of more than 5 years. The therapeutic approach depends in particular on the location of the tumor. Tectal-mesencephalic tumors which become symptomatic with signs of an occlusive hydrocephalus should be treated with shunt placement or ventriculocisternostomy only, as these gliomas remain stable without tumor progression over years and even decades. Close clinical and radiologic follow-up examinations are thus sufficient in these patients. Focal radiotherapy should be considered only for patients with tumor progression. Focal and cystic non-diffuse brainstem gliomas, in particular at the cerebellomedullary junction, are usually amenable to partial resection with the use of modern neurosurgical techniques (Edwards et al. 1994). Early postoperative radiotherapy can also frequently be dispensed with in cases of residual tumor (Pierre-Kahn et al. 1993). The recommendation for patients of this group with stable symptoms after partial resection and non-progressing residual tumor consists of an observation phase with neurologic and neuroradiologic follow-up at regular intervals. Over the first 2 years, follow-up examinations should be scheduled at 3- to 6-month interval, and at 6- to 12-month intervals thereafter. Insofar as clinically justifiable, the time to onset of radiotherapy should be extended as far as possible, to avoid additional endocrinologic and neurologic damage. If radiotherapy is required, small radiation volumes, low daily doses, and multiple daily fraction doses should be administered (Kortmann et al. 2003a). To ensure the success of therapy, total tumor doses of more than 45 Gy have to be used. A total radiation dosage of 54 Gy administered in daily fractions of 1.6–1.8 Gy is generally recommended (Kortmann et al. 2003b). Stereotactic radiation therapy is feasible for the treatment of selected tumors. The object of a number of investigations currently underway is the use of systemic chemotherapy with the aim of extending the time period to the onset of radiotherapy or to
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completely dispense with it. In more than half of the children included in the studies, a 3-year postponement of tumor progression was observed for the majority of the investigated chemotherapy combinations. A number of studies have investigated the use of carboplatin at different dosages and combinations. Further data have been reported on the use of cyclophosphamide, actinomycin D, ifosamide, etoposide and topotecan. The HIT-LGG 1996 Protocol of the “Working Group Brain Tumors” of the German Society of Pediatric Hematology and Oncology reported on the use of carboplatin and vincristine over a period of 53 weeks (Gnekow et al. 2000). Ninety-four percent of patients achieved a clinical and radiologic response, while only 6 out of 84 children had to undergo radiotherapy for tumor progression. The progression-free interval after 36 months ranged at 72%. In the currently underway pan-European follow-up study SIOP-LGG 2004, the efficacy of intensified induction chemotherapy is also investigated in children older than 5 years.
Prognosis Favorable prognostic factors in adult brainstem gliomas include an age of onset below 40 years, symptom duration of more than 3 months, a Karnofsky Index above 70%, absent contrast enhancement or tumor necrosis on MRI, and the histology of a low-grade glioma (Guillamo et al. 2001). Patients with diffuse, intrinsic low-grade brainstem gliomas have a median survival time of 7.3 years and a good response to radiotherapy, while malignant brainstem gliomas- comparable to supratentorial glioblastomas – were characterized by a median survival time of only 11 months. Adults with tectal gliomas of the mesencephalon had a good survival prognosis of more than 5 years after hydrocephalus therapy, although the reported case number was very small. Considered together, diffuse adult brainstem gliomas have a substantially higher 5-year survival rate than pediatric brainstem gliomas which have a survival time of 10–12 months after maximum therapy (Mandell et al. 1999). Leptomeningeal dissemination of the glioma occurs in more than 10% of patients, in particularly in patients with primary tumors located in close proximity to the ventricle (Guillamo et al. 2001).
4.5.2.7 Ependymomas Epidemiology and Classification Ependymomas arise from neoplastic ependymal cells and grow along the cerebrospinal pathways. The primary
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Their anatomic relationship with the cerebrospinal fluid compartment is a frequent cause of occlusive hydrocephalus. Disturbance of consciousness, apathy, vigilance disturbance, and early morning vomiting are indicative of a significant increase in intracranial pressure due to blockage of the cerebrospinal fluid circulation.
Diagnostics and Differential Diagnosis Fig. 4.41 Ependymoma. Images obtained in a 27-month-old boy with progressive gait ataxia for 6 weeks, but without clinical signs of increased intracranial pressure. Mildly contrast-enhancing ependymoma arising from the cerebellar vermis and filling the fourth ventricle. Massive occlusive hydrocephalus. T1-weighted MRI with contrast enhancement: (a) axial, (b) coronary
manifestation is in the fourth ventricle or the foramen of Luschkae, from where the tumor mass may extend to the cerebellopontine angle and the medulla oblongata (Fig. 4.41). Spinal manifestations are frequently observed. The special case of the ependymoma of the filum terminale (WHO Grade I) corresponds histopathologically to the distinct subtype of the myxopapillary ependymoma. Ependymomas manifest preferentially in the first 2 decades of life, and, in up to two thirds of patients they are characterized by primarily infratentorial growth. The annual incidence in children is 0.2:100,000. WHO Grade II tumors are differentiated histologically from anaplastic WHO Grade III ependymomas. Variants such as the subependymoma or myxopapillary ependymoma are classified as WHO Grade I. Two to 9% of all neuroepithelial tumors are ependymomas (Louis et al. 2007).
Etiopathogenesis The molecular pathology of ependymomas is varied. The heterogeneity of the disease and small sample sizes makes the identification of pivotal genetic aberrations difficult. While losses of genetic information on chromosome 22q, 6p, 9, 10, 13 and 17 are predominant in these tumors, gains of 1q have also been reported (Hirose et al. 2001). Of interest are the differences between spinal ependymomas, which frequently show gains on chromosome 7.
Clinical Findings Depending on their location, infratentorial ependymomas manifest with different brainstem and cerebellar symptoms.
Sixty percent of ependymomas are infratentorial. They usually arise from the floor of the fourth ventricle and extend in a craniocaudal direction through the foramina of Magendie and Luschkae before continuing into the basal cisterns. The development of cysts, as well as an extension into the cisterna magna and the cerebellopontine angle cisterns suggests the presence of an ependymoma. These are commonly hyperintense in T2-weighted MRI sequences. Calcifications may be present. Necroses are indicative of an anaplastic component, while differentiation from a malignant glioma is not possible with the use of imaging alone. Contrast agent administration results in a pronounced enhancement of the solid tumor components.
Therapy The therapy of choice in both pediatric and adult patients is a complete macroscopic tumor resection with concurrent confirmation of the diagnosis. The extent of the resection is of prognostic significance, but may be accomplished in only approximately 70% of patients due to the often infiltrative growth pattern, and the frequent location of the tumor in the floor of the fourth ventricle (Veelen-Vincent et al. 2002). Owing to the high local recurrence rate, postoperative radiotherapy with a minimum dose of 50 Gy is requisite in incompletely resected and malignant WHO Grade III ependymomas. Craniospinal irradiation should be performed in patients with preoperative detection of tumor cells in the cerebrospinal fluid and spinal metastases. The recommendation is more difficult with regard to prophylactic cerebrospinal radiation for completely resected ependymomas of WHO Grade II. The available data are inconsistent and the recommended procedures vary widely. There are, however, reports of local recurrences after completely resected infratentorial WHO Grade II ependymomas (Pollack et al. 1995). The German Society of Pediatric Hematology and Oncology guidelines therefore recommend local postoperative radiotherapy for all non-metastatic ependymomas independent of the histologic grade (Timmermann et al. 2000).
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Prognosis
Etiopathogenesis
Children older than 3 years treated with postoperative irradiation and chemotherapy have a median survival rate of 75% after 3 years (Timmermann et al. 2000). The progression-free survival ranges at about 60%. Children with metastases died within 2 years. The extent of the resection is of crucial importance for survival. Survival after complete resection ranged at 91% after 3 years, and at only 56% without complete resection. Involvement of the brainstem or cranial nerves as a result of infiltrative growth has an unfavourable prognosis, since these patients are a priori excluded from complete resection.
Medulloblastomas originate from primitive neuroectodermal precursor cells and may contain glial as well as neuronal elements. On the molecular level they vary significantly from gliomas. Glioma-associated molecular alterations are not found in medulloblastomas. Isochromosome 17q represents the most common chromosomal aberration in 30–40% of tumors. The loss of chromosomal arm 17p is compensated by duplication of the long arm 17q. The assumed loss of a tumor suppressor gene as a result of the described chromosomal aberration has not yet been identified. Recent studies report on alteration of the hedgehog signalling pathway by genetic alterations of the long arm of chromosome 9.
4.5.2.8 Medulloblastomas Epidemiology The WHO defines medulloblastomas as a malignant invasive embryonal tumor of the cerebellum (Louis et al. 2007). Seventy percent of all patients with medulloblastomas are younger than 15 years of age, with the disease peak occurring from about the 5th–9th year of life. With a ratio of 1.5:1, boys are more frequently affected than girls. Medulloblastoma is the second most common CNS tumor and the most common malignant pediatric tumor after pilocytic astrocytomas. Medulloblastomas are always highly malignant and are neuropathologically classified as WHO Grade IV. Several subtypes, the desmoplastic, nodular, or the large cell variant can be delineated. Medulloblastomas represent only 1% of all adult brain tumors (Fig. 4.42). The occurrence of medulloblastomas in patients more than 50 years of age is a rarity.
Fig. 4.42 Adult medulloblastoma. Images obtained in a 30-year-old woman with progressive vertigo. Inhomogeneous contrast-enhancing de novo medulloblastoma in the cerebellar region with perifocal edema and fourth ventricle compression. T1-weighted MRI after paramagnetic contrast enhancement: (a) axial; (b) coronary
Clinical Findings As a result of their growth in the cerebellum, medulloblastomas manifest with a cerebellar syndrome with and without concomitant brainstem and cranial nerve symptoms. Oculomotor disturbances are frequently observed due to the complex circuitry of the connecting fibres like the medial longitudinal fasciculus and others in the brainstem and the important role of the cerebellum in ocular movements.
Diagnostics and Differential Diagnosis Medulloblastomas are most often localized in the cerebellum and the fourth ventricle. They are characterized by local infiltrative growth and spread along the cerebrospinal fluid pathways. An accompanying leptomeningeal spread and solid CNS metastases are frequently found at the time of initial diagnosis. Preoperative lumbar puncture whenever feasible should be performed to detect seeding via the cerebrospinal fluid pathways. Diagnostic imaging prior to lumbar puncture is essential to exclude the presence of a space-occupying mass in the posterior cranial fossa. A spinal and cranial MR diagnosis with and without contrast agent administration are the diagnostic procedures of choice. Pronounced, but inhomogeneous contrast enhancement is often observed (Fig. 4.42). Desmoplastic and nodular subtypes of medulloblastomas, which are typically found in adolescents and young adults, chiefly involve the cerebellar hemispheres. They have a welldefined, hyperintense appearance, so that differentiation from a posterior fossa meningioma is occasionally difficult.
Therapy In view of their high malignancy grade, medulloblastomas require an aggressive therapeutic approach. Basic therapy
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consists of primary resection aimed at removal of the lifethreatening local tumor mass, the cerebrospinal fluid blockage, and achievement of the most complete macroscopic tumor excision possible. Primary cerebrospinal fluid shunt placement should be avoided due to the possibility of extra cerebral seeding of metastases. Infiltrative tumor growth and the high rate of cerebrospinal fluid metastases hinder the complete resection of a medulloblastoma; the surgical procedure must therefore be followed by craniospinal irradiation. The recommended dosage for radiotherapy of the spine ranges from 24–36 Gy, followed by local irradiation of the posterior cranial fossa with up to 54 Gy (Kortmann et al. 1999). CNS metastases are treated locally with a dose from 45–50 Gy. Cure rates from 40–50% have been achieved with combined surgery and radiation therapy. Medulloblastomas are sensitive to chemotherapy. The effectiveness of nitrosoureas such as CCNU in combination with vincristine was significantly enhanced with the adjuvant administration of cisplatin (Packer et al. 1999). The described combination therapy yielded a progression-free survival of 80% at 5 years. Postoperative long-term chemotherapy successfully deferred radiotherapy in children younger than 3 years of age. Moreover, adjuvant intrathecal administration of methotrexate can make subsequent irradiation superfluous (Rutkowski et al. 2005). Surgery and chemotherapy can be repeated in patients with recurrence. Despite previous radiotherapy, special radiation focus techniques can offer additional therapeutic options in individual patients.
Prognosis The 10-year survival rates without adjuvant chemotherapy range at 40%. Complete resection and a non-disseminated disease comprise an average risk while all other constellations lead to a high risk disease. Unfavourable prognostic factors include young age, primary metastases at initial diagnoses and postoperative residual tumor (Zeltzer et al. 1999). Recurrences may still occur after 6–10 years, generally in the region of primary tumor manifestation. Postoperative radiation and chemotherapy has achieved median 5-year survival rates of approximately 85% (Zeltzer et al. 1999).
4.5.2.9 Gangliogliomas
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over several years (Silver et al. 1991). Malignization of the glial component only rarely leads to the development of an anaplastic ganglioglioma (WHO Grade III). Gangliogliomas are frequently associated with hamartomas and grow chiefly supratentorially in the temporal lobe. Infratentorially they grow preferentially in the brainstem, but rarely occur in the spinal cord.
Etiopathogenesis Findings of systematic studies on the molecular pathology and etiopathogenesis of gangliogliomas are currently rare. Gain of chromosome 7 is the most frequent alteration (Louis et al. 2007). Clinical Findings Clinical symptoms of infratentorial gangliogliomas depend on their location in the brainstem (see Sect. 4.5.1, p. 67). In addition to focal brainstem lesions, signs of long pathways involvement are frequently observed. As in all brainstem tumors, the clinical history of gangliogliomas is generally short. Diagnosis cMRI is the diagnostic imaging modality of choice whenever feasible. Gangliogliomas are characterized by an extremely heterogeneous appearance, both on sequences with and without contrast-enhancement. Although cystic components can be adequately differentiated from solid elements, these imaging criteria are only rarely sufficient for a reliable differential diagnosis. Therapy Surgical dissection constitutes the therapy of choice. Regular follow-up examinations are required in incompletely resected gangliogliomas of the brainstem. Radiotherapy is reserved for primary or secondary malignant gangliogliomas (WHO Grade III), although available data on the efficacy are sparse. The question as to the validity of adjuvant chemotherapy remains unanswered (Silver et al. 1991).
Epidemiology
4.5.2.10 Tumors of the Choroid Plexus
Gangliogliomas are mixed tumors consisting of a welldifferentiated ganglional component and a generally astrocytic glial element. They correspond predominantly to WHO Grade I and II and are characterized by a benign course
Epidemiology Pediatric tumors of the choroid plexus are rare, accounting for 2–4% of all CNS tumors in children. Seventy percent of these
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tumors are found in children under the age of 2 years. Differentiation is made between benign plexus papillomas (WHO Grade I) and plexus carcinomas (WHO Grade III). These tumors occur predominantly in the lateral ventricles and less often in the third ventricle. In adults they are more commonly found in the fourth ventricle. Plexus carcinomas usually infiltrate the cerebellum. Etiopathogenesis Findings of systematic studies on the molecular pathology and etiopathogenesis of tumors of the choroid plexus are still lacking.
Clinic Increased cerebrospinal fluid production is the principal sign of choroid plexus tumors and leads to an almost obligatory development of hydrocephalus.
Diagnosis On imaging, choroid plexus tumors are visualized as well vascularised, mostly intraventricular space-occupying masses. Cysts and calcifications may be present. The process may partly project through the foramina of Luschka into the cerebellopontine angles. A perifocal edema is only moderate in benign plexus papillomas. Enlargement of the lateral ventricles is an indication of the presence of hydrocephalus.
Differential Diagnosis Malignant plexus carcinomas can be differentiated from benign plexus papillomas based on a strongly pronounced edema and contrast enhancement in the periventricular cerebellar medulla. Further to the detection of choroid plexus tumors, good vascularization of this region gives rise to the finding of bronchial carcinoma metastases and hypernephromas, which cannot be differentiated with the use of imaging techniques. In rare cases a meningioma, a so-called ventricular meningioma, may be found in the choroid plexus. This occurs typically, but not exclusively, in young men. Of importance in the differential diagnosis are the clinical indications of an existing tumor disease (bronchial or renal cell carcinoma) and the manifestation of additional space-occupying masses in the CNS (multiple brain metastases) to enable an image classification of the disease.
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Therapy and Prognosis The therapy of choice – for plexus papillomas as well as for the plexus carcinomas – is the surgical removal of the tumor. The extent of the resection is of crucial prognostic significance (Wolff et al. 2002). The majority of children with plexus carcinomas die because of an incomplete resection resulting in early disease progression. The 10-year survival of patients with incomplete plexus carcinoma resection is 35%, and ranges at 77% in those with completely removed plexus carcinomas. The validity of radiation therapy has been demonstrated in adults but systematic investigations are, however, lacking (Wolff et al. 2002). Due to insufficient data it is equally unclear whether children younger than 3 years of age will benefit from irradiation or chemotherapy. A current study showed a beneficial effect in this age group for the postoperative use of carboplatin, in particular in patients with plexus carcinomas (Fouladi et al. 2009).
4.5.3 Extrinsic Brainstem Tumors 4.5.3.1 Metastases Epidemiology Brain metastases from cancers are increasingly and early diagnosed with the use of modern diagnostic imaging techniques (MRI). While improved oncologic therapies lead to prolonged survival times, the intact blood brain barrier hinders most chemotherapeutics to reach the brain parenchyma enabling already metastasized but dormant tumor cells to survive in this privileged niche of the body. These cells are the cause for isolated and/or late CNS metastases in the course of the disease. Autopsy studies showed brain metastases in up to 30% of all tumor patients, with the clinically non-apparent metastases significantly outbalancing the symptomatic ones. Brain metastases are often a sign of advanced tumor disease, although they appear in up to 10–20% of cancer patients as the initial manifestation of a malignant disease. In addition to small-cell/non-small-cell lung cancer, breast cancer, and malignant melanoma, gastrointestinal and renal cell carcinomas often metastasize into the CNS (Fig. 4.43). Contradicting former results, late studies do not show a disproportionate seeding of metastases from pelvic and gastrointestinal tumors in the posterior cranial fossa (van der Sande et al. 2009). Metastases from breast, colon and renal cancer are often single, whereas melanoma and lung cancers appear more often with multiple brain metastases (Norden et al. 2005).
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hydrocephalus, associated with symptoms of nausea, vomiting, and disturbances of consciousness.
Differential Diagnosis
Fig. 4.43 Cerebellar metastasis. Images obtained in a 65-year-old patient with a gastric carcinoma. Clinical symptoms included hemiataxia left, nausea, and vertigo. T1-weighted axial MRI (a) prior to and (b) after paramagnetic contrast enhancement
Etiopathogenesis The mechanisms involved in the pathogenesis of brainstem metastases are thus far only incompletely understood. The so-called cascade theory hypothesizes that, depending on the localization of primary tumor, the upstream or downstream ‘filter organ’ is particularly often invaded by tumor cells carried in the bloodstream. This hypothesis serves to explain why lung carcinomas frequently spread requires the brain. Metastatic spread premises the detachment of prerequisite tumor cells (metastasis initiating stem cells) from the primary tumor and their invasion of the bloodstream. The tumor cell emboli then pass through the capillaries and invade the downstream organ. Since 20% of the cardiac output flows through the brain, hematogenous metastatic spread may be assumed for the majority of brain metastases. The predilection in major vascular junction zones and the gray/white matter junction further supports the hypothesis of vascular tumor emboli, as these regions typically harbour narrow capillary diameters (Hwang et al. 1996). The molecular and immunologic causes of the specific brain tropism of different carcinomas still remain unknown. In contrast, local growing malignancies like nasopharyngeal carcinomas only rarely involve the CNS and do so as a result of continuous growth i.e. from the bony skull.
Clinical Findings Metastases with infratentorial growth constitute a life-threatening condition that often calls for immediate action. Due to rapid growth and the generally pronounced perifocal edema, acute brainstem and cerebellar symptoms in tumor patients are highly suspicious of brain metastases in the posterior cranial fossa. Cerebellar symptoms with ataxia, intention tremor and gait disturbances are commonly found. The spaceoccupying effect carries the risk for an acute occlusive
Due to their high incidence, acute brainstem symptoms are in the first instance suspicious of ischemia and much less frequent hemorrhages in the vertebrobasilar circulation. Tumor patients are often older and often have concomitant vascular risk factors (atherosclerosis, diabetes mellitus, lipometabolism disturbances, nicotine abuse [!]), so that vascular brainstem symptoms have to be considered in the differential diagnosis. Fluctuating symptoms are particularly more common in basilar artery thromboses. Paraneoplastic coagulation disturbances are only rarely causative factors of ischemias in the vertebrobasilar circulation. However, paraneoplastic syndromes such as rhombencephalitis, limbic encephalitis, and paraneoplastic cerebellar degeneration in addition to other entities have to be included, especially in the differential diagnosis of small cell lung cancer. In some instances antinuclear neuronal antibodies (ANNA) may be of particular use in making this diagnosis. Leptomeningeal metastasis represents an important differential diagnosis between multiple cranial nerve deficits, cerebrospinal fluid disturbances, as well as headache and solid brainstem metastases. Since tumor patients with or without chemotherapy are immunosuppressed, an infectious genesis should always be excluded. This applies in particular to listeria meningitis, which often manifests with the clinical picture of rhombencephalitis and brain abscesses of different origin.
Therapy The therapy of brain metastases with a known or unknown primary tumor depends on the patient’s general state of health assessed with the Karnofsky Index, tumor stage (extracerebral tumor load), the number of brain metastases, age and demonstration of concomitant leptomeningeal dissemination. The new graded prognostic assessment of the radiation oncology group was lately introduced as a prognostic scale (Sperduto et al. 2008). The aim of surgical intervention in patients with single brain metastases in the posterior cranial fossa with or without a known primary tumor is removal of the space-occupying mass as well as of a possible cerebrospinal fluid blockage, and to enable a histologic diagnosis. This may be followed by irradiation and/or chemotherapy. In patients with multiple, i.e. more than three supra- and/ or infratentorial metastases, or concomitant leptomeningeal spread, in addition to the absence of an indication of
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a primary cerebral lymphoma (biopsy confirmation, no extirpation), a neurosurgical procedure should be carried out only in exceptional cases, e.g. in the presence of particularly large and space-occupying metastases. If the therapeutic benefit is justifiable in relation to the performance status and life expectancy, whole brain irradiation with a total dose of 30–40 Gy can be administered as a palliative measure. In cases of active extracerebral tumor activity, new metastatic spread to the brain is, however, to be expected. Hypofractionated stereotactic radiotherapy and radiosurgery are new and effective methods for use in addition to whole brain radiation and surgical therapy. Nevertheless, the threat posed by therapy-associated edema carries a significantly higher risk in the posterior cranial fossa than in supratentorial lesions. Furthermore, the greater risk for radiation necrosis associated with radiosurgery requires limitation of the irradiated volume to a few cubic centimeters. Rarely tumor-type specific chemotherapy is an option for selected patients, as most of them are heavily pretreated and are in a bad clinical condition. Prognosis The median survival time in intracranial metastatic spread without therapy is usually 1–2 months after diagnosis (Sperduto et al. 2008). This time period may be shorter for metastases of the brainstem or the cerebellum, due to the described life-threatening complications. Palliative whole brain irradiation can extend the survival time to 4–5 months.
4.5.3.2 Schwannomas of the Cerebellopontine Angle Epidemiology Although acoustic schwannomas of the vestibulocochlear nerve are not brainstem tumors in the strict sense, they are discussed below, because they can, together with other tumors of the cerebellopontine angle cause secondary brainstem symptoms and cranial nerve deficits, in particular of the vestibulocochlear, facial and trigeminal nerves, as a result of displaced growth outside the brainstem. Schwannomas of the vestibulocochlear nerve account for the vast majority of tumors of the cerebellopontine angle, followed by meningiomas as the second most common lesion. While unilateral acoustic schwannomas occur sporadically, bilateral acoustic schwannomas are pathognomonic in patients with neurofibromatosis Type II (NF-2) (Fig. 4.44).
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Fig. 4.44 Bilateral vestibular Acoustic schwannomas. Images obtained in a 17-year-old male patient with neurofibromatosis type II. The bilateral vestibular schwannomas are pathognomonic for the disease. T1-weighted MRI with paramagnetic contrast enhancement: (a) axial; (b) coronary
Etiopathogenesis Acoustic Schwannomas are benign, well-defined WHO Grade I tumors, which arise from Schwann cells of the inferior vestibular nerve. They commonly result from mutation in the NF-2 tumor suppressor gene on the long arm of chromosome 22 encoding merlin as a gene product.
Clinical Findings The primary clinical symptom of acoustic schwannomas is slowly progressive unilateral hearing loss without an identifiable otologic cause. It is frequently accompanied by tinnitus. In some patients, an abrupt loss of hearing may be the initial symptom. Vertigo and vertigo attacks associated with peripheral vestibulopathy may be present. A little regarded early symptom is Hitselberger’s sign, consisting of hypesthesia of the external auditory canal, of which the patient becomes aware on touch or ear rinsing. Very large tumors can lead to compression of the pontomedullary brainstem with contralateral hemiparesis (Fig. 4.45). Patients with cerebellar flocculus involvement may show posture and gait ataxia, as well as eye movement disturbances. Compression of the trigeminal nerve leads to facial hypesthesia; involvement of the basal cranial nerve groups IX–XI is associated with soft palate paralysis and swallowing disturbances. Filling of the posterior cranial fossa reserve spaces can produce an occlusive hydrocephalus. Cerebrospinal fluid analysis typically identifies a significantly elevated total protein level (>1 g/L), which can, in rare cases, lead to development of a resorptive hydrocephalus as the result of impaired cerebrospinal fluid resorption.
4.5 Brainstem Tumors
Fig. 4.45 Vestibular schwannoma. Images obtained in a 52-year-old male patient with a large vestibular schwannoma and subsequent cerebellar and brainstem compression. Clearly apparent expansion of the tumor in the internal acoustic meatus. T1-weighted axial MRI (a) prior to and (b) after paramagnetic contrast enhancement
Diagnosis MRI is the imaging modality of choice in the diagnosis of acoustic schwannoma and petrosal bone meningioma. Schwannomas have smooth borders and show a relatively homogeneous contrast enhancement (Fig. 4.44). These tumors may occasionally have a cystic component, and in contrast to meningiomas of the cerebellopontine angle they rarely calcify. Improved diagnostic imaging techniques today enable increased detection of oligosymptomatic tumors only a few millimeters in size and an intrameatal location. The MRI examination thus offers not only the possibility of an early diagnosis, but also permits the follow-up of tumor growth over a specified period of time. MRI is often supplemented by a CT bone window scan of the petrousal bone. If this shows enlargement of the internal acoustic meatus, acoustic schwannoma is a more likely diagnosis than a petrousal bone meningioma. Functional tests should include a pure tone audiogram, a vestibular test, and recording of acoustic evoked potentials. The latter are almost always pathologic in schwannomas of the cerebellopontine angle.
Differential Diagnosis Meningiomas of the cerebellopontine angle need to be considered first in the differential diagnosis of schwannomas. Other possible differential diagnoses are trigeminal nerve neurinomas and facial nerve schwannomas.
Therapy There are, on principle, three therapeutic options: microsurgical tumor resection, stereotactic radiosurgery, and a
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conservative approach consisting of regular MRI examinations and a hearing test (watchful waiting). The decision regarding therapy is determined chiefly by the size and location of the tumor, as well as by the patient’s general state of health. In the presence of small tumors without clinical symptoms, but a poor general state of health, a conservative approach is generally preferred. Surgical resection is indicated in patients with progressive hearing loss or other symptoms related to the respective tumor size. If only a partial resection is carried out with consideration of the patient’s poor state of health, this may be followed by stereotactic radiosurgery (Samii and Matthies 1997). Microsurgical dissection of symptomatic acoustic schwannoma continues to be the standard of care. The resection of smaller tumors is in particular recommended for younger patients. The aim of microsurgery is complete removal of the tumor. The only exceptions warranting a subtotal tumor resection are large tumors with preoperative hearing loss or a low life expectancy. The earlier an acoustic schwannoma is surgically removed, the greater is the chance of preserving cochlear, facial and trigeminal nerve function (Samii and Matthies 1997). Preoperative tumor size is the crucial factor for the clinical result. Facial nerve function was preserved in 96% of patients with tumors <2 cm and a House-Brackmann Grade I or II, in 74% of cases with tumors from 2–4 cm in size, yet in only 38% of patients with tumors >4 cm (Gormley et al. 1997). In 61% of patients auditory acuity is reduced even before surgery. An incidence rate of approximately 22% has been reported for trigeminal neuropathies (Pollack et al. 1995). Stereotactic radiation therapy and radiosurgery are increasingly used as an alternative to primary resection, also of small tumor entities. Focal radiation is capable of halting the growth of an acoustic schwannoma, but the tumor volume can be reduced in more than 80% of patients (Prasad et al. 2000). Current long-term results in patients younger than 40 years with small tumors show that acoustic acuity was preserved in 87% and that cranial nerves V and VII were spared in 90% of cases (Lobato-Polo et al. 2009); the issue is not tumor removal but control of tumor growth. The disadvantage of surgically induced complications such as cerebrospinal fluid fistula and wound infection has to be weighed against the delayed effects of radiation. This applies to both tumor therapies and side effects, so that in 2–17% of cases varying degrees of facial paresis may be present, and an exacerbation of hearing loss may be found in up to 62% of patients, even in the long-term course of disease. Facial hypesthesia associated with trigeminal nerve damage is expected to develop in approximately 4–19% of cases, while other cerebral nerve dysfunctions are rare (Pollack et al. 1995). A perioperative mortality rate of approximately 1% has been reported by several large centers (Gormley et al. 1997; Samii and Matthies 1997).
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Prognosis
Etiopathogenesis
An average tumor growth of approximately 3 mm per year has been observed in patients with untreated acoustic schwannomas (Charabi et al. 1995). Complete removal of the tumor is, however, achievable in the majority of cases (Samii and Matthies 1997). After complete microsurgical resection a very low recurrence rate of <1% has been reported for patients without NF-2. The described recurrence rate was sustainable over a median follow-up period of 65 months (Gormley et al. 1997).
Cytogenetic studies of meningiomas have shown losses of chromosome 22 or long arm deletions of chromosome 22 within the neurofibromatosis locus (Zang 2001). The occurrence of meningiomas after exposure to cranial irradiation has been confirmed.
4.5.3.3 Meningiomas Epidemiology and Classification Meningiomas are extracerebral, most often benign lesions, whose origin can be attributed to degenerative changes in the arachnoidal cap cells. Depending on their localization, they are classified as convexity, falx and tentorial meningiomas. Histologically they are divided into three grades based on the WHO classification system, with WHO Grade I meningiomas representing the most common type. They are further divided into nine histologic subtypes. At increasing degrees of anaplasia, meningiomas are assigned to WHO Grade II, and at increased mitotic activity they are defined as WHO Grade III. Meningiomas may grow to be quite large before any clinical symptoms appear, because the brain can adjust to the presence of slowly growing masses over a long period of time. However, decompensation of increasing intracranial pressure can lead to life threatening symptoms. Meningiomas occur most often in older patients and are relatively rare in children and young adults (Fig. 4.46).
Clinical Findings As with other tumors, size and localization play a crucial role in the development of clinical symptoms in patients with meningiomas. Meningiomas of the posterior fossa may cause ataxia or symptoms of occlusive hydrocephalus. Tentorial meningiomas invading this region or the tentorial notch can become symptomatic with brainstem compression, ataxia and hemiparesis. In contrast, petroclival meningiomas and meningiomas of the craniocervical junction (Fig. 4.46) manifest with neck pain and occipital headache later followed by gait or auditory disturbances, as well as vertigo, and thus mimic the complaints associated with schwannomas of the cerebellopontine angle. Depending upon the direction of tumor growth, additional cranial nerves of the cerebellopontine angle may be involved.
Diagnosis CCT and cMRI enable the reliable visualization of meningiomas. As a result of their hypercellularity, meningiomas have a hyperdense appearance even without contrast enhancement; on cMRI they are viewed as isointense in T1-weighted, and as iso- or hyperintense in T2-weighted sequences. Calcifications are frequently present. Ninety percent of meningiomas are characterized by strong, homogeneous contrast enhancement. The generally broad-base attachment to the meninges is frequently thickened and shows strong meningeal contrast enhancement beginning at the points of attachment (dural tail sign). Of importance for the therapy is detection of growth into the dural sinuses which occurs frequently.
Differential Diagnosis Meningiomas in the brainstem region have to be differentiated primarily from schwannomas and neurinomas of cranial nerves of the cerebellopontine angle.
Fig. 4.46 Meningeoma. Images obtained in a 25-year-old male with progressive tetraparesis. Homogenous contrast-enhancing meningeoma, with pontomedullary brainstem compression from ventral. T1-weighted MRI after paramagnetic contrast enhancement: (a) sagittal; (b) coronary
Therapy The typically space-occupying and non-infiltrative growth of meningiomas makes the complete neurosurgical removal the
4.5 Brainstem Tumors
therapy of choice for these tumors. In particular in patients with large meningiomas and in older patients, the most common postoperative complication is secondary hemorrhage into the resection cavity. A further frequent complication is the occurrence of perifocal edema, which requires administration of steroids. In cases with smaller asymptomatic meningiomas, in particular older patients, the spontaneous course can initially be observed with imaging follow-up at 6-month intervals. Especially in the region of the posterior cranial fossa and the cranial nerves, a small part of the tumor may be spared with consideration of preservation of function, although at the risk of an increased recurrence rate. In these patients, the remaining tumor can be successfully treated with radiosurgery (Colombo et al.2009). Medical treatment of recurrent benign, multiple or anaplastic meningiomas remains of uncertain value even with long-lasting somatostatin analogues (Chamberlain et al. 2007).
Prognosis Complete resection of meningiomas is associated with a low recurrence rate. The most common recurrences have been reported for the posterior cranial fossa and the region of the cavernous sinus, where radical tumor resection is often impossible without damage to the cranial nerves. The indication for postoperative irradiation with the aim of preventing tumor recurrence should be considered in these patients. Regular – initially 6-monthly, later yearly – MRI follow-up examinations are indicated in all patients, to ensure early detection and therapy of recurrent tumor. Recurrence of meningiomas can occur even many years after therapy.
4.5.3.4 Hemangioblastomas Epidemiology and Etiopathogenesis Capillary hemangioblastomas are associated with an inherited autosomal dominant von Hippel-Lindau syndrome in up to 25% of patients. Histological the tumor consists of neoplastic stromal cells, endothelial cells and mast cells and numerous capillaries of unclear origin. Fewer than 2% of intracranial tumors are capillary hemangioblastomas (Donaldson et al. 2006). They are classified as WHO Grade I tumors. The occurrence of multiple lesions and an atypical location outside the cerebellum are highly suggestive of a von Hippel-Lindau syndrome. In contrast, 10% of tumors in the posterior cranial fossa correspond to benign hemangioblastomas. Although the readily differentiable, highly vascularized space-occupying masses are preferentially located in the cerebellum and the medulla oblongata, they may also be solid or cystic tumors (Wanebo et al. 2003). The incidence
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peak occurs in the age group 30–50 years, the onset in patients with von Hippel-Lindau syndrome is usually before age 30. The most common localization in 85% of patients from this group is the cerebellum. Hemangioblastomas rarely occur in a supratentorial location. Capillary hemangioblastomas are caused by mutations in the von Hippel-Lindau gene (VHL) on chromosome 3p25. The resulting inactivity of the gene product (pVHL) mediates an enhanced expression of the vascular endothelial growth factor (VEGF), platelet factor b (PDGF-b), the transforming growth factor a (TGF-a) and erythropoietin (Kaelin 2002). Clinical Findings The clinical cardinal symptoms of von Hippel-Lindau disease comprise visual disturbances and cerebellar symptoms due to the manifestation of capillary hemangioblastomas in these organs (synonym: retinocerebellar angiomatosis). Hemorrhages in the region of the brainstem and cerebellum can cause lifethreatening symptoms as a result of the space-occupying effect. Also in the foreground are clinical neurologic manifestations of vertigo, headache, and cerebellar symptoms. In addition to the cerebral manifestations, there is an increased incidence of malignant renal cell carcinomas, and pheochromocytomas, as well as of pancreatic tumors and cysts. Diagnosis and Differential Diagnosis Diagnostic imaging (cMRI) often discloses a relatively small tumor nodule with a concomitant large cystic space-occupying mass, which may, depending on the protein content, be visualized as hypointense or hyperintense (contingent upon weighting of the MRI image). Hemangioblastomas are highly vascularized with corresponding intensive contrast agent uptake. In cases of doubt, conventional angiography visualizes the hemangioblastoma as a highly vascularized tumor node. Hemangioblastomas may induce an erythropoietindependent polycythemia as a paraneoplastic syn drome. Therapy Neurosurgical resection of a hemangioblastoma and the accompanying cyst represents the therapy of choice (Jagannathan et al. 2008). In the presence of large tumors, preoperative devascularization with an embolization procedure can be effective in reducing tumor volume to enable operability. Beneficial effects have also been reported for the application of fractionated radiotherapy techniques and radiosurgery but only for solid hemangioblastomas (Wang et al. 2005).
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Prognosis The prognosis after complete resection of an infratentorial hemangioblastoma is usually favorable, although recurrence or new tumors can develop in 10% of cases. The survival prognosis in von Hippel-Lindau patients is dependent upon the various possible malignant extracerebral tumor diseases.
4.6 Traumatic Brainstem Lesions Raimund Firsching, Dieter-Heinrich Woischneck, and Stefan Schreiber
4.6.1 Epidemiology Craniocerebral injuries are the leading cause of death in humans before the age of 40 (Firsching and Woischneck 2001). In Germany, the annual incidence of death from craniocerebral trauma is approximately 7–10 cases per 100,000 inhabitants (Bouillon et al. 1998). The epidemiologic significance of traumatic brain injury is currently only incompletely known, due to the lack of reported data. Results of systematic neuropathologic investigations providing useful epidemiologic data are currently not available. While older pathologic studies reported brainstem lesions as a cause of coma and death (Oppenheimer 1968; Crompton 1971; Budzilovic 1976), more recent investigators rarely identified brainstem lesions as causal factors of disastrous outcomes (Mitchell and Adams 1973). Computed tomography (CT) has been used since 1975 as the method of choice in patients with craniocerebral injuries. CT is, on principle, suitable to show relevant brain tissue injuries requiring surgical therapy, in particular intracranial hemorrhages. The technique is, however, unsuitable for visualizing injuries to the brainstem. The reason for this is of a physical nature: the brainstem posterior to the petrous pyramid cannot be clearly visualized by transversal slice CT imaging. As a rule, only artefacts are produced, i.e. false images visible as hypodense or hyperdense layers and areas. Neither the brainstem nor its injuries can therefore be appropriately assessed with CT imaging. Only insufficient attention has been given to this inadequacy. The shortcomings of CT were not fully understood until the availability of magnetic resonance imaging (MRI) (Firsching et al. 1998). Yet, CT dominated clinical practice for more than 25 years, with brainstem lesions being found in fewer than 10% of unconscious patients who underwent careful CT evaluation (Hashimoto et al. 1993). Fatal courses were frequently observed, although CT did not adequately – or at all – visualize brain injuries. In these patients, a diffuse brain injury therefore served as an explanation for the
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occurrence of coma and death. The described diffuse brain injuries have thus far been histologically confirmed in only a few individual cases (Adams et al. 1977), and results of a statistically relevant comparison between CT and histologic findings have not been published until today. Despite this scientific impreciseness, diffuse brain injury, which is defined as a diffuse injury to axons in the white matter (Adams et al. 1982), is regarded as the most important cause of coma and death by many scientists. After initial reports of posttraumatic injuries detected using MRI, the incidence of brainstem lesions was found to be substantially higher than previously shown on CT. At a presumed incidence rate of 80% for severe craniocerebral injuries with prolonged unconsciousness, the annual incidence ranges at approximately five cases per 100,000 inhabitants.
4.6.2 Etiology In individual patients the development of traumatic brainstem lesions is to some extent uncertain. Animal studies in dogs have shown that pontine hemorrhage can occur when supratentorial space-occupying lesions cause herniation into the foramen magnum (Duret 1878). Experimentally produced traumatic brainstem lesions in dogs, “Duret hemorrhages”, were perceived as hemorrhages indirectly due to a trauma, which developed as the result of an increase in intracranial pressure. They were therefore understood as a secondary, but not as a primary result of compression, directly related to the hemorrhage caused by the injury. These observations made more than 100 years ago in dog brains continue to have an impact on our understanding of the etiology of traumatic brainstem lesions today. Because MRI, the only imaging technique capable of a sufficiently accurate visualization of brainstem lesions in living patients, is only in exceptional cases available during the first 24 h, only a small number of reports are published on brainstem lesions in the early phase after craniocervical trauma. A number of important conclusions may nevertheless be drawn from published first observations: • In isolated examples of initially conscious patients without neurologic disturbances after craniocervical trauma, who later developed an epidural hematoma which could not be removed sufficiently early, MRI did not document brainstem hemorrhages, but showed brainstem lesions without bleeding (Firsching et al. 2003). Based on the history and the course, these necroses of the brainstem can be conclusively identified as secondary brainstem lesions. A potentially fatal increase in intracranial pressure thus does not always induce brainstem hemorrhages as commonly assumed based on the Duret findings. It may be assumed that alterations occurring in the dog brain after craniocerebral trauma develop differently from those in the human brain.
4.6 Traumatic Brainstem Lesions
• While earlier histologic studies frequently reported detection of brainstem lesions after craniocerebral trauma (Oppenheimer 1968; Crompton 1971; Budzilovic 1976), in more recent studies pathologists concluded that brainstem lesions do not occur in isolation. The scientists nevertheless conceded that if they were found, this would be only in association with supratentorial lesions, and at most in 10% of patients (Mitchell and Adams 1973). • In a series of 176 patients with craniocerebral trauma resulting in unconsciousness, early MRI was performed within 8 days after trauma (Firsching et al. 2003). The probability of detecting a brainstem lesion with the use of MRI in patients who remained unconscious longer than 24 h was greater than 80%. This is obviously in sharp contrast to the neurophathologic observation of a maximum incidence rate of 10%. Since it appears unlikely that the histologic examination would miss lesions visualized on MRI, a different reason for the variation in the reported detection rates of brainstem lesions must be presumed. A plausible explanation is the fact that a histologic examination is possible only in patients with a fatal course, and that it is therefore representative of only a selected group of patients. MRI can be used both in patients with fatal courses and living patients, and thus enables differentiation between lesions with a higher chance for survival after craniocerebral trauma and those with a fatal outcome. It remains unclear, why the detection rates of injuries to the brainstem using MRI are substantially higher than those reported by older neuropathologic studies. In the abovementioned study, MRI showed the presence of hemorrhage in 90% of brainstem lesions. In all cases the patients were unconscious on admission. A course characterized by an interval of consciousness and sudden onset of coma is clinically suggestive of an intact brainstem immediately after primary trauma. This was observed in only three patients in this series with an epidural hematoma; these patients did not have brainstem hemorrhage, but had brainstem injuries without associated bleeding. • Brainstem hemorrhages have been detected as early as 6 h after craniocerebral trauma. This gives rise to the assumption that most brainstem injuries with concomitant hemorrhage are the direct result of the primary trauma instead of being chiefly due to increased intracranial pressure. The hypothesis proposed by Mitchell and Adams (1973) that the brainstem is protected by its location posterior to the clivus is put into question based on the findings of magnetic resonance imaging. It may, in contrast, be assumed according to currently available MRI data that brainstem lesions are a common occurrence in unconscious patients after craniocerebral trauma. The suggestion that its anatomic location serves to protect the brainstem from injury can no longer be regarded as valid. The results of MRI studies indicate that brain tissue contusions may be observed in any part
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of the brain. According to these findings, the majority of brainstem lesions are primary lesions, i.e. they are the direct result of the traumatic injury, while secondary brainstem lesions are less often identifiable.
4.6.3 Clinical Findings Following the evaluation of MRI findings in unconscious patients within 1 week after trauma and their comparison with the clinical course (Firsching et al. 2003), the following classification was made according to four grades of severity: • Grade I: injury to the cerebral hemisphere and/or the corpus callosum with intact brainstem (Fig. 4.47) • Grade II: unilateral brainstem injury at any level of the brainstem, with or without Grade I injuries to the corpus callosum and/or the cerebral hemispheres (Fig. 4.48) • Grade III: bilateral injury to the mesencephalon with or without Grade II injury – unilateral lesion at any level of the brainstem and/or injury to the cerebral hemispheres and/or the corpus callosum (Fig. 4.49) • Grade IV: bilateral injury to the pons with or without Grade III injury – bilateral mesencephalic lesions and/or unilateral brainstem lesion at any rostral level and/or injury to the hemispheres and/or the corpus callosum (Fig. 4.50) The clinical significance of the location of lesion as revealed by MRI in terms of 3-month survival rate, and the quality of life after a minimum follow-up of 6 months was assessed using the Glasgow Outcome Scale; the assessment of the duration of coma was based on the number of days the patient remained unconscious. The classification into Grades I – IV was shown to be highly significantly related to outcome. The relation of outcome with the location of lesions as depicted by MRI is shown in Table 4.18. The brainstem was intact in only 39% of patients. The majority of patients had evidence of a brainstem lesion. All brainstem lesions – except two – with or without any other lesion of the cerebral hemispheres usually occurred concurrently with injuries to the hemispheres and the corpus callosum. A lesion to the corpus callosum was observed in 29% of patients. Due to their low incidence, cerebellar lesions were not considered as an individual entity. MRI showed a cerebellar lesion in only 3% of patients, all of whom survived. In two thirds of patients, cerebellar hemorrhages occurred in combination with supratentorial injuries (Grade I), and in one third with an additional unilateral brainstem injury (Grade II). Although isolated injuries to the medulla oblongata may be found after craniocerebral trauma, these are not associated with disturbance of consciousness. The duration of amnesia or coma is traditionally regarded as an important clinical measure for the severity of craniocerebral injury (Tönnis et al. 1949). The above mentioned
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a
b
c
Fig. 4.47 (a) Schematic representation of a brainstem lesion Grade I: exclusively supratentorial lesions (39 %); (b–c) Fourteen-year-old boy after a traffic accident. MRI on day 2 after the accident: no brainstem lesion but large traumatic hemorrhagic lesion of the basalganglia at the
a
left side. Duration of coma: 3 days. The child survives with mild physical disabilities. (Images courtesy Deutscher Ärzteverlag GmbH, Dtsch Ärzteblatt (2003) 100:A1868–A1874)
b
Fig. 4.48 (a) Schematic representation of a brainstem lesion Grade II: unilateral brainstem lesion (with or without Grade I lesion (22 %); (b) image obtained in a 12-year-old boy after a traffic accident. MRI on day 2 after the accident: unilateral brainstem lesion. Duration of coma: 7 days. The child survives with mild disabilities. (Images courtesy Deutscher Ärzteverlag GmbH, Dtsch Ärzteblatt (2003) 100: A1868–A1874)
study (Firsching et al. 2003) also assessed the relationship between the duration of coma and the location of the lesion shown on MRI. All patients were sedated only to the level required for adequate ventilation. The established correlation was highly significant (Table 4.18). When the lesion was confined to the cerebral hemispheres and the corpus callosum (Grade I), the mean coma duration was approximately 3 days. Patients with a unilateral brainstem lesion (Grade II) had a mean duration of coma of 6.6 days, while the mean length of coma ranged at around 12 days in patients with bilateral mesencephalic lesions.
The period of emergence from coma in the presence of bilateral pontine lesions was not observed in this series of 176 patients. Since publication of the present study we have observed isolated cases with survival and emergence from coma of patients with bilateral pontine lesions; these appear to represent a rare exception. All patients with a Grade I, II, or III lesion who died transiently regained consciousness before death. A corpus callosum lesion was associated with mean coma duration of 5.6 days; mean duration of coma was approximately 6 days in the absence of a lesion to the corpus callosum (see Figs. 4.51 and 4.52).
4.6 Traumatic Brainstem Lesions Fig. 4.49 (a) Schematic representation of a brainstem lesion Grade III: bilateral lesion to the mesencephalon or mesencephalic midline lesion (with or without Grade II lesion; 19%); (b) 18-yearold male after a traffic accident. MRI on day 4 after craniocerebral trauma. Duration of coma: 11 days; 12 months after the accident: patient regetative state. (Images courtesy Deutscher Ärzteverlag GmbH, Dtsch Ärzteblatt (2003) 100:A1868–A1874)
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a
b
a
b
Fig. 4.50 (a) Schematic representation of a brainstem lesion Grad IV: bilateral lesion to the pons (with or without Grade III lesion; 20 %); (b) Image obtained in a 71-year-old male after a fall. MRI: bilateral pontine lesion. Patient died after 2 weeks and remained unconscious until the time of death. (Images courtesy Deutscher Ärzteverlag GmbH, Dtsch Ärzteblatt (2003) 100:A1868–A1874)
4.6.4 Diagnosis and Differential Diagnosis The most important clinical finding in case of a suspected brainstem lesion is prolonged unconsciousness, which is synonymous with coma. The definition of the clinical findings of
coma were: eyes are closed for a prolonged period of time without being opened in response to painful stimuli or spontaneously, no obeying of verbal commands. Spontaneous movements or movements in response to pain stimuli are possible (Frowein 1976). The immediate definite diagnosis of a
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Table 4.18 Treatment results according to MRI findings Number Classification of MRI Grade of findings cerebral lesion on MRI
Lethal outcome
Apallic patients
Severely disabled patients
Mildly disabled patients
Patients without disability
Mean duration of coma (in days)
Grade I
68 of 176 (= 39%)
Exclusively supratentorial lesion; intact brainstem
3 (4.5%)
0
4
16
45
2.9
Grade II
38 of 176 (= 22%)
Unilateral brainstem lesion at any level with or without an additional Grade I lesion
6 (15.7%)
0
8
16
8
6.6
Grade III
34 of 176 (= 19%)
Bilateral mesencephalic lesion with or without additional Grade II lesion
8 (23.5%)
9
13
4
0
12.2
Grade IV
36 of 176 (= 20%)
Bilateral pontine lesion with or without additional Grade III lesion
3 (97.3%)
0
0
0
0
No emergence from coma
35 30
29%
28.2%
Without corpus callosum lesion
With corpus callosum lesion
%
25 20 15 10 5 0
Fig. 4.51 Comparison of lethality without and with corpus callosum lesion. No statistically significant difference
7 6
6.1 5.5
5 Days
traumatic brainstem lesion cannot always be made clinically without the use of imaging modalities. Animal studies have indicated that extensor responses of the extremities were associated with a dysfunction of the mesencephalon. Over many years, evidence of brainstem lesions has been shown with the use of electroneurophysiologic methods, in particular with evoked potentials, somatosensory evoked potentials, and early acoustic evoked potentials (Firsching 1987). The method of choice is imaging with the use of MRI. T1-, T2- and diffusion weighted imaging, as well as FLAIR sequences represent valuable diagnostic tools. Imaging in transverse, coronary and sagittal sections are useful. Regarding the timing of examination, consideration has to be given to the great importance of the interval from the accident to MRI, since the magnetic effect is altered at the increasing resorption of blood degradation products, and edemas. Fresh hemorrhages may under certain conditions not be differentiable in the initial hours. In the above mentioned series of patients bilateral mesencephalic lesions were found in all patients with an apallic syndrome. Approximately 30% of the bilateral mesencephalic lesions were associated with the clinical picture of apallic syndrome. The findings of another investigation (Kampfl et al. 1998), however, showed bilateral mesencephalic brainstem damage in only 70% of patients with apallic syndrome. An interval between injury and MRI from 3–6 months on average was reported by the study, so that edema, as a sign of damage to the cerebral substance, may be identifiable in the early phase only, and cannot be conclusively imaged at a later time, when the edema has been reabsorbed and the brainstem injury has lead to slight shrinkage of the brainstem. An early examination
4 3 2 1 0
Without corpus callosum lesion
With corpus callosum lesion
Fig. 4.52 Duration of coma without and with corpus callosum lesion. No statistically significant difference
4.6 Traumatic Brainstem Lesions
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Table 4.19 Comparison of histologic findings and results using imaging techniques in brainstem lesions Histologic Age CT finding MRI Survival findings (years) finding after accident (days) 71
• Acute subdural hematoma
Grade IV 25
• Swelling of the brain 40
• Supratentorial contusions
Grade IV 60
• Swelling 70
• Supratentorial contusions
Grade IV
6
Grade III
9
No patient had signs of diffuse axonal injury; in conformity with MRI findings, only focal lesions were identified
• Mesencephalon displacement 31
• Edema • Swelling
is therefore ideal for conclusive identification of a posttraumatic brainstem injury. The optimal time for the examination appears to be within 1 week after the trauma. With unconscious patients the examination needs to be achievable also in intubated and ventilated patients, which predicates the availability of specialized equipment. In Table 4.19 the histologic findings (in four out of 176 patients), clinical data, CT and MRI findings are juxtaposed for comparison. Although based on the clinical and CT findings, a diffuse brain injury might have been suspected, this could not be confirmed histologically in any of the patients. Accurate histologic confirmation was achieved only for the multifocal lesions detected on MRI.
4.6.6 Prevention of a Secondary Brainstem Lesion There is no question that an increase in intracranial pressure via mechanisms of brain tissue displacement can lead to brainstem compression at the tentorial notch and the foramen magnum. The success of surgical resection of an epidural hematoma in the middle cranial fossa in an unconscious patient, who is awake and without neurologic disturbances after the operation, is attributable to sufficiently early brainstem decompression. A similar effect of decompression is observed in patients with acute deterioration of consciousness after infarction of a middle cerebral artery. In patients with a critical increase in intracranial pressure with brain swelling and edema after craniocerebral trauma, wide decompressive craniectomy can be a life-saving measure, and therefore represents the most reliable therapeutic option (see Fig. 4.53). A further, although somewhat less certain measure to lower intracranial pressure is to elevate the patient’s upper body to 30°. This option is, however, controversially discussed among some authors, who argue that the cerebral perfusion pressure, i.e. the difference between arterial pressure and intracranial pressure, is not affected by upper body elevation. The absolute intracranial
4.6.5 Therapy Causal therapy of a traumatic brainstem lesion is generally not possible. A contusion (Latin contundere: “to crush”, “to bruise”) refers to the destruction of brain tissue structure. Once brain tissue is destroyed, there is almost no evidence that new brain cells regrow, and only partial recovery is to be expected. Therapy is therefore limited to measures applied to support the recovery process and to avoid secondary injuries. Unconscious patients with brainstem lesions require immediate intensive care treatment. Intubation is essential since an unconscious patient is at risk of becoming incapable of spontaneous breathing and losing cranial nerve function, as well as of aspiration of blood or vomit. Additional therapeutic measures comprise stabilization of vital, i.e. respiratory and circulatory functions.
Fig. 4.53 (a) Images obtained in a 12-year-old female accident victim with anisocoria, unconsciousness, and a narrow acute subdural hematoma right. (b) Four hours after surgery for the subdural hematoma, exacerbation with fixed pupils of both eyes and slit ventricles on CT. Immediately followed by decompression craniotomy. Anisocoria after the second surgical intervention. (c–d) MRI demonstrates frontal contusions, the brainstem is intact. Duration of coma: 2 days
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4.6.7 Prognosis Comparable to the non-existence of two identical snow crystals in nature, so far no two exactly identical brain lesions resulting from craniocerebral trauma have been identified on MRI. The significance of individual brain structures in regard to coma and death continues to be highly controversially discussed. The above mentioned study (Firsching et al. 2003) therefore attempted to investigate the relation of specific lesion locations detected using MRI with mortality and outcome of survivors: The clinical findings 6 months after craniocerebral trauma were classified according to the Glasgow Outcome Scale. There was a highly significant correlation between clinical findings and the location of the brain injury (Table 4.18). The majority of patients with an intact brainstem (66% of patients) did not develop permanent physical disability. In patients with unilateral brainstem lesions (Grade II) this rate was reduced to 21%; every patient with a bilateral mesencephalic lesion (Grade III) developed permanent disability. Mild disability was most frequently observed in Grade II lesions, while the
1,0 0,8 Survival probability
pressure is, nevertheless, generally lowered. Hyperventilation represents a further therapeutic measure. Yet, hyperventilation applied over a period of several hours, may exert an adverse effect on cerebral blood perfusion. It is generally agreed that medical therapeutic options for lowering intracranial pressure involving the brainstem are limited. The administration of mannitol can lead to a decrease in intracranial pressure by an osmotic effect, but this decrease is only transient (<1 h); repeated use appears to produce the opposite effect of exacerbating brain edema. Hyperosmolar saline solutions are currently investigated by a number of scientific studies, saluretics have not been shown to produce a sustainable effect thus far. Sedation with phenothiazines, morphine derivatives, benzodiazepines and propofol do not lower intracranial pressure per se. Sedation is indicated only in agitated patients with inadequate spontaneous breathing, who breathe against the ventilator and resist adequate ventilation. The concept of interrupting or alleviating the cascade of sequelae after craniocerebral trauma which eventually lead to increased intracranial pressure by inducing artificial hibernation, the curative coma, has a long tradition (Laborit and Hugenard 1954). Reductions in brain metabolism and energy requirements are hypothesized to alleviate the effects of increased intracranial pressure, and to ensure progressive regeneration after trauma. The methods applied for this purpose, barbiturate coma and hypothermia, have not yet been shown to be beneficial despite intensive scientific efforts.
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0,6 Grade I lesion Grade II lesion Grade III lesion Grace IV lesion
0,4 0,2 0 0
6 12 18 24 30 36 Number of months after the accident
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Fig. 4.54 Kaplan-Meier function. Survival in relation to the brain injury after Grade I –IV classification
highest incidence of severe disabilities was found in patients with a Grade III lesion. 96% of patients in a vegetative state had a bilateral mesencephalic lesion. Twenty-nine percent of patients who were unconscious for more than 24 h after craniocerebral trauma had a fatal outcome. A highly significant correlation was found between mortality and location of the intracranial lesion. The mortality rate ranged at 4.5% in patients with an intact brainstem. Altogether a mortality rate of 41% was found in all patients with a brainstem injury, including unilateral or bilateral lesions at any level in the brainstem. A Kaplan-Meier survival curve is shown in Fig. 4.54. Comparable studies are currently not available.
4.6.8 Summary MRI is of eminent importance for the investigation of traumatic brainstem lesions. It constitutes the diagnostic method with the greatest prognostic significance available today. The functional integrity of the brainstem is of vital importance, as the mortality rate associated with injuries to the brainstem is tenfold higher than that in patients with an intact brainstem. This fundamental prognostic differentiation can only be achieved with the use of MRI. An additional factor is the highly significant correlation between the outcome of survivors and the location of the brain lesion. A recent study identified bilateral mesencephalic injury as the only location associated with vegetative state (Firsching et al. 2003). Previous diagnostic imaging with CT was shown to be inappropriate for an early prognosis, because it is incapable of demonstrating the lesion, which represents the most important prognostic indicator in itself. In patients with prolonged unconsciousness, CT frequently does not provide a finding that might serve as a satisfactory explanation for prolonged coma. In addition, the size of the contusion visualized on CT often does not
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correlate with the outcome (Frowein et al. 1991). In patients with an unfavorable course or fatal outcome after craniocerebral trauma and no abnormal findings or, at most, trivial injuries on CT, it has been suggested that coma and possibly death may be attributable to a diffuse lesion that was not detected on CT. These histological lesions have been described as diffuse axonal injuries and are typically found in the white matter (Adams et al. 1982). It has further even been recommended that the diagnosis “diffuse brain injury” should be made in a patient who remains unconscious for 6 h after craniocerebral trauma, when CT fails to disclose a space-occupying intracranial hemorrhage or other lesions (Gennarelli 1982). This usage implies, however, that a histologic diagnosis is established in the absence of a histologic examination. Even though the CT-assisted diagnosis of diffuse brain injury is in individual patients not verifiable in survivors and has not yet been systematically investigated in these patients after death, the term diffuse axonal injury is frequently used worldwide. This is in contrast to the neuropathologic view (Adams et al. 1982) that only the neuropathologist, who can identify axons, is able to make this diagnosis. The present series showed that patients who were unconscious for longer than 7 days without demonstrable space- occupying hemorrhage on CT – a finding which might give rise to the suspicion of a diffuse brain injury – invariably had a brainstem lesion as revealed by MRI. A diffuse axonal injury was found in none of the patients available for autopsy and histologic examination, but the focal brainstem lesions identified earlier on MRI were confirmed. The functions regulated within the pons appear to be of fundamental importance for consciousness. On the basis of the present MRI findings, emergence from coma appears, on principle, possible in all lesions involving the brain parenchyma that are located o utside the pons.
4.7 Degenerative Brainstem Diseases Andres Ceballos-Baumann
4.7.1 Syndrome-Orientated Classification The degenerative brainstem diseases discussed here are classified by neurologists depending on associated symptoms, as movement disorders, and include mostly parkinsonian syndromes. Anatomically these diseases are linked chiefly with the basal ganglia. The motor disturbance represents the most prominent symptom in movement or basal ganglia disorders. The associated neuropsychological problems may have an even more compromising effect on the patient than the motor abnormalities.
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The current conceptualization of movement disorders includes diseases and syndromes that are associated with disturbances in the initiation and performance of voluntary and involuntary motor tasks. This definition does not include a number of diseases that also exert an effect on mobility: peripheral and central pareses, myopathies, rheumatic and orthopedic diseases, sensory deficits with an impact on movement coordination, as well as apraxias and other neuropsychological disturbances associated with motor symptoms. Movement disorders, provided they cannot be assigned to a pattern with a well-defined organic pathology (i.e. dyskinesias, dystonias, tics, tremor, chorea), are traditionally classified as basal ganglia diseases. This provides a common denominator, at least for a rough neuroanatomic localization of the function disturbances and the pathologic abnormality. The basal ganglia constitute the grey nuclear complexes deep within the cerebral hemispheres (the striatum, putamen, and caudate nucleus, the internal and external globus pallidus, and the amygdaloid nucleus) with a close relationship to the brainstem. Also included for reasons of functional unity are structures within the brainstem, such as the subthalamic nucleus and the substantia nigra. Recent neuropathologic studies (Braak et al. 2004) have shown that the initial cell alterations in Parkinson’s disease do not occur in the substantia nigra, but in other parts of the brain. In the presymptomatic early phase of Parkinson’s disease, stage 1 and 2 according to Braak, specific nuclear regions constituting part of the vegetative nervous system (glossopharyngeal and vagus nerves), and the olfactory nerve with the respective nuclear regions are initially affected. Hyposmia may therefore be an early sign of Parkinson’s disease. Cell alterations also occur in the caudal part of the brainstem (medulla oblongata) and the adjacent pons. The concept of an extrapyramidal system is no longer valid today. On the one hand, apart from the basal ganglia and the pyramidal system, additional brain structures, such as the thalamus and the cerebellum are involved in motor function and, on the other hand, the basal ganglia are directly interconnected with structures in the frontal cortex. Furthermore, the umbrella term ‘extrapyramidal diseases’ covers syndromes for which no primary pathology has thus far been demonstrated in the basal ganglia (e.g. idiopathic dystonia, essential tremor). The diagnosis of movement disorders is largely supported by the medical history of the patient and the neurologic examination. The classification of movement disorders depends upon the clinical phenomenology, because the primary location of the function disturbance is not known in a large number of movement disorders, different localizations may be possible – in which the brainstem involvement may either be central or accessory – or the disturbance is understood only in the context of a superordinate neuronal system. To simplify, movement disorders can be classified phenomenologically according to a too much – hyperkinesias – or a too little – hypokinesias – in motor function. The group
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of hypokinesias comprises parkinsonian or akinetic-rigid syndromes. Hyperkinesias include a number of movement disorders such as tremor, dystonia, athetosis, chorea, tics, myoclonus, dyskinesias, and ballism. The most important movement disorders with brainstem pathology, in particular Parkinson syndromes, are discussed in this chapter. In view of the large number of functional connections between basal ganglia and the brainstem, the differentiation is in some way arbitrary. Emphasis is placed on disorders with evidence for the central role of the brainstem, or those which are of importance for differential diagnostic evaluation. The different Parkinson syndromes can be defined as brainstem diseases, since the substantia nigra and the subthalamic nucleus are located in the brainstem and not specifically in the basal ganglia, even though, for reasons of functional unity, the subthalamic nucleus and the substantia nigra are counted among the basal ganglia. Typical movement and/or basal ganglia disorders that are less closely related to the brainstem as, e.g. dyskinesias, dystonias, tics, chorea, myoclonus, acathisia, restless leg syndrome, are discussed only briefly. Furthermore, only a brief outline can be made of the continuously growing available therapeutic options, in particular for Parkinson disease and tremor syndromes. Please refer to the respective monographs (CeballosBauman and Conrad 2005) for further reading.
4 Diseases Table 4.20 Diagnosis of idiopathic Parkinson’s syndrome (IPS) (according to Hughes et al. 1992a) – Queen’s Square Criteria according to the guidelines of the German Society of Neurology Step I: Can a nonspecific Parkinson’s syndrome (parkinsonism) be diagnosed? • Bradykinesia (slowed ability in initiating and performing voluntary movements with slowing and amplitude reduction of movements) Plus • One of the following key symptoms: – Resting tremor (4–6 Hz) – Rigor – Postural instability (disturbed postural reflexes) that can not be attributed chiefly to visual, vestibular, cerebellar or proprioceptive disturbances Step II: Can exclusion criteria for IPS be identified? • Medical history: apoplectic course, craniocerebral trauma, encephalitis • Oculogyral crises • Remissions • Neuroleptics at the onset of symptoms • More than one relative with Parkinson’s syndrome • Exclusively bilateral signs after 3 years • Supranuclear gaze paresis • Cerebellar signs • Early pronounced autonomous disturbances • Positive Babinski’s sign • Tumor or communicating hydrocephalus on CCT
4.7.2 Parkinson Disease The term Parkinson disease (Parkinson’s disease) will be used below to refer specifically to Parkinson disease as an entity in contrast to parkinsonism or parkinsonian syndromes, that can be differentiated clinically (= parkinsonism, parkinsonoids, Pseudo-Parkinson disease) (Table 4.21) based on specific criteria (Table 4.20). Overlapping of Parkinson disease with other syndromes and etiologies most likely leads to mixed syndromes due the high incidence of the disorders.
• Early dementia with speech and memory disturbances and apraxia • Absent response to high doses of L-dopa (after exclusion of malabsorption) • Methyl-phenyl-tetrahydropyridine (MPTP) exposure Step III: Can prospective positive criteria for IPS be identified? (three or more required for the diagnosis of IPS) • Unilateral onset • Resting tremor • Progressive disease • Persistent left-right asymmetry in the course • Very favorable response (70-100 %) to L-dopa • Severe dopa-induced dyskinesias
4.7.2.1 Epidemiology Parkinson disease symptoms are very common in the elderly. The prevalence rate is higher than 10% in the group of 65–74 year olds, and higher than 40% in patients older than 85 years (Bennett et al. 1996). In contrast, the prevalence of Parkinson’s disease in the strict sense, ranges at 1.8% in the group of patients older than 65 years, and up to 2.6% in individuals aged 85–89 years (de Rijk et al. 2000). The prevalence of Parkinson’s disease is nearly identical in men and women.
• Positive L-dopa effect longer than 5 years • Course >10 years
4.7.2.2 Etiology Characteristic structures of Parkinson disease as well as of other neurodegenerative diseases are spherical intraneuronal inclusion bodies discovered by Friedrich Levy (later Frederic Lewy) in 1912. Lewy bodies are ubiquitin-immunoreactive intraneuronal eosinophilic inclusion bodies and comprise primarily a-synuclein and ubiquitin. Cells use ubiquitin to
4.7 Degenerative Brainstem Diseases Table 4.21 Clinical classification of Parkinson’s syndrome (According to German Society of Neurology 2005 guidelines) Group Course of disease Idiopathic Parkinson’s syndrome • Akinetic-rigid type (IPS) • Equivalence type • Tremor dominant type • Monosymptomatic resting tremor (rare variant) Symptomatic (secondary) Parkinson’s syndrome and frequent differential diagnoses
• Vascular (subcortical vascular encephalopathy) • Normal pressure hydrocephalus • Drug induced – Classical neuroleptics, antiemetics, reserpine – Lithium – Calcium antagonists: cinnarizine, flunarizine • Tumor • Posttraumatic • Toxin induced (e.g. carbon monoxide, manganese) • Inflammatory (AIDS encephalopathy or rare encephalitides) • Metabolic (e.g. Wilson’s disease, hypoparathyroidism) • Depression • Essential tumor
Parkinson’s syndromes that may occur with other neurodegenerative diseases (atypical Parkinson’s syndromes)
• Multisystem atrophy (MSA) Parkinson type (MSA-P) or cerebellar type (MSA-C) • Progressive supranuclear gaze paresis (PSP) • Corticobasal degeneration (CBG) • Dementia of Lewy body type (DLBT) • Spinocerebellar atrophies (various subtypes)
mark, among others, faulty proteins destined for degradation. a-synuclein has been identified as a component of synaptophysin-immunoreactive presynaptic axonal endings, suggestive of its active role in the synaptic vesicle transport. Mutations in the a-synuclein gene have a negative effect on the structure of this normally non-folded protein and lead to auto-aggregation and the formation of amyloid-like filaments. The first mutation in the a-synuclein gene was demonstrated in 1997 (Polymeropoulos 1997). The expressed protein of the mutated a-synuclein can form clumps. The characteristic protein inclusions (Lewy bodies) have been found in cell cultures as well as in studies of transgenic animal when both synuclein and the protein synphilin-1 are present. The gene for the second form of Parkinson’s disease was found in 1998 (Kitada 1998). Based on results of biochemical analyses it was shown that parkin is involved in faulty protein degradation as a ubiquitin-protein ligase. An
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additional gene (PARK5) UCHL1 (ubiquitin-carboxy- terminal hydrolase L1) discovered in Parkinson patients is also involved in the ubiquitin-mediated protein degradation. The identification of this gene supports the assumption of faulty cellular metabolism of these proteins, so that the mutations promote the abnormal protein aggregation directly or indirectly. The clinical findings depend on the localization of the inclusion bodies and the related nerve cell loss. Parkinson’s disease develops in patients with primarily subcortical involvement, while dementia with Lewy bodies occurs in cases of pronounced cortical involvement. Typical of the neuronal degeneration in Parkinson disease is the occurrence of Lewy bodies in the substantia nigra, the substantia innominata, the locus caeruleus, and the dorsal vagus nucleus. In this setting, Parkinson disease is characterized by a loss of melanized dopaminergic neurons with reactive gliosis in the zona compacta of the substantia nigra with emphasis on the ventrolateral aspects (Dickson 2009). However, the neuropathological differential diagnosis of parkinsonism has become increasingly based on fundamental molecular underpinnings, with recognition that the genetics of parkinsonism is heterogeneous and includes disorders that are associated with and without Lewy bodies. Furthermore, Lewy bodies are not disease specific; they are also found in Alzheimer’s disease, Down’s syndrome, multisystem atrophy, progressive supranuclear paresis, corticobasal degeneration, motor neuron disease, and neurodegeneration with iron accumulation. In up to 20% of patients with parkinsonism diagnosed as Parkinson disease in prospective clinico-neuropathologic brain bank studies and compilations of case studies with the retrospective use of clinical diagnostic criteria, the neuropathologic examination did not identify any of the characteristic alterations, in particular the presence of Lewy bodies in the substantia nigra. Reported instead are alternative neuropathologic syndromes, such as progressive supranuclear paresis, multiple system atrophy, Alzheimer’s disease, and multifactorial cerebral processes (Hughes et al. 1992b). These criteria are nevertheless helpful, since the clinical diagnosis of Parkinson disease made at specialized centers is in 90% of cases in agreement with the neuropathologic diagnosis established later: the relatively large proportion of false-negative diagnoses suggests that the clinical experience of Parkinson disease is greater than previously assumed (Hughes et al. 2002). The current clinical definitions of Parkinson disease can therefore be of an only tentative nature. An improved understanding of the genetic principles of Parkinson disease will form the basis for a new classification of the different diseases subsumed under this nosologic entity. The symptomatic threshold for the onset of clinically identifiable motor signs of Parkinson’s disease ranges at a
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nigral cell loss of approximately 60% (Fearnley and Lees 1991). The neurodegenerative process is, however, not limited to the substantia nigra. Additional regions of the brainstem (locus ceruleus, ventral midbrain tegmentum, dorsal raphe nucleus, dorsal vagal nucleus) as well as the amygdala, the thalamus, the hypothalamus, Meynert’s basal nucleus, and the cortex are involved to various degrees. The striate body remains largely intact. The varying clinical features of Parkinson disease may be accounted for by the differently pronounced and distributed neuropathologic alterations. The presence of Lewy bodies in the basolateral nucleus of the amygdala was, for example, found to be associated with the occurrence of hallucinations in non-demented patients (Harding et al. 2002). Degenerative nerve cell changes are further found in the intermediolateral nucleus of the spinal cord, the sympathetic and parasympathetic ganglia, as well as in the myenteric plexus of the intestinal wall, which have a role in autonomic abnormalities as, e.g. constipation and orthostatic dysregulation, in the further course of Parkinson disease (Braak and Del Tredici 2008). Almost 200 years after the initial description of the disease by James Parkinson, the cause of neuronal degeneration in Parkinson’s disease still remains unknown. It is unlikely that a single cause will ever be identified. Parkinson disease represents a complex clinical picture with different underlying, mutually interactive processes. The numerous gene loci that have been described since 1997 further testify to the etiologic complexity and the polygenic etiology of this disease. The leading hypotheses on the etiopathogenesis are based on the assumption of a cytotoxic effect of oxygen radicals occurring in the metabolism of dopamine (the oxidative stress hypothesis). Defects of cellular radical detoxification mechanisms, disturbances in the mitochondrial energy metabolism (complex-1 defect of the mitochondrial respiratory chain), are suggested as possible triggers of pathologic oxidative stress. The mitochondrial complex-1 inhibition may play a central role in this process, as it promotes the aggregation of a-synuclein and the apoptosis in dopaminergic neurons due to the defective degradation of these proteins (Dawson and Dawson 2003). The pathologic deposition of proteins such as a-synuclein and their insufficient degradation by the proteasome is at the center of the pathogenetic cascade. The discovery of a number of monogenic hereditary variants of the disease has provided important new information on the molecular basis of the pathogenesis. The possibility of neuroprotection may become a reality in the not too distant future. More than 15 gene loci have thus far been postulated for Parkinson disease and other neurodegenerative forms of parkinsonism, and a number of mutated genes and their proteins have already been cloned. The gene loci have been described related to the chronologic sequence of their discovery as PARK 1, 2, 3, 4, etc.
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4.7.2.3 Clinical Presentation Parkinson’s disease is characterized by the typical constellation of motor symptoms, comprising slowness of ongoing movements or bradykinesia (here synonymous with bradykinesia and hypokinesia as the fundamental cardinal symptom, without which the diagnosis of an nonspecific Parkinsonism cannot be established), increased muscle tone (rigidity), asymmetric distal extremity tremor and disturbance of reflexive postural compensatory movements. Most patients also show subclinical abnormalities in prefrontal brain functions already at the onset and develop non-motor symptoms in the course of disease, in particular neuropsychological alterations and variable signs of autonomic dysfunction. In advanced stages, the akinetic aspect is increasingly in the foreground, and difficulties in starting movement after rising from a sitting position, inability to pass through doorways or between chairs (motor blockades, freezing), as well as difficulties turning over while lying down. In extreme cases bradykinesia may lead to complete loss of physical movement and the patient may require constant care. Bradykinesia is the most disabling among the cardinal motor symptoms of the disease and should therefore be at the center of all therapeutic efforts. The classic Parkinson resting tremor (pill rolling tremor) is the most reliable diagnostic predictor of the presence of Parkinson disease. According to one study, resting tremor occurs at least once in the course of all patients with neuropathologically confirmed Parkinson’s disease. The absence of tremor over a period of several years should give rise to the differential diagnostic consideration of other Parkinson variants. In most patients, tremor constitutes the predominant, and in less that 50% of cases the initial symptom. At all stages of Parkinson disease, a higher frequency postural tremor may develop in addition to the classic resting tremor. Motor impairment due to tremor occurs chiefly in the setting of a combined resting and postural tremor. In Parkinson’s disease, bradykinesia, rigidity, as well as resting tremor are usually unilateral at the onset, and asymmetric in the course of disease. A bilaterally symmetrical symptom onset is, as a rule, indicative of a different type of Parkinsonism. Disturbances of reflexive compensatory movements after the passive deflection of equilibrium, the so-called postural reflexes, occur regularly only in the later course of Parkinson disease. They manifest primarily spontaneously as insecurity in posture and gait movements. Pronounced disturbances of postural reflexes combined with gait disturbance and axial bradykinesia respond poorly to dopaminergic medications and represent unfavorable prognostic indicators. Pronounced vertical gaze pareses are not compatible with the diagnosis of Parkinson’s disease and speak for the presence of a progressive supranuclear paresis.
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The speech of patients with Parkinson’s disease sounds monotonous and unnatural owing to the decreased volume of speech and variation in pitch. Many patients feel significantly restricted in their communicative ability, since they are not – or only inadequately – able to convey their emotions. The altered speech makes patients appear withdrawn, afraid or disinterested and, conversely, causes a change in the communicative attitude of the dialog partner toward the patient. The reduced activity of the facial musculature which often lends a mask-like expression to the face also causes the patient to appear depressed, apathetic, and less likeable. Significant psychiatric morbidity has been reported for Parkinson disease and, although not as widely investigated, also for other parkinsonian syndromes. The use of psychiatric testing enables the assessment of specific neuropsychologic deficits already in the initial stages of the disease. In view of their high prevalence and importance, in particular depressions have been insufficiently investigated, underappreciated, and are only rarely appropriately treated in Parkinson patients. They represent the most common psychiatric disturbances in Parkinson disease and affect approximately 40% of patients. Anxiety disturbances have also been observed in up to 40% patients, and are frequently found in combination with depression (in approximately 20%). Independent of the motor impairment, they represent a decisive factor in the reduced quality of life in Parkinson patients, which is characterized by complex reciprocal effects of anxiety and motor impairment. L-dopa independent variations in motor function, such as anteropulsion and blocking phenomena, may be increased under conditions of high anxiety. There are, on the other hand, older reports of the disappearance of the symptoms under conditions of extreme stress. The term kinesia paradoxa was introduced by Babinski to describe this phenomenon (Babinski et al. 1921). Depending on the definition and patient selection, different studies have reported a prevalence rate of depression in parkinsonian patients ranging from 3% to more than 90%. In studies using a (semi) structured interview to establish DSM criteria, the reported prevalence of major depressive disorder was 19%, while in studies using DSM criteria without a structured interview, the reported prevalence of major depressive disorder was 7% (Reijnders 2008). The manifestation of dementia early in the clinical course represents an exclusion criterion for the diagnosis of Parkinson disease and mandates careful evaluation of the initial diagnosis and drug therapy. Parkinson patients with cognitive deficits are particularly prone to medication-induced mental confusion and hallucinations. Other causes of dementia associated with Parkinson’s disease that require different therapeutic regimes as, e.g. normal pressure hydrocephalus (NPH), subcortical arteriosclerotic encephalopathy (SAE), progressive supranuclear gaze paresis (PSP), corticobasal degeneration (CBD), or diffuse Lewy body dementia must be excluded.
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The core of cognitive performance impairments in Parkinson disease are prefrontal brain function disturbances associated with difficulties in making rapid changes between alternative problem solving strategies, perseveration tendencies, and deficits in the generation of internal action plans. Parkinson patients have psychologically measurable cognitive abnormalities early in the course, that involve primarily attention, memory, visual-spatial abilities, and cognitive speed. The diagnosis of dementia can be difficult in Parkinson’s disease, since milder deficits in mental flexibility, cognitive speed, and learning ability do not have a significant effect on the activities of the patients’ daily life already limited by existing motor symptoms; in many patients the criteria for dementia are therefore not fulfilled. Every day activities may be extremely limited due to the motor symptoms, so that it is difficult to determine if the cognitive disturbances have an additional disabling effect. Reports on the prevalence of dementia in Parkinson patients vary widely, with prevalence rates ranging from 17% to 42%. The risk of dementia appears to be age dependent and is about three times higher than in the age matched normal population (The risk factors for dementia include early hallucinations and akinetic-dominant forms (Aarsland 2003)). The differentiation from Lewy body dementia is difficult. Neuroleptics (especially haloperidol) are contraindicated in all patients and should never be given. The exception is Seroquel which in small doses may help decrease hallucinations. After 20 years of follow up virtually all surviving Parkinson patients have dementia (Hely 2008). The question as to whether motor slowing occurs concurrently with cognitive slowing (bradyphrenia) in Parkinson patients remains debatable. It is difficult to separate independent slowing of cognitive processes from the motor problem in Parkinson’s disease on the one hand and from the prefrontal function disturbances on the other hand. The early onset of autonomic dysfunction with symptomatic orthostatic hypotension, potency and bladder voiding disturbances with or without incontinence is a differential diagnostic sign for the presence of parkinsonism within the context of multiple system atrophy. A number of vegetative symptoms nevertheless also occur regularly in patients with Parkinson disease. They are less pronounced than the symptoms of autonomic dysfunction in multiple system atrophy. Careful questioning reveals the presence of primary somatosensory symptoms in 40% of Parkinson patients. These comprise chiefly pain, paresthesias and sensations of numbness. The sensory symptoms are not associated with verifiable deficits in the neurological examination. Findings using functional imaging and somatosensory evoked potentials are clearly in support of a sensory processing disturbance at the level of the basal ganglia.
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4.7.2.4 Diagnosis The diagnosis of Parkinson’s disease should always be established on the basis of clinical findings. Imaging modalities are of importance primarily in the differential diagnosis within the different Parkinson syndromes. The findings of cranial CT and MRI of the brain are without pathology in patients with Parkinson’s disease. Structural imaging is not mandatory in the presence of typical clinical findings and course of disease. In patients with prominent gait ataxia, atypical symptoms and rapid disease progression imaging examinations are required (normal pressure hydrocephalus, subcortical arteriosclerotic encephalopathy). Pharmacologic testing of the response of Parkinson symptoms to dopamine receptor stimulation (L-dopa test) is expedient. Patients with disease onset before the age of 50 should undergo a slit lamp examination for Kayser-Fleischer’s rings and a blood and urine analysis for the detection of copper and ceruloplasmin as a screening examination for Wilson’s disease. The following consensus exists on the diagnosis of Parkinson disease according to neuropathologic criteria: a substantial degeneration of dopaminergic neurons with gliosis under formation of Lewy bodies has to be identified in the pars compacta of the substantia nigra. The onset of bradykinesia, rigidity, and resting tremor in Parkinson disease is always unilateral and remains asymmetrically pronounced in the course of disease. The presence of a bilaterally symmetric symptom onset signifies a different form of Parkinsonian symptom. A positive response to L-dopa is currently regarded as an essential diagnostic criterion for the presence of Parkinson disease.
4.7.2.5 Differential Diagnosis A Parkinson disease in the strict sense of the definition has to be distinguished from parkinsonism. Secondary parkinsonian syndromes and parkinsonian syndromes in the context of other neurodegenerative diseases have to be differentiated from Parkinson disease (Table 4.21). The term atypical parkinsonian syndrome or Parkinson plus syndrome is used to describe these syndromes. This definition serves to indicate the presence of additional clinical symptoms that are absent, at least in the early stages, in Parkinson’s disease, such as dementia, dysautonomia as well as ataxia. Among the most important secondary parkinsonian syndromes are drug induced and so-called vascular syndromes. The other secondary parkinsonian syndromes of, e.g. toxic or traumatic causes are of comparatively lesser importance. The common occurrence of postencephalitic parkinsonian syndromes (so-called encephalitis lethargica)
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in the first half of the last century is almost never observed in clinical practice today. The medical history is of importance, particularly in elderly patients, and should include detailed questions on the intake of supposedly innocuous substances, such as gastric medications (metoclopramide), calcium antagonists and parenterally administered neuroleptics like fluspirilene. The term vascular parkinsonism is primarily used to describe the poorly defined area of Parkinson-related motor signs, in particular the parkinsonian gait in association with a subcortical arteriosclerotic or vascular encephalopathy (SAE or SVE).
4.7.2.6 Therapy Parkinson disease was the first neurodegenerative disease with a successful clarification of the causal pathophysiology and the possibility of a therapeutically highly effective neurotransmitter substitution. While this has led to significant improvement in both the quality of life and the life expectancy of the affected patients, modern antiparkinsonian therapy has also given rise to such new and complex problems as the long term L-dopa syndrome. The medical therapy of many Parkinson patients is either too aggressive, or they may receive the wrong medication. This is in some cases accounted for by the difficult differentiation of Parkinson’s disease from other parkinsonian symptoms and essential tremor, so that patients without a definite diagnosis may be treated with antiparkinsonian agents. In other patients, medical therapy may need to be adapted to the treatment of preexisting parkinsonian syndromes which can cause complicating overlapping in the course of the disease. Dopamine substitution using the dopamine precursor substance DOPA and direct action dopamine agonists represents the basis of Parkinson disease therapy. An unequivocal response to these medications is one of the essential criteria for Parkinson disease diagnosis. The most important medications for the therapy of a parkinsonian syndrome (dopaminergic agents) include L-dopa in fixed combination with a decarboxylase inhibitor (‘L-dopa preparations’), so-called COMT inhibitors (catechol-Omethyltransferase inhibitors): entacapone, tolcapone, monoamine oxidase (MAO)-B inhibitors (selegiline, rasagiline), and dopamine agonists from the group of ergot alkaloids (bromocriptine, lisuride, pergolide, dihydroergocriptin, cabergoline), or the non-ergot derivates (apomorphine, pramipexole, ropinirole, rotigotine, piribedil). Other drugs without primarily dopaminergic action for the treatment of Parkinson’s disease include, e.g. budipine and amantadine. Information on specific indications and side effects of the complex parkinsonian pharmacotherapy and its overlapping with other forms of therapy such as deep brain stimulation is provided in specialized reference books.
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Deep brain stimulation (DBS) involves the implantation of electrodes for continuous high frequency electrical stimulation of specific areas of the brain; it has been approved for the therapy of akinesia and tremor in North America and Europe. The ventralis intermediate nucleus (Vim) of the thalamus has been the preferred surgical target for the treatment of parkinsonian tremor for many years, but this has been challenged by the subthalamic nucleus (STN) which was introduced because of its effect on akinesia. Deep brain stimulation of either target possesses high therapeutic efficacy against tremor in Parkinson disease. The effect of the STN stimulation on the akineticrigid symptoms and tremor is similar to the effect observed with L-dopa therapy. Stimulation of the globus pallidus internus (GPi) is particularly effective against DOPA-dyskinesias. Patients with STN stimulation required a lower dose of dopaminergic agents than did those undergoing GPi stimulation (Follett et al. 2010; Williams et al. 2010). Depending on the reporting centers, the rates for mortality or irreversible, compromising morbidity range from 0.5% to 3%. This highly effective, although complex procedure, is currently indicated for otherwise treatment-refractory pronounced on-off fluctuations, dopamine-induced dyskinesias and tremor. The degree of L-dopa-responsiveness, i.e. the improvement in motor function under L-dopa therapy, is a predictor of the success of the surgical intervention; the benefit is greater in younger than in older patients. Specific contraindications include dementia, serious preexisting psychiatric disorders, as well as cerebral atrophy. Axial symptoms such as bulbar function, balance and gait do not tend to improve with deep brain stimulation in the STN. The pedunculopontine nucleus is a new target which is being investigated to improve freezing in Parkinson disease (Ferraye et al. 2010; Moro et al. 2010). Medical management should be supplemented with physiotherapy, occupational therapy, voice, speech, and swallowing therapy and in the later course of Parkinson disease. This applies in particular to advanced stages of disease when medication-refractory symptoms such as freezing, gait and balance disturbances, or voice, speech and swallowing disturbances become more prominent. Physiotherapy can improve the gait pattern and postural instability of the patient, and demonstrate strategies for the prevention of movement blockades or falls. The exercises can also help turning over when lying down or standing up from sitting. Active as well as passive movement therapy is felt to be beneficial by patients with rigor-related muscle pain. It further serves both as contraction prophylaxis and to improve posture. Despite the continuously growing number of medications and the availability of complex treatment options such as deep brain stimulation and medication pumps, physiotherapy and speech therapy are gaining increasingly in importance. This is due to the fact that the dominant problems in the further course of Parkinson disease like falling, gait, voice, speech and swallowing disturbances are difficult to treat with pharmacotherapy or deep brain stimulation.
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Physiotherapy assumes a special position as it is prescribed by physicians and given preference by both patients and self-help organizations. There is increasing research going on to support the beneficial therapeutic effect of both physioand voice therapy in Parkinson patients. However, implementation of specialized physiotherapy has so far not been shown to change health outcomes for patients with Parkinson disease, whereas it appears to reduce overall health-care costs in Parkinson patients (Munneke et al. 2010).
4.7.2.7 Course and Prognosis The DATATOP study of 800 de novo Parkinson patients observed the course of Parkinson disease under dopaminergic therapy: after approximately 5 years, 50% of patients developed “wearing off” symptoms (decreased drug efficacy about 4–6 h after intake, as well as nocturnal or early morning akinesia before the first daily dose, afternoon akinesia; 30% of patients showed dyskinesia and 25% freezing symptoms (motor blocks, sudden freezing of gait frequently occurring on passing through narrow spaces, or inability to initiate gait). Younger patients had an increased probability of a wearing off phenomenon, while freezing phenomena were more prevalent in women and older patients. The reported annual mortality rate was 2.1% (Parkinson-Study-Group 1998).
4.7.3 Parkinsonism with Early Onset of Dementia 4.7.3.1 Lewy Body Disease Lewy body disease is regarded as a still young clinically discrete entity (Kosaka et al. 1976). Yet, this concept of Lewy body dementia as such is also subject to criticism: it is claimed that Lewy body disease does not represent a discrete entity, but is merely a mixed or special form of Parkinson disease or Alzheimer’s disease. The characteristic histopathologic (Lewy bodies) and molecular characteristics (a-synuclein) of both Parkinson disease and Lewy body disease support a common pathologic process. The differentiation of dementia with Lewy bodies has nevertheless direct consequences in the management of the patient, because significant differences exist between the initial symptoms, prognosis and therapy of Lewy body dementia and Parkinson disease and Alzheimer’s disease. There is a paucity of population-based data on the incidence. Fifteen to 25% of dementia symptoms occurring in patients older than 65 years have been attributed to Lewy body disease. A community-based study performed in London showed only
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11% of all causes of dementia to be associated with Lewy body disease, thus ranking it in third place after Alzheimer’ disease and cerebrovascular diseases (Stevens et al. 2002). Clinical features typically include fluctuating cognitive deficits, vigilance fluctuations, and detailed visual hallucinations. The patients develop parkinsonism already early in the course of disease. Hallucinations may manifest as vivid optic hallucinations involving complex scenes with bizarre episodes. Parkinsonism represents the cardinal motor signs, in addition to unexplainable falls and hypersensitivity to neuroleptics (McKeith et al. 2005). The cognitive symptoms may be similar to those of Alzheimer’s disease; characteristic features in comparison with Alzheimer’s disease are pronounced fluctuations in attention, which may in some instances lead to the misdiagnosis of a convulsive disorder. The clinical onset of Lewy body disease is usually after age 70, the reported survival times from the occurrence of the initial symptoms range from 2–5 years (Hansen and Samuel 1997). Smooth transitions may be observed from Lewy body disease, to Alzheimer’s and vascular dementia, in addition to various mixed forms of these diseases. While parkinsonian motor symptoms usually occur in the advanced stages of Alzheimer’s dementia, they serve as diagnostic criteria for Lewy body dementia already in the early stages, or at least early in the course of the disease (Table 4.22). The combination of a Parkinson syndrome and dementia was detected in 80% of patients with Lewy body disease, while a Parkinson syndrome was present in only 7% of patients with Alzheimer’s disease and 10% of vascular dementia patients (Ballard et al. 2000). The differentiation between Parkinson disease with dementia and Lewy body dementia is academic when dementia and parkinsonism occur in close temporal sequence. Visual hallucinations in Lewy body dementia (73%) typically occur in the early course, and in Parkinson disease (50%) in the later course of disease. Parkinsonism without Lewy-bodies (e.g. in multiple system atrophy, vascular parkinsonism, PSP and CBD) rarely show a propensity for visual hallucinations (Williams and Lees 2005). To enable differentiation of Lewy body dementia from Parkinson disease, the revised 2005 diagnostic criteria for Lewy body dementia stipulate that the diagnosis of Parkinson disease can be established when dementia occurs in parallel to or within 12 months after onset of parkinsonism (McKeith et al. 2005, see Table 4.22). Parkinson disease with dementia is present when dementia onset is more than 1 year after the onset of parkinsonism. The following symptoms suggest the presence of Lewy body dementia vs. the diagnosis of dementia in Parkinson disease: • • • •
Prominent memory impairment Aphasia/apraxia Impaired spatial orientation Relatively mild parkinsonism
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• Vivid visual non-drug induced hallucinations • Pronounced variations in attention
4.7.3.2 Subcortical Vascular Encephalopathy, Vascular Parkinsonism and Normal Pressure Hydrocephalus Due to the high prevalence of vascular diseases, the overlapping entities subcortical vascular encephalopathy (SVE), vascular parkinsonism, and normal pressure hydrocephalus (NPH) constitute a common differential diagnosis in the coincidence of dementia and parkinsonism. They are occasionally subsumed under the term pseudo-parkinsonism or Parkinson plus syndrome (see p. 93). The cardinal symptom is a gait disorder. The gait pattern is characterized by small steps, pronounced difficulties in gait initiation, and blockades (magnetic gait). In contrast to Parkinson’s disease, the gait is broader based in SVE and NPH, owing to the accompanying postural instability; upper body mobility – gestures, arm swings while walking, truncal posture – is usually normal and at times even exaggerated (“rowing motions of arms while walking”). The term lower body parkinsonism is used in the American literature to describe this system constellation (Fitzgerald and Jankovic 1989). In some patients, the gait disturbance may be associated with an isolated gait initiation failure (Atchison et al. 1993). While gait flow is normal, the patients initially appear to be glued to the floor as they are trying to ambulate. These patients fulfil the criteria for parkinsonism, since they usually also have a pronounced bilaterally symme tric lower extremity brady/hypokinetic syndrome (brady/ hypokinesia as the cardinal symptom) and postural instability (= postural instability as a supportive symptom) (see Table 4.23). Comparable to other forms of Parkinsonism, dementia in SVE and NPH corresponds to the dysexecutive type, also referred to as subcortical dementia. A differentiation between the different subcortical dementia etiologies (Lewy body dementia, SVE, NPH, progressive supranuclear gaze paresis) is not possible using psychological testing. Not only the term subcortical vascular encephalopathy (SVE) is used for the syndromic diagnoses of vascular dementia and vascular parkinsonism (Baezner et al. 2003), but many other, frequently overlapping terms have been applied. The term vascular parkinsonism dates back to an article titled ‘Arteriosclerotic parkinsonism’ (Critchley 1929). With the exception of the poor L-dopa response, the author described the identical aspects of crucial importance for the diagnosis of vascular parkinsonism used today (Kalra et al. 2010) (Table 4.23).
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Table 4.22 Revised criteria for the clinical diagnosis of Lewy body dementia (= LBD; according to McKeith et al. 2005) Cardinal symptoms (prerequisites for the clinical diagnosis of possible or probable LBD) • Dementia: progressive loss of cognitive abilities of a magnitude which presupposes a disturbance in normal social/and or occupational functioning • Memory impairment: prominent or persistent memory impairments do not in all cases manifest in the early stages, but regularly become evident in the further course • Deficits observed in the assessment of attention, executive functions, and visuospatial abilities; these may typically be particularly prominent Core symptoms (two are sufficient for a probable LBD diagnosis, one for a possible LBD diagnosis) • Fluctuating cognition with pronounced variations in attention and vigilance • Recurrent visual hallucinations, typically well formed and detailed • Spontaneous features of parkinsonism Suggestive symptoms (in the absence of core symptoms, one or more suggestive symptoms are sufficient for a possible LBD diagnosis, a probable LBD diagnosis should not be established based on the suggestive characteristics alone) • REM sleep behavior disorder • Severe sensitivity to neuroleptics • Low dopamine transporter uptake in the basal ganglia on SPECT or PET scans Supportive symptoms (frequently present, although their diagnostic specificity has not been demonstrated) • Frequent falls and syncope • Transient, unexplained loss of consciousness • Prominent autonomic dysfunction (e.g. orthostatic hypotension and urinary incontinence) • Hallucinations of other modalities • Systematized delusions • Depression • Relatively small number of involved medial temporal lobe structures on CCT/MRI imaging • Generalized reduced uptake on SPECT/PET perfusion scan with reduced occipital activity • Abnormal MIBG myocardial scintigraphy (reduced uptakes) • Pronounced slow wave activity in the EEG with transient sharp waves in the temporal lobe Diagnosis of LBD is improbable • In the presence of focal neurologic signs or indications of relevant cerebrovascular disturbances on structural imaging • In the presence of other organic disorders or cerebral diseases, sufficient to serve as an explanation for the clinical syndrome • If the first manifestation of parkinsonism occurs at a time when high grade dementia is already present Temporal sequence of symptoms • The diagnosis of LBD should be made when dementia occurs prior to or concurrently with parkinsonism (if present). The term dementia in idiopathic Parkinson syndrome (IPS) or Parkinson’s disease dementia (PDD) should only be applied to dementia occurring in the course of a clinically confirmed idiopathic Parkinson syndrome (see Table 4.20). In this clinical setting, a term should be chosen which represents the most appropriate description of the clinical situation. The umbrella term Lewy body disease for IPS and LBD may be appropriate in these cases. The 1-year rule (in IPS, the onset of parkinsonism should have occurred 1 year prior to the initial manifestation of dementia symptoms) recommended by current guidelines continues to be valid for scientific study designs with a focus on the differentiation between Lewy body dementia and dementia in IPS Table 4.23 Characteristic features of vascular parkinsonism • Vascular risk factors • Lower body more strongly affected than the upper body • Gait ataxia • Postural instability • Absence of resting tremor • DOPA responsiveness is an area of debate: virtually no response (Winikates and Jankovic 1999; favorable response to L-dopa in some cases with lacunae surrounding the substantia nigra (Zijlmans et al. 2004); response to DOPA described for Binswanger’s disease (Mark et al. 1995)
Binswanger’s disease is often used synonymously for SVE, when dementia and a gait disorders are prominent in the setting of generalized subcortical vascular pathology (Fig. 4.55). The neuroradiological finding of ventricular enlargement is the hallmark of a condition named normal pressure hydrocephalus (NPH). The clinical differentiation between SVE with parkinsonism which affects chiefly the lower extremities and NPH is often difficult, since both NPH (Krauss et al. 1996) and SVE are closely associated with arterial hypertension, and the symptoms, including bladder
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Fig. 4.55 (a–b) Transversal FLAIR sequences; images obtained in a patient with frontal gait disturbance or vascular parkinsonism and dementia (Binswanger’s disease). The periventricular hyperintensities are more pronounced in regions around the dorsal horns. A comparison with normal pressure hydrocephalus (Fig. 4.56) reveals an inner and outer atrophy, which also involves the segments proximal to the vertex, as well as additional, prominent subcortical vascular lesions, such as lacunae
disturbances, are similar in the later course of disease. Subcortical vascular disease leads to loss of white matter and enlargement of the ventricular system. The rubbery white matter also lacks normal support for the ventricles and adds to the ventricular enlargement seen in SAE (Binswanger disease). According to the initial describers, two signs of the clinical triad (gait ataxia, incontinence and dementia) have to be identified to establish the diagnosis of NPH. Gait ataxia corresponds to the frontal gait disturbance or lower body parkinsonism described above and constitutes the obligatory cardinal symptom. The presence of cerebral atrophy as the cause for enlarged ventricular enlargement must be excluded. Communicating cerebrospinal fluid spaces are the prerequisite for the differentiation from obstructive hydrocephalus (Fig. 4.56).
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Fig. 4.56 (a) Transversal and (b) sagittal MRI (FLAIR sequence); images obtained in a 74-year-old patient with normal pressure hydrocephalus and broad based magnetic gait with difficulties in gait initiation and threshold apprehension (lower-body parkinsonism). Dispropor tionate lateral ventricular enlargement and loss of caudate head waisting of the anterior horns of the lateral ventricles, with generally absent cortical atrophy (“soldered cerebellar gyri near the vertex”), as well as rounding of the temporal horn without or only mild hippocampal atrophy
4.7.3.4 Frontotemporal Lobar Degeneration The term frontotemporal lobar degeneration or Pick’s complex encompasses a group of dementia disorders with focal neuropsychiatric symptoms and the possible occurrence of parkinsonism in all of the subgroups at different stages of the disease. The similarities in the neuropathology, as well as overlapping of the clinical symptoms in the course of the different diseases ranging from frontotemporal dementia, primary progressive aphasia, corticobasal degeneration to supranuclear gaze paresis have led to coining the above umbrella terms (Hodges et al. 2004; Kertesz 2003). Although parkinsonism is somewhat in the background of other disease entities of this group, corticobasal degeneration has a more prominent role here, owing to the finding that both parkinsonism and dementia are usually approximately equally in the foreground.
4.7.3.3 Parkinsonism in Alzheimer’s Dementia
4.7.3.5 Progressive Supranuclear Gaze Palsy
In contrast to Lewy body dementia where parkinsonism is one of the diagnostic criteria present early in the course, it manifests only in the advanced stages of Alzheimer’s dementia in the strict sense. The results of comparison studies with age-matched controls reported that 23% of outpatients with Alzheimer’s dementia had a diagnosis of parkinsonism, while parkinsonism was not found in any of the controls (Merello et al. 1994). Signs of motor parkinsonism in patients with Alzheimer’s dementia are associated with advanced age and an unfavorable course (Lopez et al. 1997). Due to the daily overuse of neuroleptic medication in the treatment of geriatric patients, it is often difficult to differentiate primary signs of motor parkinsonism from neuroleptic-induced iatrogenic extrapyramidal motor effects.
Progressive supranuclear gaze palsy (PSP) (or SteeleRichardson-Olszewski syndrome) refers to a disorder frequently associated with parkinsonism, whose differentiating clinical symptom is a supranuclear vertical gaze palsy. Because other signs in addition to those of a typical Parkinson disease are also present, PSP is counted among the so-called Parkinson plus syndromes (p. 93). The term Steele-Richardson-Olszewski syndrome is used synonymously with PSP. The syndrome is named after the Canadian physicians who, in the early 1960s, described the brains of patients who developed PSP between the ages of 50 and 60 (Steele et al. 1964). The clinical diagnosis of progressive supranuclear palsy (PSP) relies on identification of characteristic signs and symptoms. A proportion of
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pathologically diagnosed cases do not develop these classic features, prove difficult to diagnose during life and are considered as atypical PSP. There are two clinical phenotypes recognized which have been named Richardson’s syndrome and PSP-parkinsonism. Cases of Richardson’s syndrome are characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction. The PSP-parkinsonism patients are characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and are frequently confused with Parkinson’s disease (Williams et al. 2005).
4.7.3.6 Epidemiology PSP is assumed to be the second most common form of neurodegenerative parkinsonism. The prevalence is 1–2:100,000 population. The annual incidence per 100,000 population is about 5.3 for the group of 50–99-year-olds and is therefore higher than the reported prevalence of 3:100,000 for multiple system atrophy. PSP occurs mostly in the elderly (incidence per 100,000 is 1.7 in 50–59-year-olds; 14.7 in 80–99-yearolds). The mean survival time consistently reported by different studies is 5–7 years (1–17) years. Males are slightly more often affected. Contrary to previously reports arterial hypertension is not a significant risk factor for PSP, although cerebrovascular disease can masquerade clinically as PSP (Colosimo et al. 2003).
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4.7.3.8 Clinical Course Vertical gaze paresis in conjunction with a symmetrical parkinsonism is the hallmark of PSP. These signs are found in the early course of the disease (Table 4.24). Gaze paresis
Table 4.24 Clinical criteria for the diagnosis of progressive supran uclear gaze palsy (According to Litvan et al. 1996) Possible PSP diagnosis • Slowly progressive disorder with earliest onset at age 40 (generally later) • Vertical supranuclear gaze palsy upward and/or downward, or slowing of vertical saccades and postural instability and falls within the first year of onset • No concurrent diseases serving as identifiable cause of the symptoms Probable PSP diagnosis • Criteria as ‘Possible PSP diagnosis’ • Vertical supranuclear gaze palsy instead of slowing of vertical saccades Define PSP diagnosis • Criteria as ‘possible PSP diagnosis’ and ‘Probable PSP diagnosis’ • Histopathologic confirmation of the characteristic subcortical alterations Supportive symptoms for the diagnosis of PSP • Vertical supranuclear gaze palsy upward or downward • Slowing of vertical saccades • Prominent postural instability within the first year of onset
4.7.3.7 Etiology The post-mortem examination of the brain of a PSP patient demonstrates the loss of nerve cells predominantly in the brainstem; primarily in the; • • • • •
Pallidosubthalamic complex Substantia nigra pars compacta Superior colliculus Periaqueductal central gray matter Pretectal regions with the respective nuclei responsible for the control of eye movements and • Pontine nuclei Atrophy of the pallidum may occur in advanced stages of PSP. A substantial number of tau-positive neurofibrillary tangles and neuropil threads, as well as nerve cell loss and gliosis are detected in the affected areas. In contrast to Alzheimer’s disease, these neurofibrillary alterations are composed of straight filaments. Comparable to Parkinson’s disease, a severe reduction in dopamine is present in the substantia nigra and the striatum, in addition to a loss of cholinacetyl-transferase activity in the striatum. PSP is classified in the group of so-called tauopathies due to the presence of neurofibrillary tangles and neuropil threads.
• Symmetrical hypokinetic-rigid symptoms, more prominent proximal than distal • Abnormal neck posture, primarily retrocollis • Poor or absent response to oral L-dopa therapy • Dysphagia and dysarthria in the early course of disease • Cognitive impairment early in the course, with the presence of at least two of the following symptoms: • Apathy, impaired abstractive ability • Slow word flow • Disturbed utilization and imitation behavior • Prefrontal signs Exclusion criteria for PSP • Whipple’s disease • Positive family history • Systemic disease or other identifiable cause of the symptoms • Hallucinations unrelated to dopaminergic medications • Cortical dementia of the Alzheimer type • Prominent cerebellar symptoms early in the course of disease • Early onset of autonomic nervous system disturbances (prominent orthostatic dysregulation, incontinence) • Neuroradiologic confirmation of a relevant structural lesion (basal ganglia or brainstem infarctions, lobar atrophy) • Prominent asymmetry of clinical signs of parkinsonism
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downward is considered to be a more specific sign for PSP than upward gaze paresis, since weakness in shifting of the gaze upward represents a normal phenomenon in the aging process and is frequently observed in patients with Parkinson disease. The most prominent signs of parkinsonism in PSP include posture and gait instability with frequent falls, in particular backward falls – often present already at disease onset – and rigidity (described as dystonia in the original publication), as well as symmetrical poverty of movement (akinesia, brady/hypokinesia). Resting tremor and lateral asymmetry of the symptoms (stiffness on the left or right side) typical for Parkinson disease are absent in PSP. Conversely, a number of symptoms are present already in the early years after disease onset, which may be present in Parkinson disease only after a long course, such as articulation, voice and swallowing disturbances (so-called pseudo bulbar paralysis), nearly complete loss of blinking with eyes wide open, which accentuates the characteristic “astonished” look attributable to impaired eyelid opening or closure in 20% of patients. In contrast to Parkinson disease, patients with PSP develop clinically apparent dementia (>50% of patients) in the early stages. While bradyphrenia, attention deficits, and lack of initiative are hallmarks of PSP, speech and mathematical ability – different from the Alzheimer type – are relatively intact. Memory performance as well as cognitive ability and recall memory are affected in both forms of dementia, but are surprisingly long preserved in PSP. Disturbance of gait or unsteady walking, regularly described as dizziness by the patients, is the most common reason for physician consultation. A low voice and articulation difficulties represent additional early causes for consultation. Poverty of movement (akinesia) and rigidity (muscle stiffness) are focussed chiefly on the musculature of the spine and result in difficulties walking and initiation of gait. Getting up from a seated position becomes difficult. This is not related to palsy or muscle weakness, but the wish to get up from the chair cannot be transformed into motor action. Gait is usually upright in patients with PSP in contrast to Parkinson disease patients. Stiffness of the (rigidity/dystonia) spinal musculature is often indicated by hyperextension of the neck. The patients are unable to turn over in bed without assistance. Akinesia is increased in the further course and the classic antiparkinsonian medications typically do not provide substantial relief. The patients are generally confined to bed in the late stages of the disease. Some patients are characterized by emotional instability with uncontrollable crying or laughter. Muscular stiffness may affect changes in the joints. Swallowing disturbances occurring in the advanced stages of PSP represent a risk for the aspiration of food or gastric contents. As a consequence, many patients die from pneumonia.
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4.7.3.9 Diagnosis and Differential Diagnosis Although the diagnosis is made clinically, the definitive diagnosis mandates neuropathologic confirmation. It also requires the presence of at least one complaint leading to the complete loss of upward and downward gaze in the course of the disease which may also be found in other neurodegenerative diseases. The diagnosis is difficult, in particular at the onset of PSP. Additional typical features of PSP that enable differentiation from Parkinson disease and other Parkinson plus syndromes are shown in Table 4.24. The EEG is normal in most patients. Brain imaging (CT, MRI) usually shows enlarged ventricles (especially the third ventricle with enlargement of the interpeduncular cistern and the cisterna magna), as well as a diminished size of the midbrain (Fig. 4.57). In contrast to findings in multiple system atrophy, the cerebellum is, as a rule, not decreased in size, although atrophy of the cerebral cortex may be present, particularly in the region of the frontal and the temporal lobes. 4.7.3.10 Therapy While complete relief of symptoms is often achieved in the early phase of Parkinson disease with an appropriate dopaminergic combination therapy (dopa preparations and dopamine agonists), this is the case in only 10% of PSP patients, who have an only modest and transient improvement compared to those with Parkinson disease. The general rule for the management of PSP is: more is less, in particular since antiparkinsonian agents may even have a negative effect. In a formalized therapeutic attempt to be carried out for diagnostic purposes with the use of a dopa preparation (slow increments over 1–2 weeks up to 1,000 mg of the respective agent per day, distributed over at least three
Fig. 4.57 Transverse T1-weighted MRI obtained in a patient with advanced progressive supranuclear palsy. Enlarged interpeduncular, ambient and superior cerebellar cisterns in midbrain atrophy (“Mickey mouse sign”) with reduced anterioposterior midbrain diameter to below 14 mm. Enlargement of the lateral ventricles and the aqueduct, as well as temporal atrophy
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daily doses), careful monitoring is required to ensure that the condition is not worsened. In a study of patients with a definite diagnosis of PSP, dopaminergics were associated with a slight improvement of parkinsonian symptoms in some of the patients, but lead to confusion and feelings of dizziness – particularly on standing up – in about half of the study population (Kompoliti et al. 1998). A report on the assessment of dopamine agonists did not find any beneficial effects for pramipexole (Weiner et al. 1999). Occasional painful involuntary muscle spasms (dystonias) were observed in one patient who took dopaminergic therapy; the effects subsided with discontinuation of these medications (Barclay and Lang 1997). The frequently observed levator inhibition (apraxia of eyelid opening = atypical blepharospasm = eyelid spasm) becomes symptomatic or is exacerbated under dopaminergic therapy (Defazio et al. 1999). Botulinum toxin injections into the eyelids are helpful and may be effective in improving this severely debilitating symptom. In view of the finding that dopaminergic therapy usually does not lead to an improvement of PSP symptoms, adamentan derivatives (amantadine-HCl or sulphate, not more than 2–3 × 100 mg per day, alternatively memantine) should be administered, even though no reliable data on the effectiveness of this treatment are currently available (Kompoliti et al. 1998). There are isolated reports of modest to impressive therapeutic effects of low-dose (25–75 mg/day) amitriptyline (Engel 1996). The effectiveness of this substance has been shown for the therapy of uncontrollable laughter or crying (affective incontinence). Donepezil is the only cholinesterase inhibitor currently approved for the therapy of Alzheimer’s-type dementia which has been investigated in a formal clinical trial (Litvan et al. 2001). Although the study reported an improvement in memory test scores, mobility and performance of activities of daily living scores were worsened to a degree that the improvement in memory function was completely overshadowed and donepezil could not be recommended for the therapy of patients with PSP. Some patients benefit significantly from walking training and subsequent assisted walking with a walker or other walking aids. As PSP progresses further, function-activating therapies (neuropsychology, physical therapy, occupational therapy, voice, speech and swallowing therapy) are gaining increasingly in importance to compensate for the lost capabilities. This is due to continuing or increasing PSP-related problems as, e.g. falling tendency, gait, speech and swallowing disturbances, or dementia, despite the growing availability of medications and complex procedures such as deep brain stimulation. The choice of suitable therapeutic aids, as well as an adaptation of the domestic environment to the physical disability is essential. Outpatient and/or in-hospital care may become necessary. Family members may be subject to physical and mental stress, for which they should turn to self-help groups or seek psychotherapeutic counselling.
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4.7.3.11 Corticobasal Degeneration Corticobasal degeneration (CBD) (syn. corticobasal ganglionic degeneration = CBGD) was first described in the 1960s (Rebeiz et al. 1968). Neuropathologically the process involves primarily the cortex – with pronounced frontoparietal asymmetric atrophy, which is particularly distinctive near the central sulcus. In addition to cortical nerve cell loss, neuronal death and gliosis are also found in the striatum, globus pallidus, claustrum, amygdaloid complex, thalamus, subthalamic nucleus, nucleus ruber, substantia nigra, and less commonly, in the dentate nucleus and some brainstem nuclei. The volume of the white matter, the cerebral peduncles and the substantia nigra is asymmetrically reduced. The neuropathologic diagnosis of CBD is based on showing tau-positive neuronal inclusions, oligodendroglial coiled bodies, and so-called astrocytic plaques. The insidious onset of the classic syndrome occurs around age 60, and is in many patients similar to a typical Parkinson disease with a pronounced lateral asymmetry of brady/hypokinetic symptoms. Other characteristic symptoms include the alien limb phenomenon (feeling of alienness of a limb), as well as dystonia, pyramidal tract signs, insecurity of posture and gait, oculomotor disturbances, prefrontal signs such as grasp reflexes, and aphasic disturbances in the later stages. The disorder is apparently not diagnosed when dementia represents the most prominent or initial symptom. However, dementia was found to be the prominent initial symptom in patients with neuropathological confirmation of CBD (Grimes et al. 1999). The clinical finding of asymmetry corresponds to a focal cortical atrophy disclosed on MRI (Fig. 4.58). The response to L-dopa is only very slight in about one quarter of CBD patients. The disease progresses slowly and medical therapy of the dementia symptoms is currently not
Fig. 4.58 Transverse T2-weighted MRI obtained in a patient with corticobasal degeneration. Demonstration of pronounced focal frontoparietal cortical asymmetric atrophy (right) contralateral to the initially affected upper extremity, here concentrated around the postcentral and supramarginal gyri. At the onset of the disease, the visualized atrophy is apparent only on right-left comparison
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available. Occupational therapy and physiotherapy (therapy for apraxia and dystonia) as well as the appropriate use of therapeutic aids are indicated for the treatment of the frequently severe symptoms.
4.7.3.12 Rare Parkinsonian Syndromes with Dementia The diseases discussed thus far occur almost exclusively in older adults. Parkinsonian syndromes with dementia (Table 4.25) are rare in young patients. Metabolic disorders (e.g. metachromatic leukodystrophy, early systemic degenerations), dystonias and other hyperkinetic movement patterns dominate in this group of patients. The occurrence of Wilson’s disease in patients older than 50 years has not been described thus far. This copper metabolism disturbance is most often accompanied by parkinsonian features and neuropsychiatric symptoms such as dementia (Walshe and Yealland 1992). In patients with Huntington’s disease, in particular those with the rare young adult- onset Westphal variant and pantothenate kinase-2-(PANK2-)associated neurodegeneration (= NBIA syndrome [NBIA = neurodegeneration with brain iron accumulation, also neuroaxonal dystrophy, formerly Hallervorden-Spatz syndrome]) (Fig. 4.59), the disorder generally manifests as a combination of parkinsonism and dementia already at the time of onset (Hayflick et al. 2003). In about one third of patients with non-classic variants of Creutzfeld-Jakob disease Parkinson dementia syndromes are present that are not associated with the otherwise typical EEG abnormalities and myoclonus (Maltete et al. 2006). Whipple’s disease, a very rare, treatable parkinsonian syndrome with dementia, usually associated with ataxia is to be mentioned in the discussion of these syndromes (Matthews et al. 2005). Table 4.25 Significance of dementia in different parkinsonian syndromes Syndrome Significance of dementia Idiopathic Parkinson’s syndrome
−/+
Multiple system atrophy
−/+
Lower body parkinsonism in subcortical vascular encephalopathy (SAE) and normal pressure hydrocephalus
+
Corticobasal degeneration
++
Progressive supranuclear gaze palsy (PSP)
++
Huntington’s disease, PANK (pantothenate kinase-associated neurodegeneration = NBIA syndrome (neurodegeneration with brain iron accumulation)
+++
Creutzfeld-Jakob disease, etc.
++++
Diffuse Lewy body disease
++++
Alzheimer’s type dementia
++++
Fig. 4.59 (a–b) Transverse T2-weighted MRI obtained in a patient with an akinetic-rigid syndrome in NBIA. Hyperintense symmetrical putamens in T2-weighting (“eye of the tiger” sign on MRI when the image is turned with the frontal brain pointing down)
4.7.4 Multiple System Atrophy The term multiple system atrophy (MSA) was introduced in 1969 (Graham and Oppenheimer 1969). It is viewed today as a sporadic disorder which is clinically characterized by a combination of parkinsonian symptoms and disturbances of the autonomic nervous system, the cerebellum and/or the pyramidal tract. MSA therefore summarizes the diagnoses striatonigral degeneration, olivopontine cerebellar atrophy and Shy-Drager syndrome. In accordance with consensus criteria these types are defined as MSA-P (MSA with predominantly parkinsonian symptoms; approximately 80%) and MSA-C (MSA with predominantly cerebellar symptoms: approximately 20%) (Gilman et al. 1999; Deuschl and Elble 2000) (see Table 4.26). 4.7.4.1 Epidemiology The estimated annual prevalence of MSA is 6.4:100,000, at an annual incidence of 0.5:100,000; the ratio of male/female patients is 1.3:1 (Schrag et al. 1999). The onset of MSA occurs between the ages of 45 and 69 in 92.5% patients, and between 70 and 79 years in 4% of patients. The youngest patient affected by MSA was 31, and the oldest 78 years old (Quinn 1994). 4.7.4.2 Etiology Histopathologic examination shows neuronal cell loss and gliosis in different structures of the central nervous system. The dominant degenerative alterations in MSA-P are found in the striatum, the globus pallidus and the substantia nigra, while chiefly the inferior olive, additional pontine nuclei, the medial cerebellar peduncle and the cerebellar cortex are affected in MSA-C. The autonomic symptoms are attributable to involvement of the intermediolateral cell column and
4.7 Degenerative Brainstem Diseases Table 4.26 Diagnostic criteria and exclusion criteria for multiple system atrophy (MSA) (According to Gilman et al. 1999) Domain 1: autonomic disturbances • Orthostatic hypotension (fall >30 mmHg systolic or 15 mmHg diastolic after 3 min) • Urinary incontinence or incomplete bladder voiding, alone or in combination with erectile dysfunction in males Domain 2: Parkinson syndrome (parkinsonism) • Bradykinesia • Rigor • Postural instability (not caused by a disturbance of visual, vestibular, cerebellar, or proprioceptive function) • Tremor (resting tremor, postural tremor, or both) The criterion for the presence of parkinsonism is fulfilled, when bradykinesia and a minimum of one of the features 2-4 is identified.
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Onuf’s nucleus in the spinal cord and to neuronal death in the pontine micturition center. The essential neuropathologic criterion for the diagnosis of MSA is the demonstration of glial cytoplasmic inclusions. These comprise a-synuclein, ubiquitin, and tau-positive inclusions identified in the oligodendrocytic cytoplasm and nucleus, as well as in the neuronal nucleus, cytoplasm, and axon. The demonstration of a-synuclein has led to classification of MSA as an a-synucleinopathy. Lewy bodies are, however, not found in this clinical picture. The death of central or preganglionic autonomic neurons is responsible for the autonomic dysfunction in MSA, while the autonomic disturbances in Parkinson disease are mediated by damage to postganglionic nerve cells (Oertel and Möller 2005).
Domain 3: cerebellar disturbances • Gait ataxia • Dysarthria (ataxic) • Limb ataxia • Sustained gaze-evoked nystagmus The criterion for the presence of cerebellar dysfunction is fulfilled, when gait ataxia and a minimum of one of the features 2-4 is identified. Domain 4: corticospinal tract disturbance • Positive Babinski’s sign combined with pathologically increased muscular proprioceptive reflexes Pyramidal tract signs do not constitute a criterion for the diagnosis of MSA Evaluation Possible MSA • One criterion plus two features from two separate other domains; in parkinsonism a poor response to levodopa qualifies as one feature, so that only a second feature is required Probable MSA • Criterion for autonomic disturbance plus poorly levodopa responsive parkinsonism or cerebellar disturbance Definite MSA • Only on pathologically confirmed high density of glial cytoplasmic inclusion bodies in association with a combination of degenerative changes in the nigrostriatal olivopontocerebellar pathways Exclusion criteria for the diagnosis of MSA • Onset of symptoms under 30 years of age • Positive family history • Systemic diseases or other identifiable causes for symptoms according to domains 1-4 • Hallucinations unrelated to medication • Diagnostic-Statistic-Manual (DSM) criteria for dementia • Prominent slowing of vertical saccades or vertical supranuclear gaze palsy • Signs of a focal cortical dysfunction such as – Aphasia – Alien limb sign – Parietal dysfunction • Metabolic, molecular genetic or imaging confirmation of an alternative causes for symptoms according to domains 1-4
4.7.4.3 Clinical Findings Up to 41% of MSA patients have autonomic nervous system disturbances in the initial stage of the disease. A determining factor for the diagnosis in males is impotence, which may have been present for a number of years prior to the diagnosis, or urinary incontinence in both males and females. Other important questions relating to the patient history include orthostatic hypotension which may, e.g. manifest as extreme dizziness and/or syncope after sudden standing. Other characteristic features of MSA are atypical irregular resting, postural and/or kinetic tremor (60% of patients), as well as stimulus sensitive myoclonus and dystonias (46% of patients, 25% of whom have antecollis; Quinn 2005). Suggestive of brainstem dysfunction is the diagnosis of REM sleep disturbance in almost 90% of MSA patients, which can precede the manifestation of MSA by several years (Iranzo et al. 2005). The chiefly nocturnal inspiratory stridor in MSA may be a further indication of brainstem dysfunction (Vetrugno et al. 2007). Patients with MSA-P usually do not show a long-term response to L-dopa therapy. In the early stage, up to 30% of patients may show a favorable response to dopaminergic substances, while a positive L-dopa response is observed in 10% of patients in the advanced stage. It is therefore recommended to determine the response to L-dopa with the use of a standardized protocol. According to UPDRS part III (Unified Parkinson’s Disease Rating Scale = motor part) criteria, a positive reaction to L-dopa is defined as a 30% improvement following a 3-month course of therapy with a minimum dose of 1,000 mg L-dopa.
4.7.4.4 Diagnosis The diagnosis of MSA can be made clinically based on consensus criteria, but a number of these criteria can be clarified only in the course of the disease (Table 4.26). Available data records documenting the sensitivity and specificity of individual, or a combination of additional
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investigations are insufficient for the differential diagnosis of possible MSA, i.e. early parkinsonism. MRI may be regarded as the most useful examination in clinical practice. It often enables detection of basal ganglia and brainstem disturbances in vivo. Possible changes visualized on T2-weighted cranial MRI are in particular hyperintensities and hypointensities of the putamen, a hyperintense margin on the border between the putamen and the claustrum, in addition to the so-called hot cross bun sign within the pons. In addition to routine MRI examinations, MRI-based volumetry of the striatum and brainstem, diffusion-weighted MRI, as well as MIBG scintigraphy and sonographic imaging of the brain parenchyma may be helpful in the differential diagnosis of a parkinsonian syndrome (Wenning et al. 2004). The extent to which these techniques will become established routine diagnostic procedures remains to be seen. Electromyography with the demonstration of external anal sphincter muscle denervation has been proposed as a diagnostic measure for the differentiation of MSA from other parkinsonian syndromes. Pathologic spontaneous activity has, however, also been reported for PSP and advanced Parkinson’s disease. Positive results may also be observed, e.g. after transabdominal prostatectomy, other surgical interventions in the pelvic region, and in multiparous women, so that this examination must be viewed critically (Giladi et al. 2000). 4.7.4.5 Differential Diagnosis MSA is most frequently confused with Parkinson’s disease or progressive supranuclear palsy (PSP). A mild limitation of upward gaze is non-specific and may also be observed in MSA-P. In addition to the classic signs defined in the consensus criteria (Table 4.26), such as autonomic disturbances, cerebellar and pyramidal tract signs, as well as a poor response to dopaminergic stimulation, the following symptoms are important criteria for the diagnosis of MSA-P: • Early gait ataxia in the absence of dementia (in contrast to PSP) • Frequent falls • Early need for wheelchair use • Rapid disease progression • Prominent hypophonic dysarthria • Pain unresponsive to L-dopa • Arterial hypertension (supine position) • Contractures • Affective incontinence • Violaceous or cold extremities unrelated to the intake of medication Sporadic and familial late onset ataxias constitute the most important differential diagnosis of MSA-C. Patients within
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the group of autosomal dominantly inherited spinocerebellar ataxias are also part of the differential diagnosis. (Wenning et al. 2004; Oertel and Möller 2005).
4.7.4.6 Therapy In contrast to patients with Parkinson’s disease, approximately two thirds of MSA-P patients show no, or only a poor response to L-dopa therapy. A slight effect is generally more readily observed when the substance is discontinued. The remaining third showed a moderate to good response to L-dopa. Comparable to patients with Parkinson’s disease, about 10% of all patients with MSA report an improvement in symptoms. Up to 13% of patients with advanced stage MSA continue to show a favorable response to L-dopa. As a rule, all types of responses to L-dopa are diminished over a period of 1–2 years. The favorable response to L-dopa in up to one third of all MSA-P patients justifies a therapeutic attempt with a sufficiently large daily dose (1,000 mg). In very rare cases, MSA patients who do not show any response to an adequate dose of L-dopa report improvement following the administration of dopamine agonists. In order to prevent worsening of the orthostatic hypotension, domperidone cover should be considered in determining the appropriate dose of L-dopa or dopamine agonists. Amantadine represents a therapeutic option in the absence of a clinical response to either L-dopa, or dopamine agonists. Even low dose dopaminergics (e.g. 50 mgL-dopa) can produce severe craniocervical dystonias in patients with MSA. The therapeutic challenge in these patients consists of giving a dopaminergic dose sufficiently large to alleviate limb akinesia without compromising the speech and swallowing disturbances due to dystonia. An option in the presence of focal dystonias is the injection of botulinum toxin. The therapy of inspiratory stridor with botulinum toxin is difficult. Good results have been reported for long-term therapy with CPAP (Iranzo et al. 2004). Initial measures in the treatment of orthostatic hypotension include elastic compression stockings, increased salt intake, and elevating the head of the patient’s bed. Drug therapy with appropriate doses of midrodrine (Gutron®) and/or long-term therapy with fludrocortisone (Astonin-H®) may be helpful in patients who remain symptomatic. Desmopressin (Minirin®) can be effective in patients with nocturnal polyuria (Suchowersky et al. 1995). Exacerbation of orthostatic hypotension is known to occur in MSA patients receiving sildenafil (Viagra®) for erectile dysfunction (Hussain et al. 2001). Peripherally acting anticholinergics as, e.g. oxybutynin can be useful in the treatment of urinary incontinence, but are a frequent cause of increased urinary retention.
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4.7.4.7 Prognosis The median survival time from symptom onset is approximately 9 years (range: 2–17 years). Pneumonia is the most common cause of death in MSA patients. The median age at death reported for 48 out of 100 patients originally included in the study was 65 years (Wenning et al. 2004).
4.7.5 Tremors Tremor represents a common and complex clinical problem with either direct (Holmes’ tremor, palatal tremor) or indirect (pathophysiology of essential tremor) brainstem involvement. Tremor therefore represents either a characteristic psychophysiological phenomenon (e.g. fear), or can manifest as a symptom of a large number of neurologic and medical diseases (e.g. thyroid disorders). Tremor can also be an undesirable effect of a great number of medications (e.g. lithium, virtually all psychopharmaceuticals, betasympathomimetics). Diagnostic classification is crucial in the selection of effective therapy. In particular in patients with tremor, the decision on further therapeutic procedures often has to be made based alone on the results of both a thorough medical history and neurologic examination. Nevertheless, misdiagnoses with farreaching consequences are not uncommon. Essential tremor is often misdiagnosed as Parkinson’s disease and the patients may occasionally be subjected over a number of years to an ineffective, expensive treatment, or even to antiparkinsonian therapy leading to the development of serious side effects. 4.7.5.1 Epidemiology The incidence rate of tremor, independent of etiology, is about 20% in patients older than 65 years (Bennett et al. 1996). Depending on the results reported by different studies, 0.31–1.7% of the population suffer from essential tremor. The prevalence increases significantly with age (5.5% after age 40; 12.5% in patients older than 70 years). Tremor can be seriously debilitating and lead to complete social withdrawal. Many affected individual do not seek professional advice, because “shaking” is frequently regarded as part of the “normal” aging process. Tremor does, however, not only affect older individuals. In addition to a peak incidence for the onset of essential tremor in the 6th decade of life, a further peak in incidence occurs in the 2nd decade of life. 4.7.5.2 Etiology The neuropathology of Parkinson’s disease is well described in the literature. In contrast to hypokinesia as the cardinal
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symptom, tremor is considerably less well understood. No abnormal neuropathologic findings have thus far been reported for essential tremor, the most common type of tremor. A dysfunction in the pathways between the cerebellum, basal ganglia, thalamus, and the sensomotor cortex, in particular between the olive, red nucleus, and the cerebellum, has been hypothesized. Symptomatic tremor types, such as Holmes’s tremor, or secondary palatal tremor with olivary hypertrophy are suggestive of involvement of many different structures from the thalamus to the basal ganglia and the brainstem. Holmes’s tremor, the prototype of tremor conditions according to the pathophysiologic understanding of tremor will be discussed briefly. Holmes’s tremor combines a parkinsonian resting tremor with an action and postural tremor that may occur as the result of a cerebellar lesion and in severe cases of essential tremor. Several of its aspects correspond to findings in animal models of tremor. It has been shown that a resting and intention tremor in monkeys can be induced only by the concurrent occurrence of a lesion to the cerebellothalamic pathways and an injury to the nigrostriatal pathways in the brainstem. An additional prerequisite is a lesion to parts of the red nucleus. Indications of an involvement of both the cerebellothalamic and nigrostriatal systems have further been noted in humans. In most cases tremor is classified as symptomatic. The most frequent causal factors include brainstem/cerebellar injuries (Benedikt’s syndrome), olivopontocerebellar atrophies, and injuries to the brainstem, the midbrain, or the thalamus. In Parkinson’s disease it can occur if additional brainstem lesions are present. The majority of all posttraumatic tremors after midbrain compression also fall into this category, or can be classified as cerebellar tremors. 4.7.5.3 Clinical Findings Tremor is by definition a movement disorder, characterized by rhythmic, oscillating (sinusoidal) muscle movements of similar amplitude. The movements are attributable to either reciprocal alternating or synchronous contractions of antagonistic muscles. Tremor can be classified according to its etiology, activation conditions, and topologic distribution. Of particular clinical importance is the differentiation between the activation conditions for resting and action tremor (postural and kinetic tremor), since a resting tremor (with 4–6 Hz) is characteristic of parkinsonism and requires a fundamentally different therapy from essential tremor treatment, one of whose cardinal symptoms is a postural tremor. The discrete fine postural and action tremor found in the extremities of healthy individuals is described as physiologic tremor. It is heightened under conditions of physical exhaustion, anxiety and strong emotions. Caffeine, asthma medications, such as theophylline and betasympathomimetics as, e.g.
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salbutamol, are classic examples of pharmacologic enhancers of physiologic tremor. According to current knowledge, physiologic tremor may also be enhanced by lithium, amphetamines, caffeine and steroids, making the phenomenologic differentiation from essential tremor impossible. This tremor is a rapid small amplitude flexion/extension motion of the outstretched fingers. Essential tremor is a generally monosymptomatic, slowly progressive clinical picture without additional neurologic findings. Psychosocial stress exacerbates the symptoms. The arms are most frequently affected (90%), followed by the head (50%), the voice (30%), the legs and the chin (15%). The handwriting becomes illegible and activities like drinking from a cup are increasingly difficult. The patient may be forced to hold the cup in both hands, or use a straw as a drinking aid. This tremor is best seen by holding the arms outstretched and flexed in a so-called bat wing posture. The tremor usually has a rotatory motion. The tremor often increases on intention movements for example touching the finger and then the nose. Patients with an unfavorable course may find it impossible to eat soup with a spoon, or sign a document. Individuals with certain occupations (e.g. dentists, surgeons, precision mechanics) have to undergo occupational retraining or take early retirement. Familial tremor occurs in roughly 50% of patients. Individually different amounts of alcohol may lead to a substantial transient decrease in shaking in approximately 50–70% of patients with essential tremor. The tremor regularly rebounds, however, when the alcohol has been metabolized after 3–4 h. Sensitivity to alcohol serves as a differential diagnostic indicator of essential tremor. Essential tremor in the elderly is often described as “senile tremor”. This description is both obsolete and misleading, as it is suggestive of an independent tremor entity. A detailed examination enables the differential diagnosis of a resting and/or postural tremor also in elderly patients. In patients with mixed syndromes, atypical variants of essential tremor, or an early parkinsonism may be assumed if a preexisting essential tremor is suspected. Neuroleptics are often identified as causal factors. The so-called dystonic tremor affects primarily the head or the hand, manifesting as a tremorous spasmodic torticollis or writer’s cramp. It usually arises more irregularly than essential tremor and shows a similar favorable response to botulinum toxin as essential head tremor. In addition to rare tremors occurring in neuropathies, a number of additional tremor forms, e.g. resting tremor, exist in the context of parkinsonism. Holmes’s tremor is often referred to by a number of different names (midbrain tremor, myorhythmia, rubral tremor, brachium conjunctivum tremor, Benedict’s syndrome). The new nomenclature avoids inappropriate topographic definitions and is reminiscent of the scientist who
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first described this tremor, Gordon Holmes. The tremor is characterized by • A combination of resting, action, and postural tremors • Low tremor frequency (2.5–5 Hz) and • A typical latency period from the underlying brainstem and cerebellar injury to the occurrence of the tremor, provided the time of the injury can be defined (e.g. brainstem insult) The latency period may be from days to years. The clinical symptoms of this tremor can be subsumed under the combination of a parkinsonian-like resting tremor and cerebellar intention tremor. The patients often exhibit additional signs of brainstem and cerebellar damage. In particular the proximal sections of the arms are affected. The very lowfrequency Holmes’ tremor is frequently irregular and less rhythmic than other forms of tremor. The patients are seriously disabled by the tremor. The affected extremities generally become unusable. Both sides may be involved depending on the extent of the damage. Palatal tremor was formerly called palatal myoclonus or palatal nystagmus, although it meets all criteria for tremor. With consideration of the pathophysiologic mechanisms it may even be defined as the prototype of a tremor per se. It has since been shown that two variants can be differentiated: • Symptomatic palatal tremor occurs after damage to the dentate-olivary pathways, it is associated with typical pseudohypertrophy of the inferior olive; the responsible muscle is the levator veli palatini muscle. The patient complaints are generally attributable to brainstem and cerebellar injuries, while the tremor is often an accidental finding of the clinical examination. Only if additional muscles are involved in the hyperkinesia, tremor-related complications arise as a result of oscillopsy, when pendular nystagmus develops synchronously with the tremor, or when the extremity muscles are involved in the form of a resting, postural or intention tremor. • Essential palatal tremor, which is apparently not associated with olivary hypertrophy (Deuschl et al. 1994), is characterized by one, yet extremely irritating complaint of an objectively audible clicking sound occurring synchronously with the tremor. The clicking sound is made by spasmodic contractions of the tensor veli palatini muscle. Rhythmic myoclonus may correspond to the original definition of the tremor. They manifest as slow, rhythmic hyperkinesias, commonly accompanied by signs of an additional brainstem and/or cerebellar function disturbance. Further possible rhythmic segmental hyperkinesias without other function disturbances may be indicative of spinal myoclonus. They can, for example, affect one of the extremities. In these
4.8 Abnormalities of Brainstem Development
cases, nerve lesions or spinal affections (tumor, myelitis) are occasionally found.
4.7.5.4 Diagnosis and Differential Diagnosis The diagnosis can generally be established clinically. The report in the medical history of tremor occurring only while eating (soup!) or writing, generally speaks against the presence of parkinsonism. Resting tremor in Parkinson’s disease involves distal extremity segments, but not the head, the chin or the voice. Tremor involving these regions serves as an indication of essential tremor. It is essential to exclude causes of enhanced physiologic tremor and conditions with the phenomenologic resemblance of an essential tremor syndrome (e.g. Wilsons’s disease in patient under age 50) with the use of appropriate examinations. Further differential diagnoses which usually do not represent a serious problem include partial continuous epilepsy, rhythmic myoclonus, and clonus as a result of increased muscle extension reflexes. Patients with early stage parkinsonism who have a postural and intention component in addition to resting tremor pose a differential diagnostic problem. This also applies to patients with monosymptomatic intention tremor, dystonic and psychogenic tremor.
4.7.5.5 Therapy The decision regarding initiation of medical therapy has to be made on an individual basis and depends on the subjective degree of incapacity. A low-grade postural tremor can be extremely embarrassing for a sales person with customer contact, while a mason with the same symptoms may not consult a physician. Differentiation must be made between intention and resting tremor. Regardless of the etiology, the attempt to treat intention tremors should be made with the use of the same medical therapy recommended for essential tremor. A patient with resting tremor should receive probative drug therapy with similar medications used for the treatment of Parkinson’s disease. Many patients with essential tremor do not require longterm medical therapy. The patients may be afraid of developing Parkinson’s disease or multiple sclerosis. In these cases counselling is required. If further symptomatic therapy is indicated, it may be assumed that about half of the patients with essential tremor will benefit from medical therapy. Propranolol and primidone are the most extensively investigated substances. While the titration of primidone is difficult in 30% of patients, chronic undesirable effects of propranolol lead to the discontinuation of therapy in 20% of patients. More than 10% of patients developed a tolerance to both medications within a
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period of 1 year (Ceballos-Baumann and Boecker 2000). It is essential to avoid the abrupt discontinuation of long-term therapy with beta-receptor blockers or primidone. Therapeutic attempts in patients with Holmes’ tremor should consist of a combination of sufficiently large doses of L-dopa and a decarboxylase inhibitor (approx. 1,000 mg).
4.8 Abnormalities of Brainstem Development Wolfgang Wagner The most important abnormalities of brainstem development comprise the different Chiari malformations and DandyWalker malformation, as well as several very rare disease entities as, e.g. Joubert syndrome and rhombencephalosynapsis. Congenital aqueduct stenosis (aqueduct atresia) also falls into this category. Indirectly, impairments of the brainstem due to developmental abnormalities of neighboring structures can also be included among this group of conditions (e.g. arachnoid cysts of the posterior cranial fossa, craniocervical junction constriction in achondroplasia and basilar impression).
4.8.1 Chiari Malformations In two reports published at the end of the nineteenth century, the pathologist Hans Chiari described four forms of pathologic changes in the cerebellum, the pons, and the medulla oblongata, which he characterized as follows: • Type I due to cerebellar tonsillar herniation (to caudal beyond the level of the foramen magnum) • Type II due to caudal displacement of the cerebellum/ cerebellar vermis, lower brainstem, and fourth ventricle, into the cervical spinal canal • Type III due to herniation of the cerebellum into an occipitocervical encephalocele • Type IV due to cerebellar hypoplasia without caudal displacement (Koehler 1991) The described malformations were originally regarded as an embryologic-pathoanatomic continuum, a view that had to be revised on the basis of study results published in the past few decades (Milhorat et al. 1999). The by far most important of these malformations (Type I and II) will be discussed below, Type III is extremely rare (Chiari himself described only a single case). Strictly speaking, Type IV does not belong to this group and was only later added to the above classification scheme by Chiari.
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common symptom is pain in the back of the head and the neck area followed by feelings of retroorbital pressure, visual disturbances, vertigo, balance and hearing abnormalities, disturbances of the caudal cranial nerves, as well as other brainstem and cerebellar signs. A common feature of these symptoms is that they are increased on exertion and Valsalva maneuvers. Spinal symptoms as, e.g. weakness, paresthesias, and joint pain are seen in almost all patients with accompanying syringomyelia, although they occur (also somewhat less often) in the absence of syringomyelia.
4.8.1.1 Chiari Malformation Type I This malformation is characterized by a developmental unproportional relationship between a very small volume of the posterior cranial fossa and a normal metencephalon (not malformed) volume. This regularly leads to displacement of the outer cerebrospinal fluid spaces above, or behind and below the cerebellum with subsequent chronic tonsillar herniation, compression of neural structures, as well as abnormal cerebrospinal fluid dynamics (Milhorat et al. 1999). 4.8.1.2 Epidemiology
4.8.1.5 Diagnosis
The condition is rare, precise figures of incidence are not available. Women are significantly more often affected than men (women : men approx. 3:1). The results obtained by an analysis of past family medical histories of the patients strongly support the hypothesis of a genetic influence (Milhorat et al. 1999).
The disturbance of the embryologic development underlying the primary forms has been attributed to an aberrant development of the paraxial mesoderm. In the so-called secondary or acquired form, a Chiari I malformation may also be found in craniosynostoses, achondroplasia, and other disorders leading to compression within the posterior cranial fossa.
The diagnosis is usually made with magnetic resonance imaging (MRI). MRI shows an obliteration of the outer cerebrospinal fluid spaces above the cerebellum, and typically tonsillar herniation (caudal to the foramen magnum). Flow sensitive sequences also show restricted or abolished cerebrospinal fluid flow in the cisterna magna or the retrocerebellar subarachnoidal space (Fig. 4.60a). Syringomyelia was detected in 65% and scoliosis in 42% of patients among a large, clinically symptomatic population (Milhorat et al. 1999). In some cases, the cerebrospinal fluid obstruction may lead to the development of obstructive hydrocephalus (Decq et al. 2001). Displacement of the odontoid process with dorsal inclination and subsequent brainstem compression has also been described (Grabb et al. 1999; Tubbs et al. 2003).
4.8.1.4 Clinical Findings
4.8.1.6 Differential Diagnosis
The initial symptoms most often manifest between the ages of 10 and 40 years (Milhorat et al. 1999). By far the most
In making the differential diagnosis of the so-called acquired forms, consideration must be given to other diseases
4.8.1.3 Etiology
a
Fig. 4.60 Images obtained in a 15-year-old girl with sudden onset of severe neck pain, hemiparesis left, and pathologic somatosensory evoked potentials. (a) MRI identifies pronounced tonsillar herniation with compression in the posterior cranial fossa. Compression of the lower brainstem is increased due to dorsal displacement of the dens
b
axis. In the mid-cervical spinal cord, pronounced syringomyelia with spinal cord distension. (b) At the time of examination – 3 months after cerebellar tonsil resection – improvement of the clinical symptoms. MRI does not demonstrate any (dorsal) lower brainstem compression. Partial retrogression of the cervical syringomyelia
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associated with compression (e.g. tumors) in the posterior cranial fossa, even though MRI findings are generally typical in these cases.
4.8.1.7 Therapy Surgical therapy consists of decompression in the region of the craniocervical junction (bony decompression), possible dural enlargement, resection or “shrinking” of the cerebellar tonsils using electrocoagulation (Alden et al. 2001; Weprin and Oakes 2001; Yeh et al. 2006), and hydrocephalus therapy if indicated (Decq et al. 2001). Ventral decompression via a transoral approach may be required in rare cases of an associated pronounced displacement of the odontoid process (Grabb et al. 1999).
4.8.1.8 Prognosis The prognosis after Chiari I decompression is usually favorable; in some patients a possibly associated syringomyelia may resolve after craniocervical junction decompression, obviating the need for additional surgical intervention (Fig. 4.60b).
4.8.1.9 Chiari Malformation Type II This malformation, against its historical background also described as Arnold-Chiari malformation, is nearly always associated with open spina bifida; conversely, virtually all patients with this dysrhaphic disturbance have a Chiari type II malformation. The cerebellum (particularly the vermis), brainstem and the fourth ventricle are displaced caudally into the cervical spinal canal, the neural structures show inner and outer dysplasias. Caudal displacement of the medulla oblongata with spinal cord adhesion in the cervical spinal canal leads to cervicomedullary kinking. In some cases the anterior cerebellar surface also covers the lateral and ventral brainstem (cerebellar inversion). The mesencephalic tectum often shows tectal beaking. An accompanying hydrocephalus occurs in more than 80% of patients. Also present are cerebral malformations (e.g. corpus callosum hypoplasia, enlarged massa intermedia, aqueductal stenosis) of varying degree. The volume of the bony posterior cranial fossa is reduced, while the foramen magnum is enlarged (McLone and Dias 2003; Weprin and Oakes 2001).
4.8.1.10 Epidemiology Because the Chiari type II malformation is almost always associated with open spina bifida (and vice versa), the
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incidence or prevalence of neural tube defects serves as an indicator of the frequency of Chiari II malformations. The incidence ranges from 0.1:1,000 live births in Africa to 12.5:1,000 live births in Ireland. The significant difference in these rates remains unchanged when members of different ethnic groups emigrate to other geographic regions (Cohen and Robinson 2001). A correlation has been shown between (preconceptional) folic acid prophylaxis and reduction in the prevalence of Chiari type II malformations.
4.8.1.11 Etiology The primary cause of the neural tube defect (dysrhaphia) present in open spina bifida (commonly as lumbosacral myelomeningocele) and Chiari II malformation is attributed to a disturbance of the embryonic process of primary neurulation at the end of the fourth week after conception. A number of etiologic factors also play an important role. The prophylactic effect of (preconceptional) folic acid intake is in support of exogenous factors, and the varying prevalence of the disease in different populations, as well as familial clustering are suggestive of genetic influences.
4.8.1.12 Clinical Findings Apart from the typical stigmata of open spina bifida (or hydrocephalus if applicable), the most common symptoms in infancy comprise signs of brainstem dysfunction, such as swallowing and respiratory abnormalities, paralysis of the vocal cords with stridor, loss of the gag reflex, additional cranial nerve deficits, as well as opisthotonus. Prominent symptoms in older children include neck pain, sensory symptoms, pareses, increasing upper extremity spasticity, scoliosis, trunk and extremity ataxia, as well as cerebellar nystagmus (Weprin and Oakes 2001; McLone and Dias 2003). Intellectual development is usually not or only slightly impaired. Important in the therapy of these patients is to be aware of a shunt in place for an associated hydrocephalus, and consideration of the fact that the abovementioned Chiari II symptoms (in particular in acute or subacute phases) can be triggered or enhanced as a result of increased intracranial pressure due to shunt insufficiency.
4.8.1.13 Diagnosis An adequate imaging diagnosis requires cranial MRI including the craniospinal junction (Fig. 4.61), as well as of the complete vertebral column to enable assessment of all CNS segments. In addition to the clinical examination, electrophysiological techniques can be used to quantify brainstem function disturbances (Koehler et al. 2000).
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degree of neurologic recovery after neurosurgical decompression depends on the severity of the preoperative deficits, and apparently also on the age of the patient: the earlier the Chiari II malformation becomes symptomatic, the poorer the prognosis. A mortality rate of 50% has been reported in infants up to 6 months of age, while older children have significantly better chances of recovery (Weprin and Oakes 2001).
4.8.2 Dandy-Walker Malformation Fig. 4.61 Images obtained in an 8-month-old infant with lumbosacral myelomeningocele (surgical care immediately after birth) and associated hydrocephalus (ventriculo-peritoneal shunt). (a) Median sagittal MRI: Chiari II malformation with severe cerebellar herniation, mesencephalic tectal beaking, corpus callosum hypoplasia, extensive interthalamic adhesion and cervical syrinx. (b) Axial MRI at the level of the pontobulbar junction: posterior cranial fossa “filled” with cerebellar tissue, the ventral cerebellar surface also covers the lateroventral surface of the brainstem (cerebellar inversion). Neither the Chiari II malformation nor syringomyelia is clinically symptomatic at the time of examination
4.8.1.14 Differential Diagnosis The possibility of shunt failure needs to be considered, in particular in the presence of acute or subacute clinical symptoms of Chiari II malformation (always think first: it’s the shunt) (McLone and Dias 2003). The differential diagnosis of a Chiari I malformation should be excluded in the rare occurrence of an only mild Chiari II malformation in patients with open spina bifida, as both entities are fundamentally different embryologically and clinically.
4.8.1.15 Therapy Surgical intervention is required in the presence of brainstem compression (dorsal decompression of the craniocervical junction; possibly caudal opening of the fourth ventricle). This procedure does not permit elimination of intrinsic brainstem dysplasias (which may be the cause of the symptoms in the absence of extrinsic pressure). In cases of shunt insufficiency as the trigger of Chiari II symptoms, shunt revision or, alternatively, endoscopic ventriculostomy (compare section “Aqueductal stenosis”) is required (Wagner et al. 2002).
The Dandy-Walker malformation represents a fetal developmental disturbance of the cerebellum or the roof of the fourth ventricle with absent fusion of the cerebellar hemispheres (absence of vermis formation), and possible atresia of the foramina at the fourth ventricle exit. Anatomically it is characterized by aplasia or hypoplasia of the vermis, enlargement of the posterior cranial fossa with upward displacement of the tentorium and confluence of the sinuses, as well as cystic enlargement of the fourth ventricle filling almost the entire posterior cranial fossa. In this setting, associated malformations are found in the remaining CNS (e.g. absent corpus callosum, occipital encephalocele, dysplasias of pontine/bulbar nuclear regions, with embryological origin, comparable to the cerebellum, from the rhombic lip (Roessmann 1995)). Hydrocephalus is present in 90% of patients and is partly due to accompanying aqueductal stenosis. Systemic (e.g. cardiac) abnormalities have been reported in one fourth of patients by autopsy studies (Arai and Sato 2001).
4.8.2.1 Epidemiology The estimated incidence ranges from 1:25,000 to 1:30,000 births, girls appear to be more commonly affected than boys. Dandy-Walker malformation is the causal factor of perinatal hydrocephalus in 1–4% of cases (Arai and Sato 2001; Cinalli et al. 2004a).
4.8.2.2 Etiology The etiology of the malformation in the early fetal period is not fully understood. A number of exogenous and genetic influences appear to play a role in this context (Cinalli et al. 2004a).
4.8.1.16 Prognosis
4.8.2.3 Clinical Findings
Chiari II malformation is the leading cause of death in lethal courses of open spina bifida in the first 2 years of life. The
The most prominent clinical symptoms are caused by the accompanying hydrocephalus (compare section “Aqueductal
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stenosis”); possible additional symptoms include eye movement disturbances, spasticity, ataxia, hemiparesis and tetraparesis. Also present is mental retardation, whose severity correlates with the degree of hyperplasia or aplasia of the cerebellar vermis (Klein et al. 2003). In 70–90% the symptoms manifest as early as within the 1st year of life (primarily hydrocephalus associated); motor retardation, cerebellar signs and cranial nerve deficits are in the foreground in older children. 4.8.2.4 Diagnosis Magnetic resonance imaging (MRI) is the diagnostic procedure of choice; it is capable of showing the described anatomic characteristics, and enables planning of the neurosurgical therapy suitable for the individual patient (Fig. 4.62). 4.8.2.5 Differential Diagnosis Dandy-Walker malformation in the strict sense has to be differentiated from cerebellar hypoplasia with fourth ventricle enlargement, but without an enlarged posterior cerebral fossa (sometimes and terminologically non-uniformly also defined as Dandy-Walker variant), as well as from mega cisterna magna (enlargement of the cerebellomedullary cistern without cerebellar malformation) (Barkovich 2000; Cinalli et al. 2004a). The presence of an arachnoid cyst in the posterior cranial fossa, as well as an isolated fourth ventricle has to further be excluded. In these cases, MRI visualizes a normal (albeit compressed) vermis, a normal location for the confluence of the
Fig. 4.63 (a) Images obtained in a (pre-term) 2.5-year-old girl with post-hemorrhagic hydrocephalus treated with a ventriculoperitoneal shunt. Median-sagittal MRI with ballooned isolated fourth ventricle, membrane-shaped aqueduct closure, substantial compression of the cerebellum dorsal and of the brainstem ventral. Normal cerebral vermis. Clinical findings: delayed psychomotor development, strabismus, impaired movement, particularly of the right upper extremity. Pathologic somatosensory evoked potentials. (b) Situation 4 months after aqueductal plasty with stenting. The fourth ventricle is markedly smaller (although still large), unfolding of both the cerebellum and the brainstem. Clinical evidence of progress of psychomotor development, incomplete resolution of strabismus
sinuses, and permits differentiation, for example, of a retrocerebellar arachnoidal cyst from the (normal sized) fourth ventricle (Barkovich 2000). The so-called isolated fourth ventricle typically occurs in the context of an early childhood (primarily post-hemorrhagic) hydrocephalus with relative supratentorial ventricular system shunt overdrainage; other characteristic Dandy-Walker malformations are absent (Fig. 4.63).
4.8.2.6 Therapy Neurosurgical therapy is aimed at eliminating increased pressure both in the posterior cranial fossa and in the supratentorial space with the use of intracranial or extracranial cerebrospinal fluid drainage. Under ideal conditions, neuroendoscopic fenestration is sufficient; drainage of the fourth ventricle as well as of the supratentorial ventricle via a ventriculoperitoneal or cystoperitoneal shunt (or a combination of both) is required in most patients.
4.8.2.7 Prognosis Fig. 4.62 Images obtained in a 6-month-old girl with Dandy-Walker malformation. (a) Median-sagittal MRI: substantial enlargement of the posterior cranial fossa with cystic enlargement of the fourth ventricle, marked hypoplasia of the cerebellar vermis, upward displacement of confluence of the sinuses, absent corpus callosum. (b) Axial MRI on the level of the posterior cranial fossa: absent fusion of cerebellar hemispheres, broad junction from the fourth ventricle to the Dandy-Walker cyst, as well as supratentorial enlargement of the temporal horns of the lateral ventricle as a sign of hydrocephalus. The child received a ventriculoperitoneal shunt and currently has (aged 3 years) only minor neurologic abnormalities
The prognosis for survival is determined by the effectiveness of hydrocephalus therapy; success rates of more than 80% have been reported in this context (Arai and Sato 2001). Mental retardation, however, is not (only) determined by the degree of the cerebrospinal fluid circulation disturbance; the favorable influence of neurosurgical therapy is therefore limited. Patients with “isolated” forms of Dandy-Walker malformation, only moderate malformation of the vermis, no
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additional CNS malformations, and early effective hydrocephalus therapy have the best prognosis.
4.8.3 Aqueductal Stenosis Perinatal aqueductal stenosis (or atresia of the aqueduct) is one of the most common causes of congenital hydrocephalus. Based on pathoanatomic findings as well as on embryologic considerations it may be regarded as a prenatally acquired condition rather than a genuine developmental disturbance (“idiopathic aqueductal stenosis”) (Roessmann 1995). An exception is the rare hereditary form of aqueductal stenosis – the so-called X-linked hydrocephalus (BickersAdams-Edwards syndrome); this is associated with additional malformations such as corpus callosum agenesis, or bilateral absence of the pyramids in the medulla oblongata, and agenesis of the corticospinal fiber systems (Costa and Hauw 1995; Roessmann 1995). Further findings include aqueductal stenosis in the context of other CNS malformations (Chiari II malformation, Dandy-Walker malformation). The cerebrospinal fluid flow disturbance via the aqueduct is causal in the development of a triventricular occlusive hydrocephalus (enlargement of the supratentorial ventricles 1–3 upstream of the passage obstruction; normal size of the fourth ventricle below the obstruction).
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gaping cranial sutures, increasing head circumference, sunset phenomenon of the eyes, and possibly venous stasis in the region of the galea. Other neurologic and mental functions (with early therapy of hydrocephalus) are essentially normal. In contrast, thumb position defects (adduction position), spasticity, as well as severe motor and mental retardation are found in X-linked hydrocephalus.
4.8.3.4 Diagnosis Triventricular hydrocephalus can already be demonstrated in the unborn child with the use of ultrasound (possibly also MRI), in newborns and infants with ultrasonography, MRI and CT scans. Ultrasonographic depiction becomes difficult after fontanelle closure in early childhood. MRI is the modality of choice capable of showing typical triventricular hydrocephalus, displacement of the floor of the fourth ventricle to basal, as well as the absence of a flow signal within the aqueduct.
4.8.3.5 Differential Diagnosis In idiopathic aqueduct stenosis consideration has to be given to other causes, such as tectal tumors or secondary aqueduct occlusions due to adhesions after hemorrhages or meningitides.
4.8.3.1 Epidemiology
4.8.3.6 Therapy
Aqueductal stenosis is the cause of a hydrocephalus in 6–66% of cases in children and 5–49% in adults; there are significant differences in reports of the annual incidence (3.7:1,000,000 to 0.5:1,000) (Cinalli et al. 2004b). The X-linked hydrocephalus is very rare (1:30,000 male births) (Dirks 2004).
The therapy of choice in idiopathic aqueductal stenosis consists of endoscopic third ventriculostomy (ETV) with endoscopic fenestration of the floor of the third ventricle. This permits the cerebrospinal fluid to bypass the passage obstruction within the aqueduct and drain directly into the basal cisterns and thus into the outer cerebrospinal fluid spaces where it can be resorbed (Wagner and Koch 2006; Fig. 4.64b). In cases of insufficient effectiveness of the ETV (e.g. in the presence of an additional cerebrospinal fluid absorption disturbance, or repeated closure of the ventriculostoma (Wagner and Koch 2005)), placement of a ventriculoperitoneal shunt for cerebrospinal fluid drainage from the lateral ventricle into the peritoneal cavity is required. Among other factors, the success rate of ETV is dependent upon the age, and is highest (up to 80%) in children older than 1 year (Cinalli et al. 2004b; Koch-Wiewrodt and Wagner 2006).
4.8.3.2 Etiology The etiology of congenital “idiopathic” aqueductal stenosis is unknown. Secondary, acquired aqueductal stenoses occur after hemorrhages, infections, or in connection with neoplasias. 4.8.3.3 Clinical Findings The so-called idiopathic aqueductal stenoses are characterized by typical signs of increased intracranial pressure in hydrocephalus as, e.g. vomiting, disturbance of consciousness and convulsions, as well as tight fontanelles in infants,
4.8.3.7 Prognosis The prognostic outcome in idiopathic aqueductal stenosis is – providing therapy starts early enough – favorable,
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Fig. 4.64 (a) Images obtained in a 4-month-old infant with prepartal demonstration of triventricular hydrocephalus and significant progression of findings postpartum. Median sagittal MRI: enlargement of the third ventricle, normal size fourth ventricle, absent flow signal within the aqueduct (atresia). No hemorrhage, no meningitis, no other malformations. With the exception of a macrocephalus, essentially normal clinical findings. (b) Situation 10 months after endoscopic third ventricular cisternostomy: severe flow phenomenon (signal extinction) on the floor of the third ventricle as sign of a functional ventriculostoma. In the further course: persistent decrease in ventricle size and normalization of the head circumference; since the operation 5 years ago, the child has been without a shunt
although limited intellectual abilities (these were lower, the later aqueductal stenosis was clinically manifest) were found in larger series of patients. In X-linked hydrocephalus the motor and, in particular, the intellectual development of the child are notably poorer, despite adequate therapy. The prognosis in the secondary forms depends essentially on the underlying disease.
4.8.4 Rare Disturbances in Brainstem Development A number of very rare conditions are characterized by agenesis or hypoplasia of the vermis associated with other CNS malformations, including developmental abnormalities in the brainstem region. These comprise Joubert syndrome, the COACH syndrome, rhombencephalosynapsis, or tectocerebellar dysrhaphia. Very rare are syndromes associated with unilateral or bilateral aplasia, or hypoplasia of the cerebellar hemispheres, which are accompanied by developmental abnormalities of the lower brainstem (e.g. pontocerebellar hypoplasia), as well as olivopontocerebellar atrophy, Moebius’s syndrome, or developmental abnormalities in the context of chromosomal aberrations (Costa and Hauw 1995). Severe mental retardation is generally present in these cases and life expectancy is significantly shortened. The (neurosurgical) therapy is limited to the therapy of the associated hydrocephalus.
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Fig. 4.65 (a) Images obtained in a 6-month-old infant with achondroplasia. Clinical findings: respiratory disturbances, substantially reduced spontaneous motor function, spasticity of the upper extremities, markedly delayed psychomotor development. Median sagittal MRI: extensive lower brainstem compression mediated by a significantly constricted foramen magnum. (b) Findings 6 months after bony decompression (from dorsal): no brainstem compression, anatomically unfolded medulla oblongata, and marked improvement of the neurologic symptoms
4.8.5 Brainstem Impairment due to Pathologic Neighboring Structures The brainstem (even without intrinsic malformations) can be impaired due to compression from variously malformed neighboring structures. These comprise, e.g. arachnoidal cysts in the posterior cranial fossa, craniocervical junction constriction in achondroplasia (Fig. 4.65a), and basilar impressions. Diagnostic imaging is supported by MRI and (especially in bony processes) CT scanning. The clinical symptoms are the result of local brainstem compression and, in some instances, to the underlying disease. The aim of (neurosurgical) therapy is decompression of the brainstem (Fig. 4.65b).
4.9 Metabolic Brainstem Diseases Joachim Wolf and Armin Grau Metabolic diseases of the central nervous system constitute an etiologically highly heterogeneous group. They are often causal factors of more comprehensive disease patterns, that affect not only individual regions of the central nervous system as, for example the brainstem. A number of these diseases represent exceptions and become symptomatic exclusively or primarily in the brainstem. In addition to signs of cortical or cerebellar injury, various metabolic diseases are also associated with cardinal symptoms typical of the brainstem. The following chapter is limited specifically to discussion of the latter disease groups, without, however, making the claim of completeness.
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4.9.1 Central Pontine Myelinolysis
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after about 1 week, the brain is particularly vulnerable to osmotic trauma. The processes occurring under conditions of rapid hyponaCentral pontine myelinolysis (CPM) was first described in tremia correction are not merely a reversal of the initial pro1959 by Adams and co-workers as a distinct disease entity, cess, in particular since the intracellular reaccumulation of occurring in alcoholic and malnourished patients. The exisorganic molecules is decelerated. Shrinking of brain cells tence of extra pontine myelinolysis (EPM) was reported in occurs when the inorganic ionic processes within the cell are later studies. The disease is associated with symmetrical exhausted and the rise in serum osmolarity is faster than the demyelinations and often manifests following rapid correcintracellular synthesis or transport of organic substances into tion of hyponatremia. the cell (Martin 2004). Oligodendrocytes appear to be particularly vulnerable in this context; detachment of the myelin sheaths from the axons thus occurs. The osmotic changes cause 4.9.1.1 Epidemiology further injury to the endothelium, leading to the development The exact incidence rate of the disease is not known. In a of vasogenic edema and extravasation of myelin- damaging series of about 3,500 autopsies, typical changes for CPM were substances, which represents an additional mechanism of identified in 0.25% of cases (Lampl and Yazdi 2002). Fifteen demyelination. Animal studies have shown that an injury to the cases of an asymptomatic CPM were found in 3,000 routine blood-brain barrier during correction of hyponatremia is assoautopsies. It is estimated that the prevalence of asymptomatic ciated with high risk for CPM/EPM (Lampl and Yazdi 2002). The determining factor for the occurrence of CPM/EPM is CPM is at least as high as the incidence of the clinically diagnosed form (Newell and Kleinschmidt-Demasters 1996). The not the initial sodium concentration, but the rate and extent of disease is found slightly more often in men than in women, the blood sodium level correction. Preexisting alterations in the and usually occurs between 30 and 50 years; it has, however, brain due to malnutrition or prior medical conditions lead to an exacerbation of the disease. Patients with CPM/EPM often also been described in children (Lampl and Yazdi 2002). exhibit hypokalemia in addition to hyponatremia (Martin 2004). The disease can, however, also occur in patients with elevated or normal blood sodium levels or when hyponatremia is corrected 4.9.1.2 Etiopathogenesis at a rate that is considered safe. This underlines that still only Results of the majority of available studies support the incompletely known other osmotically active processes or other hypothesis that CPM and EPM are attributable to an overly pathomechanisms are involved in the pathogenesis. CPM is a disease which affects primarily the central segrapid correction of severe hyponatremia. The conditions manifest most commonly in patients with chronic hypona- ment of the pontine base with possible extension to the midtremia and complete intracellular adaptation to serum brain, very rarely also to the medulla oblongata (Martin hypoosmolarity, while only insufficient counter-regulatory 2004). Neuropathology shows a symmetrical, sharply defined mechanisms in response to rapid increase in serum osmolar- lesion of the myelin sheath, which involves all of the long ity are available. Rapid correction of the serum sodium con- pathways and is associated with a lesion as well as the loss of centration has become possible only with the introduction of oligodendrocytes. Axons and neurons are spared, inflammaintravenous fluid therapy; CPM and EPM are therefore often tory or vascular alterations do not exist (Adams et al. 1959). A particular predisposition in the pathogenesis, especially regarded as iatrogenic diseases (Brown 2000). Patients with a disturbed osmotic balance are at an of the pons, may be due to the close vicinity of oligodendroincreased risk for CPM/EPM. The formula to calculate cytes and the strongly vascularized gray matter; and thus, the serum osmolarity (serum osmolarity = 2 [Na+ + K+] + [glu- vasogenic edema and release of myelinotoxic substances cose/18] + [urea/3] mmol) emphasizes the important role may have markedly pronounced effects in this region (Lampl of sodium levels. Hyponatremia is present at levels of and Yazdi 2002). The lesion is not limited exclusively to the <136 mmol/L, and severe hyponatremia occurs at serum pons: in approximately 10% of patients with CPM, extraponconcentrations <120 mmol/L. Because free water crosses tine lesions, particularly of the cerebellum, the thalamus, the both the blood brain barrier and cell membranes, an uncom- external capsule, the hippocampus, the brainstem ganglia, pensated decrease in serum sodium levels can lead to the and at the junction between the cortex and the subcortex are entry of water into brain cells, with the subsequent develop- found (Martin 2004). In some cases, only the extrapontine ment of brain edema. Counter-regulatory mechanisms to regions are involved. maintain tonicity and brain cell volume include, in addition The diseases frequently associated with CPM include, to rapid potassium outflow, an outflow of organic molecules e.g. alcoholism and malnutrition, long-term diuretic therapy, (e.g. myoinositol, taurine and glutamate), developing over psychogenic polydipsia, conditions after burns, liver transa period of days. When the outflow of molecules ends plant and surgery of the pituitary gland. CPM and EPM occur
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only rarely in patients without severe preexisting diseases. The development of CPM and EPM is rare in patients without the described associated diseases who undergo rapid correction of hyponatremia (Martin 2004). An association with alcoholism, alcohol withdrawal symptoms or delirium tremens exists in 40% of cases, Wernicke’s encephalopathy is a common accompanying disease (Martin 2004). Hyponatremia and concurrent malnutrition are frequently found in alcoholic patients. CPM occurs in approximately 0.3% of liver transplant patients; it generally manifests within 30 days after transplant surgery and develops predominantly in patients with postoperative complications such as sepsis, or hepatic encephalopathy. Cyclosporine therapy after transplant surgery may be an additional triggering factor. The finding of hyponatremia has been reported in only a small number of liver transplant patients (Lampl and Yazdi 2002). A grossly impaired or poor nutritional status represents a predisposition for CPM, which may be accounted for by an association between nutritional deficiencies and reduced ability for the duplication of organic substances (Martin 2004). Severe burns can be another cause of CPM/EPM; there are various reports of an initial hypernatremia in patients with severe burn injuries. For only insufficiently understood reasons, CPM and EPM are rarely found in dialysis patients, who frequently have rapid changes in the sodium balance.
4.9.1.3 Clinical Findings The clinical symptoms of CPM can encompass a broad spectrum. Typical symptoms include pseudobulbar paresis with dysarthria and dysphagia due to impairment of the corticobulbar fibers, as well as an initially flaccid and later spastic tetraparesis mediated by a lesion to the pyramidal pathways in the region of the pontine base. Pupillary and oculomotor disturbances may occur in the presence of a lesion extending into the pontine tegmentum. Ataxia and cranial nerve deficits (in particular abducens and facial paresis) may be present. Disturbances of consciousness ranging in severity up to coma or a locked-in syndrome may occur in extreme instances (Martin 2004). The course of disease is typically biphasic in patients with a preexisting severe hyponatremia. Hyponatremias generally become clinically symptomatic only at levels <125 mmol/L, and manifest as encephalopathy with orientation and motivation disturbances, restlessness, headaches, nausea and vomiting, as well as muscle spasms, and in extreme cases also as epilepsy. Regulation of the sodium balance leads to a brief period of recovery, before the symptoms recur, usually after 2–7 days. The clinical (as well as radiologic and pathologic) features are, however, frequently not as characteristic as initially
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assumed, in particular since the pathologic focus may also be found in extrapontine locations (Brown 2000). Common findings in extrapontine lesions (EPM) are extrapyramidal motor symptoms, such as a parkinsonian syndrome, choreoathetosis, dystonias, or tremor, which may occur successively in the course of disease. Other possible findings include psychopathologic symptoms including mutism, affect incontinence, pathologic laughter and crying, or catatonia, as well as neuropsychologic symptoms, e.g. disturbance of attention and concentration, or short-term memory. Symptoms of EPM may also be present in CPM, a constellation which is found in approximately 40% of patients with EPM (Martin 2004). A combination of EPM and CPM can cause a severe neurologic condition, whose classification is often difficult, in particular since the symptoms frequently occur in patients with severe preexisting diseases or in intubated patients.
4.9.1.4 Diagnosis Modern imaging modalities constitute the most important diagnostic methods. Computed tomography (CT) demonstrates typical hypodensities in the central pons. Magnetic resonance imaging (MRI) nevertheless represents the method of choice, as it is capable of detecting changes occurring within days and weeks after symptom onset. Acute demyelinations are symmetrical and hypointense on T1-weighted sequences; they become hyperintense on T2-weighted MR images (Fig. 4.66). Diffusion-weighted sequences may have a particularly high sensitivity. In some patients, contrast enhancement is present during the first 4 weeks. The MRI
Fig. 4.66 Cranial MRI (T2-weighted sequence) obtained in a 55-yearold patient with chronic alcohol abuse, who was admitted to hospital for diagnostic clarification of recurrent syncopes. Visualized in the central part of the pons is a 15 × 14 × 13 mm large signal-enhanced area (signal reduction in the T1-sequence, no contrast enhancement) without a space-occupying effect as evidence of – clinically oligosymptomatic – central pontine myelinolysis. Neurologic findings showed mild bilateral intention tremor, as well as gait ataxia, bilateral gaze evoked nystagmus, and proprioceptive muscle reflexes more pronounced on the right, but no central pareses. Hyponatremia did not occur during the hospital course
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changes can occur with substantial delay, control MRI examinations are therefore advisable after 10–14 days in the presence of images without initial pathologic findings. The lesions may resolve completely after months, although MRI changes may also persist for months after clinical recovery. Early changes detected on MRI or CT often disappear completely and are suggestive of edema, which occurs prior to demyelination and is potentially reversible, while later changes are mediated by the demyelination and are usually irreversible (Lampl and Yazdi 2002). MRI provided no prognostic information in one series of patients (Menger and Jörg 1999). A prolongation of interpeak latency I–V has been described on recording of acoustic evoked potentials; the finding is, however, associated with a low sensitivity and specificity.
4.9.1.5 Differential Diagnosis Important clinical differential diagnoses of CPM include brainstem hemorrhages or ischemias, more rarely brainstem encephalitis. The differential diagnosis of a typical MRI finding may be a downward displaced interpeduncular cistern with partial volume effects (Brown 2000).
4.9.1.6 Prophylaxis In view of the finding that an overly rapid correction of hyponatremia constitutes a major cause of CPM and EPM, slow increase in the serum sodium concentrations is of crucial importance. In compliance with the rule that the rate of the correction of metabolic disturbances has to be adapted to the rate of their occurrence, chronic hyponatremia should be corrected more slowly than acute hyponatremia (Martin 2004). In cases of uncertainty, acute hyponatremia may be assumed when patients have received large amounts of fluids over at least 2–3 days without excretion of adequate amounts of free water (Lampl and Yazdi 2002). Identification of the cause of hyponatremia (syndrome of inadequate ADH secretion, sodium loss via the renal route, emesis, diarrhoea, excessive sweating, use of diuretics or the intake of excessive amounts of free water) and its correction are to be attempted in all patients. Reduced fluid intake (<1,000 mL/day) leads to the gradual normalization of serum sodium levels and serum osmolarity, with ensuing improvement in the symptoms in patients with milder hyponatremia. This therapeutic approach is, however, often problematic in intensive care patients with reduced perfusion pressure found in particular after subarachnoidal hemorrhage or stroke. Severe hyponatremia with altered levels of consciousness, convulsions, and other neurologic symptoms mandates immediate corrective therapy. Mortality rates of up to 50% have been reported for different series of
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patients with severe hyponatremia (Martin 2004). In determining the therapeutic approach, the risk for hyponatremia, in particular brain edema, should be weighed against the risk for CPM/EPM. The sodium requirement can be assessed based on the following formula: Sodium requirement (mmol) = (desired- Na + -serum-Na+) ´ 0.6 ´ body weight Administration of isotonic fluids and, only in cases of extreme sodium loss 5% NaCl solution, is recommended for the correction of the serum sodium concentration. Recommendations in the available literature vary substantially with regard to the rate of hyponatremic correction. Most studies recommend that the increase in serum sodium concentrations should in all patients be maintained at below 0.5 mmol/L/h, and not exceed 8 to (maximum) 10 mmol/L/day. The definite level below which CPM cannot occur is still unknown. The initial correction should be aimed at the establishment of mild hyponatremia. An overcorrection to hypernatremic levels must be avoided. Initial recheck examinations of electrolyte and CVD at intervals of a few hours are mandatory (Brown 2000; Lampl and Yazdi 2002; Martin 2004). In symptomatic acute hyponatremia, the initial correction can be made with 1(−2) mmol/L/h over several hours, provided the daily correction does not exceed 8–10 mmol/L/day. The aim of therapy should again be a mild hyponatremia of 125–130 mmol/L (Brown 2000). The concurrent administration of furosemide or other diuretics can be helpful in limiting the increase rate (Lampl and Yazdi 2002). Hypotonic fluids can be given after excessive corrections, to lower the serum sodium concentration to approximate pretherapeutic levels. Hypokalemia may represent an additional risk factor for the occurrence of CPM after sodium correction and should therefore also be corrected (Lampl and Yazdi 2002).
4.9.1.7 Therapy No controlled studies on the therapy of patients with manifest CPM/EPM have been found in the literature. The initial therapy should be provided in the intensive care unit. General therapeutic measures comprise adequate caloric intake, thrombosis, pneumonia and decubitus prophylaxis, as well as intubation and ventilation, as needed. Results of small case series have shown favorable responses to the isolated administration of thyroxin-releasing hormone (TRH application over several weeks), steroids, immunoglobulins (i.v.), and plasmapheresis – therapies whose importance cannot yet be conclusively assessed. The pathophysiologic hypothesis of an osmotic injury to the endothelium with the release of myelinotoxic substances
4.9 Metabolic Brainstem Diseases
due to overly rapid serum sodium correction, suggests that the administration of dexamethasone may be beneficial through its assumed endothelium protective effect. The described efficacy has been shown by animal studies. Further beneficial measures may be both plasmapheresis with the removal of myelinotoxic substances and the administration of immunoglobulins (i.v.) leading to binding of their detrimental effects (Lampl and Yazdi 2002; Martin 2004). Animal experiments and observations in two patients showed the beneficial effect of reintroduction of hyponatremia (Oya et al. 2001). Parkinsonian symptoms in the course of EPM may respond favorably to dopaminergic therapy (Martin 2004). 4.9.1.8 Prognosis In the past, when the diagnosis of CPM was made almost exclusively post mortem, the prognosis was bad, at a reported mortality rate of 90% after 6 months and severe deficits in the majority of survivors. After the introduction of imaging techniques, there was increasing evidence of milder courses of disease ranging from the regression of clinical symptoms to complete recovery, in addition to findings of asymptomatic courses. A retrospective study of 44 patients with typical neurologic findings in CPM or EPM reported a survival rate of 94% for patients whose follow-up data were available for evaluation. The prognosis in these patients was not dependent upon the degree of the neuroradiologic findings (Menger and Jörg 1999). The described results have been confirmed by other authors (Brown 2000).
4.9.2 Vitamin Deficiency Diseases Numerous hypovitaminoses can lead to disturbances of the nervous system. Preferential involvement of the brainstem is nevertheless rare and occurs primarily in vitamin B1 deficiency. Hypervitaminoses play only a subordinate role in neurologic conditions. Chronic alcohol abuse is the most common cause of hypovitaminosis in Western Europe and North America. Alcohol abuse may be associated with insufficient consumption of foods rich in vitamins, disturbed vitamin absorption, alcohol induced gastrointestinal disorders, increased vitamin requirement, and disturbed cellular vitamin utilization (Butterworth 1995). Malnutrition related to specific diets, for example a strictly vegetarian diet, or anorexia nervosa is found less often in Western countries. Malabsorption syndromes in chronic gastrointestinal diseases such as celiac disease, Crohn’s disease, chronic pancreatitis, and intestinal worm infections can also lead to vitamin deficiency. An undersupply of vitamins may also be due to an increased but unmet
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vitamin requirement during pregnancy and lactation, or in severe infectious diseases and tumors. In African and Asian countries, hypovitaminoses are commonly due to inadequate or unbalanced nutrition. A diet of polished rice, for example, can lead to thiamine deficiency, while a maize-based diet may cause niacin deficiency. Genetic disorders rarely cause hypovitaminoses (abetalipoproteinemia ® vitamin E deficiency, Hartnup syndrome ® niacin deficiency). The diseases described below are due to a deficiency in vitamins B1 and B12 and represent possible causes of brainstem disturbances. Deficiencies in other B vitamins only rarely lead to disturbances of brainstem function. In the foreground are disturbances of the peripheral nervous system (vitamin B6, B12, pantothenic acid, folic acid, niacin) and the spinal cord (vitamin B12, folic acid, niacin). Other sites of manifestation include the optic nerves (vitamin B1, B6, B12), and the cerebellum (vitamin B1, niacin). Psychopathologic changes ranging from apathy or increased irritability to psychotic symptoms, as well as epileptic seizures can manifest in all types of vitamin B deficiencies.
4.9.2.1 Vitamin B1 Hypovitaminosis Larger amounts of vitamin B1 (thiamine) are found in yeast, grains, pork, kidneys, potatoes and legumes. In addition to chronic alcoholism, thiamine deficiency may be due to tumor diseases, chronic gastrointestinal diseases with malabsorption syndrome, AIDS, anorexia nervosa, hemodialysis, and inadequate infant formulas (Kesler et al. 2005); a limited diet of polished rice has had an important role in countries of the Far East until today. An iatrogenic cause of thiamine deficiency may be total parenteral nutrition with high carbohydrates at insufficient vitamin substitution. Under conditions of insufficient supply, the endogenous thiamine store is depleted within 4–10 days. Thiamine diphosphate is an essential co-factor of the enzymes pyruvate dehydrogenase, a-ketoglutarate dehydrogenase and transketolase, which are essential for carbohydrate metabolism. Thiamine deficiency is associated with a disturbance of glycolysis, the citric acid and pentose phosphate cycle, which lead to an insufficient energy supply to the affected cells. The incomplete break down of glucose results in accumulation of pyruvate and lactate in blood and tissues, with the nervous tissue and heart muscle being most vulnerable to accumulation of acid metabolites (Langlais 1995). According to current understanding, the pathogenesis of neuronal cell injury in vitamin B1 deficiency is multifactorial. An early development is the loss of a-ketoglutarate dehydrogenase activity leading to disturbances of the citric acid cycle and subsequent mitochondrial energy production
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in endothelial cells and microglia (Hazell et al. 1998). This results in increased formation of endothelial NO synthetase, reactive oxygen metabolites and cytokines, as well as microglia activation, causing inflammatory reactions and increased oxidative stress. A functional disturbance of neuronal pyruvate dehydrogenase takes effect in later stages of thiamine deficiency. The resulting disturbance of glucose oxidation leads to energy deficiency, cell depolarization, glutamate release with NMDA (N-methyl-D-aspartate-) receptor-mediated cell injury and lactate accumulation (Desjardins and Butterworth 2005). The exact reason for selective neuronal cell injury in thiamine deficiency is unclear, but it may be related to regionally different cerebral energy requirements, differences in the thiamine turnover rate, and varying tissue antioxidant capacity. Vitamin B1 deficiency can cause different clinical pictures, including beriberi, Strachan’s syndrome, Wernicke’s encephalopathy. The type of clinical picture depends on the degree of thiamine deficiency, the acuity of the underlying deficiency, and the presence of additional vitamin deficiencies.
4.9.2.2 Beriberi Neuropathic beriberi with axonal sensorimotor, distal symmetrical polyneuropathy, and rare involvement of cranial nerves is prominent in chronic mild vitamin B1 deficiency (Djoenaidi et al. 1995). Initial symptoms occur in patients aged 20–30 years. Severe deficiencies can lead to cardiac damage with dilated cardiomyopathy and pericarditis, with the risk for acute heart failure (cardiac beriberi).
4.9.2.3 Strachan’s Syndrome The rare Strachan’s syndrome is characterized by the symptom triad of optic atrophy, posterior white column disturbance, and sensorimotor polyneuropathy in association with orogenital dermatitis. It is endemic in some regions of Africa and Asia. In addition to thiamine deficiency, vitamin B12 deficiency and toxins contained in the manioc fruit may be involved in the pathogenesis.
4.9.2.4 Wernicke’s Encephalopathy Epidemiology and Etiopathogenesis Wernicke’s encephalopathy occurs predominantly, but not exclusively in alcoholics. There are increasing reports of Wernicke’s encephalopathy after bariatric surgery (Aasheim 2008). It is unclear if a genetically determined
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decrease in transketolase activity constitutes a necessary requirement for this condition (Martin et al. 2003). The acute or subacute onset of the disease often occurs after febrile infections with symptoms of ophthalmoplegia, ataxia, as well as disturbances of orientation and consciousness; men and women are nearly equally affected, the age of onset is between 30 and 70 years. Wernicke’s encephalopathy is not rare. In a neuropathologic study, typical brain changes were found in 2% of general autopsy specimens (Harper et al. 1989), although the previous clinical diagnosis was established extremely rarely. The old name for the disease, “polioencephalitis haemorrhagica superior”, dates back to its first description in 1881 by Carl Wernicke, who attributed the observed neuropathologic changes in the form of petechial hemorrhages in the periventricular and periaqueductal gray matter to inflammatory processes. Preferentially affected regions of the brain comprise the diencephalic structures (mammillary bodies, thalamus, hypothalamus), the mesencephalon (lamina quadrigemina, periaqueductal gray matter), the pons (floor of the fourth ventricle with the dorsal vagus nuclei and vestibular nuclear regions), and the cerebellum (superior cerebellar vermis, less often the cerebellar hemispheres). Histopathology shows a mixed picture with focal demyelinations, proliferation of microglia and capillaries, hemorrhages, necroses, and atrophies (Reuler et al. 1985).
Clinic The neuropathologic predilection sites of Wernicke’s encephalopathy lead to the typical clinical symptoms of the disease. Oculomotor disturbances comprise horizontal and, less often, vertical gaze evoked nystagmuses, nuclear oculomotor disturbances, most often in the form of a unilateral or bilateral abducens paresis, internuclear ophthalmoplegia, as well as disturbances of conjugate horizontal and vertical eye movements in upgaze. The occurrence of vertical downgaze palsy is rare. All eye movements in all directions may be lost in severe cases. Miosis is present in some patients. Coordination disturbances manifest as trunk and postural ataxia. Extremity ataxia is found less often and involves primarily the lower extremities. Quantitative disturbances of consciousness from somnolence to coma can occur rapidly, but more common are initial qualitative disturbances of consciousness, such as apathy, associated with orientation and attention disturbances, and disturbances of cognition and memory. In some patients symptoms of delirium are found, ranging from agitation, hyperexcitability, increased suggestibility and delusional misinterpretations to optic and scenic hallucinations, which may be due to concurrent alcohol withdrawal. If early symptoms of the disease remain untreated, the state
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of consciousness may deteriorate to coma within days. The presence of vegetative dysregulation places patients with Wernicke’s encephalopathy at an additional risk for hypothermia and arterial hypotension. Epileptic seizures may also occur. Different combinations of symptoms are often found. In some patients, individual symptoms are in the foreground, rendering the diagnosis of Wernicke’s encephalopathy difficult. After the initial symptoms have subsided, the further course is often marked by an amnestic-confabulatory syndrome (Korsakow’s psychosis).
Diagnosis In view of the acuity of the course of disease, the diagnosis and onset of early therapy are guided by the clinical symptoms. Wrongly diagnosed and treated monosymptomatic or oligosymptomatic forms of Wernicke’s encephalopathy can lead to a fatal outcome. If Wernicke’s encephalopathy is suspected, parenteral thiamine therapy should begin immediately. A rapid improvement of the symptoms during the described therapy corroborates the initial tentative diagnosis. The diagnosis can be confirmed based on the whole blood sample taken before the administration of thiamine for the assessment of the thiamine diphosphate concentration (normal value: 28–85 mg/L) or erythrocyte transketolase activity (normal value: 90–140 mg/mL/h), whose increased activity after thiamine diphosphate supplementation (normally up to 10%) ascertains the vitamin deficiency. After the start of thiamine therapy, the differential diagnostic clarification of other inflammatory, ischemic or toxicmetabolic encephalopathies has to be supplemented by cerebrospinal fluid puncture, EEG, and brain imaging. While indication of a blood brain barrier disturbance may be detected in the cerebrospinal fluid of patients with Wernicke’s encephalopathy, inflammatory alterations are not identified. In 50% of patients, the EEG reveals a mild to moderate diffuse slowing, in some instances also bilateral synchronized delta activity, as indicators of a functional brainstem disturbance. Although the MRI examination is nonspecific, it can, nevertheless, show typical changes. In the medial thalamus, around the mesencephalic aqueduct and in the mammillary bodies bilateral hyperintense signal changes are identified in T2-weighted and FLAIR sequences, and appear in T1-weighted sequences with marked contrast enhancement (Kavuk et al. 2003; Fig. 4.67). Changes in diffusion-weighted MRI sequences in the acute phase of Wernicke’s encephalopathy are indicative of cytotoxic edema in these regions of the brain (Doherty et al. 2002). Atrophy of the mammillary bodies and enlargement of the third ventricle are prominent in the chronic stage of the disease.
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Fig. 4.67 MRI in Wernicke’s encephalopathy. Image obtained in a 51-year-old woman with subacute occurrence of orientation disturbance and lack of initiative, horizontal gaze paresis and pronounced lower extremity ataxia. The history did not show alcohol abuse, but a subtotal resection of the small intestine for mesenteric artery thrombosis 6 months previously. Hyperintense signal changes in the periaqueductal mesencephalon in T2-weighted MRI sequences
Differential Diagnosis The differential diagnosis includes intoxications, encephalitides, vertebrobasilar ischemia, infratentorial hemorrhage, as well as rapidly progressing tumors (lymphomas), an epileptic seizure state, or primarily psychiatric disorders with psychogenic stupor.
Therapy When treated early, Wernicke’s encephalopathy is potentially reversible. Parenteral high-dose thiamine therapy is indispensable due to the complete depletion of the Vitamin B1 stores. Recommended are doses substantially above the daily requirement of 1–2 mg, ranging from 100–500 mg/day intravenous or intramuscular for 3–5 days, followed by oral substitution of 300 mg/day until correction of the underlying cause of vitamin deficiency. The thiamine derivative benfotiamine is better absorbed and therefore preferred for oral application. If parenteral thiamine therapy is begun sufficiently early, the state of consciousness and the eye movement disturbances improve within a few hours, while ataxia resolves within days to weeks only. The absence of oculomotor function improvement raises doubts concerning the diagnosis of Wernicke’s encephalopathy. A residual fine beating horizontal gaze-evoked nystagmus may be found in 30% of cases, and a residual ataxic gait disturbance persists in 50% of patients. Although the risk for allergic and anaphylactic reactions is low in parenteral thiamine therapy, it can result in serious consequences for the patients. The consequences of glucose solution infusions in thiamine-deficient patients can be disastrous, and precipitate the onset of Wernicke’s encephalopathy, as the increased thiamine requirement is no longer met. The addition of
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thiamine to the required glucose infusions is therefore expedient in chronic alcoholics and malnourished patients. In addition to vitamin B1, other vitamins (folic acid, vitamin B6 and B12) should be substituted in the long-term therapy of these patients.
4.9.2.5 Course and Prognosis Wernicke’s encephalopathy is usually fatal if untreated. Despite early therapy, up to 20% of patients die in the acute phase, predominantly from severe infections or cardiovascular disorders. Three-quarters of the patients have a persistent organic psychotic syndrome. This disorder is described as Korsakow’s psychosis and is characterized by memory and learning disturbances with anterograde and retrograde amnesia, a tendency to confabulate, and concentration disturbances.
4.9.2.6 Vitamin B12 Hypovitaminosis In addition to vitamin B1 deficiency, brainstem function disturbances may also be caused by vitamin B12 hypovitaminosis. The most prominent features of this disorder consist of involvement of the spinal cord, optic nerve, peripheral nerves, as well as white matter structures of the brain, in the context of an encephalomyeloneuropathy. Patients of middle and old age are preferentially affected. The neurologic disturbances are not in all cases associated with a macrocytic hyperchromic anemia.
4.9.2.7 Etiopathogenesis The most common cause is an autoimmune disease with formation of antibodies against parietal cells of the gastric mucosa. This is associated with development of a chronicatrophic type A gastritis with intrinsic factor deficiency, leading to decreased or absent absorption of vitamin B12 (cobalamin) in the ileum. Other gastric diseases or gastric resections can also produce a selective vitamin B12 deficiency due to the lack of intrinsic factor. In addition to nonselective vitamin absorption disturbances in Crohn’s disease, ulcerative colitis, celiac disease, or after ileum resection, an insufficient vitamin supply in alcoholism and extreme malnutrition plays an important role. Furthermore, a strictly vegetarian diet can lead to a vitamin B12 deficiency, because this vitamin is found only in animal products. An increased cobalamin requirement exists during pregnancy and lactation, in intestinal infestation with broad fish tapeworm, or bacterial overgrowth in the bowels. Rare, but significant, is the production of neurologic symptoms
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by the anesthetic gas N2O in latent vitamin B12 deficiency as a result of irreversible cobalamin oxidation (Marie et al. 2000). The amount of vitamin B12 stored in the liver is 1–2 mg, so that, at a daily requirement of 1–2 mg and in the absence of cobalamin uptake, the stores are sufficient for 2–3 years. Clinical symptoms therefore occur only after this time. As a cofactor of methionine synthetase, vitamin B12 has an important function in DNA synthesis in hematopoietic tissue, as well as in methylizing reactions in the nervous system (Weir and Scott 1995). Neuropathologically white matter lesions with vacuole formation in the myelin sheath predominate, secondary axonal lesions may occur. In the early stage, these changes are found primarily in the posterior white column pathways of the lower cervical part of the spinal cord and the upper thoracic cord; the pathologic process later spreads across all pathways within the spinal cord (funicular myelopathy). It may also involve the long pathways and fiber systems in the brainstem and the cerebral white matter in the form of a combined degeneration. Additional changes may be found in the optic nerve and the peripheral nerves.
4.9.2.8 Clinical Findings The neuropathologic changes responsible for the typical neurologic symptoms of a vitamin B12 deficiency comprise paresthesias and position sense disturbance of the extremities, flaccid and spastic pareses with pyramidal pathway signs, ataxic gait and bladder voiding disturbances. In addition, psychopathologic changes with concentration and attention disturbances, psychotic symptoms and development of dementia may be present. Cranial nerve deficits may also be found. However, these symptoms never occur in isolation, but are accompanied by disturbances of the posterior white columns.
4.9.2.9 Diagnosis The assessment of serum vitamin B12 levels can serve as a helpful diagnostic method; it is, nevertheless, characterized by a low sensitivity rate. Values in the normal range (200– 900 pg/mL) do not permit the exclusion of a cellular vitamin B12 deficiency. For this reason assessment of the cobalamin metabolites methylmalonic acid and homocysteine is recommended, both of which show elevated serum concentrations in patients with vitamin B12 deficiency. The advantage of methylmalonic acid over homocysteine is that it is not influenced by the presence of folic acid deficiency (Green and Kinsella 1995). The absent evidence of macrocytic hyperchromic anemia does not exclude the presence of a relevant vitamin B12
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deficiency. The cause of cobalamin deficiency is determined from a gastrointestinal perspective. An MRI examination of the spinal column can visualize demyelinations of the posterior white columns in T2-weighted sequences as hyperintense signals already in the early stages of the disease, although these changes are nonspecific. In addition to leukoencephalopathic white matter lesions (Vry et al. 2005), hyperintense signal changes in the brainstem and cerebellum may be present in advanced phases of the disease (Katsaros et al. 1998). Subclinical optic nerve involvement should be identified early with the use of visual evoked potentials.
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untreated, the course is chronic progressive, and the disorder leads to severe disabilities. The disease can be completely cured within a few months if vitamin substitution begins no later than 3 months after the initial manifestation of symptoms. At a later onset of therapy, improvements or the prevention of disease progression is still possible. Mild psychopathologic disturbances can improve after only a few days of therapy. If the therapy is discontinued even though the cause of disease persists, initial symptoms will recur after 2–3 years.
4.9.2.13 Other Vitamin Deficiency Diseases 4.9.2.10 Differential Diagnosis The differential diagnosis should include consideration of copper deficiency myeloneuropathy, which has increasingly been discussed as an independent disease entity in recent years. Copper deficiency has been attributed to both a decreased copper absorption in gastrointestinal diseases and increased zinc intake. The clinical symptoms are very similar to those found in vitamin B12 deficiencies; polyneuropathy appears to occur in all patients with copper deficiencies. Hyperintense T2-signal changes in the posterior white columns of the cervical and thoracic spinal cord are also found in this disorder (Kumar et al. 2004). The differential diagnosis should include chronic progressive multiple sclerosis with predominant spinal involvement, compressive cervical myelopathy, viral or autoimmune-mediated myelitides or paraneoplastic syndromes.
4.9.2.11 Therapy A number of different therapeutic schemes are available for the management of neurologic symptoms. They all have a two-step high-dose parenteral substitution therapy in common. In a first step, rapid saturation of the stores is attempted with the daily intramuscular administration of 1,000 mg hydroxycobalamin or cyanocobalamin for 5–14 days. This is followed by maintenance therapy with initial weekly and later monthly intramuscular application of 1,000 mg cobalamin; this usually needs to be continued throughout the patient’s life. Attention has to be given to the possible presence of hypokalemia at the onset of therapy.
4.9.2.12 Course and Prognosis The duration, type and severity of symptoms prior to the onset of therapy are crucial for the course of disease. When
An undersupply of vitamin A can lead to development of pseudotumor cerebri. Vitamin D and K deficiencies do not cause any direct neurologic disturbances. A vitamin K deficiency in malabsorption syndromes or the intake of vitamin K antagonists, however, poses the risk of intracranial or intracerebral hemorrhage with brainstem involvement, due to reduced formation of coagulation factors II, VII, IX and X. An isolated vitamin E deficiency persisting over a number of years can cause slowly progressive spinocerebellar degeneration with limb and gait ataxia, dysarthria, nystagmus, disturbed sense of position, and diminished vibration perception, in addition to pyramidal pathway disturbances and signs of a polyneuropathy. Brainstem symptoms can include gaze and oculomotor disturbances, dysphagia, and ptosis. The neurologic symptoms are similar to those observed in Friedreich’s ataxia. Other sites of manifestation include the retina (retinal pigment degeneration) and myocardium. The causes of vitamin E deficiency are primarily acquired; less often observed are hereditary malabsorption syndromes with superimposed deficiency symptoms of other vitamins as, e.g. in the rare autosomal recessive inherited abetalipoproteinemia. A function disturbance of hepatic a-tocopherol, which normally regulates the vitamin E incorporation into lipoproteins (LDL, HDL), is found in autosomal recessive ataxia with isolated vitamin E deficiency. The main function of vitamin E is the exertion of a cell protective effect against free radicals. The diagnosis of vitamin E deficiency is made based on assessment of the serum vitamin E level. The normal serum vitamin E level ranges are 5–17 mg/L. Patients with neurologic symptoms associated with vitamin E deficiency receive significantly higher doses of the vitamin than the recommended daily requirement of 25–30 mg. After initial oral substitution with 2,000 mg/day for 2 weeks, the dose is reduced to 800 mg/day. The intramuscular injection of vitamin E represents a therapeutic option in cases of severe absorption disturbances.
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4.9.3 Hereditary Metabolic Diseases More than 300 hereditary metabolic diseases are currently known. The majority of these manifest in childhood and are therefore classified as neuropediatric conditions. There are increasing reports of later manifestations of disease in adolescents and adults with generally milder courses than the infantile or juvenile forms. Most of these diseases in adulthood are associated with some residual activity of the enzyme, but not its complete absence. Some of these can be treated effectively today, which emphasizes the need for the neurologist primarily involved in the treatment of adults to also be familiar with these diseases. A hallmark of these conditions is that they involve large parts of the central nervous system in addition to other organs and are therefore not limited to the brainstem or other brain structures. However, some of the hereditary metabolic diseases are focused on the brainstem region, and brainstem involvement may be a cofactor in others. Not all of the possible clinical pictures can be discussed in the present chapter. The emphasis in this section is on clinical pictures occurring in adolescents and adults that are associated with frequent or at least possible brainstem involvement. Only a brief outline of some of the individual clinical pictures is presented, detailed descriptions can be found in the relevant literature (Scriver et al. 2001; Hoffmann and Grau 2004). 4.9.3.1 Wilson’s Disease Epidemiology The reported incidence of the disease is approximately 1:40,000 births.
Etiopathogenesis Wilson’s disease, or hepatolenticular degeneration, is an autosomal recessive inherited metabolic disorder due to mutations within the ATPase gene (ATP7B), which is responsible in particular for hepatic and biliary copper excretion. The gene is located on chromosome 14q.3; more than 200 of the mutations responsible for Wilson’s disease and 40 normal allelic variants have been described thus far (Brewer 2005). In Europe, the mutation H1069Q is found in 30–90% of affected patients. Close genotype-phenotype correlations do not exist; environmental and other genetic factors appear to have a critical role in determining the wide spectrum of clinical pictures. The daily dietary copper intake (approx. 1–1.4 mg) ranges at 25% above the required amount. In patients with Wilson’s disease, excess copper cannot be excreted in the bile. The result is an intracellular accumulation of copper with a
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subsequent toxic effect due to impairment of mitochondrial functions and an increased formation of free radicals. An augmented storage of copper is observed in particular in the liver, the brain, the cornea, and the kidneys. Copper is not incorporated into the transport protein ceruloplasmin; the result is an increased breakdown of the latter, and its reduced availability in approximately 90% of patients. Neuronal death and astrocytic proliferation involving primarily the striatum, globus pallidus, and the thalamus then occur in the brain. In the region of the dopaminergic nigrostriatal pathways both a presynaptic and a postsynaptic lesion are found, which serves as an indication of substantia nigra involvement. In addition to direct copper accumulations, hepatic impairment leads to neurologic complications (Brewer 2005).
Clinical Findings Wilson’s disease presents as a hepatic or neuropsychiatric disease, or as a combination of both. About 40–50% of patients have primarily neurologic or psychiatric symptoms, which usually manifest between the ages of 15–40 years. The most prominent neurologic features include tremor, hypokinesia and bradykinesia, dysarthria and dysphagia, dystonias, ataxia, and, more rarely, hyperkinesias. The tremor may be expressed as resting, postural, or action tremor, as well as intention tremor, and can involve the proximal segments of the extremities. Psychotic symptoms comprise personality changes, mild dementia, affective disturbances, or schizophreniform psychoses. The neurologic symptoms are also often preceded by behavioral abnormalities or concentration deficits. The disease onset may be acute in exceptional cases (Pendlebury et al. 2004). In the early phase of neuropsychiatric courses, slit-lamp examinations almost invariably show a Kayser-Fleischer ring of the cornea. Conversely, Kayser-Fleischer rings are present in only 30–50% of patients with primarily hepatic courses and can disappear with successful therapy (Brewer 2005). Without appropriate therapy, the course of disease is slowly progressive over a 10–40 year period. Liver damage found in these patients is often only subclinical. A disease course pattern with predominantly hepatic symptoms, as well as a high incidence of intravascular hemolysis and kidney failure is usually found in patients younger than 20 years; it is fatal after only a few years if left untreated. Hepatic manifestations comprise • Hepatitis with elevated transaminases with or without icterus • Acute liver failure or • Chronic liver cirrhosis The disease rarely manifests primarily with initial kidney, pancreas or heart function disturbances.
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Diagnosis
Therapy
Diagnosis is based on the demonstration of elevated copper excretion in urine (normal: <30 mg/24 h; Wilson’s disease >100 mg/24 h), decreased total serum copper concentration (normal 85–145 mg/dL) at elevated free serum copper (normal: 10–15 mg/dL; Wilson’s disease 20–100 mg/ dL), decreased serum ceruloplasmin level (normal: 25–45 mg/dL), although this may be normal in 10–24% of patients, as well as the demonstration of a KayserFleischer ring (Brewer 2005). No additional diagnostic measures are required in the presence of typical clinical and laboratory findings. In cases of uncertainty, a liver biopsy to determine an elevated copper in the liver, or a radionuclear copper test are mandatory; these examinations further enable detection of asymptomatic heterozygotes. In view of the size of the gene and the plurality of mutations, a genetic diagnosis is generally indicated only in families with a known mutation. The examination of siblings is important, because early diagnosis exerts a favorable influence on the prognosis. Cranial MRI typically reveals mild cerebral atrophy and increased signal intensities on spin echo sequences in the putamen, globus pallidus and the thalamus, but also in the midbrain and the periaqueductal gray that may be reversible under therapy (Fig. 4.68). T2-hypointensities may in some cases be found, chiefly in the central putamen. Indications of presynaptic or postsynaptic deficits of dopaminergic neurotransmission may be apparent on SPECT (Barthel et al. 2003). Transcranial brain parenchyma sonography can detect hyperechogenicity in the lentiform nucleus which correlates with the severity of the disease (Walter et al. 2005).
Therapy is aimed at induction of a negative copper balance, either through increased renal copper excretion by means of chelate formation (D penicillamine, triethylene tetramine), or via decreased intestinal copper absorption (zinc). The initial release of toxic free copper from stores in the body under therapy with chelate formers, in particular D penicillamine, can lead to – in some patients irreversible – symptom deterioration during the first weeks of therapy. This has been observed in up to 50% of patients receiving D penicillamine, and was irreversible in 25% of the population (Brewer 2005). D penicillamine is therefore no longer considered the drug of first choice; if used, the doses have to be increased slowly (in addition pyridoxine is given for the prevention of optic nerve damage). Acute side effects, such as urticaria, fever, dyspnea, thrombocytopenia and leucocytopenia are prominent; the short-term administration of cortisone can be helpful in the prevention or alleviation of side effects. Possible long-term side effects are, among others, lupus erythematosis, nephritis, myositis or myasthenia gravis. Monitoring of blood count, liver concentrations and serum copper levels is required at intervals of approximately 2 weeks. Triethylentetramine (trientine) induces a less pronounced copper release than D penicillamine and is therefore associated with a lower risk for an initial deterioration of symptoms. A more recently introduced drug, tetrathiomolybdate, decreases the rate of copper uptake when taken with meals, and forms a complex of serum-copper when taken between meals. Higher doses did not lead to improvement. Side effects included anemia and leucocytopenia as well as elevated transaminase levels, which were reversed under reduced dose therapy (Brewer 2005). A double-blind comparison study showed a higher rate of initial neurologic symptom deterioration under triethylentetramine (6 of 23 patients) than after tetrahydromolybdate therapy (1 out of 25 patients). Three of the patients with initial symptom deterioration under triethylentetramine and died during the follow-up period. Tetrahydromolybdate may therefore be the preferred drug in patients with a neuropsychiatric course in Wilson’s disease (Brewer et al. 2006); however, it currently lacks regulatory approval in Germany and is available as a pure substance only and not in tablet form. Tetrahydromolybdate should be given for 8–16 weeks, accompanied by the time-delayed administration of zinc (Brewer 2005). Zinc decreases the intestinal absorption of copper and has Federal Drug Administration (FDA) approval for maintenance therapy. Although zinc leads to only minor side effects (gastrointestinal complaints, anemia), its disadvantage is that an adequate response is achieved only after several months (Brewer 2005). Zinc monotherapy is often recommended for maintenance therapy, deteriorations have, however, been described (Czlonkowska et al. 1996).
Fig. 4.68 FLAIR sequences obtained in a 22-year-old woman with Wilson’s disease. Symmetrical signal intensity increases (a) bilaterally in the putamen, thalamus and (b) in the midbrain at concurrent hypointensity in the globus pallidus. The patient had complained for several weeks of an increasing fine motor disturbance in the left hand, gait instability, as well as progressive concentration and memory disturbances
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Medical therapy is guided by the clinical symptoms, copper excretion in urine (aim: <0.1 mg/day) and the serum copper level (aim: 10–15 mg/dL). Foods rich in copper (e.g. liver, shellfish and nuts) should be avoided in the early phase of treatment. Liver transplantation is required in fulminant hepatitis or progressive liver cirrhosis, and may be considered in patients with progression of neurologic symptoms under medical therapy.
Prognosis Normal life expectancy and relative freedom from symptoms can be achieved when treatment begins early (mild or no symptoms). The complete regression of symptoms is rare (20%) in later phases of the disease (Stremmel et al. 1991). Symptom improvement occurs within a period of approximately 2 years; dystonia and tremor may respond less favorably to therapy than other symptoms. Testing of family members is important for early identification of affected individuals, and should be done with a haplotype analysis in patients with known mutations.
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extrapyramidal and pyramidal motor disturbances. Cognitive disturbances and retinal degenerations can occur; the course is rapid progressive and the patients lose the ability to walk within a period of 15 years. The adult variant develops more slowly (over decades) and is marked by dysarthria and palilalia, parkinsonism, pyramidal pathway lesions, and psychopathologic changes. Loss of ability to walk develops after 15–40 years (Hayflick et al. 2003). Intermediary phenotypes characterized, among others, by motor tics and symptoms of Tourette’s syndrome have also been described.
Diagnosis A typical feature is the so-called eye-of-the-tiger sign, which is visualized on T2-weighted MRI sequences in both courses of disease. It consists of bilateral symmetrical hyperintensity in the pallidum as an expression of glial scarring and a hypointensity resulting from increased iron accumulation. The detection of mutations in the PKAN gene confirms the diagnosis.
Therapy 4.9.3.2 Pantothenate Kinase-Associated Neurodegeneration Epidemiology The incidence of the disease is not yet adequately documented.
Definitive causal therapy does not exist; it is unclear if administration of pantothenate (vitamin B5) may be helpful (Hayflick et al. 2003). The low-dose administration of L-dopa can lead to long-term relief of parkinsonian symptoms. Deep brain stimulation of the internal globus pallidus can be helpful in patients with severe dystonia, although secondary deterioration can also occur after stimulation.
Etiopathogenesis 4.9.3.3 Aceruloplasminemia The autosomal recessive disease is caused by mutations in the pantothenate kinase-2 gene on chromosome 20; it is associated with disturbances of neuronal iron metabolism, leading to iron accumulation in the basal ganglia and the substantia nigra. Pantothenate kinase-associated neurodegeneration (PKAN) forms part of a group of disorders referred to as “neurodegeneration with brain iron accumulation”. The former name, Hallervorden-Spatz disease, should no longer be used in view of the documented participation of the eponymous first describers in Nazi war crimes (Hayflick et al. 2003).
Clinic The classic course of disease begins in the first decade of life and is characterized by delayed psychomotor development, gait ataxia with frequent falls, dystonia, rigor and other
Epidemiology The exact incidence is not known. Results of studies performed in Japan showed a prevalence of 1:100,000 for this ethnic group (Culotta and Gitlin 2001).
Etiopathogenesis Aceruloplasminemia is an autosomal recessive inherited disorder caused by mutations in the ceruloplasmin gene on chromosome 3q25. It leads to iron – yet not copper – accumulation in the brain, in particular in the basal ganglia. Ceruloplasmin is a ferroxidase which mobilizes iron from the reticuloendothelial system, oxidizes and incorporates it into transferrin. While the lack of ceruloplasmin leads to an
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iron overload in different tissues, it does not cause impairment of copper metabolism.
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4.9.3.5 Gaucher’s Disease Epidemiology
Clinical Findings The patients often develop insulin-dependent diabetes mellitus early in the course. Neurologic symptoms mostly develop during the fourth decade. The most common neurologic symptoms comprise ataxia, dysarthria, dystonia, mild spasticity, and cognitive impairment; all symptoms are marked by slow progression (McNeill et al. 2008). Despite the presence of iron accumulations, which may also occur in the heart and the liver, there are usually no related symptoms.
The reported prevalence ranges at approximately 1:90,000 births.
Etiopathogenesis Gaucher’s disease is a lipid storage disorder caused by a defect in the gene for enzyme b-glucocerebrosidase on chromosome 1q21. If glucosylceramide is not broken down, it accumulates in particular in the reticuloendothelial system.
Clinical Findings Diagnosis
A reduction of body iron with the chelating agent desferrioxamin appears to be useful in preventing deterioration of neurologic symptoms (Miyajima et al. 1997).
In addition to a visceral type without initial symptoms related to the central nervous system (type 1), there is an early neuropathic form (type 2) with onset in the first few months after birth, characterized by severe hepatosplenomegaly, spasticity, dysphagia, ophthalmoplegia, and a life expectancy of 2–3 years. The subacute neuropathic form (type 3) begins in childhood with fever attacks, liver and spleen enlargement, and pancytopenia. An early neurologic cardinal symptom is a supranuclear horizontal gaze palsy followed by mental retardation, choreoathetosis, myoclonias, spastic pareses, and epileptic seizures. The patients usually die in the second decade of life. The visceral clinical course manifests primarily with skeletal disorders, ochrodermia, hepatosplenomegaly, anemia and thrombocytopenia, as well as pulmonary infiltrates. In addition, an association with a parkinsonian syndrome, that shows a poor response to L-dopa therapy and manifests around age 50, has also been described (Bembi et al. 2003).
4.9.3.4 Lysosomal Metabolic Diseases
Diagnosis
The function of lysosomes in the cell consists of the hydrolytic degradation of complex macromolecules. In the presence of a genetic defect in a lysosomal enzyme, the substrate breakdown comes to a standstill at the respective stage, leading to increased accumulation of intermediary products and subsequent cellular dysfunction. The symptoms of lysosomal storage diseases are determined by the rate of substrate turnover and the sensitivity of the tissue with regard to substrate storage. The majority of lysosomal storage disorders are characterized by substantial clinical variability. With only very few exceptions (Fabry’s disease, Hunter’s disease: x-linked recessive) they comprise autosomal recessive inherited diseases.
The diagnosis is established based on measurement of the b-glucocerebrosidase activity in leukocytes.
The patients are characterized by the absence of serum ceruloplasmin, and have mild normocytic and normochromic anemia, as well as reduced serum iron at elevated serum ferritin levels. MRI visualizes a signal reduction on T2 sequences, which are particularly pronounced in the basal ganglia and represent an expression of iron overload. Genetic testing of family members is important for assessment of presymptomatic stages (Culotta and Gitlin 2001).
Therapy
Therapy Enzyme replacement therapy with modified b-glucocerebrosidase is the treatment of choice. In type 3 Gaucher’s disease this therapy has been described as leading to improvement of the non-neurologic symptoms, but to no more than a stabilization of the neurologic signs. Whether the substrate deprivation therapy currently under investigation can provide an alternative to the cost intensive substitution therapy remains to be seen.
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4.9.3.6 Fabry’s Disease
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helpful in the treatment of pain; the results of pain therapy are, however, frequently unsatisfactory (Grau et al. 2003a).
Epidemiology The prevalence ranges at around 1:100,000 live births.
Etiopathogenesis The cause of x-linked inherited Fabry’s disease is attributed to a deficiency of the enzyme a-galactosidase, which leads to accumulation of sphingolipids in vascular walls, peripheral nerves, the brain, heart, kidneys and other organs. Clinical Findings Initial manifestations in the first 2 decades of life commonly consist of very severe acrodistally pronounced pain attacks, hypohidrosis, and other disturbances of the autonomic nervous system, skin changes in the form of angiokeratomas, as well as corneal opacities. The presence of cerebral microangiopathy and arterial ectasia, occurring primarily in the basilar artery, leads to development of transient ischemic attacks and stroke in approximately 25% of affected males already before age 40. One study reports Fabry’s disease in 4.9% of male and 2.4% of female patients (18–55 years) with kryptogenic stroke (Rolfs et al. 2005). Progressive renal impairment and various cardiac diseases represent further common organ manifestations. In contrast to previous understanding, the disease does not only manifest in hemizygous males, but heterozygous women transmitting the condition also frequently develop symptoms, although these occur later and are less pronounced.
Diagnosis The diagnosis in men is established based on the detection of deficient a-galactosidase activity in leukocytes. The biochemical demonstration is often unreliable in female carriers, due to the incidental inactivation of one of the two x-chromosomes; the molecular genetic confirmation of a known mutation in the family, or gene sequencing is therefore required. Therapy The therapy of choice in all symptomatic male and female patients is intravenous enzyme replacement therapy, the efficacy of which has been confirmed in two placebo controlled, randomized Phase III studies. Antiepileptics are
4.9.3.7 Niemann-Pick Type C Disease Epidemiology The estimated prevalence is 1:150,000 births.
Etiopathogenesis The disease is subject to a defect in the transport of unesterified cholesterol from the lysosomes to the cell membrane and the endoplasmic reticulum due to mutations in the NPC1(95%) or NPC2 genes (5%).
Clinical Findings The cardinal symptom is a marked slowing of the rapid vertical gaze saccades, leading to the development of supranuclear vertical and later also horizontal gaze paresis. Additional symptoms, characteristic especially of later onset cases that represent approximately 5% of all patients and manifest at a mean age of 30 years include dementia, psychoses, ataxia, dysarthria, dystonias, gelastic cataplexy, and splenomegaly. In some cases parkinsonism, dysphagia, epileptic seizures, and spastic pareses are found.
Diagnosis The diagnosis is supported by identification of typical storage cells in the bone marrow. It is confirmed by two specialized tests of fibroblasts (skin biopsy) with the demonstration of an intracellular cholesterol metabolism disturbance or by molecular genetic testing.
Therapy In early 2009, miglustat, an inhibitor of glycosphingolipid synthesis, was approved in the European Union for the treatment of Niemann Pick Type C disease. In a randomized placebo-controlled study of 29 patients over a 12-month period, miglustat was shown to improve horizontal saccadic eye movement velocity (primary endpoint) (Patterson et al. 2007). Cholesterol levels are undisturbed in NPC and there is no evidence of a beneficial effect by statins on the neurologic course (Grau et al. 2003).
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4.9.3.8 GM2 Gangliosidoses
Clinical Findings
Epidemiology
The classic infantile form is characterized by an immune deficiency with repeated infections, hepatosplenomegaly, lymphadenopathy, leukocytopenia, and a lymphoproliferative syndrome as an early cause of death. In the foreground of the adult form manifesting between later childhood and early adult age are ataxia, tremor, parkinsonism, dementia, and polyneuropathy. Gaze and cranial nerve disturbances have also been observed. Other typical features include partial albinism and foot deformities.
The prevalence of Tay-Sachs and Sandhoff’s disease in nonJewish Americans ranges at 1:300,000 births, respectively; the prevalence of Tay-Sachs disease is significantly higher in Ashkenazi Jews.
Etiopathogenesis GM2 gangliosidoses occur as a result of a deficiency in enzyme b-hexosamidase (Hex), which is present in the form of two isoenzymes (Hex A and B). A clinical differentiation cannot be made between the biochemical variants HexA deficiency (Tay-Sachs disease), HexA and B deficiency (Sandhoff’s disease), and an activator deficiency.
Diagnosis Eosinophil, peroxidase-positive giant granules in leukocytes (Fig. 4.69) are the most prominent diagnostic feature (Fig. 4.69). T2-weighted MRI sequences can show both cerebral atrophy and a signal hyperintensity in the substantia nigra.
Clinical Findings Cardinal symptoms of the chronic course of disease with onset between childhood and the third decade of life comprise spinocerebellar disturbances, and symptoms of motoneuron dysfunction. In single cases, gaze palsies, parkinsonism, dystonias, tremor, choreoathetosis, cognitive decline, and polyneuropathies occur.
Therapy In the infantile form, bone marrow transplants have been successful in the therapy of hematologic and immunologic defects. The improvement of a rapidly progressive neuropathy under cortisone therapy has been reported; parkinsonian symptoms can be relieved with the use of dopaminergics (Jacobi et al. 2005).
Diagnosis The diagnosis is based on demonstration of decreased HexAand/or HexB activity in serum, leukocytes or fibroblasts.
Therapy There is currently no specific treatment for GM2 gangliosidoses.
4.9.3.9 Chediak-Higashi Syndrome Epidemiology There are no reports on the prevalence of this rare disorder.
Etiopathogenesis Chediak-Higashi syndrome arises from a mutation in the lysosomal trafficking regulator gene (LYST, chromosome 1q42), a protein whose function is only incompletely known.
Fig. 4.69 Giant granules in neutrophilic granulocytes in a 22-year-old patient with partial oculocutaneous albinism. The patient’s history showed repeated infections and a pathologic bleeding tendency, as well as progressive gait ataxia during the previous 2 years. The neurologic examination demonstrated spastic paraparesis with bilateral Babinski’s signs, hypomimia and rigor of all extremities as an expression of a parkinsonian syndrome, signs of sensorimotor polyneuropathy; cognitive disturbances were found on neuropsychologic testing
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4.9.3.10 Other Lysosomal Metabolic Diseases Oligosaccharidoses are glycoprotein storage diseases, including, among others, fucosidosis, a- and b-mannosidosis, as well as sialidosis. Cardinal symptoms in a- and b-mannosidosis vary from hearing loss to coarsening of facial features, mental retardation and skull bone as well as other bone dysplasias. Spastic pareses, ataxias and psychiatric symptoms may occur in the juvenile form of a-mannosidosis. Sialidosis (cherry-red spot myoclonus syndrome), which arises from a N-acetyl neuraminidase enzyme deficiency, is characterized by the occurrence of retinal cherry-red spots, as well as progressive vision disturbance, severe myoclonias, ataxia, epileptic seizures, and dysarthria as the most common neurologic symptoms. The analysis of the oligosaccharide pattern in urine constitutes a screening test for oligosaccharidoses, followed by leukocyte enzyme assays. Specific therapies do not yet exist.
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may occur quite some time before the onset of the neurologic symptoms. The patients generally die before age 60.
Diagnosis The diagnosis is based on demonstration of an elevated plasma cholestanol level.
Therapy Cerebrotendinous xanthomatosis is a treatable disease that responds favorably to chenodeoxycholic acid replacement therapy (Chenofalkä, 15 mg/kg BW/day, cost of therapy/ day approx. 2 EUR). The resulting negative feedback mechanism leads to 7a-hydroxylase inhibition and thus to a gradual fall of the cholestanol level. The described treatment has been shown to inhibit disease progression in most patients, a slight improvement was found in individual cases. The treatability of the disease makes early diagnosis imperative.
4.9.3.11 Cerebrotendinous Xanthomatosis Epidemiology Results of systematic investigations are not available. More than 200 patients have been diagnosed to date; the disorder may be grossly underdiagnosed.
Etiopathogenesis Cerebrotendinous xanthomatosis is caused by an autosomal recessive inherited sterol-27-hydroxylase (CYP27) enzyme deficiency, leading to increased cholestanol production at a decreased formation of the bile acid (chenodeoxycholic acid) from cholesterol. Cholestanol and cholesterol accumulate in the CNS (and other organs) with subsequent development of xanthomas, demyelinations, and atrophy in cerebellum but also brainstem, basal ganglia, spinal cord, and the cerebral cortex.
4.9.3.12 Leukodystrophies Leukodystrophies are due to a defect in the formation and maintenance of myelin in the brain and spinal cord. They are characterized by a very heterogeneous etiology and belong, from a systematic point of view, to different groups of diseases, such as lysosomal (metachromatic leukodystrophy, Krabbe’s disease), peroxisomal (e.g. adrenoleukodystrophy) mitochondrial and other disorders (for further information see Hoffmann and Grau 2004; Scriver et al. 2001).
4.9.3.13 Metachromatic Leukodystrophy Epidemiology The cumulative prevalence for all forms ranges from 1:40,000 to 1:100,000 live births.
Clinical Findings
Etiopathogenesis
Neurologic symptoms generally manifest in the second or third decade of life. The most common findings are spastic pareses, cognitive decline, cerebellar signs, polyneuropathy, and epileptic seizures. Brainstem involvement may be identified by the occurrence of a typical dysarthria with a rapid speech pattern and frequent iterations, dysphagia, a parkinsonian syndrome, and palatal myoclonias. Additional clinical findings such as cataracts, xanthomas, and chronic diarrhoea
Metachromatic leukodystrophy (MLD) is a disease inherited in an autosomal recessive pattern, caused by a deficiency of the enzyme arylsulfatase A (more rarely cofactor saposin A). This results in an accumulation of sulphated glycolipids and leads to myelin instability and diffuse demyelination, sparing the U-fibers. The neuropathologic symptoms observed in particular in infantile MLD are indicative of brainstem involvement.
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Clinical Findings The infantile and juvenile forms of MLD are characterized by progressive spastic tetraparesis, behavioral abnormalities, cognitive disturbances, optic nerve atrophies, demyelinating polyneuropathy and ataxia. In the foreground of the adult form with onset between age 16 and 60 are psychiatric symptoms, progressive dementia, incontinence, and a slowly progressive spastic tetraparesis. Bulbar disturbances may be present as well as extrapyramidal symptoms (dystonia, chorea), optic nerve atrophy, or polyneuropathy.
Diagnosis MRI visualizes demyelination progressing from the ventricles to the periphery. Cerebrospinal fluid analysis frequently detects an elevated protein concentration. The diagnosis is confirmed by the demonstration of reduced arylsulfatase A activity (ASA) in leukocytes or other cells. This is best combined with analysis of sulfatides in a 24-h urine collection, which is, if analysed alone, abnormal in cases of a rare activator protein deficiency. An ASA pseudodeficiency without clinical symptoms is found in 2% of the population.
Therapy Different therapies as, e.g. enzyme replacement therapy (Phase I/II study) and the use of (genetically modified) autologous hematopoietic stem cells are currently under investigation (Biffi et al. 2008). Symptomatic therapies of spasticity, and dysphagia are of prime importance.
4.9.3.14 Other Leukodystrophies Krabbe’s disease is an autosomal recessive disorder (incidence approx. 1:100,000) arising from a deficiency of the enzyme galactocerebrosidase (demonstration in leukocytes or fibroblasts). The classic infantile form with onset between the ages of 3 and 6 months is characterized by hypersensitivity to external stimuli and a general increase in tonicity, which is followed by a loss of muscle tone during the development of polyneuropathy, in addition to loss of eyesight and hearing, as well as bulbar disturbances as an indication of brainstem involvement. The patients rarely live beyond 2 years of age. Later (including the adult form) variants with onset up to the 6th decade of life have been described. Spastic pareses, optic nerve atrophy, dementia, cerebellar signs and ocular motor function disturbances, as a further expression of brainstem involvement, as well as a commonly moderate
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polyneuropathy are typical features of these variants. The protein level in cerebrospinal fluid is often elevated. The transplantation of hematopoietic stem cells may have a positive therapeutic effect in patients in the slowly progressive form, or if it is carried out before the manifestation of neurologic deficits. The X-linked inherited adrenoleukodystrophy is caused by a metabolic disturbance of very long-chain fatty acids and commonly manifests as a childhood or juvenile form (behavioral abnormalities, cognitive decline, visual and auditory disturbances, gait disturbances, a rapid course leading to apallic syndrome and death), or as an adrenomyeloneuropathy (onset mostly in the 2nd–4th decade of life; slow progression, spastic pareses, rectovesical disturbances, symptoms of polyneuropathy). Both types are frequently accompanied by adrenal insufficiency (Addison’s disease, typical hyperpigmentation of the hands, mouth and pharynx), although the latter form may also occur in isolation. An olivopontocerebellar course with ataxia and variable combinations of brainstem symptoms has been described in 1–2% patients, who were primarily of Japanese descent (Moser et al. 2001). The diagnosis is made by detection of increased plasma levels of very long-chain fatty acids. In early stages of neurological involvement, bone marrow transplantation may be helpful. Lorenzo’s oil does not prevent neurological decline. Adrenal insufficiency requires treatment with corticosteroids. Alexander disease is a very rare disorder caused a mutation in the gene for glial fibrillary acidic protein (GFAP). In addition to infantile forms, juvenile and adult forms have been reported resembling multiple sclerosis with the cardinal symptoms of ataxia, tetrapareses, bulbar and pseudobulbar symptoms. Various new disease entities have been described in recent years, including one form with brainstem and spinal cord involvement. The etiology of many leukodystrophies continues to be poorly understood. Expert networks are available for consultation in cases of uncertainty (www.aps-med.de, link “LeukonetUnklar”).
4.9.3.15 Neurotransmitter Defects Neurotransmitter defects are heterogeneous disorders in the domain of neurotransmitters (among others glycine, GABA, biogenic amines, acetylcholine, vitamin B6) with a demonstrated number of monogenic defects. The typical cardinal symptoms in infants, in addition to muscular hypertonicity, include epileptic seizures refractory to therapy, psychomotor retardation, and ocular symptoms, such as ptosis, miosis, and oculogyric crises. In the course of disease, ataxia and extrapyramidal symptoms with evening exacerbation (dystonias, tremor, parkinsonism) are frequently present. The diagnosis in the majority of neurotransmitter defects is based on the quantitative
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metabolite analysis in cerebrospinal fluid, followed by identification of enzyme activity and molecular analyses. Two of these disorders are highlighted below. A stunted growth pattern is common, mental retardation is found in some cases.
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BW); the success of therapy may not be apparent until after 2–3 months.
4.9.3.17 Tyrosine Hydroxylase Defects 4.9.3.16 Segawa Syndrome Epidemiology The estimated worldwide incidence of GTPCH deficiency ranges at 0.5:1,000,000.
Etiopathogenesis Hereditary dominant mutations in the guanosine triphosphate cyclohydrolase-I (GTPCH-I) gene are found in the majority of patients, less commonly noted are hereditary recessive mutations in the tyrosine hydroxylase-(TH) gene. A neuropathologic finding is the loss of nigral melanin-containing neurons.
L-dopa-responsive dystonia (s. Segawa syndrome) as well as other phenotypes may be found in this only recently described disease. Blood pressure, blood glucose and temperature regulation defects can occur during the perinatal period. An initially decreased muscle tone, and extrapyramidal motor function symptoms (parkinsonism, tremor, chorea) become apparent after age 2. Typical signs comprise phasic oculogyral crises with conjugate upward gaze, bilateral miosis and ptosis, as well as mental retardation. Therapy with low-dose L-dopa has been shown to be very effective and can lead to normalization of development.
4.9.3.18 Neuronal Ceroid Lipofuscinoses Epidemiology
Clinical Findings The degree of clinical symptoms is age-dependent and highly variable. In younger children, dystonia and gait disturbance start in the lower limbs, but progress to the entire body in older patients. In the majority of cases (approx. 75% of patients) significant worsening of the symptoms occurs as the day progresses; this often disappears, however, in the 4th decade of life. An additional postural tremor and parkinsonism may develop in adolescence. A short stature is common, mental retardation can be found in some patients. The described symptoms may not occur until later in life.
The group of neuronal ceroid lipofuscinoses (NCL) constitutes one of the most common neurodegenerative disorders of childhood and adolescence; in Germany, the cumulative prevalence of the infantile and juvenile forms ranges at approximately 1:100,000 (Kohlschütter and Goebel 2004). Precise incidence rates for the adult forms have not been reported.
Etiopathogenesis
The initial diagnosis is made with consideration of the typical clinical phenotype and the responsiveness to L-dopa therapy. It is confirmed on identification of the mutation, since different neurotransmitter disturbances may have a similar phenotype and exhibit a non-specific L-dopa response. In all cases of generalized dystonia, a L-dopa sensitive dystonia should be included in the differential diagnosis (Hoffmann and Assmann 2004).
Neuronal ceroid lipofuscinoses are heterogeneous disorders with the common characteristic of a pathologic intracellular accumulation of ceroid lipofuscin, a wax-like substance. Although ubiquitous demonstrable, it usually causes relevant damage almost only to the retina and the nervous system. While neuronal changes are further found in the brainstem, excessive accumulation of lipofuscins is noted chiefly in the cortex. Six genes are currently known where mutations can lead to NCL, the disorders are, nevertheless, differentiated according to the age at symptom onset. The pathogenesis of the adult form (Kufs’ disease), which appears to be both recessive and dominantly inherited, is unclear; the gene locus has not yet been identified.
Therapy
Clinic
Low-dose L-dopa therapy is usually very effective. Some patients may, however, require higher doses (approx. 10 mg/kg
Common characteristics of the infantile (Santavuori-Haltia disease), late infantile (Jansky-Bielschowski disease, and
Diagnosis
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juvenile NCL (Spielmeyer-Vogt disease, Batten’s disease) include vision loss, epilepsies, myoclonias, progressive dementia, and gait disturbances. The adult form begins between the ages 11 and 50 and manifests initially either with dementia and behavioral abnormalities followed by cerebellar and extrapyramidal motor function disturbances (chiefly facial dyskinesias), or begins with progressive myoclonus epilepsy, dementia and ataxia followed by pyramidal and extrapyramidal disturbances. Blindness does not develop; death ensues on average 12 years after onset of the disorder (Bercovic et al. 1988; Kohlschütter and Goebel 2004). Parkinsonian symptoms may arise from both, presynaptic nigral and postsynaptic striatal degeneration (Nijssen et al. 2002).
Diagnosis The diagnosis in the infantile and juvenile forms is established based on the electron microscopic evidence of granular or curvilinear inclusions in lymphocytes, skin or rectal biopsies, the demonstration of an enzyme defect (palmitoyl protein thioesterase, pepinase, battenin) in leukocytes or other cells, and the molecular genetic examination of the respective gene. Diagnostic criteria for adult NCL are incompletely established; skin and brain biopsies can show the characteristic changes in the ultrastructure (Bercovic et al. 1988).
Therapy Currently there is no causal therapy, palliative therapeutic measures are in the foreground. Epileptic seizures may be controlled with valproate or lamotrigin.
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Clinical Findings Characteristic features are episodic, acute encephalopathies with confusion, agitation, irritability, bizarre behavior or psychoses, which may be presaged by balance disturbance, vomiting, lack of appetite, and headaches. Coma and death can occur in extreme cases due to brainstem involvement, or pronounced brain edema. A high protein intake, fasting, medical therapy with valproate and the peripartum period represent trigger factors for the episodes.
Diagnosis Detection of elevated plasma ammonia levels during an episode serves as the initial diagnostic indicator (this may return to normal during intervals); a further differentiation of the individual clinical pictures is based on the plasma amino acid profile and assessment of the urinary orotic acid level.
Therapy Urea cycle defects are potentially treatable disorders. Therapy of acute episodes consists of the administration of sodium benzoate and sodium phenylacetate, or of hemodialysis in patients with severe hyperammonemia. An additional therapeutic requirement is the establishment of an anabolic state of metabolism. Therapeutic measures during the interval consist of restricted protein intake, and supplementation with arginine and sodium phenylbutyrate. Catabolic states of metabolism must be avoided or receive rapid treatment. The described therapeutic approaches have led to significant improvement in the prognosis of urea cycle defects (Grau and Hoffmann 2004).
4.9.3.19 Urea Cycle Defects Epidemiology The reported cumulative incidence is 1:8,000 live births (OTC deficiency approx. 1:14,000).
Etiopathogenesis Six inborn enzyme defects in the urea cycle are responsible for disturbances in nitrogen excretion. The most common defect is the x-linked ornithine transcarbamylase deficiency; the other types are autosomal recessively inherited.
4.9.4 Mitochondrial Encephalomyopathies 4.9.4.1 General Mitochondrial encephalomyopathies constitute multisystem disorders based on changes in mitochondrial energy metabolism, and are commonly due to genetic defects. Clinical pictures of mitochondrial disorders vary widely. The consolidation of frequently associated symptoms appears appropriate, in particular since attribution to a particular syndrome can facilitate the search for a causal genetic defect.
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At the biochemical level, mitochondrial disorders in the strict sense are due to disturbances of the oxidative phosphorylation mechanism and the respiratory chain, with resulting impaired aerobic energy production. This is compensated by massive proliferation of mitochondria, which is histopathologically confirmed by the presence of ragged red fibers in muscle tissue. An episode of the disorder can be triggered by stress, physical exertion, and infections, as an increased energy requirement of the cell may lead to subsequent decompensation of the impaired oxidative phosphorilation mechanism. The result is an increase in anaerobic glycolysis. Mitochondrial disorders in the broader sense are due to defects in the mitochondrial substrate transport, mitochondrial substrate processing, and citric acid cycle. The discussion of these diseases is beyond the scope of the present chapter.
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genome occur in the form of point mutations, deletions and duplications. Multiple deletions of the mitochondrial genome arise from mutations in nuclear encoded genes, whose gene products are responsible for stabilization of the mitochondrial DNA (Hirano and Di Mauro 2001). A large number of additional nuclear gene mutations accountable for the development of mitochondrial diseases have been discovered in recent years. The clinical symptoms associated with a mitochondrial DNA mutation can vary significantly within a family, depending on the degree of heteroplasmy. Furthermore, various gene mutations are capable of causing a similar phenotype, so that genotype and phenotype do not correlate in mitochondrial disorders.
Clinical Findings Epidemiology Mitochondrial disorders are more frequent than previously thought. A prevalence of at least 12:100,000 population is currently assumed (Chinnery et al. 2000). Initial clinical manifestations can occur at any age. Severe courses of disease are found particularly in mitochondrial disorders with onset in infancy and childhood. Etiopathogenesis Both nuclear gene defects and mitochondrial DNA mutations may be causal factors of mitochondrial disease. The exclusively maternally inherited mitochondrial DNA contains about 16,500 base pairs and codes for 13 proteins of the respiratory chain, as well as for ribosomal and transfer RNA. The remaining roughly 600 mitochondrial proteins are encoded by the nuclear genome. Encoding of mitochondrial proteins by two genomes explains why in some instances the pattern of inheritance is strictly maternal, and in accordance with the laws of Mendelian inheritance in others. Cells contain a variable number of copies of the mitochondrial genome. A specific mutation does, as a rule, not occur in all genome copies. The degree of heteroplasmy describes the proportion of mutant mitochondrial DNA in the total mitochondrial genome of this tissue and can undergo changes in the course of multiple cell divisions. When the mitochondrial mutation load exceeds a certain threshold value, multisystem disease symptoms may occur as a result of a critical decrease in energy production in the affected cells. This threshold value is dependent upon the type and locus of the mutation in the mitochondrial genome. Changes in the mitochondrial
The spectrum of clinical symptoms extends from mild courses in adults, to the most severe disturbances in infancy and early childhood. Organs with a high energy requirement are most strongly affected in mitochondrial diseases. These include the central and peripheral nervous system, the heart and skeletal muscle, the retina, inner ear, liver, kidneys and endocrine organs. Common disease manifestations are shown in Table 4.27. The most important of the numerous clinically defined disease syndromes associated with brain stem involvement are described below: MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa), Leigh’s disease, and Kearns-Sayre syndrome. Other mitochondrial syndromes with an involvement of the nervous system are either rarely or never diagnosed based on brainstem symptoms: MERRF syndrome (myoclonus epilepsy with ragged red fibers), chronic progressive external ophthalmoplegia (CPEO), Leber’s hereditary optic neuropathy (LHON), and myoneurogastrointestinal encephalopathy (MNGIE).
Diagnosis Diagnostic assessment of a mitochondrial disorder requires an interdisciplinary approach. In addition to the patient history and clinical findings of various organ systems, the diagnosis is supported by laboratory, electrophysiologic, imaging, myohistologic and molecular genetic testing. Elevated serum lactate levels at rest are found in about half of the patients. Cerebrospinal fluid lactate
4.9 Metabolic Brainstem Diseases Table 4.27 Frequent disease manifestations in mitochondrial disorders Organ system Manifestations Skeletal musculature
• Strain intolerance • Proximal myopathy • Ocular muscle pareses • Ptosis
Peripheral nervous system
• Axonal neuropathy
Central nervous system
• Epileptic seizures • Myoclonias • Ataxia • Dystonia • Chorea • Parkinsonism • Dementia • Migraine
Eye
• Optic nerve atrophy • Cataract • Retinal pigment degeneration
Heart
• Cardiomyopathy • Impulse formation and excitation conduction disturbances
Ear
• Labyrinthine deafness
Endocrine organs
• Short stature • Diabetes mellitus • Hypoparathyroidism
Gastrointestinal tract
• Exocrine pancreas insufficiency • Hepatopathy • Gastrointestinal motility disturbances
Kidney
• Renotubular disturbances
concentrations are elevated in two thirds of cases; elevated protein levels in cerebrospinal fluid are also frequently present. Muscle enzymes are rarely within the abnormal range. Under conditions of aerobic stress during light exercise on the bicycle ergometer, a pathologic increase in the serum lactate level due to a disturbance in mitochondrial energy gain is observed in approximately 90% of patients. Further laboratory tests are needed to show endocrine involvement. Electrophysiologic studies can demonstrate or confirm subclinical or clinical involvement of the peripheral nervous system and the musculature (electroneurography, electromyography), as well as of the central nervous system, including the optic nerve (EEG, visual evoked potentials) (Jackson et al. 1995). Brain imaging using CT can visualize calcifications of the basal ganglia. MRI reveals typical changes in patient with MELAS syndrome or Leigh’s disease, in addition to frequently present nonspecific changes (leukoencephalopathy, cortical atrophy, cerebellar atrophy) in other mitochondrial diseases (Barragan-Campos et al. 2005). Important examinations performed by other medical specialists include: ophthalmologic evaluations for the
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a
b 1
2
3
1
2
3
–16,5 kb –12 kb
330 bp 213 bp
117 bp
Fig. 4.70 Molecular genetic testing in mitochondrial disorders. (a) Demonstration of mitochondrial DNA deletion by Southern blot analysis in muscle tissue (track 1: normal control with only wild type band at 16.5 kb); track 2: singular deletion of approx. 4.5 kb; track 3: multiple deletions. (b) Demonstration of point mutation 3243A → G of mitochondrial DNA by restriction fragment length polymorphism (RFLP) analysis (track 1: degree of heteroplasmy 8%; track 2 degree of heteroplasmy 24%; track 3: normal control). (Figure courtesy of PD Dr. M. Deschauer, Halle, Germany)
assessment of retinal alterations or a cataract, ENT examinations for the identification of labyrinthine deafness, as well as cardiologic examinations for the evaluation of the myocardium and the impulse formation and excitation conduction system. A muscle biopsy constitutes the keystone in the diagnosis of mitochondrial diseases. Typical changes comprise ragged red fibers in the Gomori’s trichrome stain, cytochrome C oxidase negative muscle fibers (histochemical confirmation), enlarged abnormal mitochondria with paracristalline inclusion bodies (electron microscopy), and disturbed activity of the respiratory chain complexes (biochemical confirmation). Muscle tissue samples have to further be obtained for the subsequent molecular genetic analysis because of the elevated degree of heteroplasmy compared to blood cells. (Fig. 4.70). Complex extensive mitochondrial mutation screening is required in individual cases.
Differential Diagnosis In view of the broad spectrum of clinical pictures with multisystemic involvement and the widely divergent age of disease onset, numerous inherited and not inheritable metabolic disorders have to be included in the differential diagnosis. Autoimmune diseases with involvement of the central or peripheral nervous system have to further be considered. These encompass multiple sclerosis, sarcoidosis, collagenoses, and systemic vasculitides. Because the symptoms of mitochondriopathies occasionally have an acute onset, cerebral ischemias or encephalitides must be excluded from consideration.
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Therapy Symptomatic therapeutic measures are of prime importance. Patients requiring antiepileptic therapy should not receive valproate, as it exerts a negative effect on the mitochondrial energy metabolism. Valproate not only lowers the plasma carnitine concentration and leads to an inhibition of the b-oxidation, but also disturbs the mitochondrial pyruvate metabolism. Disturbances in the cardiac excitation conduction system may necessitate early cardiac pacemaker implantation. Other symptomatic measures comprise gastroenterologic, endocrinologic, ENT and ophthalmologic therapeutic approaches. Consistent treatment of infections and temperature reducing measures can prevent the development of critical disease progression. Positive effects of numerous substances (ubichinone, idebenone, creatinin monohydrate, L-carnitine, vitamins B1, B2, C, E, K) on mitochondrial metabolic function have been reported by individual case studies. Larger studies have not found a beneficial effect following the use of these substances thus far (Horvath et al. 2008). A carefully planned schedule of endurance training appears to reduce exercise intolerance in patients with CPEO (Jeppesen et al. 2006).
4.9.4.2 MELAS Syndrome Etiopathogenesis MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) is one of the most common mitochrondrial diseases. It is usually maternally inherited. Molecular genetic analysis shows a transition A → G in the mitochondrial DNA at position 3243 in the leucine tRNA gene in over 80% of patients; a point mutation at position 3271 of this gene is found in an additional 10–15% of patients. Biochemical testing discloses a reduced activity of respiratory chain complexes I and IV.
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limb ataxia and dysarthria. Neuropsychologic deficits up to the complete picture of dementia can develop. Frequent concomitant symptoms include labyrinthine deafness, degeneration of the retinal pigment, proximal myopathy, cardiomyopathy, short stature, and diabetes mellitus.
Diagnosis Typical image morphologic features identified on CCT and MRI are pronounced temporoparietal-occipital confluent or multifocal lesions to the gray and white matter, extending beyond the vascular territory (Fig. 4.71a). These appear hyperintense in FLAIR and T2-weighted sequences, and are seen having entered a shrinking process in later studies (Fig. 4.71b). The neuropathologic correlate of these brain lesions has not yet been identified. Diffusion-weighted MRI sequences in acute episodes are suggestive of focal cytotoxic edema (Wang et al. 2003), while SPECT studies give rise to the assumption of a focal cortical hyperemia, and focal epileptiform activity is demonstrable on EEG examinations. It has been hypothesized that the episodic neuronal hyperexcitability associated with an extremely high energy requirement might lead to the breakdown of the cellular energy supply on the basis of a respiratory chain function disturbance (Iizuka et al. 2002). Atrophic changes may be detected in the brainstem and the cerebellum. The diagnosis is guided by the findings of molecular genetic analyses in muscle tissue.
Clinical Findings Clinical manifestations of this syndrome are characterized by substantial variability. Initial manifestations may occur from early childhood to advanced adult age. Typical symptoms are stroke-like episodes in children and younger adults with acute and only partially reversible homonymus hemianopia or hemiparesis, and without imaging morphologic demonstration of ischemic lesions. Additional common features include recurrent vomiting, migraine-like headaches, and epileptic seizures that frequently precede the stroke-like episodes. Symptoms suggestive of brainstem or cerebellar involvement are
Fig. 4.71 MELAS syndrome. Images obtained in a 32-year-old woman with grand mal series in known epilepsy with childhood onset, as well as diabetes mellitus Type 1, and bilateral deafness also present in the mother. Clinically homonymous hemianopsia to right. The molecular genetic diagnosis showed point mutation in mitochondrial DNA at position 3243. (a) On CCT, hypodense area parietooccipital left and bilateral basal ganglia calcifications. (b) FLAIR-weighted MRI sequence 2 weeks later, showing multilocular hyperintense signal changes and shrinking process around the dorsal horn of left lateral ventricle
4.9 Metabolic Brainstem Diseases
Therapy See Sect. 4.9.4.1 4.9.4.3 Leigh’s Disease Leigh’s disease is one of the most common mitochondrial diseases in early childhood. Initial manifestations of the disease in younger adults have, however, been reported. The disease was first described by Leigh in 1951 as subacute necrotizing encephalomyelopathy. The underlying genetic defects are manifold. Etiopathogenesis The syndrome can be both maternally, autosomal recessively and x-linked recessively inherited. A typical point mutation of the mitochondrial genome is found at position 8993 in a mitochondrially encoded subunit of ATPase 6, which is responsible for approximately 20% of the clinical manifestations. The phenotype in this mutation is dependent upon the degree of heteroplasmy. At a mutation rate of more than 90% the patients develop a maternally inherited Leigh’s syndrome (MILS), at a mutation rate below 70% the affected person may be asymptomatic. Mutations between 70% and 90% lead to a NARP (neuropathy, ataxia, retinitis pigmentosa) syndrome (Tatuch et al. 1992). The more common nuclear genome mutations comprise numerous defects in the genes responsible for the subunits of respiratory chain complexes I and IV. Clinical Findings The most prominent symptoms in the infantile form with onset usually before the age of 2 years include delayed psychomotor development and muscular hypotonia with poor sucking ability and loss of head control. The further course of disease is characterized by pyramidal, extrapyramidal, and cerebellar disturbances with spasticity, dystonia and ataxia. The symptoms indicative of frequent brainstem involvement include disturbances of motor gaze control, nystagmuses and cranial nerve deficits, disturbance of respiratory regulation with episodic hyperventilation and apneic phases, as well as dysarthria and dysphagia. Further symptoms include generalized epileptic seizures and myoclonias, in rare cases also symptoms of polyneuropathy and optic nerve neuropathy. The disease onset is often acute during or after febrile infections, or following surgical intervention. The disease course is often progressive and the patients die within a few years from the onset of symptoms. Benign episodic courses
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are rarely described. Isolated cases of sustained symptom improvement have been reported (Goldenberg et al. 2003). Infantile bilateral striatal necrosis with dystonia and impaired vision represents a special form of Leigh’s syndrome. The onset of NARP syndrome is generally later and follows a less dramatic course than Leigh’s syndrome. It is characterized by the combination of primary sensory polyneuropathy, ataxia and retinal pigment degeneration. Epileptic seizures and dementia may also be noted.
Diagnosis Ragged red fibers are rarely found in Leigh’s syndrome. Biochemical analyses occasionally show decreased activity of respiratory chain complexes I and IV, as well as of pyruvate dehydrogenase and pyruvate decarboxylase. Elevated lactate concentrations in serum and cerebrospinal fluid do not represent necessary prerequisites for the diagnosis. The information provided by cerebral MRI imaging is significantly more conclusive. Typical hyperintense symmetrical lesions to the basal ganglia, the thalamus, midbrain (periaqueductal and in the tegmentum), the pons, the medulla oblongata, the cerebellum and the spinal cord are viewed in T2-weighted sequences. The histopathologic correlates of these lesions include focal demyelinations, spongiform necroses, vascular proliferations and glioses. The distribution of the lesions and the underlying histologic alterations are similar to those observed in Wernicke’s encephalopathy, with the exception of absent signal intensity changes in the mammillary bodies. MRI changes found in a NARP syndrome do not include T2-hyperintense lesions, while cerebral or pontomesencephalic atrophy may be revealed. The molecular genetic identification of the mitochondrial point mutation at position 8993 is a valuable diagnostic indicator in patients with maternally inherited Leigh’s syndrome.
Therapy See Sect. 4.9.4.1
4.9.4.4 Kearns-Sayre Syndrome Etiopathogenesis Kearns-Sayre syndrome (KSS) is, as a rule, a sporadic disorder. Singular extended mitochondrial DNA deletions form the genetic basis in about 90% of patients. The most common deletion at a typical localization comprises more than
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4,900 base pairs. The significance of an associated cerebral folic acid deficiency as a partial cause of CNS disturbances and extended demyelinations visualized on MRI is still unknown in patients with KSS (Pineda et al. 2006).
Clinical Findings Clinically, a continuum of symptom severity exists and extends from chronic progressive external ophthalmoplegia (CPEO) with prominent impairment of external ocular muscle function and ptosis to a “CPEO plus” with additional symptoms of proximal and bulbar myopathy, cardiac irregularity, or endocrine disturbances up to KSS. KSS is characterized by external ophthalmoplegia and retinal pigment degeneration, and disease onset before 20 years of age (Schmiedel et al. 2003). At least one of the following additional symptoms must be present: • Disturbances of the cardiac impulse formation and excitation conduction system • Cerebellar ataxia • Elevated protein levels in cerebrospinal fluid of at least 100 mg/dL Typical concomitant symptoms are a proximal myopathy and involvement of the bulbar musculature, labyrinthine deafness, stunted growth, endocrinopathies, such as diabetes mellitus or hypothyreosis, an axonal polyneuropathy, and signs of dementia. Spastic pareses and extrapyramidal symptoms are rare.
Diagnosis A typical finding is a markedly elevated protein level in cerebrospinal fluid above 100 mg/dL. The cerebrospinal fluid lactate level is also elevated in the majority of patients with KSS. Imaging commonly reveals changes in brain morphology. The severity of these changes varies, however, from patient to patient. Bilateral calcifications of basal ganglia and a leukoencephalopathy may often be detected on CCT, while MRI T2-weighted images visualize the cerebral white matter, the brainstem and thalamus as hyperintense areas. Signal changes in the basal ganglia are frequently seen in the globus pallidus.
Differential Diagnosis In the differential diagnosis, consideration has to be given to an autosomal recessive variant with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO syndrome), caused by mutations in the nuclear POLG1 gene (Milone et al. 2008).
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Therapy As with all other mitochondriopathies, symptomatic therapy is of prime importance in KSS. In view of the frequent finding of dysrhythmia and the risk of sudden cardiac death, early implantation of a cardiac pacemaker constitutes a therapeutic consideration.
4.10 Vascular Cranial Nerve and Brainstem Compressions Frank Thömke and Peter P. Urban
4.10.1 Vascular Compression of Cranial Nerves Vascular compression of different cranial nerves, e.g. the trigeminal and the facial nerve, can be the cause of characteristic disorders, such as trigeminal neuralgia and hemifacial spasm. The improvement of neuroradiologic testing methods has led to the assumption of a similar pathomechanism in other cranial nerve disturbances. MRI with thin CISS (constructive interference in steady state) sequences has proven to be particularly suitable for demonstration of neurovascular compressions. It is generally assumed that continuous vascular pulsations lead to the segmental demyelination of the respective cranial nerve. The transition zones between central (oligodendrocytes) and peripheral (Schwann cells) myelin in close proximity to the brainstem are regarded as particularly vulnerable to this pathomechanism. The described demyelination gives rise to pathologic ephaptic impulse conduction between neighboring demyelinated axons. The resulting paroxysmal irritative symptoms are in the foreground of the clinical symptoms. The development of permanent neurologic deficits is less commonly found.
4.10.1.1 Oculomotor Nerve Compression Vascular compression of the oculomotor nerve can be the cause of neurologic deficits manifesting as incomplete oculomotor palsy (Hashimoto et al. 1998; Tilikete et al. 2000; Versino et al. 2005), which may be associated with the irritative symptoms subsumed under the clinical picture “idiopathic” ocular neuromyotonia (Tilikete et al. 2000; Versino et al. 2005). Vascular oculomotor nerve compression may also cause episodic diplopia with normal clinical findings in the interval between episodes (Thömke and Gawehn 2006, Fig. 4.72).
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Fig. 4.72 Vascular compression at the exit zone of the left oculomotor nerve due to an ectatic basilar artery as the cause of brief episodes of diplopia; normal clinical finding in the interval. Regression of symptoms under gabapentin. (a) MRI with CISS sequences; (b) T1w-3D sequences. Arrow left = basilar artery, arrow right = oculomotor nerve
The clinical key symptom of ocular neuromyotonia consists of recurrent short episodes during which the patient perceives two images of one object. The duration of the individual episodes is generally less than 30 s, the frequency of occurrence may range from 20–30 times per day. Episodes of diplopia can often – but not always – be provoked by prolonged gaze-holding in a certain eccentric eye position. Episodes of diplopia are characterized by the transient contraction of one or more extraocular muscles followed by their delayed relaxation. The result is an initial defective position of the bulb in the functional direction of the affected muscles, followed by restricted mobility and the production of maximum squint in the opposite direction. EMG of the affected muscles shows a series of high frequency (150–300 Hz) discharges with sudden onset and end, as well as groups of low frequency (about 50 Hz) discharges. Clinical and electromyographic findings of “idiopathic” ocular neuromyotonia can be explained by abnormal spontaneous discharges due to ephaptic impulse conduction between neighboring, partially demyelinated axons at the site of the segmental compression demyelination as a result of the vessel-nerve contact (Tilikete et al. 2000). Treatment with anticonvulsives, such as carbamazepine (2–4 × 200–600 mg/day) and gabapentin (3–4 × 400– 600 mg/day) was found to be beneficial in individual patients.
4.10.1.2 Trochlear Nerve Compression Vascular compression of the trochlear nerve leads to development of superior oblique myokymia (Samii et al. 1998; Hashimoto et al. 2001; Yousry et al. 2002; Ehongo et al. 2003). Cardinal symptoms include paroxysmal monocular vertical oscillopsias and, although not in all patients, oblique diplopia. Characteristic findings are rapid, small amplitude inward rotatory movements of one eye that can only be demonstrated by slit lamp examinations or ophthalmoscopy.
Vertical divergence of the eyes with the affected eye in a lower position may be detected in some cases. The duration of the described attacks usually ranges from 10–20 s; the frequency of monocular eye movements may vary between 3 and 9 Hz, at amplitudes from 0.5° and 2°. Clinical findings in the intervals between attacks are normal. Successful therapy with anticonvulsives, such as carbamazepine (2–4 × 200–600 mg/day), phenytoin (150–400 mg/day), gabapentin (3–4 × 400–600 mg/day), and, in some patients, baclofen (30 mg/day) has been described. In the absence of a favorable response to these substances, the injection of botulinum toxin into the superior oblique muscle may be attempted, before tenotomy of this muscle is considered in therapy-refractory courses with severely disabling defective vision. It remains unclear if therapy-refractory cases – in analogy to trigeminal neuralgia – can profit from surgical decompression. Owing to the very small size of the trochlear nerve, this procedure is associated with a high risk of iatrogenic nerve injury (Samii et al. 1998; Scharwey et al. 2000).
4.10.1.3 Trigeminal Nerve Compression Idiopathic trigeminal neuralgia is the most widely known neurovascular compression syndrome (so that, strictly speaking, it does not constitute an “idiopathic”, but a symptomatic disorder). Women are more often affected by trigeminal neuralgia; the onset is typically after age 40, and the incidence is higher at more advanced ages. The annual incidence ranges at 3.4 per 100,000 among men and at 5.9 per 100,000 among women (Katusic et al. 1990; Love and Coakham 2001; Glocker et al. 2006). The cardinal symptom is shock-like shooting pain of maximal intensity, typically triggered by activities such as speaking, eating, drinking, chewing, or tooth brushing, but may also occur spontaneously. Most commonly affected are the second and third trigeminal branches, either alone or jointly, while isolated involvement of the first trigeminal
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branch is rare. Bilateral trigeminal neuralgias are also rare (in up to 5% of patients) (Katusic et al. 1990; Love and Coakham 2001; Glocker et al. 2006). The individual pain attacks can last from only seconds to one (several) minute(s), but they may recur as often as 100 times per day in severe cases. During the attacks the individual has excruciating pain, which can affect the overall quality of life significantly. The dread of provoking further attacks leads patients to avoid activities with a possible triggering effect as, e.g. eating or drinking, so that a significant weight loss may occur. When left untreated, or if inadequately treated, the individual may withdraw from society, develop reactive depression, and become suicidal. No abnormal findings are detected during the pain-free intervals, in particular no permanent sensory deficits in the facial region. Modern MRI techniques (3D-CISS sequences) enable the demonstration of a vessel-nerve contact at the entry zone of the trigeminal nerve in up to 90% of patients (Fig. 4.73); this constellation was, however, also detected in about 25% of controls (Boecher-Schwarz et al. 1998). In addition to pathologic ephaptic impulse conduction between partially demyelinated neighboring axons at the site of segmental compression demyelination, the sensitization of central interneurons has been discussed, and was attributed to deafferentiation resulting from peripheral axonal degeneration. The differential diagnosis must include symptomatic trigeminal neuralgias, e.g. tumors in the cerebellopontine angle (acoustic neurinoma), skull base tumors, trigeminal neurinomas, or brainstem angiomas. In younger patients consideration has to be given to multiple sclerosis, which may be associated with foci of demyelination in the region of the intrapontine trigeminal nerve. Approximately 2% of patients with MS develop trigeminal neuralgia at the onset or in the course of the disease, and about 2.5% of patients with trigeminal neuralgia have MS (Jensen et al. 1982; Hooge and Redekop 1995; Solaro et al. 2004). In contrast to patients with idiopathic trigeminal neuralgia, patients with symptomatic trigeminal neuralgia frequently show permanent deficits and are often not completely pain-free in the interval between individual pain attacks.
Fig. 4.73 Vascular compression of the right trigeminal nerve at the entry zone caused by an ectatic superior cerebellar artery in a 68-year-old patient. (a) Axial T1w slice (0.8 mm) at the level of the nerve entry into the brainstem (black arrow) with signal extinction (flow void) of the superior cerebellar artery (white arrow), which is viewed settling into the angle to the pons; (b) the coronal T1w reconstruction further accentuates the close neighborhood of the nerve and vessel (arrow)
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Good success rates have been reported for therapy with anticonvulsives. Carbamazepine (2–4 × 200–600 mg/day) and oxcarbazepine (3–4 × 400–600 mg/day) are regarded as the first line drugs. A successful emergency treatment in patients with a particularly high incidence of pain attacks is the intravenous administration of phenytoin (750 mg infusion concentrate over 1–2 h. Caveat: ECG monitoring of possible bradycardia response; separate intravenous access, because phenytoin can flocculate with various substances). Second line drugs in addition to phenytoin include lamotrigine (200–400 mg/day) and baclofen. If medical therapy is not successful, a number of surgical and radiosurgical procedures are available, whose indication has to be carefully considered for each patient individually. In addition to microvascular decompression, which should be performed at specialized centers only, the gasserian ganglion can also be treated percutaneously (thermocoagulation, glycerine or alcohol injections). Gamma Knife radiation has been widely accepted as a therapeutic option in recent years.
4.10.1.4 Abducens Nerve Compression All patients with vascular compression of the abducens nerve reported thus far had the clinical finding of abducens nerve palsy (Ohtsuka et al. 1996; Nakanishi et al. 1999; Narai et al. 2000; Ohashi et al. 2001; Goldenberg-Cohen and Miller 2004).
4.10.1.5 Facial Nerve Compression Vascular compression of the facial nerve is a causal factor of hemifacial spasm (Fig. 4.74). Typical characteristics are involuntary synchronous contractions of all muscles innervated by the facial nerve. The spasms are usually limited to the periorbital musculature at the onset of the disorder, and may affect all muscles on one side of the face innervated by the facial nerves, including the platysma muscle in the later course. The tonic, paroxysmal muscle contractions last several
4.10 Vascular Cranial Nerve and Brainstem Compressions
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Fig. 4.74 (a–b) Facial hemispasm right. MR imaging shows the vessel-nerve contact with the AICA (anterior inferior cerebellar artery) crossing over the facial nerve right
seconds and recur at irregular intervals up to several times per minute. A spasm may occasionally be caused by a voluntary movement, but it usually occurs spontaneously without ascertainable external provocation. After a course of several years, pathologic synkinesis may appear on voluntary innervation of the affected side, and is occasionally accompanied by discrete facial nerve palsy, e.g. in form of a “signe des cils”. This may derive from vascular compression occurring at the exit site of the facial nerve from the brainstem, which initially affects the medullary sheaths and thus gives rise to the development of ephaptic impulses. It may, however, also lead to an axonal lesion that promotes the regeneration and aberrant sprouting of the axons. A characteristic electrophysiologic finding is the synchronous reflex response distribution on electrical stimulation of the first trigeminal branch to all muscles innervated by the facial nerve on the side of the face affected by the hemifacial spasm. Under normal conditions only the orbicularis oculi muscle is activated by an electrically elicited blink reflex. In contrast to other vascular cranial nerve compressions, a beneficial effect of anticonvulsive therapy is neither sustainable nor completely satisfactory. The majority of patients receive adequate symptomatic therapy with regular botulinum toxin injections. Even though the procedure is not completely risk free, surgical decompression according to Janetta may be considered in cases refractory to therapy. A significant complication is the occurrence of vasospasm in the artery crossing the facial nerve (usually the anterior inferior cerebellar artery), leading to brainstem ischemia and hypacusis (Schulze-Bonhage and Ferbert 2000). 4.10.1.6 Vestibulocochlear Nerve Compression The cardinal symptoms of vestibular paroxysmia (Dieterich 1999) include brief (lasting from seconds to several minutes) recurrent episodes of rotatory and positional vertigo attacks
with loss of equilibrium and unstable gait, nausea and occasional vomiting. Some patients also have unilateral tinnitus and/or hearing impairment during the attacks; in rare patients this may also be permanent. The vertigo attacks can, but do not have to, be triggered or prolonged by certain head-holding positions. The clinical findings between individual attacks are often normal, but hypoexcitability of the horizontal semicircular canal or hearing loss may be detected. Vascular compression of the vestibulocochlear nerve in the nerve entry zone has been hypothesized as a possible cause of vestibular paroxysmia (Brandt and Dieterich 1994) (Fig. 4.75). The diagnosis is guided by the respective clinical findings and MRI demonstration of a vessel-nerve contact. Vesselnerve contacts are, nevertheless, often found in controls and patients without recurrent vertigo attacks, so that these findings are not contributory to the final diagnosis. Therapy with anticonvulsives such as carbamazepine (2 × 300–600 mg in depot form) or gabapentin (3 × 300–600 [800] mg) was shown to be very effective. Recently, several patients with unilateral paroxysmal tinnitus attacks, due to vascular compression of the ipsilateral cochlear nerve have been described (Brantberg 2010; Nam et al, 2010). Carbamazepine relieved the symptoms. 4.10.1.7 Glossopharyngeal Nerve Compression The nature of the pain in glossopharyngeal neuralgia is similar to that of trigeminal neuralgia, with the pain originating in the region of areas with sensory innervation by the glossopharyngeal nerve. The most common locations of pain in descending order are: the ear, tonsils, larynx, and base of the tongue (Steinbach 2003). Frequently reported trigger mechanisms include swallowing, chewing, coughing, speaking and, in some instances, touching of the external auditory canal.
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Fig. 4.75 (a–b) Vestibular paroxysmia. MRI shows vessel-nerve contact with the vestibulocochlear nerve right being crossed by a vascular loop
Typical signs in support of the diagnosis are a pain attack precipitated by touching of the tonsil, and cessation of the pain following topical anesthesia (e.g. 10% lidocaine spray) of the tonsil or the pharynx. This clinical picture is characterized by shock-like shooting pain, which usually persists for seconds to a few minutes. Some patients report the presence of persistent dull pain, feelings of pressure, or burning sensations. Concomitant symptoms of pain attacks such as coughing, hoarseness, or hypersalivation may also be described. In about 10% of cases the pain attacks are accompanied by symptoms ranging from bradycardia to asystole, to a fall in blood pressure with syncopes of still only incompletely understood origin. It has been hypothesized that the excitation impulse is transmitted to the vagus nerve, thus leading to the development of reflex bradycardia and asystole. The overall incidence of glossopharyngeal neuralgia is very low, with a slightly higher predominance in favor of the left side. Reports of bilateral occurrence are rare. An etiologic differentiation has to be made from symptomatic glossopharyngeal neuralgias caused, e.g. by tumors and other space-occupying masses in the posterior cranial fossa, the nasopharynx, the tongue, parotid gland, and the tonsils. Glossopharyngeal neurinomas are rare and generally associated with very few symptoms. In Eagle’s syndrome, the glossopharyngeal nerve is compressed by a long styloid process. Multiple sclerosis is significantly less often the cause of symptomatic glossopharyngeal neuralgia than of trigeminal neuralgia. The etiologic clarification of glossopharyngeal neuralgia is accomplished with the use of thin-slice MR imaging of the medulla oblongata, the base of the skull, and the further course of the glossopharyngeal nerve, possibly with CISS sequences at a spatial resolution of 0.5 mm and a slice thickness of 0.7 mm, as well as contrast agent infusion for improved visualization of the vessel-nerve contact in the vicinity of the brainstem. Analogous to trigeminal neuralgia, the initial therapeutic measure consists of the administration of carbamazepine (2–4 × 200–600 mg/day) as monotherapy or in combination
with gabapentin (3–4 × 300–600 mg/day). With a view to the known high success rate, microvascular decompression of the glossopharyngeal and the vagus nerve is indicated when medical therapy fails. However, due to the close proximity to neurovascular centers of the lateral medulla oblongata, this procedure is associated with a higher perioperative risk than decompression in trigeminal neuralgia. When surgical intervention is indicated, the relatively high rate of spontaneous remission of up to 80% also has to be considered. Spontaneous remissions lasting months to years have been described.
4.10.2 Arterial Hypertension Secondary to Brainstem Compression An association between arterial hypertension and compression of the medullary brainstem at the level of the entry and exit zone of the glossopharyngeal and vagus nerves has repeatedly been suggested, in which a left lateral compression appears to be more common (Geiger 2001). Among the neurons in the ventrolateral medulla, excitatory neurons are responsible for the regulation of sympathetic nervous system tone. The assumed location of this pressure area in humans is in the retro-olivary sulcus at the entry and exit zone of the glossopharyngeal and vagus nerves. This region receives information from baroreceptors of the carotid sinus via the glossopharyngeal nerve, and from baroreceptors of the aortic arch via the vagus nerve. Additional close connections exist between this region and the nucleus of the solitary tract, where the baroreceptor reflex is first synapsed. Connections to neurons of the caudal ventrolateral medulla oblongata – the depressor area – are running in the opposite direction and inhibit the activity of neurons in the pressure area. There are still a number of open questions. Good results obtained following surgical decompression document the
Further Reading
importance of neurovascular compression in the described small series of patients. The frequent demonstration of neurovascular compression in hypertensive patients further supports the significance of this pathomechanism. These findings are, however, in contrast to results of other studies where no significant difference was found between the incidence of neurovascular compressions in hypertensive and normotensive patients (Geiger 2001). MRI demonstration of the described compression in an individual patient does not permit to draw any conclusions as to its etiologic significance, since vesselbrainstem contacts are also found in individuals with normal blood pressure. Possible surgical interventions should currently be considered solely in therapy-refractory patients with severe hypertension, and be performed only in the course of prospective studies conducted at specialized clinics.
Further Reading 4.1.1 “Brainstem Infarctions” Amarenco P, Hauw JJ (1990) Cerebellar infarction in the territory of the superior cerebellum: a clinicopathologic study of 33 cases. Neurology 40:1383–1390 Arnold M, Nedeltchev K, Schroth G, Baumgartner RW, Remonda L, Loher TJ, Stepper F, Sturzenegger M, Schuknecht B, Mattle HP (2004) Clinical and radiological predictors of recanalisation and outcome of 40 patients with acute basilar artery occlusion treated with intra-arterial thrombolysis. J Neurol Neurosurg Psychiatry 75:857–862 Auer A, Felber S, Schmidauer C, Waldenberger P, Aichner F (1998) Magnetic resonance angiographic and clinical features of extracranial vertebral artery dissection. J Neurol Neurosurg Psychiatry 64:474–478 Bamford J, Warlow CP (1988) The evolution and testing of the lacunar hypothesis. Stroke 19:1074–1082 Bamford J, Sandercock P, Dennis M, Burn J, Warlow C (1991) Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 337:1521–1526 Bassetti C, Bogousslavsky J, Barth A, Regli F (1996) Isolated infarcts of the pons. Neurology 46:165–174 Bernasconi A, Bogousslavsky J, Bassetti C, Regli F (1996) Multiple acute infarcts in the posterior circulation. J Neurol Neurosurg Psychiatry 60:289–296 Bhadelia RA, Bengoa F, Gesner L, Patel SK, Uzun G, Wolpert SM, Caplan LR (1986) Acute vertebral-basilar thrombosis. Angiologicclinical comparison and therapeutic implications. Acta Radiol Suppl 369:38–42 Bogousslavsky J, Regli F, Maeder P, Meuli R, Nader J (1993) The etiology of posterior circulation infarcts: a prospective study using magnetic resonance imaging and magnetic resonance angiography. Neurology 43:1528–1533 Bogousslavsky J, Maeder P, Regli F, Meuli R (1994) Pure midbrain infarction: clinical syndromes, MRI, and etiologic patterns. Neurology 44:2032–2040 Bousser MG, Ross Russell R (1997) Cerebral venous thrombosis. WB Saunders, London Brückmann H, Ferbert A, del Zoppo GJ, Hacke W, Zeumer H (1986) Acute vertebral-basilar thrombosis. Angiologic-clinical comparison and therapeutic implications. Acta Radiol Suppl 369:38–42
331 Caplan LR (1980) Top of the basilar syndrome. Neurology 30:72–79 Caplan LR (1989) Intracranial branch atheromatous disease: a neglected, understudied and underused concept. Neurology 39: 1246–1250 Caplan LR, Tettenborn B (1992) Vertebrobasilar occlusive disease. Review of selected aspects. 2: posterior circulation embolism. Cerebrovasc Dis 2:320–326 Caplan LR, Gorelick RR, Hier DB (1986) Race, sex, and occlusive cerebrovascular diseases. A review. Stroke 17:648–655 Caplan LR, Amarenco P, Rosengart A, Lafranchise EF, Teal PA, Belkin M, DeWitt LD, Pessin MS (1992) Embolism from vertebral artery origin occlusive disease. Neurology 42:1505–1512 Caplan LR, Wityk RJ, Glass TA et al (2004) New England medical center posterior circulation registry. Ann Neurol 56:389–398 Chambers BR, Norris JW, Shurvell BL, Hachinski VC (1987) Prognosis of acute stroke. Neurology 37:221–225 Chaves CJ, Pessin MS, Caplan LR, Chung CS, Amarenco P, Breen J, Fine J, Kase C, Tapia J, Babikian V, Rosengart A, DeWitt LD (1996) Cerebellar hemorrhagic infarction. Neurology 46:346–349 Choi KD, Shin HY, Kim JS, Kim SH, Kwon OK, Koo JW, Park SH, Yoon BW, Roh JK (2005) Rotational vertebral artery syndrome: oculographic analysis of nystagmus. Neurology 65:1287–1290 Cruz-Flores S, de Assis Aquino Gondim F, Leiva EC (2004) Brainstem involvement in hypertensive encephalopathy: clinical and radiological findings. Neurology 62:1417–1419 Dimitrijeski B, Villringer A, Koennecke HC, Hartmann A (2006) Systemic thrombolysis in patients with posterior circulation stroke. J Neurol 253(2):35 Du B, Wong EH, Jiang WJ (2009) Long-term outcome of tandem stenting for stenoses of the intracranial vertebrobasilar artery and vertebral ostium. Am J Neuroradiol 30:840–844 Eckert B, Kucinski T, Pfeiffer G, Groden C, Zeumer H (2002) Endovascular therapy acute vertebrobasilar occlusion: early treatment onset as the most important factor. Cerebrovasc Dis 14:42–50 Eckert B, Koch C, Thomalla G, Kucinski T, Grzyska U, Roether J, Alfke K, Jansen O, Zeumer H (2005) Aggressive therapy with intravenous abciximab and intra-arterial rtPA and additional PTA/stenting improves clinical outcome in acute vertebrobasilar occlusion. Stroke 36:1160–1165 Edgell RC, Yavagal DR, Drazin D, Olivera R, Boulos AS (2008) Treatment of vertebral artery origin stenosis with anti-proliferative drug-eluting stents. J Neuroimaging 20:175–179 Edwards NM, Fabian TC, Claridge JA, Timmons SD, Fischer PE, Croce MA (2007) Antithrombotic therapy and endovascular stents are effective treatments for blunt carotid injuries: results from longterm followup. J Am Coll Surg 204:1007–1013 Ferbert A, Brückmann H, Drummen R (1990a) Clinical features of proven basilar artery occlusion. Stroke 21:1135–1142 Fisher CM (1977) Bilateral occlusion of basilar artery branches. J Neurol Neurosurg Psychiatry 40:1182–1189 Fisher CM, Caplan LR (1971) Basilar artery branch occlusion: a cause of pontine infarction. Neurology 21:900–905 Fitzek S, Fitzek C (2005) Verlauf und Funktionserholung bei isolierten Hirnstamminfarkten. Klin Neuroradiol 15:99–108 Fitzek S, Fitzek C, Urban PP, Marx J, Hopf HC, Stoeter P (2001) Time course of lesion development in patients with acute brain stem infarction and correlation with NIHSS score. Eur J Radiol 39:180–185 Freitag HJ (1993) Local intraarterial thrombolysis in cerebrovascular disease. Biomed Prog 6:20–24 Fujiwara H, Momoshima S, Kuribayashi S, Sasamura H (2005) Hypertensive encephalopathy of brain stem with minimal supratentorial involvement: a rare manifestation of hypertensive enecephalopathy. Radiat Med 23:504–507 Georgiadis D, Arnold M, von Buedingen HC, Valko P, Sarikaya H, Rousson V, Mattle HP, Bousser MG, Baumgartner RW (2009)
332 Aspirin vs anticoagulation in carotid artery dissection: a study of 298 patients. Neurology 72:1810–1815 Glass TA, Hennessey PM, Pazdera L, Chang HM, Wityk RJ, Dewitt LD, Pessin MS, Caplan LR (2002) Outcome at 30 days in the New England medical center posterior circulation registry. Arch Neurol 59:369–376 Graf J, Skutta B, Kuhn FP, Ferbert A (2000) Computed tomographic angiography findings in 103 patients following vascular events in the posterior circulation: potential and clinical relevance. J Neurol 247:760–766 Hacke W, Zeumer H, Ferbert A, Bruckmann H, del Zoppo GJ (1988) Intra-arterial thrombolytic therapy improves outcome in pati ents with acute vertebrobasilar occlusive disease. Stroke 19: 1216–1222 Hassler O (1967a) Venous anatomy of the human midbrain. Arch Neurol 16:404–409 Hassler O (1967b) Arterial pattern of human brainstem. Normal appearance and deformation in expanding supratentorial conditions. Neurology 17:368–375 Häussler B (1996) Epidemiologie des Schlaganfalls. In: Mäurer HC, Diener HC (Hrsg). Der Schlaganfall. Thieme, Stuttgart Heinemann LA, Barth W, Garbe E, Willich SN, Kunze K (1998) Epidemiologic data of stroke. Data of the WHO-MONICA Project in Germany. Nervenarzt 69:1091–1099 Hennerici M, Klemm C, Rautenberg W (1988) The subclavian steal phenomenon: a common vascular disorder with rare neurologic deficits. Neurology 38:669–673 Hennerici M, Hacke W, von Kummer R, Hornig C, Zangemeister W (1991) Intravenous tissue plasminogen activator for the treatment of acute thromboembolic ischemia. Cerebrovasc Dis 1(suppl 1): 124–128 Hommel M, Besson G, Le Bas JF, Gaio JM, Pollak P, Borgel F, Perret J (1990) Prospective study of lacunar infarction using magnetic resonance imaging. Stroke 21:546–554 Huemer M, Niederwieser V, Ladurner G (1995) Thrombolytic treatment for acute occlusion of the basilar artery. J Neurol Neurosurg Psychiatry 58:227–228 Indredavik B, Bakke F, Slordahl SA, Rokseth R, Haheim LL (1999) Stroke unit treatment. 10-year follow-up. Stroke 30: 1524–1527 Jackson MJ, Schaefer JA, Johnson MA, Morris AA, Turnbull DM, Bindoff LA (1995a) Presentation and clinical investigation of mitochondrial respiratory chain disease. A study of 51 patients. Brain 118:339–357 Kang DW, Lee SH, Bae HJ et al (2000) Acute bilateral cerebellar infarcts in the territory of the posterior inferior cerebellar artery. Neurology 55:582–584 Kim JS (2003) Pure lateral medullary infarction: clinical-radiological correlation of 130 acute, consecutive patients. Brain 126:1–9 Korogi Y, Takahashi M, Nakagawa T, Mabuchi N, Watabe T, Shiokawa Y, Shiga H, O’Uchi T, Miki H, Horikawa Y, Fujiwara S, Furuse M (1997) Intracranial vascular stenosis and occlusion: MR angiographic findings. Am J Neuroradiol 18: 135–143 Krampla W, Schmidbauer B, Hruby W (2008) Ischaemic stroke of the artery of Percheron. Eur Radiol 18:192–194 Krasnianski M, Winterholler M, Neudecker S, Zierz S (2003) Klassische alternierende medulla-oblongata-syndrome. Eine historischkritische und topodiagnostische analyse. Fortschr Neurol Psychiatry 71:397–405 Krasnianski M, Neudecker S, Zierz S (2004) Klassische alternierende syndrome der Brücke. Eine historisch-kritische und topodiagnostische analyse. Fortschr Neurol Psychiatry 72: 460–468 Krasnianski M, Müller T, Stock K, Zierz S (2006) Between Wallenberg syndrome and hemimedullary lesion. J Neurol 253: 1442–1446
4 Diseases Krespi Y, Gurol ME, Coban O, Tuncay R, Bahar S (2001) Venous infarction of brainstem and cerebellum. J Neuroimaging 11: 425–431 Kruit MC, Launer LJ, Ferrari MD, van Buchem MA (2005a) Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA study. Brain 128:2068–2077 Kuehnen J, Schwarz A, Neff W, Hennerici M (1998) Cranial nerve syndrome in thrombosis of the transverse/sigmoid sinuses. Brain 121:381–388 Kumral E (2008). In: Caplan LR (ed) Behcets disease in uncommon causes of stroke, 2nd edn. Cambridge University Press, Cambridge, pp 67–74 Kumral E, Bayülkem G, Evyapan D (2002) Clinical spectrum of pontine infarction. J Neurol 49:1659–1670 Kumral E, Kisabay A, Atac C, Kaya C, Calli C (2005) The mechanism of ischemic stroke in patients with dolichoectatic basilar artery. Eur J Neurol 12:37–44 Li F, Liu KF, Silva MD, Omae T, Sotak CH, Fenstermacher JD, Fisher M, Hsu CY, Lin W (2000) Transient and permanent resolution of ischemic lesions on diffusion-weighted imaging after brief periods of focal ischemia in rats: correlation with histopathology. Stroke 31:946–954 Lindsberg PJ, Mattle HP (2006) Therapy of basilar artery occlusion. Stroke 37:922–928 Linfante I, Llinas RH, Schlaug G, Chaves C, Warach S, Caplan LR (2001) Diffusion-weighted imaging and National Institutes of Health Stroke Scale in the acute phase of posterior-circulation stroke. Arch Neurol 58:621–628 Liu GT, Crenner CW, Logigian EL, Charness ME, Samuels MA (1992) Midbrain syndromes of Benedikt, Claude, and Nothnagel: setting the records straight. Neurology 42:1820–1822 Marquardt L, Kuker W, Chandratheva A, Geraghty O, Rothwell PM (2009) Incidence and prognosis of > or = 50% symptomatic vertebral or basilar artery stenosis: prospective population-based study. Brain 132:982–988 Marx JJ (2005) Strukturell-funktionelles Hirnstamm-Mapping auf der Basis klinischer, kernspintomographischer und elektrophysiologischer Befunde. Habilitationsschrift, Johannes Gutenberg-Universität Mainz, Germany Marx JJ, Thoemke F (2009) Classical crossed brain stem syndromes: myth or reality? J Neurol 256:898–903 Marx JJ, Mika-Gruettner A, Thoemke F, Fitzek S, Fitzek C, Vucurevic G, Urban PP, Stoeter P, Hopf HC (2002) Electrophysiological brainstem testing in the diagnosis of reversible brainstem ischemia. J Neurol 249:1041–1047 Marx JJ, Thoemke F, Mika-Gruettner A, Fitzek S, Vucurevic G, Urban PP, Stoeter P, Dieterich M, Hopf HC (2004) Diffusion-weighted MRI in vertebrobasilar ischemia. Application, sensitivity, and prognostic value. Nervenarzt 75:341–346 Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J (2001) Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 345:1740–1746 McCarron MO, McKinstry CS (2008) Vanishing brainstem edema. J Stroke Cerebrovasc Dis 17:156–157 Mehler MF (1989) The rostral basilar artery syndrome: diagnosis, etiology, prognosis. Neurology 39:9–16 Mizutani T, Aruga T, Kirino T, Miki Y, Saito I, Tsuchida T (1995) Recurrent subarachnoid hemorrhage from untreated ruptured vertebrobasilar dissecting aneurysms. Neurosurgery 36:905–911 Nahser HC, Henkes H, Weber W, Berg-Dammer E, Yousry TA, Kuhne D (2000) Intracranial vertebrobasilar stenosis: angioplasty and follow-up. Am J Neuroradiol 21:1293–1301 Nasreddine ZS, Saver JL (1997) Pain after thalamic stroke: right diencephalic predominance and clinical features in 180 patients. Neurology 48:1196–1199 Neumann-Haefelin T, Wittsack HJ, Wenserski F, Siebler M, Seitz RJ, Modder U, Freund HJ (1999) Diffusion- and perfusion-weighted
Further Reading MRI. The DWI/PWI mismatch region in acute stroke. Stroke 30:1591–1597 Norrving B, Cronqvist S (1991) Lateral medullary infarction: prognosis in an unselected series. Neurology 41:244–248 Pessin MS, Chimowitz MI, Levine SR, Kwan ES, Adelman LS, Earnest MP, Clark DM, Chason J, Ausman JI, Caplan LR (1989) Stroke in patients with fusiform vertebrobasilar aneurysms. Neurology 39:16–21 Pfadenhauer K, Eßer M, Weber H, Wölfle KD (2005) Vertebrobasiläre Ischämie als Komplikation der Arteriits temporalis. Nervenarzt 76:954–959 Pfefferkorn T, Mayer TE, Schulte-Altedorneburg G, Bruckmann H, Hamann GF, Dichgans M (2006) Diagnosis and therapy of basilar artery occlusion. Nervenarzt 77:416–422 Provenzale JM, Allen NB (1996) Neuroradiologic findings on polyarteritis nodosa. Am J Neuroradiol 17:1119–1126 Reuter U, Hämling M, Kavuk I, Einhäupl KM, Schielke E for the German vertebral artery dissection study group (2006) Vertebral artery dissections after chiropractic neck manipulation in germany over three years. J Neurol 253:724–730 Saposnik G, de Tilly LN, Caplan LR (2008) Pontine warning syndrome. Arch Neurol 65:1375–1377 Savitz S, Caplan LR (2008). In: Caplan LR (ed) Dilatative arteriopathy (Dolichoectasia) in uncommon causes of stroke, 2nd edn. Cambridge University Press, Cambridge, pp 479–482 Savitz SI, Ronthal M, Caplan LR (2006) Vertebral artery compression of the medulla. Arch Neurol 63:234–241 Schievink WI, Michels VV, Piepgras DG (1994a) Neurovascular complications of heritable connective tissue disorders. Stroke 25:889–903 Schievink WI, Mokri B, Piepgras DG (1994b) Spontaneous dissections of cervicocephalic arteries in childhood and adolescence. Neurology 44:1607–1612 Schmidt D (2000) Die klassischen Hirnstammsyndrome. Definitionen und Geschichte. Ophthalmologe 97:411–417 Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle HP, Engelter ST, Tanne D, Muir KW, Molina CA, Thijs V, Audebert H, Pfefferkorn T, Szabo K, Lindsberg PJ, de Freitas G, Kappelle LJ, Algra A (2009) Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study. Lancet Neurol 8:724–730 Schulte-Altedorneburg G, Brückmann H (2006) Bildgebende diagnostik beim Hirnstamminfarkt. Nervenarzt 77:731–744 Schulte-Altedorneburg G, Droste DW, Popa V, Wohlgemuth WA, Kellermann M, Nabavi DG, Csiba L, Ringelstein EB (2000) Visualization of the basilar artery by transcranial color-coded duplex sonography: comparison with postmortem results. Stroke 31:1123–1127 Schwamm LH, Koroshetz WJ, Sorensen AG, Wang B, Copen WA, Budzik R, Rordorf G, Buonanno FS, Schaefer PW, Gonzalez RG (1998) Time course of lesion development in patients with acute stroke: serial diffusion- and hemodynamic-weighted magnetic resonance imaging. Stroke 29:2268–2276 Shuabib A (1991) Stroke from other etiologies masquerading as migraine stroke. Stroke 22:1068–1074 Silverman IE, Liu GT, Volpe NJ, Galetta SL (1995) The crossed paralyses. The original brain-stem syndromes of Millard-Gubler, Foville, Weber, and Raymond-Cestan. Arch Neurol 52:635–638 Smith E, Delargy M (2005) Locked-in syndrome. BMJ 330:406–409 Steinke W, Mangold J, Schwartz A, Hennerici MJ (1997) Mechanisms of infarction in the superficial posterior cerebral artery territory. Neurology 244:571–578 Subramanyan R, Joy J, Balakrishnan KG (1989) Natural history of aortoarteritis (Takayasu’s disease). Circulation 80:429–474 Turney TM, Garraway WM, Whisnant JP (1984) The natural history of hemispheric and brainstem infarction in Rochester, Minnesota. Stroke 15:790–794
333 Tzourio C, Bousser MG (1997) Migraine: a risk factor for ischemic stroke in young women. Stroke 28:2569–2570 Vuilleumier P, Bogousslavsky J, Regli F (1995) Infarction of the lower brainstem. Clinical, aetiological and MR-topographical correlations. Brain 118:1013–1025 Weimar C, Kley C, Kraywinkel K, Schacker A, Riepe M, Wimmer ML, Goertler M, Diener HC (2002a) Clinical presentation and prognosis of brain stem infarcts. An evaluation of the stroke databank of the German Stroke Foundation. Nervenarzt 73:166–173 Wilkinson IMS, Russell RWR (1972) Arteries in the head and neck in giant cell arteritis: a pathological study to show the pattern of arterial involvement. Arch Neurol 27:378–387 Williams D, Wilson T (1962) The diagnosis of major and minor syndromes of basilar insufficiency. Brain 85:741–774 Wolf JK (1971) The classical brain stem syndromes: translations of the original papers with notes on the evolution of clinical neuroanatomy. Charles C. Thomas, Springfield Yoshimoto Y, Hoya K, Tanaka Y, Uchida T (2005) Basilar artery dissection. J Neurosurg 102:476–481
4.1.2 “Intraparenchymatous Brainstem Hemorrhages” AWMF-Leitlinie: Intrazerebrale Blutung (2007). http://www.uniduesseldorf. de/AWMF/; letzter Zugriff. Accessed 2 Dec 2007 Bereczki D, Liu M, Prado GF do, Fekete I (2001) Mannitol for acute stroke. Cochrane Database Syst Rev; CD001153 Broderick JP, Adams HP Jr, Barsan W, Feinberg W, Feldmann E, Grotta J, Kase C, Krieger D, Mayberg M, Tilley B, Zabramski JM, Zuccarello M (1999) Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 30:905–915 Caplan L, Goodwin J (1982) Lateral brainstem tegmental hemorrhage. Neurology 32:252–260 Chung C-S, Park C-H (1992) Primary pontine hemorrhage: a new CT classification. Neurology 42:830–834 Dziewas R, Kremer M, Lüdemann P, Nabavi DG, Dräger B, Ringelstein EB (2003) The prognostic impact of clinical and CT parameters in patients with pontine hemorrhage. Cerebrovasc Dis 16:224–229 Ferbert A, Buchner H, Brückmann H (1990b) Brainstem auditory evoked potentials and somatosensory evoked potentials in pontine hemorrhage. Brain 113:49–63 Haines SJ, Mollman HD (1993) Primary pontine hemorrhagic events. Hemorrhage or hematoma? Surgical or conservative treatment? Neurosurg Clin N Am 4:481–495 Jung HH, Baumgartner RW, Hess K (2000) Symptomatic secondary hemorrhagic transformation of ischemic Wallenberg’s syndrome. J Neurol 247:462–464 Kimura K, Ogata J, Minematsu K, Yasaka M, Yamaguchi T (2001) Massive pontine hemorrhagic infarction associated with embolic basilar artery occlusion. Intern Med 40:658–661 Knudsen KA, Rosand J, Karluk D, Greenberg SM (2001) Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 56:537–539 Komiyama M, Boo YE, Yagura H, Yasui T, Baba M, Hakuba A, Nishimura S (1989) A clinical analysis of 32 brainstem haemorrhages; with special reference to surviving but severely disabled cases. Acta Neurochir Wien 101:46–51 Kupersmith MJ, Kalish H, Epstein F, Yu G, Berenstein A, Woo H, Jafar J, Mandel G, DeLara F (2001a) Natural history of brainstem cavernous malformations. Neurosurgery 48:47–53
334 Lee S-H, Kwon S-J, Kim KS, Yoon B-W, Roh J-K (2004) Topographical distribution of pontocerebellar microbleeds. Am J Neuroradiol 25:1337–1341 Liu K-D, Chung W-Y, Wu H-M, Shiau C-Y, Wang L-W, Guo W-Y, Pan DH-C (2005) Gamma knife surgery for cavernous hemangiomas: an analysis of 125 patients. J Neurosurg Suppl 102:81–86 Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner T (2005) Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 352:777–785 Moulin T, Tatu L, Vuillier F, Berger E, Chavot D, Rumbach L (2000) Role of a stroke data bank in evaluating cerebral infarction subtypes: patterns and outcome of 1776 consecutive patients from the Besancon Stroke Registry. Cerebrovasc Dis 10:261–271 Nakajima K (1983) Clinicopathological study of pontine hemorrhage. Stroke 14:485–493 Porter RW, Detwiler PW, Spetzler RF, Lawton MT, Baskin JJ, Derksen PT, Zabramski JM (1999) Cavernous malformations of the brainstem: experience with 100 patients. J Neurosurg 90:50–58 Poungvarin N, Bhoopat W, Viriyavejakul A, Rodprasert P, Buranasiri P, Sukondhabhant S, Hensley MJ, Strom BL (1987) Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med 316:1229–1233 Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF (2001) Spontaneous intracerebral hemorrhage. N Engl J Med 344:1450–1460 Rabinstein AA, Tisch SH, McClelland RL, Wijdicks EFM (2004a) Cause is the main predictor of outcome in patients with pontine hemorrhage. Cerebrovasc Dis 17:66–71 Sandalcioglu IE, Wiedemayer H, Secer S, Asgari S, Stolke D (2002) Surgical removal of brain stem cavernous malformations: surgical indications, technical considerations, and results. J Neurol Neurosurg Psychiatry 72:351–355 Takahama H, Morii K, Sato M, Sekiguchi K, Sato S (1989) Stereotactic aspiration in hypertensive pontine hemorrhage: comparative study with conservative therapy. No Shinkei Geka 17:733–739 Weimar C, Kley C, Kraywinkel K, Schacker A, Riepe M, Wimmer MLJ, Goertler M, Diener HC (2002) Klinische Präsentation und Prognose von Hirnstamminfarkten. Nervenarzt 73:166–173 Wessels T, Möller-Hartmann W, Noth J, Klötzsch C (2004) CT findings and clinical features as markers for patient outcome in primary pontine hemorrhage. Am J Neuroradiol 25:257–260
4.1.3 “Perimesencephalic Subarachnoid Hermorrhage and Cerebral Superficial Siderosis” Angstwurm K, Schielke E, Zimmer C, Kivelitz D, Weber JR (2002) Superficial siderosis of the central nervous system: response to steroid therapy. J Neurol 249:1223–1225 Ausman JI (2002) Perimesencephalic nonaneurysmal subarachnoid hemorrhage: What is it? What are we missing? Surg Neurol 57:211 Brilstra EH, Hop JW, Rinkel GJ (1997) Quality of life after perimesencephalic haemorrhage. J Neurol Neurosurg Psychiatry 63: 382–384 Canhao P, Falcao F, Melo TP, Ferro H, Ferro J (1999) Vascular risk factors for perimesencephalic nonaneurysmal subarachnoid hemorrhage. J Neurol 246:492–496 Fearnley JM, Stevens JM, Rudge P (1995) Superficial siderosis of the central nervous system. Brain 118:1051–1066
4 Diseases Hamill RC (1908) Report of a case of melanosis of the brain, cord and meninges. J Nerv Ment Dis 35:594 Hop JW, Brilstra EH, Rinkel GJ (1998) Transient amnesia after perimesencephalic haemorrhage: the role of enlarged temporal horns. J Neurol Neurosurg Psychiatry 65:590–593 Ildan F, Tuna M, Erman T, Göcer AI, Cetinalp E (2002) Prognosis and prognostic factors in nonaneurysmal perimesencephalic hemorrhage. A follow-up study in 29 patients. Surg Neurol 57:160–166 Koeppen AH, Dickson AC, Chu RC, Thach RE (1993) The pathogenesis of superficial siderosis of the central nervous system. Ann Neurol 34:646–653 Kumar N, Cohen-Gadol AA, Wright RA, Miller GM, Piepgras DG, Also JE (2006) Superficial siderosis. Neurology 66:1144–1152 Leussink VI, Flachenecker P, Brechtelsbauer D, Bendszus M, Sliwka U, Gold R, Becker G (2003) Superficial siderosis of the central nervous system: pathogenetic heterogeneity and therapeutic approaches. Acta Neurol Scand 107:54–61 Linn FH, Rinkel GJ, Algra A, van Gijn J (1998) Headache characteristics in subarachnoid hemorrhage and benign thunderclap headache. J Neurol Neurosurg Psychiatry 65:791–793 Marquardt G, Niebauer T, Schick U, Lorenz R (2000) Long term follow up after perimesencephalic subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 69:127–130 Müller-Forell W, Welschehold S, Köhler J, Schicketanz KH (2002) Subarachnoidalblutung ohne Aneurysmanachweis. Radiologe 42: 871–879 Ramgren B, Cronqvist M, Rommer B, Brandt L, Holtas S, Larsson E-M (2005) Vertebrobasilar dissection with subarachnoid hemorrhage: a retrospective study of 29 patients. Neuroradiology 47:97–104 Rinkel GJ, van Gijn J (1995) Perimesencephalic haemorrhage in the quadrigeminal cistern. Cerebrovasc Dis 5:312–313 Rinkel GJE, Wijdicks EFM, Vermeulen M, Hasan D, Brouwers PJAM, van Gijn J (1991a) The clinical course of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Ann Neurol 29:463–468 Rinkel GJE, Wijdicks EFM, Hasan D, Kienstra GE, Franke CL, Hageman LM, Vermeulen M, van Gijn J (1991b) Outcome in patients with subarachnoid hemorrhage and negative angiography according to pattern of hemorrhage on computed tomography. Lancet 338:964–969 River Y, Honigman S, Gomori JM, Reches A (1994) Superficial hemosiderosis of the central nervous system. Mov Disord 9:559–562 Ruigrok YM, Rinkel GJ, Vermeulen M, Algra A, van Gijn J (2000) Perimesencephalic hemorrhage and CT angiography: a decision analysis. Stroke 31: 2976–2983 Schievink WI, Wijdicks EF (1997) Pretruncal subarachnoid hemorrhage: an anatomically correct description of the perimesencephalic subarachnoid hemorrhage (letter). Stroke 28:2572 Sloan MA, Alexandrov AV, Tegeler CH, Spencer MP, Caplan LR, Feldmann E, Wechsler LR, Neell D, Gomez CR, Babikian VL, Lefkoitz D, Goldman RS, Armon C, Hsu CY, Goodin DS (2004) Assessment: transcranial doppler ultrasonography: report of the therapeutics and technology assessment subcommitee of the american academy of neurology. Neurology 62:1468–1481 Topcuoglu MA, Ogilvy CS, Carter BS, Buonanno FS, Koroshetz WJ, Singhal AB (2003) Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other neuroimaging tests. J Neurosurg 98: 1235–1240 Urban PP, Szegedi A, Müller-Forell W, Hopf HC (1999) Superficial siderosis of the CNS as a rare differential diagnosis of chronic low back pain. J Neurol 246:980–981 van Calenbergh F, Plets C, Goffin J, Velghe L (1993) Non-aneurysmal subarachnoid hemorrhage: prevalence of perimesencephalic hemorrhage in a consecutive series. Surg Neurol 39:320–323
Further Reading van der Schaaf IC, Velthuis BK, Gouw A, Rinkel GJE (2004) Venous drainage in perimesencephalic hemorrhage. Stroke 35:1614–1618 van Gijn J, Rinkel GJE (2001) Subarachnoid haemorrhage: diagnosis, causes and management. Brain 124:249–278 van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A (1985) Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 35:493–497 Wanke I, Dörfler A, Forsting M (2004) Intracranial aneurysms. In: Forsting M (ed) Intracranial vascular malformations and aneurysms. Springer, Heidelberg, pp 143–247 Wijdicks EFM, Schievink WI (1997) Perimesencephalic nonaneurysmal subarachnoid hemorrhage: first hint of a cause? Neurology 49:634–636
4.1.4 “Vascular Malformations” Aminoff MJ (1973) Vascular anomalies in the intracranial duramater. Brain 96:601–612 Auffray-Calvier E, Desal HA, Freund P, Laplaud D, Mathon G, De Kersaint-Gilly A (1999) Capillary telangiectasias: angiographically occult vascular malformations-MRI symptomatology apropos of 7 cases. J Neuroradiol 26:257–261 Berlis A, Tatagiba M, Schumacher M (2004) Atypische angiomatöse DVA (developmental venous anomaly). Fortschr Röntgenstr 176: 618–622 Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U (2002) Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 25:1–53 Cognard C, Spelle L, Pierot L (2004) Pial arteriovenous malformations. In: Forsting M (ed) Intracranial vascular malformations and aneu rysms. Springer, Berlin/New York, pp 39–100 Crum BA, Link M (2004) Intracranial dural arteriovenous fistula mimicking brainstem neoplasm. Neurology 62:2330–2331 Ferroli P, Sinisi M, Franzini A, Giombini S, Solero CL, Broggi G (2005) Brainstem cavernomas: long-term results of micro neurosurgical resection in 52 patients. Neurosurgery 56:1203–1214 Forsting M, Wanke I (2004) Developmental venous anomalies. In: Forsting M (ed) Intracranial vascular malformations and aneurysms. Springer, Berlin/New York, pp 1–13 Hashimoto H, Iida J, Kawaguchi S, Sakaki T (2004) Clinical features and management of brain arteriovenous malformation in elderly patients. Acta Neurochir Wien 146:1091–1098 Huang YP, Wolf BS (1964) Veins of the white matter of the cerebral hemispheres (the medullary veins). AJR 92:739–755 Huddle DC, Chaloupka JC, Sehgal V (1999) Clinically aggressive diffuse capillary telangiectasia of the brain stem: a clinical radiologicpathologic case study. AJNR Am J Neuroradiol 20:1674–1677 Iwasaki M, Murakami K, Tomita T, Numagami Y, Nishijima M (2006) Cavernous sinus dural arteriovenous fistula complicated by pontine venous congestion: a case report. Surg Neurol 65:516–519 Khaw AV, Mohr JP, Sciacca RR, Schumacher HC, Hartmann A, Pile-Spellman J, Mast H, Stapf C (2004) Association of infratentorial brain arteriovenous malformations with hemorrhage at initial presentation. Stroke 35:660–663 Krings T, Ozanne A, Chng SM, Alvarez H, Rodesch G, Lasjaunias PL (2005) Neurovascular phenotype in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1 day – 60 years. Neuroradiology 47:711–720 Küker W, Forsting M (2004) Cavernomas and capillary telangiectasias. In: Forsting M (ed) Intracranial vascular malformations and aneurysms. Springer, Berlin/New York, pp 15–38
335 Kupersmith MJ, Kalish H, Epstein F, Yu G, Berenstein A, Woo H, Jafar J, Mandel G, DeLara F (2001b) Natural history of brainstem cavernous malformations. Neurosurgery 48:47–53 Lasjaunias P (ed) (1997) Venous anomalies and malformations. In: Vascular diseases in neonates, infants and children. Interventional neuroradiology management. Springer, Berlin/New York, pp 445–471 Liscák R, Vladyka V, Simonova G, Vymazal J, Novotny J (2005) Gamma knife surgery of brain cavernous hemangiomas. J Neurosurg Suppl 102:207–213 Lucas CP, Zabramski JM, Spetzler RF, Jacobowitz R (1997) Treatment for intracranial dural arteriovenous malformations: a meta- analysis from the English language literature. Neurosurgery 40:1119–1130 McCormick WF, Hardman JM, Boulter TR (1968) Vascular malformations (“angiomas”) of the brain, with special reference to those occurring in the posterior fossa. J Neurosurg 28:241–251 McLaughlin MR, Kondziolka D, Flickinger JC, Lunsford S, Lunsford LD (1998) The prospective natural history of cerebral venous malformations. Neurosurgery 43:195–200 Moriarity JM, Wetzel M, Clatterbuck RE, Javedan SJ, Sheppard JM, Hoenig-Rigamonti K, Crone NE, Breiter SN, Lee RR, Rigamonti D (1999) The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 44:1166–1173 Mull M, Reinghardt J, Bertalanffy H, Thron A (1995) Pre- and postoperative findings in cavernous malformation of the CNS: diagnostic limitations and pitfalls. Neuroradiology 37(Suppl 1):S49 Okazaki H (1989) Fundamentals of neuropathology. Morphological basis for neurologic disorders, 2nd edn. Igaku-Shion, New York/ Tokyo, pp 70–82 Osborn A (1994) Diagnostic neuroradiology. Mosby-Year-Book, St. Louis Plummer NW, Gallione CJ, Srinivasan S, Zawistowski JS, Louis DN, Marchuk DA (2004) Loss of p53 sensitizes mice with a mutation in CCM1 (KRIT1) to development of cerebral vascular malformations. Am J Pathol 165:1509–1518 Porter JL, Willinsky RA, Harper W, Wallace MC (1997) Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 87:190–197 Rabinstein AA, Tisch SH, McClelland RL, Wijdicks EFM (2004b) Cause is the main predictor of outcome in patients with pontine hemorrhage. Cerebrovasc Dis 17:66–71 Rigamonti D, Spetzler RF (1988) The association of venous and cavernous malformations: report of four cases and discussion of the pathophysiological, diagnostic, and therapeutic implications. Acta Neurochir (Wien) 92:100–105 Rigamonti D, Johnson PC, Spetzler RF, Hadley MN, Drayer BP (1991) Cavernous malformations and capillary telangiectasia; a spectrum within a single pathological entity. Neurosurgery 28:60–64 Russel D, Rubinstein L (eds) (1977) Pathology of tumors of the nervous system, 4th edn. Williams & Wilkins, Baltimore pp 116–145 Saito Y, Kabayashi N (1981) Cerebral venous angiomas: clinical evaluation and possible etiology. Radiology 139:87–94 Sinclair J, Kelly ME, Steinberg G (2006) Surgical management of posterior fossa arteriovenous malformations. Neurosurgery 58:189–201 Stapf C (2006) The neurology of cerebral arteriovenous malformations. Rev Neurol 162:1189–1203 Szikora I (2004) Dural arteriovenous malformations. In: Forsting M (ed) Intracranial vascular malformations and aneurysms. Springer, Berlin/New York, pp 101–141 Takahashi S, Tomura N, Watarai J, Mizoi K, Manabe H (1994) Dural arteriovenous fistula of the cavernous sinus with venous congestion of the brain stem: report of two cases. Am J Neuroradiol 20:886–888 Wong JH, Awad IA, Kim JH (2000) Ultrastructural pathological features of cerebrovascular malformations: a preliminary report. Neurosurgery 46:1454–1459
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4.1.5 “Basilar Migraine/Vestibular Migraine” Baier B, Winkenwerder E, Dieterich M (2009) “Vestibular migraine”: effects of prophylactic therapy with various drugs. A retrospective study. J Neurol 256:436–442 Best C, Eckhardt-Henn A, Tschan R, Bense S, Dieterich M (2009a) Psychiatric morbidity and comorbidity in different vestibular vertigo syndromes: results of a prospective longitudinal study over one year. J Neurol 256:58–65 Best C, Eckhardt-Henn A, Tschan R, Dieterich M (2009b) Why do subjective vertigo and dizziness persist over one year after a vestibular vertigo syndrome? Ann NY Acad Sci 1164:334–337 Bickerstaff ER (1961) Basilar artery migraine. Lancet i:15–17 Bisdorff AR (2004) Treatment of migraine related to vertigo with lamotrigine: an observational study. Bull Soc Sci Med Grand Duche Luxemb 2:103–108 Bousser M-G, Welch KM (2005) Relation between migraine and stroke. Lancet Neurol 4:533–542 Brandt T, Strupp M (2006) Migraine and vertigo: classification, clinical features, and special treatment considerations. Clinical Review. Headache Currents 3:12–19 Cutrer FM, Baloh RW (1992) Migraine-associated dizziness. Headache 32:300–304 Diener HC, Putzki N, Berlit P (2008) Leitlinien für die Diagnostik und Therapie in der Neurologie. Kommission Leitlinien der Deutschen Gesellschaft für Neurologie. 3. Aufl, 4th edn. Thieme, Stuttgart/ New York Dieterich M, Brandt Th (1999) Episodic vertigo related to migraine (90 cases): vestibular migraine? J Neurol 246:883–892 Eckhardt-Henn A, Best C, Bense S, Breuer P, Diener G, Tschan R, Dieterich M (2008) Psychiatric comorbidity in different organic vertigo syndromes. J Neurol 255:420–428 Furman JM, Marcus DA, Balaban CD (2003) Migrainous vertigo: development of a pathogenetic model and structured diagnostic interview. Curr Opin Neurol 16:5–13 Goadsby PJ (2000) The pharmacology of headache. Prog Neurobiol 62:509–525 Griggs RC, Nutt JG (1995) Episodic ataxias as channelopathies. Ann Neurol 37:285–287 Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders, 2nd edn. Cephalalgia 24(Suppl 1):9–160 Ishiyama A, Jacobson KM, Baloh RW (2000) Migraine and benign positional vertigo. A Otol Rhinol Laryngol 109:377–380 Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130:2484–2493 Kruit MC, Launer LJ, van Buchen MA, Terwindt GM, Ferrari MD (2005b) MRI findings in migraine. Rev Neurol Paris 161:661–665 Lee H, Lopez I, Ishiyama A, Baloh RW (2000) Can migraine damage the inner ear? Arch Neurol 57:1631 Neuhauser H, Lempert T (2004) Vertigo and dizziness related to migraine: a diagnostic challenge. Review. Cephalalgia 24:83–91 Neuhauser H, Leopold M, van Brevern M, Arnold G, Lempert T (2001) The interrelations of migraine, vertigo and migrainous vertigo. Neurology 56:436–441 Neuhauser H, Radtke A, von Brevern M, Lempert T (2003) Zolmitriptan for treatment of migrainous vertigo: a pilot randomized placebocontrolled trial. Neurology 60:882–883 Neuhauser HK, Radtke A, von Brevern M, Feldmann M, Lezius F, Ziese T, Lempert T (2006) Migrainous vertigo: prevalence and impact on quality of life. Neurology 67:1028–1033 Olesen J (2005) Vertigo and dizziness related to migraine: a diagnostic challenge. Letter to the editor. Cephalalgia 25:761–763
4 Diseases Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffmann SM, Lamerdian JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutation in the Ca2+ channel gene CACNL1A4. Cell 87:543–552 Radke A, Lempert T, Gresty MA, Brookes GB, Bronstein AM, Neuhauser H (2002) Migräne und Menière’s disease. Is there a link? Neurology 59:1700–1704 Rasmussen BK (1993) Migraine and tension-type headache in a general population: precipitating factors, female, hormones, sleep pattern and relation to lifestyle. Pain 53:65–72 Richter F, Bauer R, Lehmenkühler A, Schaible HG (2008) Spreading depression in the brainstem of the adult rat: electrophysiological parameters and influences on regional brainstem blood flow. J Cereb Blood Flow Metab 28:984–994 Silberstein SD, Lipton RB (1993) Epidemiology of migraine. Neuroepidemiology 12:179–194 Strupp M, Kalla R, Dichgans T, Freilinger T, Glasauer S, Brandt T (2004) Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 62:1623–1625 Strupp M, Zwergal A, Brandt T (2007) Episodic ataxia type 2. Neurotherapeutics 4:267–273 Strupp M, Versino C, Brand T (2010) Migrainous vertigo/vestibular migraine. In: Nappi G, Moskowitz MA (eds) Handbook clinical neurology, vol 97. Elsevier, New York, pp 747–763, Chap. 62 Vitkovic J, Paine M, Rance G (2008) Neuro-otological findings in patients with migraine- and nonmigraine-related dizziness. Audiol Neurootol 13:113–122 Von Brevern M, Radtke A, Clarke AH, Lempert T (2004) Migrainous vertigo presenting as periodic positional vertigo. Neurology 62: 469–472 Weiller C, May A, Limmroth V, Jüpter M, Kaube H, van Schayck R, Coenen HH, Diener HC (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1:658–660
4.2 Inflammatory Brainstem Diseases Bitsch A, Prange H (2005) Neue Virustatika. Akt Neurol 33:257–262 Brandt T, Dichgans J, Diener HC (2003) Therapie und Verlauf neurologischer Erkrankungen. 4. Aufl. Kohlhammer, Stuttgart Deisenhammer F, Bartos A, Egg R, Gilhus NE, Giovannoni G (2006) Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol 13:913–922 Deutsche Gesellschaft für Neurologie. Leitlinien für Diagnostik und Therapie in der Neurologie. 3. Aufl. 2005; www.dgn.org Dewhurst S (2004) Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system. Herpes 11(Suppl 2): 105A–111A Drevets D, Leenen P, Greenfield R (2004) Invasion of the central nervous system by intracellular bacteria. Clin Microbiol 17(2): 323–347 Fischer S, Graham M, Kuehnert M, Kotton CN, Srinivasan A, Marty FM, Comer JA, Guarner J, Paddock CD, DeMeo DL, Shieh WJ, Erickson BR, Bandy U, DeMaria A Jr, Davis JP, Delmonico FL, Pavlin B, Likos A, Vincent MJ, Sealy TK, Goldsmith CS, Jernigan DB, Rollin PE, Packard MM, Patel M, Rowland C, Helfand RF, Nichol ST, Fishman JA, Ksiazek T, Zaki SR (2006) Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med 354:2235–2249 Goh KJ, Tan CT, Chew NK, Tan PS, Kamarulzaman A, Sarji SA, Wong KT, Abdullah BJ, Chua KB, Lam SK (2000) Clinical features of
Further Reading Nipah virus encephalitis among pig farmers in Malaysia. N Engl J Med 342(17):1229–1235 Griffiths P (2004) Cytomegalovirus infection of the central nervous system. Herpes 11(Suppl 2):95A–104A Haglund M, Gunther G (2003) Tick-borne encephalitis-pathogenesis, clinical course and long-term follow-up. Vaccine 21(Suppl 1): S11–S18 Hayes E, Sejvar J, Zaki S, Lanciotti R, Bode A, Campbell G (2005) Virology, pathology, and clinical manifestations of west nile virus disease. Emerg Infect Dis 11(8):1174–1179 Hemachudha T, Laothamatas J, Rupprecht CE (2002) Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 1(2):101–109 Huang C-C, Liu C-C, Chang Y-C, Chen C-Y (1999) Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341(13):936–942 Husstedt I, Gregor N, Kraemer C, Frese A, Kloska S, Evers S (2004) Opportunistische ZNS-Erkrankungen bei HIV und AIDS. Psychoneuro 30(12):655–660 Kaiser R (2005) Neuroborreliose und Frühsommer-Meningoenzephalitis – Gemeinsamkeiten und Unterschiede. Fortschr Neurol Psychiatr 73:750–764 Kellinghaus C, Schilling M, Lüdemann P (2004) Neurosarcoidosis: clinical experience and diagnostic pitfalls. Eur Neurol 51:84–88 Kennedy PG (2004) Viral encephalitis: causes, differential diagnosis, and management. J Neurol Neurosurg Psychiatry 75:10–15 Kidd D, Steuer A, Denman AM, Rudge P (1999) Neurological complications in Behcet’s syndrome. Brain 122:2183–2194 Koskiniemi M, Rantalaiho T, Piiparinen H, von Bonsdorff CH, Färkkilä M, Järvinen A, Koskiniemi S, Mannonen L, Muttilainen M, Linnavuori K, Porras J, Puolakkainen M, Räihä K, Salonen EM, Ukkonen P, Vaheri A, Valtonen V (2001) Infections of the central nervous system of suspected viral origin: a collaborative study from Finland. J Neurovirol 7(5):400–408 Mancusi G, Marks B, Czerny C, Thalhammer F, Thurnher D, Riedl M, Dekan G, Knerer B (2005) Tuberculosis of the clivus and the nasopharynx. HNO 53(12):1081–1084 Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A (2000) Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry 69(3): 376–380 Maschmeyer G, Kern WV (2004) Infektionen bei hämatologischen und onkologischen Erkrankungen. Deutsche Gesellschaft für Hämatologie und Onkologie. www.dgho.de McArthur JC, Brew BJ, Nath A (2005) Neurological complications of HIV infection. Lancet Neurol 4(9):543–555 Meyding-Lamadé U (2003) Virale Infektionen. Therapieleitfaden Neurologie. 1. Aufl. Kohlhammer, Wildemann, Stuttgart Meyding-Lamadé U, Sellner J, Martinez-Torres F (2004) Klinik und Therapie der viralen Meningoenzephalitiden. Akt Neurol 31: 159–169 Nowak D, Widenka D (2001) Neurosarcoidosis: a review of its intracranial manifestation. J Neurol 248(5):363–372 Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata K, Kuwabara S (2003) Bickerstaff’s brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain 126:2279–2290 Osborne AG, Blaser SI, Salzman K (2004) Diagnostic imaging brain, 2nd edn. Amirsys, Salt Lake City Padovan CS, Sostak P, Straube A (2000) Neurologische Komplikationen nach Organtransplantation. Der Nervenarzt 71:249–58 Petereit HF, Seifert H, Geiss HK, Wildemann B (2006) Liquoranalytik in der Diagnostik erregerbedingter Erkrankungen des Zentralner vensystem. Nervenarzt 77:481–494
337 Pfister HW, Kaiser R (2003) Rationale differenzialdiagnostik und Vorgehensweise bei Verdacht auf Meningitis/Enzephalitis. Akt Neurol 30:27–34 Portegies P, Solod L, Cinque P, Chaudhuri A, Begovac J, Everall I, Weber T, Bojar M, Martinez-Martin P, Kennedy PGE (2004) Guidelines for the diagnosis and management of neurological complications in HIV infection. Eur J Neurol 11:297–304 Reiber H (2005) Liquordiagnostik. In: Thomas L (ed) Labor und diagnose. 6. Aufl. TH-Books, Frankfurt am Main, pp 1743–1784 Reske D, Petereit H-F (2004) Differenzialdiagnose chronisch- entzündlicher Erkrankungen des Zentralnervensystems. Nervenarzt 75:945–952 Robert-Koch-Institut. (Stand Januar 2008). www.rki.de Rotbart HA (2000) Viral meningitis. Semin Neurol 20(3):277–292 Rote Liste Service GmbH (2008) Rote Liste (Arzneimittelverzeichnis für Deutschland). Frankfurt am Main Schmutzhard E, Pfister HW (2001) Seltene bakterielle Infektionen des Nervensystems. Akt Neurol 28:373–382 Solomon T (2004) Flavivirus encephalitis. N Engl J Med 351(4):370–378 Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, Kennedy PG (2005) Viral encephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 12: 331–343 Stille W, Brodt H-R et al (2005) Antibiotika-Therapie, Klinik und Praxis der antiinfektiösen Therapie. 11. Aufl. Schattauer, Stuttgart Tyler KL (2004) Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including mollaret’s. Herpes 11(suppl 2):57A–64A Voltz R (2002) Paraneoplastic neurological syndromes: an update on diagnosis, pathogenesis, and therapy. Lancet Neurol 1:294–305 Wildemann B, Fogel W (2003) Therapieleitfaden Neurologie. 1. Aufl. Kohlhammer, Stuttgart Wildemann B, Oschmann P, Reiber H (2006) Neurologische Labordiag nostik. 1. Aufl. Thieme, Stuttgart
4.3 “Brainstem Involvement in Demyelinating Diseases” Alpini D, Caputo D, Pugnetti L, Giuliano DA, Cesarani A (2001) Vertigo and multiple sclerosis: aspects of differential diagnosis. Neurol Sci 22:84–87 Axer H, Ragoschke-Schumm A, Bottcher J, Fitzek C, Witte OW, Isenmann S (2005) Initial DWI and ADC imaging may predict outcome in acute disseminated encephalomyelitis: report of two cases of brain stem encephalitis. J Neurol Neurosurg Psychiatry 76:996–998 Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman CH, Comi G, Adèr HJ, Losseff N, Valk J (1997) Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 120:2059–2069 Bentley PI, Kimber T, Schapira AH (2002) Painful third nerve palsy in MS. Neurology 58:1532 Bolanos I, Lozano D, Cantu C (2004) Internuclear ophthalmoplegia: causes and long-term follow-up in 65 patients. Acta Neurol Scand 110:161–165 Bruzzone MG, Grisoli M, De Simone T, Regna-Gladin C (2004) Neuroradiological features of vertigo. Neurol Sci 25:20–23 Calcagno P, Ruoppolo G, Grasso MG, De Vincentiis M, Paolucci S (2002) Dysphagia in multiple sclerosis-prevalence and prognostic factors. Acta Neurol Scand 105:40–43
338 Capello E, Mancardi GL (2004) Marburg type and Balo’s concentric sclerosis: rare and acute variants of multiple sclerosis. Neurol Sci 25:361–363 Cheng JS, Sanchez-Mejia RO, Limbo M, Ward MM, Barbaro NM (2005) Management of medically refractory trigeminal neuralgia in patients with multiple sclerosis. Neurosurg Focus 18:13 Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG (2000) Acute encephalomyelitis, multiphasic disseminated encephalomyelitis und multiple sclerosis in children. Brain 12: 2407–2422 Da Silva CJ, da Rocha AJ, Mendes MF, Maia AC Jr, Braga FT, Tilbery CP (2005) Trigeminal involvement in multiple sclerosis: magnetic resonance imaging findings with clinical correlation in a series of patients. Mult Scler 11:282–285 De Simone R, Marano E, Brescia Morra V, Ranieri A, Ripa P, Esposito M, Vacca G, Bonavita V (2005) A clinical comparison of trigeminal neuralgic pain in patients with and without underlying multiple sclerosis. Neurol Sci 26:150–151 Fabre K, Smet-Dieleman H, Zeyen T (2001) Improvement of acquired pendular nystagmus by gabapentin: case report. Bull Soc Belge Ophthalmol 282:43–46 Falini A, Kesavadas C, Pentesilli S, Rovaris M, Scotti G (2001) Differential diagnosis of posterior fossa multiple sclerosis lesions – neuroradiological aspects. Neurol Sci 22:79–83 Fazekas F, Offenbacher H, Fuchs S, Schmidt R, Niederkorn K, Horner S, Lechner H (1988) Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis. Neurology 38:1822–1825 Feys P, Maes F, Nuttin B, Helsen W, Malfait V, Nagels G, Lavrysen A, Liu X (2005) Relationship between multiple sclerosis intention tremor severity and lesion load in the brainstem. NeuroReport 16:1379–1382 Firat AK, Karakas HM, Yakinici C, Altinok T, Alkan A, Bicak U (2004) An unusual case of acute disseminated encephalomyelitis confined to brainstem. Magn Reson Imaging 22:1329–1332 Frohman EM, Frohman TC (2003) Horizontal monocular sacadic failure: an unusual clinically isolated syndrome progressing to multiple sclerosis. Mult Scler 9:55–58 Frohman EM, Zhang H, Kramer PD, Fleckenstein J, Hawker K, Racke MK, Frohman TC (2001) MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis. Neurology 57:762–768 Frohman EM, Dewey RB, Frohman TC (2004) An unusual variant of the dorsal midbrain syndrome in MS: clinical characteristics and pathophysiologic mechanisms. Mult Scler 10:322–325 Gaymard B, Lafitte C, Glot A, de Toffol B (1992) plus-minus lid syndrome. J Neurol Neurosurg Psychiatry 55:846-848 Gee JR, Chang J, Dublin AB, Vijayan N (2005) The association of brainstem lesions with migraine-like headache: an imaging study of multiple sclerosis. Headache 45:670–677 Jain S, Proudlock F, Constantinescu CS, Gottlob I (2002) Combined pharmacologic and surgical approach to acquired nystagmus due to multiple sclerosis. Am J Ophthalmol 134:780–782 Jonsson L, Thuomas KA, Stenquist M, Engstrom M, Stalberg E, Bergstrom K, Lyttkens L, Svedberg A (2001) Acute peripheral facial palsy simulating Bell’s palsy in a case of probable multiple sclerosis with a clinically correlated transient pontine lesion on magnetic resonance imaging. ORL J Otorhinolaryngol Relat Spec 53:362–365 Marcel-Viallet M, de Seze J, Defoort-Dhellemmes S, Wyremblewski P, Vermersch P (2005) Bilateral third cranial nerve palsy triggered by an acute relapse of multiple sclerosis. Rev Neurol 161:582–585 Marrosu F, Meleci A, Cocco E, Puligheddu M, Marrosu MG (2005) Vagal nerve stimulation effects on cerebellar tremor in multiple sclerosis. Neurology 65:490 Martinez-Moreno NE, Martinez-Alarez R, Rey Portoles G, GutierrezSarraga J, Burzaco-Santurtun J, Bravo G, Martinez-Moreno NE,
4 Diseases Martinez-Alarez R, Rey Portoles G, Gutierrez-Sarraga J, BurzacoSanturtun J, Bravo G (2006) Gamma knife radiosurgery treatment of trigeminal and atypical facial pain. Rev Neurol 42:195–201 Matsumoto S, Ohyagi Y, Inoue I, Oishi A, Goto H, Nakagawa T, Yamada T, Kira J (2001) Periodic alternating nystagmus in a patients with MS. Neurology 56:276–277 Menge T, Hemmer B, Nessler S, Wiendl H, Neuhaus O, Hartung HP, Kieseier BC, Stuve O (2005) Acute disseminated encephalomyelitis: an update. Arch Neurol 62:1673–1680 Menon GJ, Thaller VT (2002) Therapeutic external ophthalmoplegia with bilateral retrobulbar botulinum toxin – an effective treatment for acquired nystagmus with oscillopsia. Eye 16:804–806 Miller D, Barkhoff F, Montalban X, Thompson A, Filippi M (2005) Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis and prognosis. Lancet Neurol 4:281–288 Nandi D, Aziz TZ (2004) Deep brain stimulation in the management of neuropathic pain and multiple sclerosis tremor. Clin Neurophysiol 21:31–39 Ozunlu A, Mus N, Gulhan M (1998) Multiple sclerosis: a cause of sudden hearing loss. Audiology 37:52–58 Papathanasiou ES, Piperidou C, Pantzaris M, Iliopoulos I, Petsa M, Kyriakides T, Kleopa KA, Papacostas SS (2005) Vestibular symptoms and signs are correlated with abnormal neurogenic vestibular evoked potentials in patients with multiple sclerosis. Electromyogr Clin Neurophysiol 45:195–201 Polman CH, Reingold SC, Edan G et al (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald criteria. Ann Neurol 58:840–846 Sadovnik AD, Baird PA (1988) The familial nature of multiple sclerosis: agecorrected empiric recurrence risk of children and siblings of patients. Neurology 38:990–991 Sastre-Garriga J, Tintore M, Rovira A, Grive E, Pericot I, Comabella M, Thompson AJ, Montalban X (2003) Conversion to multiple sclerosis after a clinically isolated syndrome of the brainstem: cranial magnetic resonance imaging, cerebrospinal fluid and neurophysiological findings. Mult Scler 91:39–43 Sastre-Garriga J, Tintore M, Rovira A, Nos C, Rio J, Thompson AJ, Monalban X (2004) Specificity of Barkhof criteria in predicting conversion to multiple sclerosis when applied to clinically isolated brainstem syndromes. Arch Neurol 61:222–224 Schon F, Hodgson TL, Mort D, Kennard C (2001) Ocular flutter associated with a localized lesion in the paramedian pontine reticular formation. Ann Neurol 50:413–416 Takado Y, Igarashi S, Akaiwa Y, Terajima K, Tanaka K, Tsuji S (2002) A case of multiple sclerosis with pathological laughing caused by pontine base lesions. Rinsho Shinkeigaku 42:519–522 Tateishi K, Takeda K, Mannen T (2002) Acute disseminated encephalomyelitis confined to brainstem. J Neuroimaging 12:67–68 Thömke F, Hopf HC (2001) Abduction paresis with rostral pontine and/ or mesencephalopathic lesions: Pseudoabducens palsy and its relation to the so-called posterior internuclear ophthalmoplegia of Lutz. BMC Neurol 18:200–202 Tintore M, Rovira A, Brieva L, Grive E, Jardi R, Borras C, Montalban X (2001) Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MR imaging criteria to predict conversion to CDMS. Mult Scler 7:359–363 Tjoa CW, Benedict RH, Weinstock-Guttman B, Fabiano AJ, Bakshi R (2005) MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis. J Neurol Sci 234: 17–24 Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285 Urban PP, Zahn M, Schranz S, Glassl U, Dieterich M (2004) Abnormal patterns of swallowing in multiple sclerosis. J Neurol 251:25
Further Reading Weber H, Pfadenhauer K, Stohr M, Rosler A (2002) Central hyperacusis with phonophobia in multiple sclerosis. Mult Scler 8: 505–509 Wegner C (2005) Pathological differences in acute inflammatory demyelinating disease of the central nervous system. Int MS J 12:13–19 Weiss N, North RB, Ohara S, Lenz FA (2003) Attenuation of cerebellar tremor with implantation of an intrathecal baclofen pump: the role of gamma-aminobutyric acidergic pathways. Case report. Neurosurgery 99:768–771 Yousry TA, Grossman RI, Filippi M (2000) Assessment of posterior fossa damage in MS using MRI. J Neurol Sci 172:S50–S53 Zaffaroni M, Baldini SM, Ghezzi A (2001) Cranial nerve, brainstem and cerebellar syndromes in the differential diagnosis of multiple sclerosis. Neurol Sci 22:S74–S78
4.4 “Paraneoplastic Brainstem Syndromes” Al-Shekhlee A, Eccher MA, Chelimsky TC (2003) Acute paraneoplastic dysautonomia. Eur Neurol 49:64–65 Auf G, Chen L, Fornes P, Le Clanche C, Delattre JY, Carpentier AF (2002) CpG-oligodeoxynucleotide rejection of a neuroblastoma in A/J mice does not induce a paraneoplastic disease. Neurosci Lett 327:189–192 Aye MM, Kasai T, Tashiro Y, Xing HO, Shirahama H, Mitsuda M, Suetsugu T, Tanaka K, Osame M, Izumo S (2009) CD8 positive T-cell infiltration in the dentate nucleus of paraneoplastic cerebellar degeneration. J Neuroimmunol 208(1–2):136–140 Baloh RW, DeRossett SE, Cloughesy TF, Kuncl RW, Miller NR, Merrill J, Posner JB (1993) Novel brainstem syndrome associated with prostate carcinoma. Neurology 43(12):2591–2596 Bataller L, Graus F, Saiz A, Vilchez JJ, Spanish Opsoclonus-Myoclonus Study Group (2001) Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 124:437–443 Benyahia B, Liblau R, Merle-Beral H, Tuorani JM, Dalmau J, Delmattre JY (1999) Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol 45:162–167 Byrne T, Mason WP, Posner JB, Dalmau J (1997) Spontaneous neurological improvement in anti-Hu associated encephalomyelitis. J Neurol Neurosurg Psychiatry 62:276–278 Carpentier AF, Rosenfeld MR, Delattre JY, Whalen RG, Posner JB, Dalmau J (1998) DNA vaccination with HuD inhibits growth of a neuroblastoma in mice. Clin Cancer Res 4:2819–2824 Corato M, Marinou-Aktipi K, Nano R, Giometto B, Cereda C, Natoli G, Facoetti A, Ceroni M (2004) Paraneoplastic brainstem encephalitis in a patient with malignant fibrous histiocytoma and atypical antineuronal antibodies. J Neurol 251(11):1415–1417 Crino PB, Galetta SL, Sater RA, Raps EC, Witte A, Roby D, Rosenquist AC (1996) Clinicopathologic study of paraneoplastic brainstem encephalitis and ophthalmoparesis. J Neuroophthalmol 16(1): 44–48 Dalmau J, Gultekin SH, Voltz R, Hoard R, DesChamps T, Balmaceda C, Batchelor T, Gerstner E, Eichen J, Frennier J, Posner JB, Rosenfeld MR (1999) Ma1, a novel neuronal and testis specific protein, is recognized by the serum of patients with paraneoplastic neurologic disorders. Brain 122:27–39 Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR (2004) Clinical analysis of antiMa2-associated encephalitis. Brain 127:1831–1844 Darnell RB (1996) Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci USA 93:4529–4536 Darnell RB, DeAngelis LM (1993) Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 341:21–22
339 Ellenberger C Jr, Campa JF, Netzky MG (1968) Opsoclonus and parenchymatous degeneration of the cerebellum. The cerebellar origin of an abnormal ocular movement. Neurology 18(11):1041–1046 Graus F, Cordon-Cardo C, Posner JB (1985) Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 35:538–543 Graus F, Keime-Guibert F, Rene R, Benyahia B, Ribalta T, Ascaso C, Escaramis G, Delattre J (2001) Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 124: 1138–1148 Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt PS, Vedeler Ch, Verschuuren JJ, Vincent A, Voltz R (2004) Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75(8): 1135–1140 Hardjasudarma M, Husain F, Fowler M, Eisenberg RL (1992) Mirfakhraee M Central pontine myelinolysis as a manifestation of the paraneoplastic syndrome. South Med J 85(4):419–421 Kararizou E, Markou I, Zalonis I, Gkiatas K, Triantafyllou N, Kararizos G, Likomanos D, Zambelis T, Vassilopoulos D (2005) Paraneoplastic limbic encephalitis presenting as acute viral encephalitis. J Neuro oncol 75(2):229–232 Keime-Guibert F, Graus F, Broet P, Rene R, Honnorat J, Broet P, Delattre JY (1999) Clinical outcome of patients with anti-Hu-associated encephalomyelitis after treatment of the tumor. Neurology 53: 1719–1723 Keime-Guibert F, Graus F, Fleury A, Rene R, Molinuevo JL, Ascaso C, Delattre JY (2000) Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 68:479–482 Kraker J (2009) Treatment of anti-Ma2/Ta paraneoplastic syndrome. Curr Treat Options Neurol 11(1):46–51 Linke R, Schröder M, Helmberger T, Voltz R (2004) Antibody-positive paraneoplastic neurological syndromes: the value of CT and FDGPET imaging for tumor diagnosis. Neurology 63(2):282–286 Pellkofer H, Schubart AS, Hoftberger R, Schutze N, Pagany M, Schuller M, Lassmann H, Hohlfeld R, Voltz R, Linington C (2004) Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain 127:1822–1830 Peterson K, Rosenblum MK, Kotanides H, Posner JB (1992) Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibodypositive patients. Neurology 42(10):1931–1937 Pillay N, Gilbert JJ, Ebers GC, Brown JD (1984) Internuclear ophthalmoplegia and “optic neuritis”: paraneoplastic effects of bronchial carcinoma. Neurology 34(6):788–791 Posner JB (ed) (1995) Paraneoplastic syndromes. In: Neurologic complications of cancer. Contemporary Neurological Series. University Press, Oxford, pp 353–385 Pranzatelli MR, Tate ED, Wheeler A, Bass N, Gold AP, Griebel ML, Gumbinas M, Heydemann PT, Holt PJ, Jacob P, Kotagal S, Minarcik CJ, Schub HS (2002) Screening for autoantibodies in children with opsoclonus-myoclonus-ataxia. Pediatr Neurol 27(5):384–387 Rinne T, Bronstein AM, Rudge P, Gresty MA, Luxon LM (1998) Bilateral loss of vestibular function: clinical findings in 53 patients. J Neurol 245:314–321 Rosenblum MK (1993) Paraneoplasia and autoimmunologic injury of the nervous system: the anti-Hu syndrome. Brain Pathol 3:199–212 Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J (2001) Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 50:339–348 Saiz A, Bruna J, Stourac P, Vigliani MC, Giometto B, Grislod W, Honnorat J, Psimaras D, Voltz R, Graus F (2009) Anti-Hu-associated brainstem encephalitis. J Neurol Neurosurg Psychiatry 80(4): 404–407
340 Schafer KH, Klotz M, Mergner D, Mestres P, Schimrigk K, Blaes F (2000) IgGmediated cytotoxicity to myenteric plexus cultures in patients with paraneoplastic neurological syndromes. J Autoimmun 15:479–484 Sharshar T, Auriant I, Dorandeu A, Saghatchian M, Belec L, Benyahia B, Mabro M, Raphael JC, Gajdos P, Delattre JY, Gray F (2000) Association of herpes simplex virus encephalitis and paraneoplastic encephalitis – a clinico-pathological study. Ann Pathol 20: 249–252 Sillevis Smitt PA, Manley GT, Posner JB (1995) Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. Neurology 45:1873–1878 Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, Toyka KV (2005) Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 365:1406–1411 Sutton IJ, Fursdon Davis CJ, Esiri MM, Hughes S, Amyes ER, Vincent A (2001) Anti-Yo antibodies and cerebellar degeneration in a man with adenocarcinoma of the esophagus. Ann Neurol 49:253–257 Sutton IJ, Barnett MH, Watson JDG, Ell JJ, Dalmau J (2002) Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J Neurol 249(11):1597–1598 Tanaka M, Tanaka K, Onodera O, Tsuji S (1995) Trial to establish an animal model of paraneoplastic cerebellar degeneration with antiYo antibody. 1. Mouse strains bearing different MHC molecules produce antibodies on immunization with recombinant Yo protein, but do not cause Purkinje cell loss. Clin Neurol Neurosurg 97:95–100 Verschuuren JJ, Dalmau J, Hoard R, Posner JB (1997) Paraneoplastic anti-Hu serum: studies on human tumor cell lines. J Neuroimmunol 79:202–210 Vigliani MC, Novero D, Cerrato P, Daniele D, Crasto S, Berardino M, Mutani R (2009) Double step paraneoplastic brainstem encephalitis: a clinicopathological study. J Neurol Neurosurg Psychiatry 80(6):693–695 Voltz R, Dalmau J, Posner JB, Rosenfeld MR (1998) T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 51:1146–1150 Voltz R, Gultekin SH, Rosenfeld MR, Gerstner E, Eichen J, Posner JB, Dalmau J (1999) A serologic marker of paraneoplastic limbic and brainstem encephalitis in patients with testicular cancer. N Engl J Med 340:1788–1795 Voltz R, Weller M, Rauer S, Blaes F (2008) Paraneoplastische syndrome. In: Diener HC (Hrsg) Leitlinien für diagnostik und therapie in der neurologie. Thieme, Stuttgart Weizmannn DA, Leong WL (2004) Anti-Ri antibody opsoclonusmyoclonus syndrome and breast cancer: a case report and a review of the literature. J Surg Oncol 87:143–145 Zee DS, Robinson DA (1979) A hypothetical explanation of saccadic oscillations. Ann Neurol 5:405–414
4.5 “Brainstem Tumors” Albright AL, Packer RJ, Zimmerman R, Rorke LB, Boyett J, Hammond GD (1993) Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children’s Cancer Group. Neurosurgery 33(6):1026–1029 Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachge sellschaften (AWMF) (2007) Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und der Gesellschaft für Pädiatrische Onkologie und Hämatologie. http://awmf.org. Ependymome. Version 10/2007
4 Diseases Balmaceda C, Critchell D, Mao X, Cheung K, Pannullo S, DeLaPaz RL et al (2006) Multisection 1 H magnetic resonance spectroscopic imaging assessment of glioma response to chemotherapy. J Neurooncol 76(2):185–191 Barker FG, Chang SM, Valk PE, Pounds TR, Prados MD (1997) 18-Fluorodeoxyglucose uptake and survival of patients with suspected recurrent malignant glioma. Cancer 79(1):115–126 Ben Amor S, Siddiqui K, Baessa S (2004) Primary midbrain germinoma. Br J Neurosurg 18(3):310–313 Bilaniuk LT, Molloy PT, Zimmerman RA, Phillips PC, Vaughan SN, Liu GT et al (1997) Neurofibromatosis type 1: brain stem tumours. Neuroradiology 39(9):642–653 Borovich B, Doron Y (1986) Recurrence of intracranial meningiomas: the role played by regional multicentricity. J Neurosurg 64(1): 58–63 Broniscer A, Gajjar A, Bhargava R, Langston JW, Heideman R, Jones D, Kun LE, Taylor J (1997) Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma. Neurosurgery 40(2):331–337 Campbell PG, Jawahar A, Fowler MR, Delaune A, Nanda A (2005) Primary central nervous system lymphoma of the brain stem responding favorably to radiosurgery: a case report and literature review. Surg Neurol 64(5):400–405 Central Brain Tumor Registry of the United States (CBTRUS) (2005) Statistical report: Primary Brain Tumors in the United States, 1998–2002. http://www.cbtrus.org. Accessed 27 Sept 2006 Chamberlain MC, Glantz MJ, Fadul CE (2007) Recurrent meningioma: salvage therapy with long-acting somatostatin analogue. Neurology 69(10):969–973 Chang DB, Yang PC, Luh KT, Kuo SH, Hong RL, Lee LN (1992) Late survival of non-small cell lung cancer patients with brain metastases. Influence of treatment. Chest 101(5):1293–1297 Charabi S, Thomsen J, Mantoni M, Charabi B, Jorgensen B, Børgesen SE, Gyldensted C, Tos M (1995) Acoustic neuroma (vestibular schwannoma): growth and surgical and nonsurgical consequences of the wait-andsee policy. Otolaryngol Head Neck Surg 113(1):5–14 Collins VP, Nordenskjold M, Dumanski JP (1990) The molecular genetics of meningiomas. Brain Pathol 1:19–24 Colombo F, Casentini L, Cavedon C, Scalchi P, Cora S, Francescon P (Feb 2009) Cyberknife radiosurgery for benign meningiomas: shortterm results in 199 patients. Neurosurgery 64(2 Suppl):A7–A13 DeAngelis LM (2001) Brain tumors. N Engl J Med 344(2):114–123 Delattre JY, Krol G, Thaler HT, Posner JB (1988) Distribution of brain metastasis. Arch Neurol 45(7):741–744 Donaldson SS, Laningham F, Fisher PG (2006) Advances toward an understanding of brainstem gliomas. J Clin Oncol 24(8): 1266–1272 Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR (1993) Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328(24):1725–1731 Edwards MS, Wara WM, Ciricillo SF, Barkovich AJ (1994) Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases. J Neurosurg 80(1):20–25 Fisher PG, Breiter SN, Carson BS, Wharam MD, Williams JA, Weingart JD, Foer DR, Goldthwaite PT, Tihan T, Burger PC (2000) A clinicopatho logic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer 89(7):1569–1576 Forsting M, Albert FK, Kunze S, Adams HP, Zenner D, Sartor K (1993) Exstirpation of glioblastomas: MR and CT follow-up of residual tumor and regrowth patterns. AJNR Am J Neuroradiol 14(1):77–87
Further Reading Fouladi M, Gururangan S, Moghrabi A, Phillips P, Gronewold L, Wallace D, Sanford RA, Gajjar A, Kun LE, Heideman R (15 July 2009) Carboplatin-based primary chemotherapy for infants and young children with CNS tumors. Cancer 115:3243–3253 Freeman CR, Kepner J, Kun LE, Sanford RA, Kadota R, Mandell L, Friedman H (2000) A detrimental effect of a combined chemotherapy radiotherapy approach in children with diffuse intrinsic brain stem gliomas? Int J Radiat Oncol Biol Phys 47(3):561–564 Gilbertson RJ, Hill DA, Hernan R, Kocak M, Geyer R, Olson J et al (2003) ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res 9:3620–3624 Gizzi MS, Lidov M, Rosenbaum D (1993) Neurosarcoidosis presenting as a tumour of the basal ganglia and brainstem: sequential MRI. Neurol Res 15(2):93–96 Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, Walters BC, Recht LD (1998) Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer 82(4):733–739 Gnekow AK, Kaatsch P, Kortmann R, Wiestler OD (2000) HIT-LGG: effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood – an interim report. Klin Pädiatr 212(4): 177–184 Gormley WB, Sekhar LN, Wright DC, Kamerer D, Schessel D (1997) Acoustic neuromas: results of current surgical management. Neurosurgery 41(1):50–58 Guillamo JS, Monjour A, Taillandier L, Devaux B, Varlet P, Haie-Meder C et al (2001) Brainstem gliomas in adults: prognostic factors and classification. Brain 124:2528–2539 Hargrave D, Bartels U, Bouffet E (March 2006) Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7(3):241–248 Hirose Y, Aldape K, Bollen A, James CD, Brat D, Lamborn K, Berger M, Feuerstein BG (2001) Chromosomal abnormalities subdivide ependymal tumors into clinically relevant groups. Am J Pathol 158(3):1137–1143 Hwang TL, Close TP, Grego JM, Brannon WL, Gonzales F (1996) Predilection of brain metastasis in gray and white matter junction and vascular border zones. Cancer 77(8):1551–1555 Jacobs AH, Dittmar C, Winkeler A, Garlip G, Heiss WD (2002) Molecular imaging of gliomas. Mol Imaging 1(4):309–335 Jacobs AH, Kracht LW, Gossmann A, Rüger MA, Thomas AV, Thiel A, Herholz K (Apr 2005) Imaging in neurooncology. NeuroRx 2(2):333–347 Jagannathan J, Lonser RR, Smith R, DeVroom HL, Oldfield EH (2008) Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 108:210–222 Jallo GI, Biser-Rohrbaugh A, Freed D (2004) Brainstem gliomas. Childs Nerv Syst 20(3):143–153 Jurcic V, Ferluga D, Jeruc J, Pogacnik T, Popovic M (2004) Hypertensive encephalopathy mimicking brainstem tumour in psychiatric patient. Folia Neuropathol 42(1):37–41 Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2(9):673–682 Kased N, Huang K, Nakamura JL, Sahgal A, Larson DA, McDermott MW, Sneed PK (2008) Gamma knife radiosurgery for brainstem metastases: the UCSF experience. J Neurooncol 86(2):195–205 Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61(3):215–225 Kortmann RD, Timmermann B, Kuhl J, Willich N, Flentje M, Meisner C, Bamberg M (1999) HIT ‘91 (prospective, co-operative study for the treatment of malignant brain tumors in childhood): accuracy and acute toxicity of the irradiation of the craniospinal axis. Results of the quality assurance program. Strahlenther Onkol 175(4): 162–169
341 Kortmann RD, Timmermann B, Taylor RE, Scarzello G, Plasswilm L, Paulsen F, Jeremic B, Gnekow AK, Dieckmann K, Kay S, Bamberg M (2003a) Current and future strategies in radiotherapy of childhood lowgrade glioma of the brain. Part I: Treatment modalities of radiation therapy. Strahlenther Onkol 179(8):509–520 Kortmann RD, Timmermann B, Taylor RE, Scarzello G, Plasswilm L, Paulsen F, Jeremic B, Gnekow AK, Dieckmann K, Kay S, Bamberg M (2003b) Current and future strategies in radiotherapy of childhood lowgrade glioma of the brain. Part II: Treatment-related late toxicity. Strahlenther Onkol 179(9):585–597 Lagares A, Gomez PA, Lobato RD, Ricoy JR, Ramos A, de la Lama A (2001) Ganglioglioma of the brainstem: report of three cases and review of the literature. Surg Neurol 56(5):315–322 Laigle-Donadey F, Doz F, Delattre JY (Nov 2008) Brainstem gliomas in children and adults. Curr Opin Oncol 20(6):662–7 Lanfermann H, Herminghaus S, Pilatus U, Hattingen E, Zanella FE (2004) Bedeutung der 1 H-MR-Spektroskopie bei der Differenzialdiagnose und Graduierung intrakranieller Tumoren. Deutsches Ärzteblatt 101(10):A 649–A 655 Leach PA, Estlin EJ, Coope DJ, Thorne JA, Kamaly-Asl ID (Oct 2008) Diffuse brainstem gliomas in children: should we or shouldn’t we biopsy? Br J Neurosurg 22(5):619–24 Leitlinien der deutschen Gesellschaft für Neurologie (DGN) (2008) Bildgebung bei Hirntumoren. http://www.dgn.org. Accessed 9 Aug 2009 Lobato-Polo J, Kondziolka D, Zorro O, Kano H, Flickinger JC, Lunsford LD (2009) Gamma knife radiosurgery in younger patients with vestibular schwannomas. Neurosurgery 65:294–300 Louis DN, Rubio MP, Correa KM, Gusella JF, von Deimling A (1993) Molecular genetics of pediatric brain stem gliomas. Application of PCR techniques to small and archival brain tumor specimens. J Neuropathol Exp Neurol 52(5):507–515 Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) (2007) World Health Organization classification of tumors of the central nervous system, 4th edn. IARC, Lyon, pp 215–217 Mandell LR, Kadota R, Freeman C, Douglass EC, Fontanesi J, Cohen ME et al (1999) There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 43(5):959–964 Massager N, David P, Goldman S, Pirotte B, Wikler D, Salmon I, Nagy N, Brotchi J, Levivier M (2000) Combined magnetic resonance imagingand positron emission tomography-guided stereotactic biopsy in brainstem mass lesions: diagnostic yield in a series of 30 patients. J Neurosurg 93(6):951–957 Miller G, Towfighi J, Page RB (1990) Spinal cord ganglioglioma presenting as hydrocephalus. J Neurooncol 9:147–152 Molloy PT, Bilaniuk LT, Vaughan SN, Needle MN, Liu GT, Zackai EH, Phillips PC (1995) Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology 45(10): 1897–1902 Mursch K, Halatsch ME, Markakis E, Behnke-Mursch J (2005) Intrinsic brainstem tumours in adults: results of microneurosurgical treatment of 16 consecutive patients. Br J Neurosurg 19(2):128–136 Neuro-Onkologische Arbeitsgemeinschaft der Deutschen Krebsgesell schaft (NOA) (2005) Leitlinien zur diagnostischen Bildgebung bei Hirntumoren. Entwurfsversion vom 08.01.2005. http://www. neuroonkologie.de. Accessed 27 Sept 2006 Norden AD, Wen PY, Kesari S (2005) Brain metastases. Curr Opin Neurol 18(6):654–61 Packer RJ, Boyett JM, Zimmerman RA, Albright AL, Kaplan AM, Rorke LB, Selch MT, Cherlow JM, Finlay JL, Wara WM (1994) Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer 74(6):1827–1834
342 Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD et al (1999) Treatment of children with medulloblastomas with reduceddose craniospinal radiation therapy and adjuvant chemotherapy: A Children’s Cancer Group Study. J Clin Oncol 17(7):2127–2136 Phillips NS, Sanford RA, Helton KJ, Boop FA, Zou P, Tekautz T, Gajjar A, Ogg RJ (2005) Diffusion tensor imaging of intraaxial tumors at the cervicomedullary and pontomedullary junctions. Report of two cases. J Neurosurg 103(Suppl):557–562 Pierre-Kahn A, Hirsch JF, Vinchon M, Payan C, Sainte-Rose C, Renier D, Lelouch-Tubiana A, Fermanian J (1993) Surgical management of brainstem tumors in children: results and statistical analysis of 75 cases. J Neurosurg 79:845–852 Pollack IF, Gerszten PC, Martinez AJ, Lo KH, Shultz B, Albright AL, Janosky J, Deutsch M (1995) Intracranial ependymomas of childhood: long-term outcome and prognostic factors. Neurosurgery 37(4):655–666 Pollack IF, Shultz B, Mulvihill JJ (1996) The management of brainstem gliomas in patients with neurofibromatosis 1. Neurology 46(6): 1652–1660 Pollock BE, Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Kelsey SF, Jannetta PJ (1995) Outcome analysis of acoustic neuroma management: a comparison of microsurgery and stereotactic radiosurgery. Neurosurgery 36(1):215–224 Prasad D, Steiner M, Steiner G (2000) Gamma surgery for vestibular schwannoma. J Neurosurg 92(5):745–759 Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352(10):978–986 Samadani U, Judy KD (2003) Stereotactic brainstem biopsy is indicated for the diagnosis of a vast array of brainstem pathology. Stereotact Funct Neurosurg 81:5–9 Samii M, Matthies C (1997) Management of 1000 vestibular schwannomas (acoustic neuromas): the facial nerve–preservation and restitution of function. Neurosurgery 40(4):684–694 Schlegel U, Westphal M, Weller M (2003) Neuroonkologie. 2., erw. Aufl. Thieme, Stuttgart/New York Schrell UM, Rittig MG, Anders M, Koch UH, Marschalek R, Kiesewetter F, Fahlbusch R (1997) Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea. J Neurosurg 86(5):840–844 Schulz-Ertner D, Debus J, Lohr F, Frank C, Hoss A, Wannenmacher M (2000) Fractionated stereotactic conformal radiation therapy of brain stem gliomas: outcome and prognostic factors. Radiother Oncol 57(2):215–223 Sekhar LN, Jannetta PJ, Burkhart LE, Janosky JE (1990) Meningiomas involving the clivus: a six-year experience with 41 patients. Neurosurgery 27(5):764–781 Silver JM, Rawlings CE III, Rossitch E Jr, Zeidman SM, Friedman AH (1991) Ganglioglioma: a clinical study with long-term follow-up. Surg Neurol 35(4):261–266 Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W (2008) A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70(2): 510–514 Stupp R, Mason WP, Van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996 Timmermann B, Kortmann RD, Kuhl J, Meisner C, Slavc I, Pietsch T, Bamber M (2000) Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the
4 Diseases German prospective trials HIT 88/89 and HIT 91. Int J Radiat Oncol Biol Phys 46(2):287–295 van der Sande JJ, van Tinteren H, Brandsma D, Jobsis GJ, Boogerd W (2009) Brain metastases in patients with pelvic or abdominal malignancy do not prevail in the posterior fossa: a retrospective study. J Neurol 256(9):1485–1487 Veelen-Vincent ML, Pierre-Kahn A, Kalifa C, Sainte-Rose C, Zerah M, Thorne J, Renier D (2002) Ependymoma in childhood: prognostic factors, extent of surgery, and adjuvant therapy. J Neurosurg 97(4): 827–835 Vos MJ, Uitdehaag BM, Barkhof F, Heimans JJ, Baayen HC, Boogerd W, Castelijns JA, Elkhuizen PH, Postma TJ (2003) Interobserver variability in the radiological assessment of response to chemotherapy in glioma. Neurology 60(5):826–830 Wanebo JE, Lonser RR, Glenn GM, Oldfield EH (2003) The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg 98(1): 82–94 Wang EM, Pan L, Wang BJ, Zhang N, Zhou LF, Dong YF, Dai JZ, Cai PW, Chen H (Jan 2005) The long-term results of gamma knife radiosurgery for hemangioblastomas of the brain. J Neurosurg 102(Suppl):225–229 Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, wong ET, Chamberlain MC, Strupp R, Lamborn KR, Vogelbaum MA, van den Bent Mj, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28: 1963–1972 Wolff JE, Sajedi M, Brant R, Coppes MJ, Egeler RM (2002) Choroid plexus tumours. Br J Cancer 87(10):1086–1091 Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neurol Oncol 4(4):278–299 Zang KD (2001) Meningioma: a cytogenetic model of a complex benign human tumor, including data on 394 karyotyped cases. Cytogenet Cell Genet 93(3–4):207–220 Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 17(3):832–845
4.6 “Traumatic Brainstem Lesions” Adams JH, Graham DJ, Murray LS, Scott G (1982) Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann Neurol 12:557–563 Adams JH, Mitchell D, Graham D, Doyle D (1977) Diffuse brain damage of immediate impact type. Brain 100:489–502 Bouillon B, Fach H, Bucheister B, Raum M (1998) Inzidenz des Schädel Hirn-Traumas – Ergebnisse einer epidemiologischen Analyse über 7 Jahre. Zentralbl Neurochir 59:4 Budzilovic GN (1976) On pathogenesis of primary lesions in blunt head trauma with special reference to the brain stem injuries. In: McLaurin RL (ed) Head injuries: second Chicago symposium on neurol trauma. Grunde Stratton, Inc., New York, pp 39–43 Crompton MR (1971) Brain stem lesions due to closed head injury. Lancet 1:669–673 Duret H (1878) Etudes expérimentales et cliniques sur les traumatismes cerebraux. Delahaye, Paris
Further Reading Firsching R, Woischneck D, Dietrich M, Klein S, Rückert A, Wittig H, Döhring W (1998) Early magnetic resonance imaging of brainstem lesions after severe head injury. J Neurosurg 5:707–712 Firsching R, Woischneck D, Reißberg S, Döhring W, Peters B (2003) Prognostische Bedeutung der MRT bei Bewußtlosigkeit nach Schädel-Hirn-Verletzung. Deut Ärztebl 100:1868–1874 Firsching R, Woischneck D (2001) The present status of neurotrauma in Germany. World J Surg 25:1221–1223 Firsching R (1987) Multimodal evozierte Potentiale neurochirurgischer Patienten in Koma und Hirntod. Habilitationsschrift, Universität zu Köln, Germany Frowein RA (1976) Classification of coma. Acta Neur 24:5–10 Frowein RA, Stammler U, Firsching R, Friedmann G, Thun F (1991) Early dynamic evolution of cerebral contusions and lacerations. Clinical and radiological findings. In: Vigouroux RP, Frowein RA (eds) Cerebral contusions, lacerations and hematomas. Springer, Wien/New York, pp 201–228 Gennarelli T (1982) Cerebral concussion and diffuse brain injuries. In: Cooper P (ed) Head injury. Williams and Wilkens, Baltimore/ London, pp 83–97 Hashimoto T, Nakamura N, Richard KE, Frowein RA (1993) Primary brain stem lesions caused by closed head injury. Neurosurg Rev 16:291–298 Kampfl A, Schmutzhard E, Franz G, Pfauser B, Haring HP, Ulmer H, Felber SD, Golaszewski S, Aichner F (1998) Prediction of recovery from post-traumatic vegetative state with cerebral magnetic- resonance imaging. Lancet 361:1763–1767 Laborit H, Hugenard P (1954) Pratique de l’hibernothérapie en chirurgie et en médecine. Masson und Co, Paris Mitchell DE, Adams H (1973) Primary focal impact damage to the brain stem in blunt head injuries. Does it exist? Lancet 1:215–218 Oppenheimer DR (1968) Microscopic lesions in the brain following head injury. J Neurol Neurosurg Psychiatry 31:299–306 Tönnis W, Loew F (1953) Einteilung der gedeckten Hirnschädigungen. Ärztl Prax 36:13–14 Tönnis W, Loew F, Bormann H (1949) Die Bedeutung der orthostatischen Kreislaufbelastungsprobe (Schellong) für die Erkennung und Behandlung gedeckter Hirnverletzungen. Klin Wochenschr 27:390–394
4.7 “Degenerative Brainstem Diseases” Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P (2003) Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 60(3):387–392 Atchison PR, Thompson PD, Frackowiak RS, Marsden CD (1993) The syndrome of gait ignition failure: a report of six cases. Mov Disord 8:285–292 Babinski J, Jarkowsk B, Plichet V (1921) Kinesie paradoxale. Mutisme parkinsonien. Rev Neurol 37:1266–1270 Baezner H, Daffertshofer M, Hennerici MG (2003) Subkortikale vaskuläre Enzephalopathie. Akt Neurol 30:266–280 Ballard C, O’Brien J, Swann A, Neill D, Lantos P, Holmes C, Burn D, Ince P, Perry R, McKeith I (2000) One year follow-up of parkinsonism in dementia with Lewy bodies. Dement Geriatr Cogn Disord 11:219–222 Barclay CL, Lang AE (1997) Dystonia in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 62:352–356 Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, Evans DA (1996) Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 334:71–76 Bower JH, Maraganore DM, McDonnell SK, Rocca WA (1997) Incidence of progressive supranuclear palsy and multiple system
343 atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 49:1284–1288 Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134 Braak H, Del Tredici K (2008) Invited article: nervous system pathology in sporadic Parkinson disease. Neurology 70:1916–1925 Ceballos-Baumann AO, Boecker H (2000) Tremor – new therapy options. Internist (Berl) 41:1353–1362 Ceballos-Bauman A, Conrad B (2005) Bewegungsstörungen. Thieme, Stuttgart/New York Ceballos-Baumann A, Gündel H (2006) Bewegungsstörungen. In: Henningsen P, Gündel H, Ceballos-Baumann A (eds) Neuro psychosomatik. Schattauer, Stuttgart Colosimo C, Osaki Y, Vanacore N, Lees AJ (2003) Lack of association between progressive supranuclear palsy and arterial hypertension: a clinicopathological study. Mov Disord 18:694–697 Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopaminealpha-synuclein adduct. Science 294:1346–1349 Critchley M (1929) Arteriosclerotic parkinsonism. Brain 52:23–83 Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822 De Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the Elderly Research Group. Neurology 54:S21–S23 Defazio G, De Mari M, De Salvia R, Lamberti P, Giorelli M, Livrea P (1999) “Apraxia of eyelid opening” induced by levodopa therapy and apomorphine in atypical parkinsonism (possible progressive supranuclear palsy): a case report. Clin Neuropharmacol 22: 292–294 Deuschl G, Elble RJ (2000) The pathophysiology of essential tremor. Neurology 54:S14–S20 Deuschl G, Toro C, Valls-Sole J, Zeffiro T, Zee DS, Hallett M (1994) Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain 117:775–788 Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, Daniels C, Deutschlander A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J (2006) A randomized trial of deepbrain stimulation for Parkinson’s disease. N Engl J Med 355:896–908 Dickson DW, Braak H, Duda JE, Duyckaerts C, Grasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8:1150–1157 Dubois B, Slachevsky A, Pillon B, Beato R, Villalponda JM, Litvan I (2005) “Applause” sign helps to discriminate PSP from FTD and PD. Neurology 64(12):2132–2133 Engel PA (1996) Treatment of progressive supranuclear palsy with amitriptyline: therapeutic and toxic effects. J Am Geriatr Soc 44:1072–1074 Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5):2283–2301 Ferraye MU, Debû B, Fraix V, Goetz L, Ardouin C, Yelnik J, HenryLagrange C, Seigneuret E, Piallat B, Krack P, Le Bas JF, Benabid AL, Chabardès S, Pollak P (2010) Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson’s disease. Brain 133:205–214 Fitzgerald PM, Jankovic J (1989) Lower body parkinsonism. Evidence for vascular etiology. Mov Disord 4:249–260
344 Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, Marks WJ Jr, Rothlind J, Sagher O, Moy C, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein JM, Stoner G, Starr PA, Simpson R, Baltuch G, DeSalles A, Huang GD, Reda DJ; (2010) CSP 468 Study Group. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med 362:2077–2091 Ghika J, Bogousslavsky J (1997) Presymptomatic hypertension is a major feature in the diagnosis of progressive supranuclear palsy [see comments]. Arch Neurol 54:1104–1108 Giladi N, Simon ES, Korczyn AD, Groozman GB, Orlov Y, Shabtai H, Drory VE (2000) Anal sphincter EMG does not distinguish between multiple system atrophy and Parkinson’s disease. Muscle Nerve 23:731–734 Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK (1999) Consensus statement on the diagnosis of multiple system atrophy [see comments]. J Neurol Sci 163:94–98 Graham JG, Oppenheimer DR (1969) Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 32:28–34 Grimes DA, Lang AE, Bergeron CB (1999) Dementia as the most common presentation of cortical-basal ganglionic degeneration. Neurology 53:1969–1974 Hansen LA, Samuel W (1997) Criteria for Alzheimer’s disease and the nosology of dementia with Lewy bodies. Neurology 48:126–132 Harding AJ, Stimson E, Henderson JM, Halliday GM (2002) Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain 125:2431–2445 Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, Gitschier J (2003a) Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 348:33–40 Hely MA, Reid NG, Adena MA, Halliday GM, Morris JG (2008) The Sydney multicenter study of Parkinson’s disease: the ineritability of dementia at 20 years. Mov Disord 23:837–844 Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM (2004) Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56:399–406 Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992b) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184 Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ (1992a) What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study (published erratum appears in (1992) Neurology 42:1436). Neurology 42:1142–1146 Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ (2002) The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125:861–870 Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ (2001) Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 71:371–374 Iranzo A, Santamaria J, Tolosa E, Vilaseca I, Valldeoriola F, Marti MJ, Munoz E (2004) Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy. Neurology 63: 930–932 Iranzo A, Santamaria J, Rye DB, Valldeoriola F, Marti MJ, Munoz E, Vilaseca I, Tolosa E (2005) Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology 65:247–252 Kalra S, Grosset DG, Benamer HT (2010) Differentiating vascular parkinsonism from idiopathic Parkinson’s disease: a systematic review. Mov Disord 25:149–156
4 Diseases Kertesz A (2003) Pick’s complex and FTDP-17. Mov Disord 18:S57–S62 Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608 Kompoliti K, Goetz CG, Litvan I, Jellinger K, Verny M (1998) Pharmacological therapy in progressive supranuclear palsy. Arch Neurol 55:1099–1102 Kosaka K, Oyanagi S, Matsushita M, Hori A (1976) Presenile dementia with Alzheimer-, Pick- and Lewy-body changes. Acta Neuropathol (Berl) 36:221–233 Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, Pollak P (2003) Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 349:1925–1934 Krauss JK, Regel JP, Vach W, Droste DW, Borremans JJ, Mergner T (1996) Vascular risk factors and arteriosclerotic disease in idiopathic normalpressure hydrocephalus of the elderly. Stroke 27: 24–29 Kuopio AM, Marttila RJ, Helenius H, Toivonen M, Rinne UK (2000) The quality of life in Parkinson’s disease. Mov Disord 15:216–223 Litvan I, Agid Y, Jankovic J, Goetz C, Brandel JP, Lai EC, Wenning G, D’Olhaberriague L, Verny M, Chaudhuri KR, McKee A, Jellinger K, Bartko JJ, Mangone CA, Pearce RK (1996) Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology 46:922–930 Litvan I, Phipps M, Pharr VL, Hallett M, Grafman J, Salazar A (2001) Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy. Neurology 57:467–473 Lopez OL, Wisnieski SR, Becker JT, Boller F, DeKosky ST (1997) Extrapyramidal signs in patients with probable Alzheimer disease. Arch Neurol 54:969–975 Louis ED, Luchsinger JA (2006) History of vascular disease and mild parkinsonian signs in community-dwelling elderly individuals. Arch Neurol 63:717–722 Maltete D, Guyant-Marechal L, Mihout B, Hannequin D (2006) Movement disorders and Creutzfeldt-Jakob disease: a review. Parkinsonism Relat Disord 12:65–71 Mark MH, Sage JI, Walters AS, Duvoisin RC, Miller DC (1995) Binswanger’s disease presenting as levodopa-responsive parkinsonism: clinicopathologic study of three cases. Mov Disord 10: 450–454 Matthews BR, Jones LK, Saad DA, Aksamit AJ, Josephs KA (2005) Cerebellar ataxia and central nervous system whipple disease. Arch Neurol 62:618–620 McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872 Merello M, Sabe L, Teson A, Migliorelli R, Petracchi M, Leiguarda R, Starkstein S (1994) Extrapyramidalism in Alzheimer’s disease: prevalence, psychiatric, and neuropsychological correlates. J Neurol Neurosurg Psychiatry 57:1503–1509 Moro E, Hamani C, Poon YY, Al-Khairallah T, Dostrovsky JO, Hutchison WD, Lozano AM (2010) Unilateral pedunculopontine stimulation improves falls in Parkinson’s disease. Brain 133:215–224
Further Reading Munneke M, Nijkrake MJ, Keus SH, Kwakkel G, Berendse HW, Roos RA, Borm GF, Adang EM, Overeem S, Bloem BR (2010) ParkinsonNet Trial Study Group. Efficacy of community-based physiotherapy networks for patients with Parkinson’s disease: a cluster-randomised trial. Lancet Neurol. 9:46–54 Oertel WH, Möller JC (2005) Multisystematrophie. In: CeballosBauman A, Conrad B (eds) Bewegungsstörungen. Thieme, Stuttgart/New York, pp 86–93 Parkinson-Study-Group (1998) Mortality in DATATOP: a multicenter trial in early Parkinson’s disease. Ann Neurol 43:318–325 Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubinstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LJ, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276: 2045–2047 Quinn N (1994) Multiple system atrophy. In: Marsden CD, Fahn S (eds) Movement disorders, vol 3. Butterworths, London, pp 262–281 Quinn NP (2005) How to diagnose multiple system atrophy. Mov Disord 20:S5–S10 Ramig LO, Sapir S, Countryman S, Pawlas AA, O’Brien C, Hoehn M, Thompson LL (2001) Intensive voice treatment (LSVT) for patients with Parkinson’s disease: a 2 year follow up. J Neurol Neurosurg Psychiatry 71:493–498 Rebeiz J, Kolodny EH, Richardson EP (1968) Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18:20–33 Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF (2008) A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 23:183–189 Schrag A, Ben-Shlomo Y, Quinn NP (1999) Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 354:1771–1775 Schrag A, Jahanshahi M, Quinn N (2000) What contributes to quality of life in patients with Parkinson’s disease? J Neurol Neurosurg Psychiatry 69:308–312 Sibon I, Fenelon G, Quinn NP, Tison F (2004) Vascular parkinsonism. J Neurol 251:513–524 Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95:6469–6473 Steele JC, Richardson JC, Olszewski J (1964) Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 10: 333–358 Stevens T, Livingston G, Kitchen G, Manela M, Walker Z, Katona C (2002) Islington study of dementia subtypes in the community. Br J Psychiatry 180:270–276 Suchowersky O, Furtado S, Rohs G (1995) Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson’s disease. Mov Disord 10:337–340 Vetrugno R, Liguori R, Cortelli P, Plazzi G, Vicini C, Campanini A, D’Angelo R, Provini F, Montagna P (2007) Sleep-related stridor due to dystonic vocal cord motion and neurogenic tachypnea/ tachycardia in multiple system atrophy. Mov Disord 22(5): 673–678 Walshe JM, Yealland M (1992) Wilson’s disease: the problem of delayed diagnosis. J Neurol Neurosurg Psychiatry 55:692–696 Weiner WJ, Minagar A, Shulman LM (1999) Pramipexole in progressive supranuclear palsy. Neurology 52:873–874 Wenning GK, Colosimo C, Geser F, Poewe W (2004) Multiple system atrophy. Lancet Neurol 3:93–103
345 Williams DR, Lees AJ (2005) Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol 4:605–610 Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, Holton JL, Revesz T, Lees AJ (2005) Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain 128(Pt 6):1247–1258 Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, Scott R, Ives N, Rick C, Daniels J, Patel S, Wheatley K (2010) PD SURG Collaborative Group. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol 9:581–591 Winikates J, Jankovic J (1999) Clinical correlates of vascular parkinsonism. Arch Neurol 56:98–102 Zijlmans JC, Katzenschlager R, Daniel SE, Lees AJ (2004) The L-dopa response in vascular parkinsonism. J Neurol Neurosurg Psychiatry 75:545–547
4.8 “Disturbances in Brainstem Development and Anlage” Alden TD, Ojemann JG, Park TS (2001) Surgical treatment of Chiari I malformation: indications and approaches. Neurosurg Focus 11:E2 Arai H, Sato K (2001) Dandy-Walker syndrome. In: McLone DG (ed) Pediatric neurosurgery. Surgery of the developing nervous system, 4th edn. WB Saunders, Philadelphia, PA, pp 483–488 Barkovich AJ (ed) (2000) Congenital malformations of the brain and skull. In: Pediatric neuroimaging, 3 rd edn. Lippincott Williams & Wilkins, Philadelphia, PA, pp 254–382 Cinalli G, Spennato P, Cianculli E, D’Armiento M (2004a) Hydrocephalus and aqueductal stenosis. In: Cinalli G, Maixner WJ, Sainte-Rose C (eds) Pediatric hydrocephalus. Springer, Mailand, pp 279–293 Cinalli G, Spennato P, Del Basso De Caro ML, Buonocore MC (2004b) Hydrocephalus and the Dandy-Walker malformation. In: Cinalli G, Maixner WJ, Sainte-Rose C (eds) Pediatric hydrocephalus. Springer, Mailand, pp 259–277 Cohen AR, Robinson S (2001) Early management of myelomeningocele. In: McLone DG (ed) Pediatric neurosurgery. Surgery of the developing nervous system, 4th edn. WB Saunders, Philadelphia, PA, pp 241–259 Costa C, Hauw JJ (1995) Pathology of the cerebellum, brain stem, and spinal cord. In: Duckett S (ed) Pediatric neuropatholgy. Williams & Wilkins, Baltimore, MD, pp 217–238 Decq P, Le Guerinel C, Sol JC, Brugieres P, Djindjian M, Nguyen JP (2001) Chiari I malformation: a rare cause of noncommunicating hydrocephalus treated by third ventriculostomy. J Neurosurg 95:783–790 Dirks P (2004) Genetics of hydrocephalus. In: Cinalli G, Maixner WJ, Sainte-Rose C (eds) Pediatric hydrocephalus. Springer, Mailand, pp 1–17 Grabb PA, Mapstone TB, Oakes WJ (1999) Ventral brain stem compression in pediatric and young adult patients with Chiari I malformations. Neurosurgery 44:520–528 Klein O, Pierre-Kahn A, Boddaert N, Parisot D, Brunelle F (2003) Dandy-Walker malformation: prenatal diagnosis and prognosis. Childs Nerv Syst 19:484–489 Koch-Wiewrodt D, Wagner W (2006) Success and failure of endoscopic third ventriculostomy in young infants: are there different age distributions? Childs Nerv Syst 22:1537–1541
346 Koehler PJ (1991) Chiari’s description of cerebellar ectopy (1891). With a summary of Cleland’s and Arnold’s contributions and some early observations on neural-tube defects. J Neurosurg 75: 823–826 Koehler J, Schwarz M, Boor R, Holker C, Hopf HC, Voth D, Urban PP, Ermert A (2000) Assessment of brainstem function in Chiari II malformation utilizing brainstem auditory evoked potentials (BAEP), blink reflex and masseter reflex. Brain Dev 22:417–420 McLone DG, Dias MS (2003) The Chiari II malformation: cause and impact. Childs Nerv Syst 19:540–550 Milhorat TH, Chou MW, Trinidad EM, Kula RW, Mandell M, Wolpert C, Speer MC (1999) Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patient. Neurosurgery 44:1005–1017 Roessmann U (1995) Congenital malformations. In: Duckett S (ed) Pediatric neuropatholgy. Williams & Wilkins, Baltimore, MD, pp 123–148 Tubbs RS, Wellons JC 3rd, Blount JP, Grabb PA, Oakes WJ (2003) Inclination of the odontoid process in the pediatric Chiari I malformation. J Neurosurg Spine 98:43–49 Wagner W, Koch D (2005) Mechanisms of failure after endoscopic third ventriculostomy in young infants. J Neurosurg (Pediatrics 1) 103:43–49 Wagner W, Koch D (2006) Hydrozephalus der Frühgeborenen im Langzeitverlauf. Pädiat Prax 67:215–226 Wagner W, Schwarz M, Perneczky A (2002) Primary myelomeningocele closure and consequences. Curr Opin Urol 12:465–468 Weprin BE, Oakes WJ (2001) The Chiari malformations and associated syringohydromyelia. In: McLone DG (ed) Pediatric neurosurgery. Surgery of the developing nervous system, 4th edn. WB Saunders, Philadelphia, PA, pp 214–235 Yeh DD, Koch B, Crone KR (2006) Intraoperative ultrasonography used to determine the extent of surgery necessary during posterior fossa decompression in children with Chiari malformation type I. J Neurosurg (Pediatrics) 105:26–32
4.9 “Metabolic Brainstem Diseases” Aasheim ET (2008) Wernicke encephalopathy after bariatric surgery: a systemic review. Ann Surg 248:714–720 Adams RD, Victor M, Mancall EL (1959) Central pontine myelinolysis. Arch Neurol Psychiatry 81:154–172 Altarescu G, Hill S, Wiggs E, Jeffries N, Kreps C, Parker CC, Brady RO, Barton NW, Schiffmann R (2001) The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher’s disease. J Pediatr 138:539–547 Barragan-Campos HM, Vallee JN, Lo D, Barrera-Ramirez CF, ArgoteGreene M, Sanchez-Guerrero J, Estanol B, Guillevin R, Chiras J (2005) Brain magnetic resonance imaging findings in patients with mitochondrial cytopathies. Arch Neurol 62:737–742 Barthel H, Hermann W, Kluge R, Hesse S, Collingridge DR, Wagner A, Sabri O (2003) Concordant pre- and postsynaptic deficits of dopaminergic neurotransmission in neurologic Wilson disease. Am J Neuroradiol 24:234–238 Bembi B, Marsala SZ, Sidransky E, Ciana G, Carrozzi M, Zorzon M, Martini C, Gioulis M, Pittis MG, Capus L (2003) Gaucher’s disease with Parkinson’s disease. Neurology 61:99–101 Bercovic SF, Carpenter S, Andermann F, Andermann E, Wolfe LS (1988) Kufs’disease: a critical reappraisal. Brain 111:27–62 Biffi A, Lucchini G, Rovelli A, Sessa M (2008) Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant 42(2):2–6
4 Diseases Brewer GJ (2005) Neurologically presenting Wilson’s disease. CNS Drugs 19:185–192 Brewer GJ, Askari F, Lorincz MT, Carlson M, Schilsky M, Kluin KJ, Hedera P, Moretti P, Fink JK, Tankanow R, Dick RB, Sitterly J (2006) Treatment of Wilson disease with ammonium tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 63:521–527 Brown WD (2000) Osmotic demyelination disorders: central pontine and extrapontine myelinolysis. Curr Opin Neurol 13:691–697 Butterworth RF (1995) Pathophysiology of alcoholic brain damage: synergistic effects of ethanol, thiamine deficiency and alcoholic liver disease. Metab Brain Dis 10:1–8 Chinnery PF, Johnson MA, Wardell TM (2000) The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48: 188–193 Culotta VC, Gitlin JD (2001) Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 3105–3126 Czlonkowska A, Gajda J, Rodo M (1996) Effects of long-term treatment in Wilson’s disease with D-penicillamine and zink sulphate. J Neurol 243:269–273 Desjardins P, Butterworth RF (2005) Role of mitochondrial dysfunction and oxidative stress in the pathogenesis of selective neuronal loss in Wernicke’s encephalopathy. Mol Neurobiol 31:17–25 Djoenaidi W, Notermans SL, Gabreels-Festen AA, Lilisantoso AH, Sudanawidjaja A (1995) Experimentally induced beriberi polyneuropathy in chickens. Electromyogr Clin Neurophysiol 35:53–60 Doherty MJ, Watson NF, Uchino K, Hallam DK, Cramer SC (2002) Diffusion abnormalities in patients with Wernicke encephalopathy. Neurology 58:655–657 Gärtner J, Kohlschütter A: www.aps-med.de. link “LeukonetUnklar” Goldenberg PC, Steiner RD, Merkens LS, Dunaway T, Egan RA, Zimmerman EA, Nesbit G, Robinson B, Kennaway NG (2003) Remarkable improvement in adult Leigh syndrome with partial cytochrome c oxidase deficiency. Neurology 60:865–868 Grau AJ, Hoffmann GF (Hrsg) (2004) Defekte des Harnstoffzyklus. In: Stoffwechselerkrankungen in der Neurologie. Thieme, Stuttgart/ New York, pp 131–138 Grau AJ, Schwaninger M, Goebel HH, Beck M (2003a) Morbus Fabry – eine lysosomale Stoffwechselerkrankung mit neuen Behandlungsmög lichkeiten. Nervenarzt 74:489–496 Grau AJ, Weisbrod M, Hund E, Harzer K (2003b) Morbus NiemannPick Typ C – eine neurometabolische Erkrankung durch Störung des intrazellulären Lipidtransports. Nervenarzt 74:900–905 Green R, Kinsella LJ (1995) Current concepts in the diagnosis of cobalamin deficiency. Neurology 45:1435–1440 Griffin LD, Gong W, Verot L, Mellon SH (2004) Niemann-Pick Type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 10:704–711 Haas R, Dietrich R (2004) Neuroimaging of mitochondrial disorders. Mitochondrion 4:471–490 Harper C, Gold J, Rodriguez M, Perdices M (1989) The prevalence of the Wernicke-Korsakoff syndrome in Sydney, Australia: a prospective necropsy study. J Neurol Neurosurg Psychiatry 52:282–285 Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, Gitschier J (2003) Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 348: 33–40 Hazell AS, Todd KG, Butterworth RF (1998) Mechanisms of neuronal cell death in Wernicke’s encephalopathy. Metab Brain Dis 13:97–122 Heller R, Grau AJ, Schäbitz WR, Schwaninger M (2002) Zerebroten dinöse Xanthomatose, eine behandelbare Stoffwechselerkrankung. Nervenarzt 73:1160–1166
Further Reading Hirano M, Di Mauro S (2001) ANT 1, Twinkle, Polg and TP. New genes open our eyes to ophthalmoplegia. Neurology 57:2163–2165 Hoffmann GF, Assmann B (2004) Neurotransmitterdefekte. In: Hoffmann GF, Grau AJ (eds) Stoffwechselerkrankungen in der Neurologie. Thieme, Stuttgart/New York, pp 92–101 Hoffmann GF, Grau AJ (eds) (2004) Stoffwechselerkrankungen in der Neurologie. Thieme, Stuttgart/New York Horvath R, Gorman G, Chinnery PF (2008) How can we treat mitochondrial encephalomyopathies? Approaches to therapy. Neuro therapeutics 5:558–568 Iizuka T, Sakai F, Suzuki N, Hata T, Tsukahara S, Fukuda M, Takiyama Y (2002) Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology 59:816–824 Jackson MJ, Schaefer JA, Johnson MA, Morris AAM, Turnbull DM, Bindoff LA (1995) Presentation and clinical investigation of mitochondrial respiratory chain disease. Brain 118:339–357 Jacobi C, Körner C, Frühauf S, Rottenburger C, Storch-Hagenlocher B, Grau AJ (2005) Presynaptic dopaminergic pathology in ChediakHigashi syndrome with parkinsonian syndrome. Neurology 64: 1814–1815 Jeppesen TD, Schwartz M, Olsen DB, Wibrand F, Krag T, Dunø M, Hauerslev S, Vissing J (Dec 2006) Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain 129:3402–3412 Katsaros VK, Glocker FX, Hemmer B, Schumacher M (1998) MRI of spinal cord and brain lesions in subacute combined degeneration. Neuroradiology 40:716–719 Kavuk I, Agelink MW, Gaertner T, Kastrup O, Doerfler A, Maschke M, Diener HC (2003) Wernicke’s encephalopathy: unusual contrast enhancement revealed by magnetic resonance imaging. Eur J Med Res 8:492–494 Kesler A, Stolovitch C, Hoffmann C, Avni I, Morad Y (2005) Acute ophthalmoplegia and nystagmus in infants fed a thiamine-deficient formula: an epidemic of Wernicke encephalopathy. J Neuro ophthalmol 25:169–172 Kohlschütter A, Goebel HH (2004) Neuronale Ceroidlipofuszinosen. In: Hoffmann GF, Grau AJ (eds) Stoffwechselerkrankungen in der neurologie. Thieme, Stuttgart/New York, pp 81–89 Kumar N, Gross JB Jr, Ahlskog JE (2004) Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 63:33–39 Lampl C, Yazdi K (2002) Central pontine myelinolysis. Eur Neurol 47:3–10 Langlais PJ (1995) Pathogenesis of diencephalon lesions in an experimental model of Wernicke’s encephalopathy. Metab Brain Dis 10:31–44 Leigh D (1951) Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 14:216–222 Marie RM, Le Biez E, Busson P, Schaeffer S, Boiteau L, Dupuy B, Via-der V (2000) Nitrous oxide anesthesia-associated myelopathy. Arch Neurol 57:380–382 Martin PR, Singleton CK, Hiller-Sturmhofel S (2003) The role of thiamine deficiency in alcoholic brain disease. Alcohol Res Health 27:134–142 Martin RJ (2004) Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry 75:22–28 McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H (2008) The neurological presentation of ceruloplasmin gene mutations. Eur Neurol 60:200–205 Menger H, Jörg J (1999) Outcome of central pontine and extrapontine myelinolysis (n = 44). J Neurol 246:700–705 Milone M, Brunetti-Pierri N, Tang LY, Kumar N, Mezei MM, Josephs K, Powell S, Simpson E, Wong LJ (2008) Sensory ataxic neuropathy with ophthalmoparesis caused by POLG-mutations. Neuromusc Disord 18:626–632
347 Miyajima H, Takahashi Y, Kamata T, Shimizu H, Sakai N, Gitlin JD (1997) Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol 41:404–407 Moser HW, Smith KD, Watkins PA, Powers J, Moser AB (2001) X-linked adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw Hill, New York, pp 3257–3301 Newell KL, Kleinschmidt-Demasters BK (1996) Central pontine myelinolysis at autopsy: a twelve year retrospective analysis. J Neurol Sci 142:134–139 Nijssen PC, Brusse E, Leyten AC, Martin JJ, Teepen JL, Roos RA (2002) Autosomal dominant adult neuronal ceroid lipofuscinosis: parkinsonism due to both striatal and nigral dysfunction. Mov Disord 17:482–487 Oya S, Tsutsumi K, Ueki K, Kirino T (2001) Reinduction of hyponatraemia to treat central pontine myelinolysis. Neurology 57: 1931–1932 Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE (2007) Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 6:765–772 Pellechia MT, Valente EM, Cif L, Salvi S, Albanese A, Scarano V, Bonuccelli U, Bentivoglio AR, D’Amico A, Marelli C, Di Giorgio A, Coubes P, Barone P, Dallapiccola B (2005) The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology 64:1810–1812 Pendlebury ST, Rothwell PM, Dalton A, Burton EA (2004) Strokelike presentation of Wilson disease with homozygosity for a novel T766R mutation. Neurology 63:1982–1983 Pineda M, Ormazabal A, Lopez-Gallardo E, Nascimento A, Solano A, Herrero MD, Vilaseca MA, Briones P, Ibanez L, Montoya J, Artuch R (2006) Cerebral folate deficiency and leukencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol 59:394–398 Reuler JB, Girard DE, Cooney TG (1985) Wernicke’s encephalopathy. N Engl J Med 312:1035–1039 Rolfs A, Böttcher T, Zschiesche M, Morris P, Winchester B, Bauer P, Walter U, Mix E, Löhr M, Harzer K, Strauss U, Pahnke J, Grossmann A, Benecke R (2005) Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 366:1794–1796 Schilsky ML (2001) Treatment of Wilson’s disease: what are the relative roles of penicillamine, trientine, and zinc supplementation? Curr Gastroenterol Rep 3:54–59 Schmiedel J, Jackson S, Schäfer J, Reichman H (2003) Mitochondrial cytopathies. J Neurol 250:267–277 Scriver CR, Beaudet AL, Sly WS, Valle D (2001) The metabolic and molecular bases of inherited disease, 8th edn. McGraw Hill, New York Stremmel W, Meyerrose K-W, Niederau C, Hefter C, Kreuzpaintner G, Strohmeyer G (1991) Wilson’s disease: clinical presentation, treatment and survival. Ann Intern Med 115:720–726 Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JT, Wherret J, Smith C, Rudd N, Petrova-Benedict R, Robinson BH (1992) Heteroplasmic mtD-NA mutation (T—G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 50:852–858 Van der Knaap M, Valk J (2002) Magnetic resonance of myelin, myelination and myelin disorders. Springer, Berlin Vry MS, Haerter K, Kastrup O, Gizewski E, Frings M, Maschke M (2005) Vitamine B12-deficiency causing isolated and partially reversible leukencephalopathy. J Neurol 252:980–982 Walter U, Krolikowski K, Tarnacka B, Benecke R, Czlonkowska A, Dressler D (2005) Sonographic detection of basal ganglia lesions in asymptomatic and symptomatic Wilson disease. Neurology 64: 1726–1732
348 Wang XY, Noguchi K, Takashima S, Hayashi N, Ogawa S, Seto H (2003) Serial diffusion-weighted imaging in a patient with MELAS and presumed cytotoxic oedema. Neuroradiology 45: 640–643 Weir DG, Scott JM (1995) The biochemical basis of the neuropathy in cobalamin deficiency. Baillières Clin Haematol 8:479–497
4.10 “Vascular Cranial Nerve and Brainstem Compression” Boecher-Schwarz HG, Bruehl K, Kessel G, Guenthner M, Perneczky A, Stoeter P (1998) Sensitivity and specifity of MRA in the diagnosis of neurovascular compression in patients with trigeminal neuralgia. A correlation of MRA and surgical findings. Neuroradiology 40:88–95 Brandt T, Dieterich M (1994) Vestibular paroxysmia: vascular compression of the eighth nerve. Lancet 342:798 Brantberg K (2010) Paroxysmal staccato tinnitus: a carbermatepine responsive hyperactivity dysfunction sympotum of the eight cranial nerve. J Neurol Neurosurg Psychiary 81:451–455 Dieterich M (1999) Neurovaskuläre Kompression des 8. Hirnnerven: Vestibularis-Paroxysmie. Akt Neurol 26:55–59 Ehongo A, Abi FH, Neugroschl C, Cordonnier M (2003) Superior oblique myokymia: secondary to neurovascular compression. Bull Soc Belge Ophthalmol 287:79–83 Geiger H (2001) Neurovaskuläre Kompression des Hirnstamms als eine mögliche Ursache der arteriellen Hypertonie. Dtsch Ärztebl 98: A3366–A3374 Glocker FX, Rösler KM, Hopf HC (2006) N. trigeminus (V): Trigeminusläsionen. In: Hopf HC, Kömpf D (Hrsg) Erkrankungen der Hirnnerven. Thieme, Stuttgart, pp 117–132 Goldenberg-Cohen N, Miller NR (2004) Noninvasive neuroimaging of basilar artery dolichoectasia in a patient with an isolated abducens nerve palsy. Am J Ophthalmol 137:365–367 Hashimoto M, Ohtsuka K, Akiba H, Harada K (1998) Vascular compression of the oculomotor nerve disclosed by thin-slice magnetic resonance imaging. Am J Ophthalmol 125:81–82 Hashimoto M, Ohtsuka K, Hoyt WF (2001) Vascular compression as a cause of superior oblique myokymia disclosed by thin-slice magnetic resonance imaging. Am J Ophthalmol 131: 676–677 Hooge JP, Redekop WK (1995) Trigeminal neuralgia in multiple sclerosis. Neurology 45:1294–1296 Jensen TS, Rasmussen P, Reske-Nielsen E (1982) Association of trigeminal neuralgia with multiple sclerosis: clinical and pathological features. Acta Neurol Scand 65:182–189
4 Diseases Katusic S, Beard CM, Bergstralh E, Kurland LT (1990) Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945–1984. Ann Neurol 27:89–95 Love S, Coakham HB (2001) Trigeminal neuralgia: pathology and pathogenesis. Brain 124:2347–2360 Nakanishi K, Akai F, Taneda M, Nakao Y (1999) Four cases of abducens palsy caused by a vascular lesion of the vertebrobasilar system. No Shinkei Geka 27:19–23 Nam E-C, Handzel O, Levine RA (2010) Carbomazepine responsive typewriter tinnitus from basilar invagination. J Neurol Neurosurg Psychiary 81: 456–458 Narai H, Manabe Y, Deguchi K, Iwatsuki K, Sakai K, Abe K (2000) Isolated abducens palsy caused by vascular compression. Neurology 55:453–454 Ohashi G, Irie K, Tani S, Ogawa T, Abe T, Hata Y (2001) Isolated abducens palsy caused by the compression of the basilar artery: a case report. No To Shinkei 53:69–72 Ohtsuka K, Sone A, Igarashi Y, Akiba H, Sakata M (1996) Vascular compressive abducens nerve palsy disclosed by magnetic resonance imaging. Am J Ophthalmol 122:416–419 Samii M, Rosahl SK, Carvalho GA, Krzizok T (1998) Microvascular decompression for superior oblique myokymia: first experience. A case report. J Neurosurg 89:1020–1024 Scharwey K, Krzizok T, Samii M, Rosahl SK, Kaufmann H (2000) Remission of superior oblique myokymia after microvascular decompression. Ophthalmologica 214:426–428 Schulze-Bonhage A, Ferbert A (2000) Spasmus facialis: Aktuelle Aspekte der operativen und medikamentösen Therapie. Dtsch Ärztebl 97:A-3184–A-3190 Solaro C, Brichetto G, Amato MP, Cocco E, Colombo B, D’Aleo G, Gasperini C, Ghezzi A, Martinelli V, Milanese C, Patti F, Trojano M, Verdun E, Mancardi GL (2004) The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology 63:919–921 Steinbach JP (2003) Kopf- und Gesichtsneuralgien: Trigeminusneuralgie und Glossopharyngeusneuralgie. In: Brandt T, Dichgans J, Diener HC (eds) Therapie und Verlauf neurologischer Erkrankungen. Kohlhammer, Stuttgart, pp 64–66 Thömke F, Gawehn J (2006) Vascular 3 rd nerve compression – a possible cause of episodic vertical diplopia? Neuro-Ophthalmology 30:125–127 Tilikete C, Vial C, Niederlaender M, Bonnier PL, Vighetto A (2000) Idiopathic ocular neuromyotonia: a neurovascular compression syndrome? J Neurol Neurosurg Psychiatry 69:642–644 Versino M, Colnaghi S, Todeschibi A, Candeloro E, Ravaglia S, Moglia A, Cosi V (2005) Ocular neuromyotonia with both tonic and paroxysmal components due to vascular compression. J Neurol 252: 227–229 Yousry I, Dieterich M, Naidich TP, Schmid U, Yousry TA (2002) Superior oblique myokymia: magnetic resonance imaging support for the neurovascular compression hypothesis. Ann Neurol 51:361–368
Index
A Abducens nerve compression, 328 lesions, 143, 167 nucleus cell, 107 Abducens nucleus, 10–11 Abducens paresis, 245 Accessory nerve lesions, 144–145 Aceruloplasminemia epidemiology, 314 etiopathogenesis, ceruloplasmin, 314–315 neurologic symptoms, 315 serum ceruloplasmin, 315 therapy, 315 Acquired nystagmus clinical classification, 119 description, 118 gaze convergence, 124–125 dissociated, INO, 120 divergence, 125–126 GEN (see Gaze-evoked nystagmus) horizontal, 123 imbalances, pursuit system, 126 periodic alternating nystagmus (PAN), 124 rebound, 119–120 seesaw and hemi-seesaw, 123–124 spontaneous, 120–121 torsional, 122–123 upbeat and downbeat, 121–122 occurrence, fixation acquired pendular nystagmus, 126–127 central position and positioning, 127 central vestibular, 127–128 pharmacotherapy central vestibular nystagmus, 127–128 fixation, pendular nystagmus, 128 pursuit imbalance, 126 saccadic oscillations macrosaccadic, 130 opsoclonus and ocular flutter, 128–129 square and macro square wave jerks, 129–130 topodiagnostic value significance, 128 types, 118 Acquired pendular nystagmus, 126–127, 138 Acute disseminated encephalomyelitis (ADEM), 249–250 Acute vertical ocular myoclonus, 168 Adrenoleukodystrophy, 319 Adrenomyeloneuropathy, 319 AICA. See Anterior inferior cerebellar artery Alexander disease, 319
Alternate hemiplegia, 156 Alternating skew deviation, 116, 117 Amyotrophic lateral sclerosis, 87 Anarthria, 148 Anterior corticospinal tract, 30 Anterior inferior cerebellar artery (AICA) pons, 34 vascular loops, 32 Anterior pretectal nucleus, 24 Apneic respiration, 163 Aqueductal stenosis, 302–303 Arboviral infections, 237 Arboviruses, 231 Area postrema, 30 Arterial circle of Willis, 32 Arterial hypertension, 330–331 Arylsulfatase A activity (ASA), 319 Ascending reticular activating system (ARAS), 164 Ascending tract (Deiters), 107 Aspergillosis, 240 Aspergillus, 231 Ataxia definition and epidemiology, 151 therapy and prognosis, 153 types ataxic hemiparesis, 151 infarction areas, 152, 153 lesion localization, 151 limb, 151 paroxysmal/acute, 152 stance and gait, 152, 153 Ataxic breathing, 163 Ataxic hemiparesis, 151 Ataxic respiration, 167 Atypical parkinsonian syndrome, 284 Auditory abnormalities, 246 Auditory pathway, 32 Automatic respiration, 167 Avellis’ syndrome, 206 B Babinski-Nageotte syndrome, 206 Baló’s disease, 250 Barrington’s nucleus, 28 Bartonella spec., 231 Basilar artery occlusion, 202–203 thrombosis, 58 Basilar migraine, 225–228 Behçet’s disease, 242 Benedict’s syndrome, 205
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350 Beriberi, 308 Bickerstaff’s encephalitis, 241 Bladder disturbances definition and epidemiology, 160 ethiopathogenesis and clinical findings acute urinary retention, 161 pontine neurons, 161 physiology and neuroanatomy, micturition parasympathetic nervous system, 160 periacqueductal gray, 161 sensory innervation, 161 Blink reflex afferent and efferent defect, 63 anatomic and physiologic principles animal model, 62 late R2 response, 62 sensory nociceptive parts, 61 clinical application pathologic, 63 stimulation, 63 supraorbital nerve, 62 upper limits, normal, 63 electromyographic recording, 61, 62 ipsilaterally absent R1-component, 65 medullary lesions, 64 pathologic patterns, 64 topodiagnostic findings, 64 B-mode sonography affective disturbances diagnosis, 61 differential diagnosis, Parkinson syndromes, 61 idiopathic Parkinson’s disease 18 F-dopamine uptake, 60 nigrostriatal dopamine system dysfunction, 60–61 substantia nigra hyperechogenicity, 60 principles and techniques device parameters, 59 hyperechogenicity, 59 mesencephalon, 59 raphe nucleus, 59, 60 substantia nigra, 59–60 Boeck’s disease, 241 Borrelia burgdorferi, 231 Borreliosis, 238 Brachium conjunctivum, 107 Brain death, 74, 84 brainstem reflexes, 169 coma/unresponsiveness, 169 confirmatory tests cerebral circulatory arrest, 170 conventional angiography, 170 electrocerebral inactivity, 170 SEPs, 170 transcranial Doppler ultrasonography, 170 definition clinical signs, 169 laboratory tests, 168 respiration absence, 169–170 Brainstem compressions, 330–331 encephalitis, 254 gliomas, 259–260 hemorrhage, 211–216 Brainstem infarctions aneurysms and megadolichobasilaris, 196 arterial hypertension, 197 basilar artery occlusion
Index arterial fibrillation, 203 caudal vertebral and middle basilar artery syndrome, 202 locked-in syndrome, 203 reticular formation, 202 “top of the basilar”, 202–203 cerebral vein thrombosis neuroimaging, 197 sinus thrombosis, 197 classic brainstem syndromes, 204–207 dissections intracranial, 195 vertebral artery, 195, 203 vertebrobasilar vascular system, 195 embolism embolus, identification, 193–194 persistent foramen ovale (PFO), 194 epidemiology atrial fibrillation, 193 cerebral ischemia, 193 topographies, 193 etiology in-situ thrombosis, 193 vertebrobasilar infarctions, 193 hemodynamics, altered ischemias, 195 transitory vertigo symptoms, 196 local atherothrombosis microvascular and macrovascular etiologies, 194 solitary pontine, 194 stenoses, 194 medulla oblongata lateral, 198 medial, 198–199 PICA, 199 Wallenberg syndrome, 199 microangiopathies lipohyalinosis, 194 small lacunar ischemias, 195 midbrain extended pontomesencephalic, 201 eye movement abnormalities, 200 mesencephalic ischemias, 201 thalamic, 200 migraine medullary migrainous infarction, 196 neurologic deficits, 196 mitochondrial disorders, 197 multiple cardiac embolisms, 202 oculomotor paresis, 201–202 PICA and AICA, 201 parenchymal imaging CT, 204 lacunar pontine and lacunar mesencephalic infarction, 207 masseter and blink reflex, 208 MRI, 204 pontine infarction, 207 pontomesencephalic infarction, 207 reversible deficits, 208 “tissue at risk”/penumbra, 208 pontine anterolateral pons, 200 basilar artery macroangiopathy, 199 bilateral, 200 brainstem vascularization, 199 dysarthria, 199–200
Index medial pontomedullary infarction, 200 proximal perforator occlusions, 199 tegmental, 200 prognosis and disease course gait ataxia, dysarthria and dysphagia, 211 substantial impairments, 210 prophylaxis balloon angioplasty, 210 cerebral ischemias, 210 vascular stenoses, 210 subclavian steal syndrome Doppler sonography, 203 hemodynamic causes, 203–204 proximal subclavian artery, 204 stenoses, 203 symptoms dysarthria and dysphagia, 198 neurologic deficits, 198 stroke, 197 supratentorial infarctions, 198 thalamic, 201 therapy GP-IIb/IIIa antagonist, 209 intraarterial lysis, 209 intracranial dissecting aneurysms, 210 IV rt-PA lysis therapy, 210 recanalization procedures, 209 suction systems, 209 vascular imaging CT angiography (CTA), 209 digital subtraction angiography, 209 distal basilar artery, 208 Doppler and duplex sonography, 208 vasculitis rheumatic diseases, 197 Takayasu’s disease, 197 vertebral artery compression, head rotation, 196–197 Brainstem neuroanatomy architecture clinical symptoms, 2 intracerebral fluid containing spaces, 2 longitudinal sections, 1–2 ascending activation system locus caeruleus, 17–18 monoaminergic neurons, 18 motor system, 18 noradrenergic locus caeruleus, 17 pedunculopontine tegmental nucleus, 17 ascending pathways auditory, 32 lemniscal systems, 31 spinocerebellar tracts, 31 spinothalamic tract, 31 descending pathways cerebellar peduncles, 30–31 corticonuclear tract, 30 corticopontine fibers, 30 dorsal longitudinal fasciculus, 30 medial longitudinal fasciculus (MLF), 30 pyramidal cells, 30 development control genes, 3 neural crest cells and placodes, 3 neuroectoderm, 2 somatoefferent and visceroefferent neurons, 3
351 external characteristics cranial nerves, 4–7 medulla oblongata, 4 mesencephalon, 3–4 pons, 4 retinal inputs, 4 eye movements, premotor control neuronal networks, 18 riMLF, 18 saccades, 18 vertical and torsional, 18 internal architecture cranial nerve nuclei, 8–16 limbic control, 18 medulla oblongata, 28–29 mesencephalon, 23–27 parasympathetic and sympathetic pathways, 21–23 pons, 27–28 reticular formation, 16–17 pons, 27–28 vascularization anastomotic ring, 28 medulla oblongata, 34 mesencephalom, 32–34 pons, 34 Schwann cells, 32 vascular territories, 32 vestibuloocular reflex lateral rectus muscle, 19 semicircular canals, 19 vestibulospinal tract, 19 Brainstem reflexes convergence, 171 corneal, 171–172 cough, 173 gag, 173 light, 170–171 masseter, 172 oculocephalic, 172–173 orbicularis oculi, 172 Brainstem tumors diagnosis cerebrospinal fluid examination, 258 differential, 258 MRI and CT, 257 MR spectroscopy, 257–258 PET, 258 therapy, 258–259 epidemiology, 255–256 etiology, 256 extrinsic hemangioblastomas, 271–272 meningiomas, 270–271 metastases, 266–268 schwannomas, cerebellopontine angle, 268–270 intrinsic choroid plexus, 265–266 ependymomas, 262–264 etiopathogenesis, 260 gangliogliomas, 265 gliomas, 259–260 medulloblastomas, 264–265 therapy, 261–262 symptoms, 256–257 Brissaud-Sicard syndrome, 205 Brown-Séquard syndrome, 158
352 C California virus, 231, 237 Candida albigans, 231 Candidoses, 240 Capillary telangiectasias, 222–223 Caput medusa, 223 Cataplexy, 162 Cavernomas, 220–222 Central hyperventilation, 163 Central mesencephalic reticular formation (cMRF), 108 Central pontine myelinolysis (CPM), 304–307 Central position and positioning nystagmus, 127 Central position nystagmus, 138 Central sleep apnea syndrome, 162–163 Central vestibular disturbances downbeat and upbeat nystagmus, 135 nystagmus syndromes acquired pendular, 138 central position, 138 periodic alternating, 137–138 seesaw/pendular, 137 vertical and torsional components, 137 plane frontal/roll, 135 horizontal/yaw, 135 sagittal/pitch plane, 135 therapy and prognosis pitch plane, 137 roll and yaw plane, 137 Central vestibular syndromes diagnostics and differential diagnosis Doppler duplex sonography, 136 oculomotor function, 136 perceptual deficits, 136 etiology brainstem and vestibulocerebellar lesions, 134 pathologic excitations, 135 vertigo attacks, 135 “graviceptive” vestibular pathways, 135–136 neuroanatomy and classification classification, 133, 134 VOR, 133 oculomotor abnormalities, 136 tonic imbalance, 135 torsional nystagmus, 136 Cerebellar peduncles, 30–31 Cerebral abscess, 238 Cerebral cryptococcosis, 240 Cerebral superficial siderosis, 219–220 Cerebral toxoplasmosis, 241 Cerebral vein thrombosis, 197 Cerebrotendinous xanthomatosis, 318 Céstan-Chenais syndrome, 206 Chediak-Higashi syndrome, 317 Cheyne–Stokes respiration, 163, 167 Chiari malformations, 297–300 pathologic changes, forms, 297 type I, 298 type II, 299–300 Chiray-Foix-Nicolesco syndrome, 205 Ciliospinal center, 23 Classic brainstem syndromes, 204 Claude’s syndrome, 205 Cluster respiration, 167 COACH syndrome, 303 Cochlear nuclei, 14
Index Collier’s sign, 114 Coma, 165 Coma stage, 166 Computed tomography (CT) cavernoma, lamina quadrigemina, 40 cisternography and angiography, 40 emergency diagnostic imaging, 39 intracerebral and extracerebral, 40 principles and techniques angiography, 39 section planes, reconstruction, 39 spatial resolution, 39 volume data set, 39 x-ray absorption, 39 risks, 40 streak artefacts, 39–40 Concentric sclerosis, 250 Consciousness, 164–168 Consciousness disturbances etiopathogenesis and classification ARAS (see Ascending reticular activating system (ARAS)) coma, brain injury, 164–165 Glasgow coma scale (GCS), 165, 166 somnolence, stupor and coma, 165 eye deviations conjugate, 167 disconjugate, 167 motor function changes, 168 movements, eye horizontal, 167–168 vertical, 168 papillary function disorders midbrain lesions, bilateral damage, 166 thalamic lesions, 166 unilateral mydriasis, 166 respiratory, 166–167 Constructive interference in steady state (CISS), 41 Contralateral dissociated disturbance, sensitivity, 199 Contralateral hemihyperhidrosis, 175–176 Contrast enhanced MR angiography (CE-MRA), 45 Convergence, 20 paresis, 111 reflex, 171 spasm, 110 Corneal reflex, 171–172 Corticobasal degeneration (CBD), 291–292 Corticobasilar degeneration, 61 Corticofacial projections, 85 Corticolingual projections, 85 Corticonuclear tract, 30 Cough reflex, 173 Coxiella burnetii, 231 Coxsackie and ECHO virus, 236 Coxsackie virus A and B, echo virus, 231 Cranial nerve lesions, 198 Cranial nerve nuclei abducens nucleus, 10–11 accessory nerve, 16 cerebrospinal fluid, 8 cochlear nuclei, 14 facial nerve, 12 hypoglossal nerve, 16 oculomotor nerve nucleus Edinger-Westphal nucleus, 9 light reaction and near response, 9–10 trigeminal nerve nucleus, 11–12
Index trochlear nucleus, 10 vagal system dorsal motor vagal nucleus, 15 glossopharyngeal nerve, 14–15 nucleus ambiguus, 16 solitary nucleus, 15 vagus nerve, 15 vestibular nuclei, 13–14 Cranial nerves, 4–8 Creutzfeld-Jakob disease, 292 Crossed syndromes, 155–156 Crossed vertical gaze palsy, 115 Cryptococcus neoformans, 231 Cuneate nucleus, 28, 31 Cuneocerebellar tract, 31 Cytomegaly virus (CMV), 231, 236 D Dandy-Walker malformation, 300–302 Degenerative brainstem diseases frontotemporal lobar degeneration, 288 Lewy body disease, 285–286 MSA (see Multiple system atrophy) Parkinson disease (see Parkinson’s disease) parkinsonism, Alzheimer’s dementia, 288 PSP, 288–289 subcortical vascular encephalopathy (SVE), 286–288 syndrome-orientated classification basal ganglia diseases, 279 diagnosis, 279 hyperkinesias and hypokinesias, 279–280 motor disturbance, 279 Parkinson syndromes, 280 tremors, 295–297 vertical gaze paresis, 289–290 Déjérine’s syndrome, 207 Demyelinating diseases, brainstem MS (see Multiple sclerosis) progressive multifocal leukoencephalopathy (PML), 250–251 Dengue virus, 231, 237 Developmental venous anomalies (DVAs), 222–223 Diagnostic imaging and interventional treatment, brainstem lesions electrophysiologic blink reflex, 61–65 EAEP (see Early acoustic evoked potentials) exteroceptive suppression, 76–81 eye movements, 90–92 LEPs, 88–90 masseter reflex, 65–70 somatosensory evoked potentials, 81–84 stapedius reflex, 92–93 transcranial magnetic stimulation (TMS), 84–88 trigemino-cervical reflex, 93 trigemino-hypoglossal silent period, 93–95 vestibulocollic reflex, 75–76 neuroradiology angiography, 47–49 computed tomography, 39–40 endovascular interventions, 49–53 magnetic resonance imaging, 40–47 native diagnostics, 38–39 ultrasound (see Ultrasound diagnostics) Dissections, 195, 203 Dissociated disturbance, sensitivity, 198 Dissociated nystagmus, 120 Disturbances
353 gastrointestinal function, 176 sweat secretion, 175–176 Divergence nystagmus, 125–126 paresis, 111 Dorsal column, 157 Dorsal longitudinal fasciculus, 30 Dorsal midbrain syndrome, 114 Dorsal motor vagal nucleus, 15 Dorsolateral and dorsomedial pontine nuclei, 107 Dorsomedial respiratory group, 29 Downbeat and upbeat nystagmus, 137 Downbeat nystagmus, 121–122, 135 Drop attacks definition and epidemiology, 161 etiopathogenesis cryptogenetic, 162 epileptic attacks, 162 internal perilymph fistula, 162 transient ischemia, 161 vertebrobasilar ischemia, 162 vestibular origin, 162 Dural arteriovenous malformations (DAVM), 225 Dysarthria/dysphagia, 147, 155, 198, 199 Dysphagia clinical picture and functional diagnostics penetration/aspiration, 150 unilateral supratentorial lesions, 150 definition and epidemiology, 149 etiopathogenesis bilateral infarctions, rostral pontine base, 150 dorsolateral medulla oblongata infarction right, 150 neuroanatomy, swallowing brainstem areas, 149 corticobulbar fibers, 149 therapy and prognosis food and liquid intake, 150 tracheostomy and exercise therapy, 151 Dysrhythmia and blood pressure disturbances, 176 Dystonia, 176 Dystonic tremor, 296 E Early acoustic evoked potentials (EAEP) evaluation Arnold–Chiari-II-malformation, 72 brain death, 74 brainstem ischemia/bleeding, 74 cavernoma left and right pontine, 73 central lesions, 72 MS, 72–74 parameters, 71 pons infarction, 72 physiologic variability interpeak latencies (IPL), 71 normal click-auditory threshold, 71 recording, 71 stimulation rarefication, 70 stimulus strength, 70–71 topographic allocation, 70 Eastern equine encephalitis virus, 231, 237 Edinger-Westphal nucleus, 9 Ehrlichia, 231 Electrooculography, 90 Embolization
354 arteriovenous angiomas/malformations (AVM), 53 berry aneurysms, 51 clipping and coiling, 51–52 coil occlusion, 52 dural arteriovenous fistulae (DAVF), 53 fusiform aneurysms, 53 stereotactic radiation, 53 Emotional incontinence, 247 Emotional paresis, 154 Enteroviruses, 71, 231, 236 Enterovirus infections, 236 Ependymomas, 262–264 Epstein-Barr virus (EBV), 231, 235 ESME virus, 231 Essential tremor, 295, 296 Exteroceptive suppression, masticatory muscle activity afferences, 76–77 evaluation, 78 interconnection ES1, 77 ES2, 78 lesions medullary, 79–81 pontine, 79 recording, 78 reference values/normal variants, 78–79 stimulation, 78 Extrapyramidal motor symptoms dystonia, 176 Parkinson’s syndrome, 176 tremor, 176 Extrinsic brainstem tumors hemangioblastomas, 271–272 meningiomas, 270–271 schwannomas, cerebellopontine angle, 268–270 Eye movements direct current recording, 90 electrooculography, 90 infrared reflective oculography, 90–91 scleral search coil technique, 92 videooculography, 91–92 Eye-of-the-tiger sign, 292, 314 F Fabry’s disease, 316 Facial myokymias, 144 Facial nerve compression, 328–329 lesions, 143–144 Facial nucleus, 12–13 Facial paresis, 154, 245–246 Fixation nystagmus, 118 Flaviviridae virus, 231, 237 Focal encephalitis, 238 Foville’s syndrome, 205 Frontotemporal lobar degeneration, 288 Fungal encephalitides, 240 G Gag reflex, 173 Gait ataxia, 199 Gangliogliomas, 265 Gasperini’s syndrome, 205 Gasping respiration, 167 Gaucher’s disease, 315 Gaze-evoked nystagmus (GEN), 118–120
Index Gaze evoked symptoms, 177 Gaze stabilization, 20–21 Gellé’s syndrome, 205 Glasgow coma scale (GCS), 165, 166 Glossopharyngeal and vagus nerve lesions, 144 Glossopharyngeal nerve, 14–15 Glossopharyngeal nerve compression, 329–330 Glossopharyngeal neuralgia, 329–330 GM2 gangliosidoses, 317 Gracile nucleus, 28, 31 Grenet’s syndrome, 205 Gustatory disturbances, 174 H Hallucinations acoustic, 174 visual, 173–174 Hanta virus, 231 Hemangioblastomas, 271–272 Hemifacial spasm, 328, 329 Hemiplegia cruciata, 155 Hemi-seesaw nystagmus, 123, 124 Hemophilus influenzae, staphylococci, 231 Hepatolenticular degeneration. See Wilson’s disease Hereditary spastic spinal paralysis, 87 Herpes simplex virus type 1 and 2 (HSV–1/2), 231, 235 Herpes viruses, 231 HIV/AIDS patients, 240–241 HIV 1 and 2, 231 Holmes’s tremor, 295, 296 Horizontal eye movement disorders convergence and divergence paresis, 111 gaze paresis etiology, 110 midbrain lesions, 110–111 unilateral pontine lesions, 110 internuclear ophthalmoplegia (see Internuclear ophthalmoplegia) lateropulsion dorsolateral medulla oblongata, 112 ipsilesional hypermetry and contralesional hypometry, 112 oblique, 112 one-and-a-half syndrome, 111 smooth pursuit disturbances olivopontocerebellar atrophy, 111 saccadic, 111 Horizontal gaze paresis, 110–111 Horizontal nystagmus, 123 Horner’s syndrome clinical findings, 131 definition, 130 ethiopathogenesis and epidemiology, 131 functional diagnostics, 132 neuroanatomy first order neurons, 130 hypothalamic neurons, 131 sympathoexcitatory pathway, 130 pharmacologic pupillary drop test, 132 sweat tests, 132–133 therapy and prognosis, 133 Hu-Ab, 252 Human herpes virus (HHV), 231 Human herpes virus type 6 and 7 (HHV–6/7), 235 Hunt and Hess classification, 217 Huntington’s disease, 292 Hypercapnia hypoventilation, 170
Index ventilator disconnection, 169–170 Hyperechogenicity, 59 Hypoglossal nerve lesions, 145 I Infarctions lateral medulla oblongata, 198 medial medulla oblongata, 198–199 Inferior colliculi, 3 Inferior olive, 29, 107 Inflammatory brainstem diseases bacterial encephalitides borreliosis, 238 legionellosis, 240 listeriosis, 239 lues/syphilis, 239 meningoencephalitis, focal encephalitis, cerebral abscess, 238 tuberculosis, 239 Whipple’s disease, 240 Behçet’s disease, 242 clinical findings aspiration, abscess, 230 disease course, 230 non-neurologic concomitant symptoms, 229 diagnosis, 230 electrophysiology and biopsy, 233 epidemiology acute bacterial meningitis, 229 Behçet’s disease, 229 early summer meningoencephalitis (ESME), 229 viruses, 228 etiology bacterial focal encephalitides, 229 viral and non-viral encephalitides, 229 imaging cranial computer tomography (CCT), 233 MRI, 232–233 immunosuppressed and HIV/AIDS patients CD4 cells, 240 cerebral toxoplasmosis, 241 CNS infections, 241 laboratory diagnostics antigen detection, PCR, 232 application, cerebrospinal fluid (CSF) analysis, 233 blood culture, 231 cerebrospinal fluid constellations, 232 neutrophilic granulocytosis, 232 procedures, 230–231 routine blood and serum analysis, 231 non-causative agent-specific encephalitides Bickerstaff’s encephalitis, 241 diagnosis, 241 parasitic and fungal encephalitides, 240 prognosis, 234–235 sarcoidosis, 241–242 SLE (see Systemic lupus erythematosis) therapy acute conditions, 233 surgical removal, 234 symptomatic, 233 viral encephalitides arboviral, 237 enterovirus, 236 herpes virus infections, 235–236 lymphocytic choriomeningitis (LCM), 238 myxovirus, 236–237 rabies (lissa) virus, 237–238
355 Influenza A and B virus, 231, 236 Infrared reflective oculography, 90–91 INO. See Internuclear ophthalmoplegia Intercalated nucleus, Staderini, 107 Internuclear ophthalmoplegia (INO), 106, 198, 244 clinical findings abduction nystagmus, 109 adduction paresis, 108–109 etiopathogenesis abduction nystagmus, 107–108 adduction paresis, 107 direct current recording, saccade, 109 disturbed inhibition, tonic resting activity, 108 posterior abnormal convergence impulses, 110 mesencephalic lesion, 109 Interstitial nucleus of Cajal (INC), 18, 24, 108, 113 Intra-axial cranial nerve lesions abducens, 143 accessory, 144–145 differential diagnosis infarctions, cerebellar arteries, 146 pseudovestibular cerebellar infarctions, 146 symptoms, 145–146 tonic resting activity, 146 unilateral peripheral injury, 146 electrophysiologic techniques, 145 epidemiology and etiopathogenesis diabetic oculomotor paresis, 141–142 ischemia, 141 multiple sclerosis, 142 facial nerve intrapontine segment, 143 myokymias, 144 glossopharyngeal and vagus, 144 hypoglossal, 145 imaging, 145 midbrain infarction, 141 oculomotor, 142 prognosis, 146 therapy, 146 trigeminal, 142 trochlear, 142 vestibulocochlear pseudovestibular syndrome, 144 “vestibular pseudoneuritis”, 144 Intracerebral bleeding (ICB), 212 Intraparenchymatous brainstem hemorrhage acute pontine tegmental, 213 basotegmental pontine, 213 cavernoma mediated, 213 diagnosis CCT, 214 cerebral catheter digital angiography, 214 differential, 214 MRI, 214 epidemiology intracerebral bleeding (ICB), 211 intracerebral hemorrhages (ICH), 211 necropsy, 211 etiology cerebral amyloid angiopathy, 212 hypertension, 212 primary and secondary intracerebral bleeding, 212 massive pontine, arterial hypertension, 212 medulla oblongata, 214
356 mesencephalic ICHs, 214 operative therapy, 215 prognosis, 216 therapy conservative, 215 decreased level, consciousness, 214 operative, 215 recombinant activated factor VII, 215 Intrinsic brainstem tumors choroid plexus, 265–266 ependymomas, 262–264 gangliogliomas, 265 gliomas, 259–260 medulloblastomas, 264–265 therapy, 261–262 Ipsilateral hemihypohidrosis, 175 Ipsilateral Horner’s syndrome, 199 Ipsilateral hypesthesia, face, 199 Ipsilateral limb kinetic ataxia, 199 J Jackson’s syndrome, 207 Japan B encephalitis virus, 231 Japanese encephalitis virus, 237 JC virus, 231 Jerky hemi-seesaw nystagmus, 123 Joubert syndrome, 303 K Kearns-Sayre syndrome (KSS), 325–326 Kinesia paradoxa, 283 Koerber–Salus–Elschnig syndrome, 114 Krabbe’s disease, 319 L Laser evoked potentials (LEPs), 88–90 Lateral corticospinal tract, 30 Lateral spinothalamic tract, 158 Lateropulsion, 112 Legionella pneumophilia, 231, 240 Legionellosis, 240 Leigh’s disease, 325 Lemniscal decussation, 158 Lemniscal systems, 31 Leukodystrophies adrenoleukodystrophy, 319 Alexander disease, 319 Krabbe’s disease, 319 metachromatic, 318–319 Lewy body dementia (LBD), 61, 287 Lewy body disease, 285–286 Light reflex, 170–171 Limb ataxia, 151 Limb kinetic ataxia, 198 Listeria monocytogenes, 231 Listeriosis, 239 Locked-in syndrome, 155, 156, 203 L-region, 28, 161 Lues (syphilis), 239 Lymphocytic choriomeningitis (LCM) virus, 231, 238 Lysosomal metabolic diseases, 315 M Macrosaccadic oscillations, 130 Macro square wave jerks, 129–130
Index Magnetic resonance imaging (MRI) brainstem, investigations acute vascular processes, 44 CE-MRA, 45 corticospinal tracts and cerebellar afferents, 44 cranial nerves, 42 diffusion weighting, 43 Ferritin deposits, 44 intracerebral lesions, 44 pathway anatomy, 44 vestibulocochlear and facial nerves, 43 Wallerian degeneration, 44 principles and techniques acoustic neurinoma, 42 aneurysm, basilar artery tip, 43 Chiari-II (Arnold–Chiari) malformation, 43 CISS (see Constructive interference in steady state (CISS)) diffusion imaging, 42 electromagnetic waves, 40–41 gradient echo sequence, 41–42 pontine cavernoma, 42 spatial encoding and resolution, 41 spin-lattice relaxation, 41 spin–spin relaxation, 41 two-dimensional steady state free precession sequence, 42 risks ferromagnetic objects, 47 pregnant women, 46 specialized methods cerebral activation, 45 diffusion tensor imaging (DTI), 45–46 intact nerve tract function, 46 right medial longitudinal fasciculus, 46 spectroscopy, 46 thalamus and brainstem glioma, 46 Ma-(Ma1-and Ma2-) Ab, 252 a-and b-Mannosidosis, 318 Marburg-type multiple sclerosis, 250 Masseter reflex, 172 abnormal, 68 anatomic principles afferents and efferents, 65 central, representation, 66 reflex arc, 66 Arnold–Chiari malformations, 69 clinical application amplitudes, 67 circumscribed dorsal mid-brain infarction, 69 dorsolateral infarction, rostral pons, 69 latency, 66–67 normative values, 68 pathologic findings, 68 reflex hammer, 66 surface electrodes, 66 electrophysiologic examination, 69 occurrence, 68–69 supratentorial/cerebellar lesions, 68 McDonald criteria, 248 Measles virus, 231, 236 Medial lemniscus, 157–158 Medial longitudinal fasciculus (MLF), 30, 107 Medial pretectal nucleus, 24 Medulla oblongata, 4 anterior spinal artery, 34 corticospinal tract fibers, 28 dorsal vascular group, 34
Index inferior olive, 28–29 PICA, 34 ventrolateral cell groups cardiovascular reflexes, 29 respiratory reflexes, 29 swallowing, vomiting and sneeze reflexes, 30–31 vertebral artery, 34 Medulla oblongata infarctions, 198–199 Medulloblastomas, 264–265 Megadolichobasilaris, 196 MELAS syndrome, 324–325 Meningiomas, 270–271 Meningococci, 231 Meningoencephalitis, 238 Mesencephalic ICHs, 214 Mesencephalon, 3–4 arterial arches, 32 dorsal vascular territory, 33 nuclear regions cerebellar nuclei and projects, 24 posterior commissure, 24 pretectum, 24 red nucleus, 25 rostral interstitial nucleus, 24 substantia nigra, 27 superior and inferior colliculi, 24–25 oculomotor and trochlear nerves, 32 vascular territory types, 34 Metabolic brainstem diseases central pontine myelinolysis, 304–307 hereditary aceruloplasminemia, 314–315 cerebrotendinous xanthomatosis, 318 Chediak-Higashi syndrome, 317–318 Fabry’s disease, 316 Gaucher’s disease, 315 GM2 gangliosidoses, 317 leukodystrophies (see Leukodystrophies) lysosomal metabolic, 315 metachromatic leukodystrophy, 318–319 neuronal ceroid lipofuscinoses, 320–321 Niemann-pick type C disease, 316–317 oligosaccharidoses, 318 pantothenate kinase-associated neurodegeneration, 314 Segawa syndrome, 320 sialidosis, 318 tyrosine hydroxylase defects, 320 urea cycle defects, 321 Wilson’s disease, 312–314 mitochondrial encephalomyopathies Kearns-Sayre syndrome, 325–326 Leigh’s disease, 325 MELAS syndrome, 324–325 vitamin deficiency beriberi, 308 malabsorption syndromes, 307 Strachan’s syndrome, 308 therapy, 311 vitamin B1 hypovitaminosis, 307–308 vitamin B12 hypovitaminosis (see Vitamin B12 hypovitaminosis) vitamin E, 311 Wernicke’s encephalopathy, 308–310 Metachromatic leukodystrophy, 318–319 Metastases, 266–268 Microangiopathies, 194–195 Microplasms, 231
357 Micturition, 160–161 Midbrain infarctions, 200–201 Migraine, 196 Millard-Gubler syndrome, 205 Minor’s iodine starch test, 132, 133 Mitochondrial disorders, 197 Mitochondrial encephalomyopathies, 321–326 Monocular depression deficiency, 115 Monocular elevation paresis, 114–115 Motor hemiparesis, 198 M-region, 28, 161 MRI. See Magnetic resonance imaging MSA. See Multiple system atrophy Multiple sclerosis (MS) auditory abnormalities, 246 cranial nerve deficits abducens paresis, 245 caudal cranial nerve injury, 246 dysphagia, 246 facial paresis, 245–246 oculomotor paresis, 245 trigeminal involvement, 245 diagnosis “black holes”, 248 clinically isolated syndrome (CIS), 248 differential, 249 evoked potentials, 247 infratentorial lesions, 248 internuclear ophthalmoplegia, 248 McDonald criteria, 248 emotional incontinence, 247 epidemiology, 243 etiopathogenesis blood-brain barrier abnormality, 243 genetic studies, 244 macrophages, 243–244 MS plaques, 243 lesions, pyramidal tract MRI, 247 sensory deficits, 246 multifocal demyelinization, 244 oculomotor disturbances downbeat nystagmus, 244 internuclear ophthalmoplegia (INO), 244 ocular flutter, 244 one-and-a-half syndrome, 245 Parinaud’s syndrome, 244–245 paroxysmal phenomena, 247 prognosis, 249 subtypes ADEM (see Acute disseminated encephalomyelitis) Baló’s disease, 250 Marburg-type, 250 therapy paroxysmal attacks, 249 pendular nystagmus, 249 tremor, 247 vertigo, balance and gait, 246 Multiple system atrophy (MSA), 61 clinical findings, 293 diagnosis consensus criteria, 293–294 differential, 294 electromyography, 294 epidemiology, 292 etiology, 292–293
358 prognosis, 295 therapy, 294 Mumps virus, 231, 236 Mutism, 148–149 Mycobacterium tuberculosis, 231, 239 Mydriasis, 166 Myxopapillary ependymoma, 219 Myxoviruses, 231 Myxovirus infections, 236–237 N Nausea and emesis, 174–175 Neuroborreliosis, 238 Neurofibromatosis type II (NF–2), 268 Neuronal ceroid lipofuscinoses (NCL), 320–321 Neuroradiology angiography AICA and SCA, 48 indirect techniques, 47 neurologic complications, 48 posterior cranial fossa, 48 radiation exposure, 49 Seldinger technique, 47 selective vertebral, 47 transient amnesia and cortical blindness, 48–49 vascular drainage, 48 vertebral artery, 47–48 conventional native diagnostics craniocervical junction, 38 dysplasia, craniocervical, 38 foramina, constrictions, 39 skull, 38 CT (see Computed tomography (CT)) endovascular interventions embolization, 51–53 recanalization, 49–51 MRI (see Magnetic resonance imaging) Neurosarcoidosis, 241 Neurotuberculosis, 239 Niemann-pick type C disease, 316 Ninhydrin sweat test, 132–133 Nipah virus, 231, 236 Normal pressure hydrocephalus (NPH), 287, 288 Nothnagel’s syndrome, 205 Nucleus ambiguus, 15–16 Darkschewitsch, 24 oculomotor nerve, 108 optic tract, 24 posterior commissure, 23 prepositus hypoglossi, 107 Nucleus of the reticularis tegmenti pontis (NRTP), 107 Nystagmus, 199 O Ocular bobbing, 168 Ocular dipping, 168 Ocular floating, 168 Ocular flutter, 128–129, 244 Ocular motility disorders acquired nystagmus (see Acquired nystagmus) horizontal convergence and divergence paresis, 111 horizontal gaze paresis, 110–111 internuclear ophthalmoplegia (see Internuclear ophthalmoplegia)
Index one-and-a-half syndrome, 111 smooth pursuit disturbances, 111–112 principles brainstem structures, 106–108 neural integrator, 106 vergences, 105–106 versions, 105 vertical dorsal midbrain syndrome, 114–115 gaze palsies and one-and-a-half syndrome, 112–113 ocular tilt reaction (OTR) and skew deviation, 115–118 oculomotor nuclear lesions, 113–114 Ocular neuromyotonia, 327 Ocular tilt reaction, 115–118 Oculocephalic reflex, 172–173 Oculogyric crisis, 115 Oculomotor nerve compression, 326–327 Oculomotor nerve lesions, 142, 167 Oculomotor nucleus, 8–10 Oculomotor nucleus lesion, 113–114 Oculomotor paresis, 245 Oligosaccharidoses, 318 Ondine’s curse, 163 One-and-a-half syndrome, 111, 167, 245 Opalski’s syndrome, 207 Opsoclonus, 128–129 Opsoclonus-myoclonus syndrome, 254 Opticokinetic eye movements, 105 Orbicularis oculi reflex, 172 P Palatal tremor, 296 Pantothenate kinase-associated neurodegeneration, 314 Pantothenate kinase–2-(PANK2-)associated neurodegeneration (NBIA) syndrome, 292 Parabrachial nuclei, 28 Paradoxical activation, masticatory musculature, 177 Parainfluenza virus, 231, 236 Paramedian pontine reticular formation (PPRF), 18, 107, 110 Paraneoplastic brainstem syndromes clinical findings middle and lower brainstem symptoms, 252–253 opsoclonus-myoclonus syndrome (OMS), 252 paraneoplasias, 253 diagnosis, 253–254 epidemiology, 251 etiology autoimmune reaction, 251–252 cytotoxic T-cells, 252 neuronal antibody, 251 immunotherapies, 254–255 prognosis, 255 Paraneoplastic encephalomyelitis, 254 Paraneoplastic neurologic syndromes (PNS), 251–255 Parasitic encephalitides, 240 Pareses alternate hemiplegia, 156 central, 154 central facial, 155 cerebellar afferents, 156 contralateral and ipsilateral motor hemiparesis, 154 course, corticofacial projections, 154 crossed syndromes, 155–156 definition and epidemiology, 153 distribution patterns, 156 hemiplegia cruciata, 155
Index locked-in syndrome, 155 peripheral, 153–154 prognosis, 157 therapy forced-use method, 157 physiotherapeutic exercises, 156 residual functional deficits, 157 verbal communication, 155 volitional and emotional, 154 Parinaud’s syndrome, 114, 205, 244–245 Parkinsonism, Alzheimer’s dementia, 288 Parkinson plus syndrome, 284 Parkinson’s disease, 60–61 anxiety disturbances, 283 autonomic dysfunction, 283 classification, 281 cognitive performance impairments, 283 DATATOP study, 285 definition, 280 dementia, 283, 290 diagnosis, 284 epidemiology, 280 etiology, 280–282 Holmes’s tremor, 295 motor and non-motor symptoms, 282 MSA, 294 neuropsychologic deficits, 283 presymptomatic early phase, 279 resting and postural tremor, 282 resting tremor, 297 therapy deep brain stimulation (DBS), 285 dopamine substitution, 284 medications, 284 physiotherapy, 285 Parkinson’s syndrome, 176 Paroxysmal (acute) ataxia, 152 Paroxysmal attacks, 249 Paroxysmal diplopia, 247 Paroxysmal dysarthria, 148 Paroxysmal OTR, 116 Paroxysmal phenomena, 247 Paroxysmal tinnitus, 329 Pathologic crying, 177 Pathologic laughter, 177 Pathologic nystagmus, 198 Pathologic yawning, 177 Pendular nystagmus, 249 Periaqueductal gray, 27 Perilymph fistula, 162 Perimesencephalic subarachnoid hemorrhage, 216–218 Periodic alternating gaze deviation (ping-pong gaze), 167–168 Periodic alternating nystagmus, 124–125, 137–138 Periodic/slowly alternating skew deviation, 117 Pial arteriovenous malformations, 223–224 Pierre-Marie-Foix and Alajouanine syndrome, 205 Pin-point pupils, 166 Plasmodia, 231 Plus-minus-lid syndrome, 245 Pneumococci, 231 Pneumotaxic center, 29 Poliomyelitis virus, 231, 236 Pons, 3 anterior inferior cerebellar artery (AICA), 34 basilar artery, 34 nuclear regions
359 abducens nucleus, 27 pontine base, 27 superior olivary nucleus, 27 Pontine infarctions, 199–200 Pontine micturition center, 28 Pontine nuclei, 27–28 Pontine tegmental hemorrhage, 213–214 Positioning nystagmus, 118 Posterior commissural syndrome, 114 Posterior commissure, 108, 113 Posterior inferior cerebellar artery (PICA), 34 “Posterior” internuclear ophthalmoplegia, 109–110 Posterior pretectal nucleus, 24 Posterior spinocerebellar tact, 31 Postural and gait ataxia, 198 Postural reflexes, 282 Postural tremor, 282 PPRF. See Paramedian pontine reticular formation Pretectal olivary nucleus, 24 Pretectal pseudo-bobbing, 168 Pretectal syndrome, 114 Pretectum, 24 Pretruncal hemorrhage, 216 Progressive multifocal leukoencephalopathy (PML), 250–251 Progressive supranuclear gaze palsy (PSP), 288–289 Progressive supranuclear gaze paresis, 61 Pseudoathetosis, 159, 177 Pupillary function, 166 R Rabies (lissa) virus, 231, 237–238 Raymond-Céstan syndrome, 205 Raymond’s syndrome, 205 Rebound nystagmus, 119 Recanalization acute dissections and occlusion, 50 acute distal basilar artery occlusion, 51 dilatation/stenting, 49–50 Doppler sonography, 49 endovascular therapy, 49 intra-arterial lysis, 50–51 mechanical thrombus removal, 51 “overstenting”, 50 stent-assisted dilatation, stenoses, 50 Recording, eye movements, 90–92 Red nucleus, 25 Reiber’s graph, 232 Reinhold’s syndrome, 206 Repetitive divergence, 168 Respiratory disturbances, 162–164 etiopathogenesis and clinic central sleep apnea syndrome., 162–163 Cheyne–Stokes respiration, 163 unilateral and bilateral lesions, 163 neuroanatomy, 162 therapy and prognosis, 163–164 Resting tremor, 282 Reverse ocular bobbing, 168 Reverse ocular dipping, 168 Rhombencephalosynapsis, 303 Ri-Ab, 252 Rickettsias, 231 Rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), 18, 108, 113 Rostral respiratory group, 29 Rotational vertebral artery occlusion, 58–59
360 Roving eye movements, 168 Rubella virus, 231 Rubella virus encephalitis, 237 S Saccades, 18, 105 Saccadic oscillations, 128 Sarcoidosis, 241–242 Schmidt’s syndrome, 206 Schwann cells, 5, 31 Schwannomas, 268–270 Scleral search coil technique, 92 Secondary parkinsonian syndromes, 284 Seesaw nystagmus, 123, 124 Seesaw/pendular nystagmus, 137 Segawa syndrome, 320 Sensory disturbances clinical findings crossed symptoms, 158 distribution pattern, 159 glossopharyngeal/trigeminal neuralgia, 159 hemihypesthesia/hemialgesia, 159 oral sensitivity disturbance, 158 “pseudoathetosis”, 159 trigeminal nerve, 158–159 trophic disturbances, 159 definition and epidemiology, 157 functional diagnostic evaluation blink reflex analysis, 160 SEPs and LEPs, 160 lesions dorsal column, 157 lateral spinothalamic tract, 158 lemniscal decussation, 158 medial lemniscus, 157–158 neuroanatomy and etiopathogenesis sensory nuclear region, 157 somatosensory afferents, 157 therapy and prognosis, 160 SEP. See Somatosensory evoked potentials Sialidosis, 318 Singultus, 174 Skew deviation, 115–118, 167, 198 Slowly/periodic alternating skew deviation, 116 Smooth pursuit, 105 Smooth pursuit eye movements, 20 Sneezing, 174 Solitary (tract) nucleus, 15 Somatosensory evoked potentials (SEP) anatomic and physiologic principles, 81 brain death, 84 description, 81 far-field potentials, 82–83 interconnection, 82 latencies, 82 lesions medullary, 83–84 pontine, 83 medial lemniscus, lesions, 83 recording, 82 stimulation, 81–82 Somnolence, 165 Sonography, brainstem, 59–61 Spastic tetraparesis, 246 Speech disorders
Index anarthria, 148 clinical picture and functional diagnostics dysarthria, 147 dysarthrophonia, 148 definition and epidemiology dysarthria, 147 mutism, 147 etiopathogenesis, 147 mutism lesion, mesodiencephalic junction, 149 periaqueductal gray, 148 therapy and prognosis, 149 transient, 149 neuroanatomy, 147 paroxysmal dysarthria, 148 Spiller’s syndrome, 207 Spinocerebellar tracts, 31 Spinothalamic tract, 31 Spontaneous nystagmus, 118, 120–126 Square wave jerks, 129–130 Stance and gait ataxia, 152 Stapedius reflex, 92–93 Steele-Richardson-Olszewski syndrome, 288–289 St. Louis encephalitis virus, 231, 237 Strachan’s syndrome, 308 Stupor, 165 Subacute scleroting panencephalitis (SSPE), 236 Subarachnoid hemorrhage (SAH). See also Vascular brainstem diseases CCT, 217 Hunt and Hess classification, 217 Subclavian steal syndrome, 58, 203–204 Subcortical vascular encephalopathy (SVE), 286, 287 Substantia nigra, 25–27 Superior colliculi, 3, 108 Superior oblique myokymia, 327 Swallowing centers, 149 Sweat secretion contralateral hemihyperhidrosis, 175–176 disturbances dysrhythmia and blood pressure, 176 gastrointestinal function, 176 ipsilateralal hemihypohidrosis, 175 Sylvian aqueduct syndrome, 114 Systemic lupus erythematosis (SLE) cortisone, therapy, 242 “neurolupus”, 242 T Ta(Ma2)-Ab, 252 Tapia’s syndrome, 206 Tauopathies, 289 Tectocerebellar dysrhaphia, 303 Thalamic infarctions, 201 Tinnitus and auditory disturbances definition, 138 diagnostic and differential diagnosis audiology devices, 139 central auditory syndromes, 139–140 clicking sounds/low frequency hissing, 139 pulsatile ear noises, 139 subjective and objective tinnitus, 139 etiology cochlear receptor/auditory afferent dysfunction, 138 description, 139 prevalence, 138
Index prognosis, 140 therapy, 140 Togaviridae virus, 231, 237 Tonic brainstem attacks, 175 Tonic horizontal gaze deviations (déviation conjugée), 167 Torsional nystagmus, 122–123 Toscana virus, 231 Toxoplasma gondii, 231 Transcranial magnetic stimulation (TMS) amyotrophic lateral sclerosis (ALS), 87 brainstem ischemia, MEPs, 86–87 corticofacial projections central motor conduction time (CMCT), 85 evaluation, 85–86 motor cortex, 85 corticolingual projections evaluation, 86 light preactivation, 85 unilateral lesion, 84 demyelinating lesion, 88 hereditary spastic spinal paralysis, 87 MS, 87 topodiagnostic significance, MEPs, 87 Traumatic brainstem lesions amnesia/coma, duration, 273–274 bilateral pontine lesions, 274 classification, 273, 274 corpus callosum lesion, 274 craniocerebral trauma, 278 CT, 278–279 diagnosis and differential diagnosis, 275–277 duration, amnesia/coma, 273–274 epidemiology computed tomography (CT), 272 MRI, 272 etiology, 272–273 grade III, 275 Kaplan-Meier function, 278 MRI, 278 prevention, secondary, 277–278 severity grades, 273 therapy, 277 Tremors, 176, 247, 249, 295–297 Treponema pallidum, 231, 239 Trigeminal involvement, 245 Trigeminal nerve compression, 327–328 lesions, 142–143 Trigeminal neuralgia, 247, 249, 327 Trigeminal nucleus, 11–12 Trigemino-cervical reflex, 93 Trigemino-hypoglossal silent period dorsolateral infarction, 94 enoral stimulation and recording device, 93 hemorrhage, cavernoma, 95 unilateral electric stimulation, 94 Trochlear nerve compression, 327 lesions, 142 nucleus, 108 Trochlear nucleus, 10 Tropheryma, 231 Tuberculosis, 239 Tumors, choroid plexus, 265–266
361 Turmarkin’s otolith crisis, 162 Tyrosine hydroxylase defects, 320 U Ultrasound diagnostics B-mode sonography clinical application, 60–61 principles and techniques, 59–60 vascular anatomic principles, 54 basilar artery thrombosis, 58 brainstem infarction/TIA, 57–58 color duplex sonography, 55 continuous wave Doppler, 54–55 pulsed Doppler sonography, 55 reference values, 56 rotational vertebral artery occlusion, 58–59 signal enhancers, 55–56 stenosis criteria, 56–57 subclavian steal syndrome, 58 Upbeat and downbeat nystagmus, 121 Upbeat nystagmus, 122, 135 Urea cycle defects, 321 V Vagus nerve, 15 Van Bogaert’s leucoencephalitis, 236 Varicella zoster virus (VZV), 231, 235–236 Vascular brainstem diseases basilar/vestibular migraine characteristics, 226 clinical-neurologic and neurootologic examination, 227 description, 225 diagnostic criteria, 226 etiology, 226 motions and motion sickness, 227 potassium channel blocker treatment, 227 prevalence and incidence, 225 prognosis, 228 therapy and prophylaxis, 227–228 vertebral artery dissection, 227 vertigo attacks, 226 cerebral superficial siderosis hemosiderin depositions, 219 myxopapillary ependymoma, 219 prognosis, 220 subpial hemosiderin depositions, 219 symptoms, 219 therapy, 220 infarctions (see Brainstem infarctions) intraparenchymatous hemorrhage clinical findings, 212–214 conservative therapy, 215 diagnosis, 214 differential diagnosis, 214 epidemiology, 211 etiology, 212 operative therapy, 215 prognosis, 215–216 therapy, 214–215 malformations (see Vascular malformations) perimesencephalic SAH anatomic variants, venous drainage, 216–217 aneurysm, 217 and aneurysmal hemorrhage, 217
362 cause, 216 CCT, 217 cerebral panangiography, 217 conservative therapy, 218 incidence, 216 low-dose heparinization, 218 prepontine, 216 psychosocial outcome, 218 ruptured aneurysm, 218 transcranial Doppler sonographic (TCD) examination, 217–218 vasospasm prophylaxis, 218 Vascular cranial nerve abducens, 328 compression trigeminal, 327–328 trochlear, 327 facial nerve, 328–329 glossopharyngeal, 329–330 oculomotor, 326–327 vestibulocochlear, 329 Vascularization, brainstem anastomotic ring, 28 medulla oblongata, 34 mesencephalon, 32–34 pons, 34 vascular territories, 32 Vascular malformations capillary telangiectasias clinical symptoms, 223 detection, 222 developmental venous anomalies (DVAs), 222–223 diagnosis, 223 genetic factors, 223 MRI, 222 therapy, 223 cavernomas vs. capillary telangiectasias, 220 cerebral, 220 CT, 222 hemorrhage risk, 221 infratentorial, localization, 220 MRI, 221 size and configuration, 220 spontaneous hemorrhages, 221 therapy, 223 dural arteriovenous (see Dural arteriovenous malformations) pial arteriovenous (see Pial arteriovenous malformations) Vascular parkinsonism, 284, 286, 287 Vascular ultrasound anatomic principles, course extracranial, 54 intracranial, 54 basilar artery thrombosis, 58 brainstem infarction/TIA, 57–58 color duplex sonography, 55 continuous wave (cw) Doppler examination technique, 54 frequency shifts, 54 pulsed Doppler sonography, 55 reference values, 56 rotational vertebral artery occlusion, 58–59 signal enhancers components, 55 contrast agents, 56 visualization, V4 segments, 56
Index stenosis criteria primary/direct, 56 secondary and tertiary, 56–57 V4/basilar artery territory, 56 subclavian steal syndrome, 58 system types, 54 Vasculitis, 197 Ventral tegmental area, 24 Vergences, 105–106 Vernet’s syndrome, 207 Version eye movements opticokinetic eye movements, 105 saccades, 105 smooth pursuit/following, 105 vestibuloocular reflex (VOR), 105 Versions, 105 Vertebral artery compression, head rotation, 196–197 Vertical eye movement disorders dorsal midbrain/pretectal syndrome crossed vertical gaze palsy, 115 etiology, 114 monocular depression deficiency, 115 monocular elevation paresis, 114–115 oculogyric crisis, 115 Parinaud’s syndrome, 114 smooth pursuit eye movements, 115 gaze palsies and one-and-a-half syndrome burst neurons, 113 posterior commissure, 113 unilateral lesion, 112 ocular tilt reaction (OTR) and skew deviation definition, 115–116 description, 116 differential diagnosis, 117–118 etiology, 117 pathomechanism, 117 types, 116 oculomotor nuclear lesions bilateral ptosis, 113 bilateral superior rectus paresis, 113 ipsilateral oculomotor palsy, 113 Vertical gaze deviations, 167 Vertical gaze palsies, 112–113 Vertigo, 199, 246 Vestibular-evoked myogenic potentials (VEMP). See Vestibulocollic reflex Vestibular migraine, 225–228 Vestibular nuclei, 13–14, 107 Vestibular paroxysmia, 329 Vestibulocochlear nerve compression, 329 lesions, 144 Vestibulocollic reflex (VCR) anatomic and physiologic principles, 75 application, 75 evaluation and reference values biphasic potential, 75 latencies, 76 peak-to-peak amplitudes, 75–76 interpretation, 76 Vestibulo ocular reflex (VOR), 105 Videooculography, 91–92 Visual hallucinations, 173–174 Vitamin B1 hypovitaminosis, 307–308
Index Vitamin B12 hypovitaminosis, 307–308, 310 Vitamin E deficiency, 311 Volitional paresis, 154 W Wallenberg’s syndrome, 204, 206 Weber’s syndrome, 205 Wernicke’s encephalopathy, 308–310 Western equine encephalitis virus, 231, 237 West Nile virus, 231 Westphal variant, 292 Whipple’s disease, 240, 292
363 Wilson’s disease, 284 cranial MRI, 313 epidemiology, 312 etiopathogenesis copper intake, 312 mutation H1069Q, 312 Kayser-Fleischer rings, 312, 313 medical therapy, 314 prognosis, 314 triethylentetramine/trientine, 313 zinc, 313 Wrong-way eyes, 167
