Essentials in Ophthalmology
Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics B. Lorenz F.-X. Borruat Editors
Essentials in Ophthalmology
Glaucoma
G. K. Krieglstein R. N. Weinreb Series Editors
Cataract and Refractive Surgery Uveitis and Immunological Disorders Vitreo-retinal Surgery Medical Retina Oculoplastics and Orbit Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics Cornea and External Eye Disease
Editors Birgit Lorenz François-Xavier Borruat
Pediatric Ophthalmology, NeuroOphthalmology, Genetics With 200 Figures, Mostly in Colour and 26 Tables
123
Series Editors
Volume Editors
Günter K. Krieglstein, MD Professor and Chairman Department of Ophthalmology University of Cologne Kerpener Straße 62 50924 Cologne Germany
Birgit Lorenz, MD, FEBO Professor and Chairman Department of Ophthalmology Universitätsklinikum Giessen and Marburg GmbH Giessen Campus Friedrichstraße 18 35392 Gießen Germany
Robert N. Weinreb, MD Professor and Director Hamilton Glaucoma Center Department of Ophthalmology University of California at San Diego 9500 Gilman Drive La Jolla, CA 92093-0946 USA
François-Xavier Borruat, MD, PD, MER Médecin-Adjoint Neuro-Ophthalmology Hôpital Ophtalmique Jules Gonin Avenue de France 15 CH-1004 Lausanne Switzerland
ISBN 978-3-540-33678-5 Springer Berlin Heidelberg NewYork
ISSN 1612-3212
Library of Congress Control Number: 2007936032
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Foreword The series Essentials in Ophthalmology was initiated two years ago to expedite the timely transfer of new information in vision science and evidence-based medicine into clinical practice. We thought that this prospicient idea would be moved and guided by a resolute commitment to excellence. It is reasonable to now update our readers with what has been achieved. The immediate goal was to transfer information through a high quality quarterly publication in which ophthalmology would be represented by eight subspecialties. In this regard, each issue has had a subspecialty theme and has been overseen by two internationally recognized volume editors, who in turn have invited a bevy of experts
to discuss clinically relevant and appropriate topics. Summaries of clinically relevant information have been provided throughout each chapter. Each subspecialty area now has been covered once, and the response to the first eight volumes in the series has been enthusiastically positive. With the start of the second cycle of subspecialty coverage, the dissemination of practical information will be continued as we learn more about the emerging advances in various ophthalmic subspecialties that can be applied to obtain the best possible care of our patients. Moreover, we will continue to highlight clinically relevant information and maintain our commitment to excellence. G. K. Krieglstein R. N. Weinreb Series Editors
Preface
Neuroophthalmology is one of the most interdisciplinary domains of ophthalmology. It encompasses disorders of both the afferent and efferent pathways whose etiologies may be genetic or acquired, e.g., metabolic, vascular, inflammatory, infectious, tumoral or paraneoplastic. The aim of this monograph is to present the most modern concepts for diagnosing and treating some of these disorders. We selected topics of particular interest due to the advent of recent diagnostic or therapeutic advances but this list is by no means exhaustive: textbooks in neuroophthalmology usually consist of several volumes! In line with the focus of this series of monographs we have included chapters of immediate clinical relevance as well as science-oriented chapters in order to also provide the reader with some insight into basic research areas that eventually will have an impact on clinical neuroophthalmology. The volume is organised in six sections: optic nerve; investigations; retinal disorders; systemic diseases; oculomotility; and rehabilitation. Part I, Optic nerve, discusses optic neuritis and multiple sclerosis, ischemic neuropathies, optic disc drusen, autosomal-dominant optic neuropathy, Leber hereditary optic neuropathy (LHON), optic nerve tumors, and traumatic optic neuropathy including treatment recommendations and experimental data on neuroprotection.
Part II, Investigations, describes and critically evaluates the most recent methods of imaging and electrophysiology of the optic nerve and the central visual pathways. Part III, Retinal disorders, provides an overview on autoimmune retinopathies and on the basic aspects of cell death as well as on actual and future issues of cell protection and cell rescue. Part IV, Systemic diseases, covers various aspects of infectious diseases from the retina to the brain, including differential diagnosis and treatment and the latest recommendations in diagnosis and management of giant cell arteritis. Part V, Oculomotility, covers the cerebral control of eye movements, mitochondrial diseases causing ocular myopathy, and therapeutic options for specific types of neurological nystagmus. Finally, Part VI, Rehabilitation, summarizes the potentials and limitations of visual rehabilitation in neuroophthalmological disorders. All chapters are written by leading authorities in their field. We are grateful to the authors for their excellent contributions and also to the publishers for their encouragement and support.
Birgit Lorenz François-Xavier Borruat
Contents
Part I Optic Nerve Chapter 1 Optic Neuritis and Multiple Sclerosis Edward J. Atkins, Valérie Biousse, Nancy J. Newman 1.1 1.1.1 1.1.2 1.1.3 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.3 1.3.1 1.3.2 1.3.3 1.4
Idiopathic Optic Neuritis . . . . . 4 Clinically Isolated Syndrome . 4 Clinical Features of Acute Idiopathic Optic Neuritis . . . . . . . . . . . . . . . . . . . . 4 Examination Findings in Acute Idiopathic Optic Neuritis . . . . . . . . . . . . . . . . . . . . 4 Natural History of Acute Idiopathic Optic Neuritis . . . . . 4 Important Studies . . . . . . . . . . 4 Visual Prognosis . . . . . . . . . . . . 5 Risk of Recurrence of Optic Neuritis . . . . . . . . . . . . . . . . . . . . 5 Risk of Developing Multiple Sclerosis . . . . . . . . . . . . . . . . . . . 5 Severity of Multiple Sclerosis in Patients Presenting with Optic Neuritis . . . . . . . . . 10 Management of Acute Idiopathic Optic Neuritis . . . . 10 Diagnosis . . . . . . . . . . . . . . . . . 11 Acute Therapeutic Options . 12 Chronic Therapeutic Options 13 Pediatric Optic Neuritis . . . . . 14
Chapter 2 Ischemic Optic Neuropathies Anthony C. Arnold 2.1 2.2 2.2.1
Introduction . . . . . . . . . . . . . . . 19 Anterior Ischemic Optic Neuropathy . . . . . . . . . . . . . . . 20 Arteritic Anterior Ischemic Optic Neuropathy . . . . . . . . . . 20
2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.1.6 2.2.2 2.2.2.1 2.2.2.2 2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.2.7 2.2.2.8 2.3
Clinical Presentation . . . . . . . Pathophysiology . . . . . . . . . . Differential Diagnosis . . . . . . Clinical Course . . . . . . . . . . . . . Diagnostic Confirmation . . . Therapy . . . . . . . . . . . . . . . . . . . Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . Pathophysiology . . . . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . Medications . . . . . . . . . . . . . . Clinical Course . . . . . . . . . . . . . Differential Diagnosis . . . . . . Therapy . . . . . . . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . Posterior Ischemic Optic Neuropathy . . . . . . . . . . . . . . .
20 22 23 23 23 24 25 25 26 27 29 30 30 31 31 32
Chapter 3 Optic Disc Drusen François-Xavier Borruat 3.1 3.2 3.3 3.4 3.5 3.5.1 3.5.2 3.5.3 3.6 3.6.1 3.6.2 3.6.3 3.6.4 3.6.5
Introduction . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . Optic Canal Size . . . . . . . . . . . Associations . . . . . . . . . . . . . . . Inherited Retinal Degenerations . . . . . . . . . . . . . Angioid Streaks and Pseudoxanthoma Elasticum . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . Paraclinical Investigations . . B-Scan Ultrasound . . . . . . . . . Scanning Laser Ophthalmoscope . . . . . . . . . . Optical Coherence Tomography . . . . . . . . . . . . . . Scanning Laser Polarimetry Electrophysiology . . . . . . . . . .
37 37 38 39 40 40 40 40 41 41 41 43 44 44
Contents
3.6.6 3.7 3.7.1 3.7.2 3.7.3 3.7.4 3.8
Retinal Angiography . . . . . . . Complications . . . . . . . . . . . . . Visual Field Defects . . . . . . . . Retinal Vascular Complications . . . . . . . . . . . . . Peripapillary Choroidal Neovascularization . . . . . . . . . Anterior Ischemic Optic Neuropathy . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . .
44 44 44 46 46 46 46
Chapter 4 Inherited Optic Neuropathies Marcela Votruba 4.1 4.2 4.2.1 4.2.1.1 4.2.1.2 4.2.1.3 4.2.1.4 4.2.1.5 4.2.1.6 4.2.2 4.2.2.1 4.2.2.2 4.2.3 4.2.3.1 4.2.3.2 4.2.4 4.2.4.1 4.2.4.2 4.2.4.3 4.2.4.4 4.2.4.5 4.2.4.6 4.2.4.7
Introduction . . . . . . . . . . . . . . . Primary Inherited Optic Neuropathies with Ocular Manifestations . . . . . . . . . . . . . Autosomal-Dominant Optic Atrophy . . . . . . . . . . . . . . . . . . Clinical Features . . . . . . . . . . . Electrophysiology . . . . . . . . . . Histopathology . . . . . . . . . . . . Molecular Genetics and the Genetic Heterogeneity of ADOA . . . . OPA4 Locus . . . . . . . . . . . . . . . OPA3 Locus: AutosomalDominant Optic Atrophy and Cataract (ADOAC) . . . . . . Recessive Optic Atrophy . . . . Clinical Features . . . . . . . . . . . OPA5 Locus . . . . . . . . . . . . . . . X-Linked Optic Atrophy . . . . Clinical Features . . . . . . . . . . . OPA2 Locus . . . . . . . . . . . . . . . Mitochondrial Disease: Leber’s Hereditary Optic Neuropathy . . . . . . . . . . . . . . . Clinical Features . . . . . . . . . . . Findings in Unaffected Relatives . . . . . . . . . . . . . . . . . . Systemic Manifestations . . . . Molecular Genetics . . . . . . . . LHON-Associated Mitochondrial Mutations . . . Genotype–Phenotype Correlation . . . . . . . . . . . . . . . . Evidence for an X-Linked Susceptibility Factor . . . . . . .
51 52 52 52 55 55 55 58 58 58 58 59 59 59 59 59 59 60 60 61 62 62 63
4.2.4.8 The Pathophysiology of LHON . . . . . . . . . . . . . . . . . . . 4.3 Primary Inherited Optic Neuropathies with Significant Systemic Features . . . . . . . . . . . . . . . . . . . 4.3.1 Autosomal-Dominant Optic Atrophy and Neurological Defects . . . . . . . . . . . . . . . . . . . 4.3.2 Autosomal-Recessive Optic Atrophy “Plus” . . . . . . . . . . . . . 4.3.3 Costeff’s Syndrome . . . . . . . . 4.3.4 Behr’s Syndrome . . . . . . . . . . . 4.3.5 Wolfram Syndrome, DIDMOAD . . . . . . . . . . . . . . . . . 4.4 Conclusions . . . . . . . . . . . . . . .
63
64 64 64 64 64 64 65
Chapter 5 Optic Nerve Tumours Tim D. Matthews 5.1 5.1.1 5.1.1.1 5.1.2 5.1.2.1 5.2 5.2.1 5.2.1.1 5.2.1.2 5.2.2 5.2.2.1 5.2.2.2 5.3 5.3.1 5.3.1.1 5.3.1.2 5.3.2 5.4
Introduction . . . . . . . . . . . . . . . Gliomas . . . . . . . . . . . . . . . . . . . NF1 . . . . . . . . . . . . . . . . . . . . . . . Meningiomas . . . . . . . . . . . . . . Retino-Choroidal Collaterals Imaging . . . . . . . . . . . . . . . . . . . Gliomas . . . . . . . . . . . . . . . . . . . Typical . . . . . . . . . . . . . . . . . . . . Masquerade . . . . . . . . . . . . . . . Meningiomas . . . . . . . . . . . . . . Typical . . . . . . . . . . . . . . . . . . . . Masquerade . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . Gliomas . . . . . . . . . . . . . . . . . . . Paediatric . . . . . . . . . . . . . . . . . Adult . . . . . . . . . . . . . . . . . . . . . Meningiomas . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . .
69 69 71 71 72 74 74 74 74 75 75 76 76 76 77 78 79 80
Chapter 6 Traumatic Optic Neuropathy: Recommendations and Neuroprotection Solon Thanos, Stephan Grewe, Tobias Stupp 6.1 6.1.1 6.1.2
Introduction . . . . . . . . . . . . . . . 83 Optic Nerve Anatomy . . . . . . 83 Traumatic Optic Neuropathy . . . . . . . . . . . . . . . 84
6.2 6.3 6.4 6.5 6.6 6.6.1 6.6.2 6.6.3 6.6.4 6.7 6.8
Contents
Review of Previous Studies on TONs . . . . . . . . . . . . . . . . . . . Histopathology of TON . . . . . Mechanisms of TONInduced Ganglion Cell Death Diagnosis of TON . . . . . . . . . . Therapeutic Concepts of TON . . . . . . . . . . . . . . . . . . . . Steroids . . . . . . . . . . . . . . . . . . . Neuroprotection . . . . . . . . . . . Surgical Decompression . . . . The Role of Ophthalmologists . . . . . . . . . . Outlook on Regeneration of the Optic Nerve . . . . . . . . . Current Clinical Practice and Recommendations . . . . .
84 87 89 89 91 91 91 91
7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.2.5.1 7.2.5.2 7.2.5.3 7.2.5.4 7.3
7.3.1.3
7.3.2 7.3.3
92
7.3.4
93
7.3.4.1 7.3.4.2 7.3.4.3 7.4
Chapter 7 Imaging the Nerve Fiber Layer and Optic Disc Marc Dinkin, Michelle Banks, Joseph F. Rizzo III Introduction . . . . . . . . . . . . . . Overview of Early Imaging Techniques . . . . . . . . . . . . . . . Optic Nerve Head Drawings . . . . . . . . . . . . . . . . . Direct Ophthalmoscopy of the Nerve Fiber Layer . . . Retinal Nerve Fiber Layer Photography . . . . . . . . . . . . . Stereoscopic Optic Nerve Head Photography . . . . . . . . Optic Nerve Head Analyzers . . . . . . . . . . . . . . . . The Topcon IMAGEnet . . . . The Humphrey Retinal Analyzer . . . . . . . . . . . . . . . . . The Rodenstock Optic Nerve Head Analyzer . . . . . . . . . . . . The Glaucoma-Scope . . . . . Modern Techniques for Optic Nerve and Retinal Nerve Fiber Layer Imaging . . . . . . . . . . . .
7.3.1.1 7.3.1.2
91
Part II Investigations
7.1 7.2
7.3.1
7.5 7.5.1 7.6 100 100 100
8.1 8.2
100
8.3
101
8.4
102 102
8.5
102 103
8.6 8.7 8.8
103
103 105 105
106 106 107 109 111 111 112 113 113 114 115
Chapter 8 Functional Neuroanatomy of the Human Visual System: A Review of Functional MRI Studies Mark W. Greenlee, Peter U. Tse
100
102
Scanning Laser Ophthalmoscopy and Tomography . . . . . . . . . . The Rodenstock System . . . The Heidelberg Laser Tomographic Scanner . . . . . The Zeiss Confocal Scanning Laser Ophthalmoscope and TopSS™ Topographic Scanning System . . . . . . . . . The Heidelberg Retinal Tomograph II . . . . . . . . . . . . . Scanning Laser Polarimetry (“GDx”) . . . . . . . . . . . . . . . . . . . Optical Coherence Tomography . . . . . . . . . . . . . . Using OCT for Glaucoma Evaluation . . . . . . . . . . . . . . . . Other Uses of OCT . . . . . . . . Ultrahigh-Resolution OCT (UHR-OCT) . . . . . . . . . . . . . . . Imaging of the Optic Nerve and Alzheimer Disease . . . . Comparing Modalities . . . . . MRI . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . .
Introduction . . . . . . . . . . . . . . Imaging the Lateral Geniculate Nucleus . . . . . . . Functional Maps of the Visual Field . . . . . . . . . . . . . . . Striate and Extrastriate Visual Areas in Human Visual Cortex (V1, V2, V3) . . . . . . . . Receptive Field Size as a Function of Retinal Eccentricity . . . . . . . . . . . . . . . Alternative Methods of Retinotopic Mapping . . . Columnar Structures within Human V1 . . . . . . . . . . . . . . . . Orientation Specificity of BOLD Responses in Visual Cortex . . . . . . . . . . . . . . . . . . .
119 121 121 121 122 124 125 125
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8.9 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18
Visual Maps of Higher Visual Function: V4 . . . . . . . . . . . . . . Visual Maps of Higher Visual Function: V3A, V3B and KO . Segmenting Extrastriate Areas and MT+ into Functional Subregions . . . . Responses to Optic Flow . . Disparity and Motion-inDepth Stimulation . . . . . . . . Interface Between Visual and Oculomotor Systems . . . . . . . . . . . . . . . . . . Parietal Lobe Maps of Visuotopic Space . . . . . . . Working Memory for Visual Stimuli . . . . . . . . . . . . . . . . . . . Role of V1 in Visual Consciousness . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . .
126 126 127 128 129 129 130 130 132 132
Chapter 9 Investigating Visual Function with Multifocal Visual Evoked Potentials Michael B. Hoffmann 9.1 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.3 9.3.1 9.3.2 9.4 9.4.1 9.4.2 9.4.3 9.5
Introduction . . . . . . . . . . . . . . Multifocal Principle and Characteristics of Multifocal VEPs . . . . . . . . . . . . . . . . . . . . . Basics – Multifocal Stimulation, Firstand Second-Order Kernels Stimulus Display for mfVEP Recordings . . . . . . . . . . . . . . . Recording mfVEPs and Practical Considerations . . . . . . . . . . . Dependence of mfVEPs on Visual Cortex Morphology . . . . . . . . . . . . . . Assessment of mfVEPs . . . . Response Magnitude . . . . . . Response Latency . . . . . . . . . mfVEP Investigations of Diseases . . . . . . . . . . . . . . . mfVEP in Glaucoma . . . . . . . mfVEP in Optic Neuritis . . . . mfVEP in Albinism . . . . . . . . Conclusion . . . . . . . . . . . . . . .
Part III Retinal Disorders Chapter 10 Autoimmune Retinopathies Jennifer K. Hall, Nicholas J. Volpe 10.1 10.2 10.3 10.3.1 10.3.1.1 10.3.1.2 10.3.1.3 10.3.1.4 10.3.2 10.3.2.1 10.3.2.2 10.3.2.3 10.3.2.4 10.3.3
139 140 140 143 143 146 148 148 149 151 152 153 154 157
10.3.3.1 10.3.3.2 10.3.3.3 10.3.3.4 10.4 10.5 10.5.1 10.5.1.1 10.5.1.2 10.5.1.3 10.5.1.4 10.5.2 10.5.2.1 10.5.2.2 10.5.2.3 10.5.2.4 10.5.3
Autoimmune Disease Overview . . . . . . . . . . . . . . . . . Autoimmune Retinopathy Overview . . . . . . . . . . . . . . . . . Paraneoplastic Retinopathies . . . . . . . . . . . . Cancer-Associated Retinopathy . . . . . . . . . . . . . Clinical Presentation . . . . . . Diagnostic Studies . . . . . . . . Pathophysiology . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . Melanoma-Associated Retinopathy . . . . . . . . . . . . . . Clinical Presentation . . . . . . Diagnostic Studies . . . . . . . . Pathophysiology . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . Bilateral Diffuse Uveal Melanocytic Proliferation . . Clinical Presentation . . . . . . Diagnostic Studies . . . . . . . . Pathophysiology . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . AutoimmuneRelated Retinopathy and Optic Neuropathy . . . . . Acute Outer Retinopathies with Blind Spot Enlargement . . . . . . . . Acute Idiopathic Blind Spot Enlargement . . . Clinical Presentation . . . . . . Diagnostic Studies . . . . . . . . Pathophysiology . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . Multiple Evanescent White Dot Syndrome . . . . . . . . . . . Clinical Presentation . . . . . . Diagnostic Studies . . . . . . . . Pathophysiology . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . Acute Zonal Occult Outer Retinopathy . . . . . . . . . . . . . .
163 164 164 164 166 166 166 168 168 168 168 169 169 169 170 170 170 171 171 172 173 173 173 173 176 176 176 176 177 178 178
10.5.3.1 10.5.3.2 10.5.3.3 10.5.3.4 10.5.3.5 10.6
Contents
Clinical Presentation . . . . . . Diagnostic Studies . . . . . . . . Pathophysiology . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . AZOOR Complex of Disease Summary . . . . . . . . . . . . . . . .
178 178 179 179 179 180
Chapter 11 Retinal Research: Application to Clinical Practice Ludwig Aigner, Claudia Karl 11.1 11.1.1 11.1.2 11.1.3 11.2 11.2.1 11.2.1.1 11.2.1.2 11.3 11.3.1 11.3.1.1 11.3.1.2
11.3.1.3
11.3.1.4
11.3.2 11.3.2.1 11.3.2.2
Introduction . . . . . . . . . . . . . Retinitis Pigmentosa . . . . . . Age-Related Macular Degeneration . . . . . . . . . . . . Glaucoma . . . . . . . . . . . . . . . Cell Death in the Retina . . . Major Characteristics and Pathways of Apoptosis Caspase-Dependent Apoptosis . . . . . . . . . . . . . . . . Caspase-Independent Apoptosis . . . . . . . . . . . . . . . . Therapeutic Strategies in Degenerative Retinal Diseases . . . . . . . . . . . . . . . . . Strategies for Neuroprotection . . . . . . Animal Models in Retinal Degeneration Research . . . . Strategies for Neuroprotection Interfering with the Induction Phase of Apoptosis . . . . . . . . . . . . . . Strategies for Neuroprotection Interfering with the Early Phase of Apoptosis . . . . . . . . Strategies Using Neuroprotective Cytokines that Showed Effects in Other Tissues . . . . . . . . . . . . . . . . . . . Cell Therapy for the Diseased Retina . . . Cell Transplantation in the Retina . . . . . . . . . . . . . Application of Transgenes or Genetically Engineered Stem and Progenitor Cells .
11.3.2.3 Endogenous Cell Replacement in the Retina . 199
Part IV Systemic disease Chapter 12 Chorioretinal Lesions in Infectious Diseases of Neuroophthalmic Interest Yan Guex-Crosier
185 185 186 186 186 187 187 188 189 189 189
190
191
191 192 193 198
Introduction . . . . . . . . . . . . . . Ocular Zoonosis . . . . . . . . . . Ocular Toxoplasmosis . . . . . Congenital Toxoplasmosis . Reactivation of Toxoplasmosis in Immunocompetent Patients . . . . . . . . . . . . . . . . . . 12.2.1.3 Ophthalmic Toxoplasmosis in AIDS Patients . . . . . . . . . . . 12.2.1.4 Neurologic Manifestation of Toxoplasmosis in AIDS Patients . . . . . . . . . . . . . . . . . . 12.2.1.5 Radiologic Manifestation of Toxoplasmosis in AIDS . . 12.2.2 Toxocariasis . . . . . . . . . . . . . . 12.2.2.1 Introduction . . . . . . . . . . . . . . 12.2.2.2 Ocular Manifestations . . . . . 12.2.2.3 Neurologic Manifestations . 12.2.3 Diseases Transmitted by Ticks . . . . . . . . . . . . . . . . . . 12.2.3.1 Introduction . . . . . . . . . . . . . . 12.2.3.2 Tick-Borne Encephalitis . . . . 12.2.3.3 Lyme Disease . . . . . . . . . . . . . 12.2.4 Cat Scratch Disease . . . . . . . 12.2.4.1 Introduction . . . . . . . . . . . . . . 12.2.4.2 Ocular and Neuroophthalmologic Manifestations . . . . . . . . . . . . 12.2.4.3 Neurologic Manifestations 12.2.4.4 Therapy . . . . . . . . . . . . . . . . . . 12.3 Sexually Transmitted Diseases . . . . . . . . . . . . . . . . . 12.3.1 Syphilis . . . . . . . . . . . . . . . . . . 12.3.1.1 Introduction . . . . . . . . . . . . . . 12.3.1.2 Ocular and Neuroophthalmologic Manifestations . . . . . . . . . . . . 12.3.1.3 Diagnostic Tests . . . . . . . . . .
12.1 12.2 12.2.1 12.2.1.1 12.2.1.2
206 206 206 206
207 209 209 209 210 210 210 210 210 210 210 211 214 214 214 215 215 215 215 215 215 216
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XIV
Contents
12.3.1.4 Therapy . . . . . . . . . . . . . . . . . . 12.3.2 Human Immunodeficiency Virus (HIV) and Ocular Infection . . . . . . 12.3.2.1 Introduction . . . . . . . . . . . . . . 12.3.2.2 HIV Retinopathy . . . . . . . . . . 12.3.2.3 CMV Retinitis . . . . . . . . . . . . . 12.4 Encephalopathies Due to Viral and NonConventional Agents . . . . . . 12.4.1 Lymphocytic Choriomeningitis Virus . . . . 12.4.2 Creutzfeldt–Jakob Disease . . . . . . . . . . . . . . . . . . 12.4.3 JC Virus and Progressive Multifocal Leukoencephalopathy . . . . 12.4.4 Herpetic Encephalopathy and Acute Retinal Necrosis Syndrome . . . . . . . . . . . . . . . . 12.5 Conclusion . . . . . . . . . . . . . . .
216 216 216 217 218
Pathophysiology of Giant Cell Arteritis . . . . . . 13.1.1 Epidemiology . . . . . . . . . . . . 13.1.2 Triggering Event . . . . . . . . . . 13.1.3 Tropism to Certain Vascular Beds . . . . . . . . . . . . . . . . . . . . . 13.1.4 Macrophage Recruitment and Vascular Injury . . . . . . . . 13.1.5 Systemic Inflammation . . . . 13.2 Clinical (Non-Ophthalmic) Manifestations of GCA . . . . . 13.2.1 Natural History . . . . . . . . . . . 13.2.2 Systemic Signs and Symptoms . . . . . . . . . . . 13.2.3 Headache and Craniofacial Pain . . . . . . 13.2.4 Auditory Manifestations . . . 13.2.5 Neurologic Manifestations 13.2.6 Occult GCA . . . . . . . . . . . . . . . 13.3 Visual Manifestations of GCA . . . . . . . . . . . . . . . . . . . 13.3.1 Transient Visual Loss . . . . . . 13.3.2 Anterior Ischemic Optic Neuropathy . . . . . . . . . . . . . .
13.3.4 13.3.5 13.4 13.4.1
220
13.4.2 13.4.3 13.5
220
13.5.1
220
13.5.2 13.5.3 13.5.4
221 222 222
Chapter 13 Giant Cell Arteritis Aki Kawasaki 13.1
13.3.3
13.5.5 13.5.6 13.6 13.6.1 13.6.2 13.6.3 13.6.4
227 227 228 228 229 230 231 231
13.7 13.7.1 13.7.1.1 13.7.1.2 13.7.1.3 13.7.1.4 13.7.2 13.7.3 13.7.4 13.7.5
231 231 232 232 232 233 233 234
Other Types of Ischemic Visual Loss . . . . Diplopia . . . . . . . . . . . . . . . . . . Orbital Manifestations . . . . . Clinical Subtypes of GCA . . Systemic Inflammatory Syndrome . . . . . . . . . . . . . . . . Cranial Arteritis . . . . . . . . . . . Large-Vessel Vasculitis . . . . Laboratory Investigations in GCA . . . . . . . . . . . . . . . . . . . Erythrocyte Sedimentation Rate . . . . . . . . . . . . . . . . . . . . . C-Reactive Protein . . . . . . . . Thrombocytosis . . . . . . . . . . Interleukin-6 and Other Cytokines . . . . . . Anemia . . . . . . . . . . . . . . . . . . Others . . . . . . . . . . . . . . . . . . . Diagnosis of GCA . . . . . . . . . Temporal Artery Biopsy . . . . American College of Rheumatology Criteria . . Role of Ultrasound . . . . . . . . Other Non-Invasive Imaging of the Cranial Arteries . . . . . Treatment and Prognosis of GCA . . . . . . . . . . . . . . . . . . . Corticosteroids . . . . . . . . . . . Starting Dose . . . . . . . . . . . . . Maintenance Dose . . . . . . . . Tapering Regimen . . . . . . . . Duration of Treatment . . . . . Visual Outcome on Corticosteroids . . . . . . . . Methotrexate . . . . . . . . . . . . Other Adjuvant Therapies . Treatment of Large-Vessel Involvement . . . . . . . . . . . . . .
235 235 236 236 236 236 237 238 238 239 239 239 240 240 240 241 241 243 243 244 244 245 245 245 245 245 246 246 247
Part V Oculomotility Chapter 14 Cerebral Control of Eye Movements Charles Pierrot-Deseilligny 14.1 14.2
Introduction . . . . . . . . . . . . . . 254 Brainstem . . . . . . . . . . . . . . . . 255
Contents
14.2.1 Horizontal Eye Movements 14.2.1.1 Final Common Pathway . . . 14.2.1.2 Premotor Structures and Afferent Pathways . . . . 14.2.2 Vertical Eye Movements . . . 14.2.2.1 Final Common Pathway . . . 14.2.2.2 Premotor Structures and Brainstem Afferents . . 14.3 Suprareticular Structures . . 14.3.1 Cerebellum . . . . . . . . . . . . . . . 14.3.2 Cerebral Hemispheres . . . . . 14.4 Abnormal Eye Movements 14.4.1 Nystagmus . . . . . . . . . . . . . . . 14.4.2 Non-Nystagmic Abnormal Eye Movements . . . . . . . . . . .
255 255 257 259 259 259 261 261 262 263 263 264
Chapter 15 Chronic Progressive External Ophthalmoplegia – A Common Ocular Manifestation of Mitochondrial Disorders Marcus Deschauer, Stephan Zierz 15.1 15.2 15.2.1 15.2.2 15.2.2.1 15.2.2.2 15.2.2.3 15.3 15.3.1 15.3.2 15.3.3
15.3.4 15.3.5 15.3.6 15.4 15.4.1 15.4.2
Introduction . . . . . . . . . . . . . . Clinical Features . . . . . . . . . . Ophthalmoplegia and Ptosis . . . . . . . . . . . . . . . . CPEO Plus: Multisystemic Involvement . . . . . . . . . . . . . . Muscle Impairment . . . . . . . Visual Impairment . . . . . . . . Specific CPEO Plus Syndromes . . . . . . . . . . . . . . . Genetics . . . . . . . . . . . . . . . . . General Mitochondrial Genetics . . . . . . . . . . . . . . . . . Single Deletions of mtDNA Defects of Intergenomic Communication with Multiple Deletions of mtDNA . . . . . . . . . . . . . . . . Point Mutations of mtDNA . . . . . . . . . . . . . . . . Coenzyme Q Deficiency . . . Genotype–Phenotype Correlation . . . . . . . . . . . . . . . Diagnostics . . . . . . . . . . . . . . . Myohistological Investigations . . . . . . . . . . . . Biochemical Investigations
267 268 268 268 268 268 268 270 270 270
271 272 273 273 274 275 275
15.4.3 Molecular Genetic Investigations . . . . . . . . . . . . 15.5 Treatment . . . . . . . . . . . . . . . . 15.5.1 Pharmacological Therapy . . 15.5.2 Symptomatic Treatment . . 15.5.3 Gene Therapy . . . . . . . . . . . . 15.6 Differential Diagnosis . . . . . 15.6.1 Oculopharygeal Muscular Dystrophy . . . . . . . . . . . . . . . 15.6.2 Myasthenic Syndromes . . . 15.6.3 Congenital Fibrosis of the Extraocular Muscles 15.6.4 Ocular Myositis . . . . . . . . . . . 15.6.5 Endocrine Ophthalmopathy . . . . . . . . . 15.6.6 Myotonic Dystrophy . . . . . . 15.6.7 Facioscapulohumeral Muscular Dystrophy . . . . . . . 15.6.8 Congenital Myopathies . . . .
275 276 276 277 277 278 278 278 279 279 279 279 279 279
Chapter 16 Treatment of Specific Types of Nystagmus Marianne Dieterich 16.1 16.2 16.2.1 16.2.1.1 16.2.1.2 16.2.2 16.2.2.1 16.2.2.2 16.3 16.3.1 16.3.1.1 16.3.2 16.3.2.1 16.3.2.2
Introduction . . . . . . . . . . . . . . Peripheral Vestibular and Ocular Motor Disorders Acute Peripheral Vestibulopathy, Vestibular Neuritis . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . Therapeutic Recommendations . . . . . . . . Superior Oblique Myokymia . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . Therapeutic Recommendations . . . . . . . . Supranuclear Ocular Motor Disorders . . . . . . . . . . . . . . . . . Central Vestibular Disorders Vestibular Syndromes in the Sagittal (Pitch) Plane Central Ocular Motor Disorders . . . . . . . . . . . . . . . . . Acquired Pendular Nystagmus . . . . . . . . . . . . . . . Opsoclonus and Ocular Flutter . . . . . . . . . . . . . . . . . . .
284 284 284 286 287 288 288 288 289 289 289 294 294 296
XV
XVI
Contents
305 307
17.3.3.1 Hemianopic Reading Disorder . . . . . . . . . . . . . . . . . 17.3.3.2 Hemianopic Orientation Disorder . . . . . . . . . . . . . . . . . 17.3.4 Cortical Visual Impairment 17.4 Diagnostic Procedures to Examine Reading Ability 17.5 Rehabilitation Programs . . . 17.5.1 Visual Aids in Reading Disorders . . . . . . . . . . . . . . . . . 17.5.2 Visual and Other Aids in Spatial Orientation Problems . . . . . . . . . . . . . . . . . 17.5.3 Training . . . . . . . . . . . . . . . . . . 17.5.3.1 Training for Patients with Circumscribed Scotomas in the Central Field . . . . . . . . . . . . . . . . . . . . . 17.5.3.2 Training for Patients with Homonymous Field Defects . . . . . . . . . . . . . . . . . . 17.5.4 Counseling Regarding Public Support . . . . . . . . . . . . 17.6 Summary and Conclusions
307
Subject Index . . . . . . . . . . . . . . . . . 321
Part VI Rehabilitation Chapter 17 Rehabilitation in Neuroophthalmology Susanne Trauzettel-Klosinski Introduction . . . . . . . . . . . . . . Psychophysics of Normal Reading . . . . . . . . . . . . . . . . . . 17.3 Diseases of the Visual Pathways and their Functional Deficits . . . . . . . . 17.3.1 Optic Neuropathies . . . . . . . 17.3.1.1 Central Scotomas . . . . . . . . . 17.3.1.2 Arcuate Scotomas: Nerve Fiber Bundle Defects . . . . . . 17.3.1.3 Ring Scotomas . . . . . . . . . . . . 17.3.1.4 Constricted Fields . . . . . . . . . 17.3.1.5 The Impact of Visual Field Defects on Reading Performance . . . . . . . . . . . . . 17.3.2 Optic Chiasmal Syndromes 17.3.3 Suprachiasmatic Lesions of the Visual Pathways . . . . .
17.1 17.2
301 302 303 303 303 305 305 305
308 310 311 311 312 312 313 314
314 315 316 316
Contributors
Ludwig Aigner, Prof. Dr. Klinik und Poliklinik für Neurologie der Universität Regensburg Im Bezirksklinikum Universitätsstraße 84 93053 Regensburg Germany Anthony C. Arnold, MD, Prof. Neuro-Ophthalmology Division Director, UCLA Optic Neuropathy Center Jules Stein Eye Institute UCLA Department of Ophthalmology 100 Stein Plaza Los Angeles, CA 90095-7005 USA Edward J. Atkins, MD Division of Neurology University of Saskatchewan RUH Box 239 103 Hospital Drive Saskatoon, SK, S7N 0W8 Canada Michelle Banks, MD 100 Stein Plaza Los Angeles, California USA Valérie Biousse, MD, Prof. Departments of Ophthalmology and Neurology Emory University Neuro-ophthalmology Unit Emory Eye Center 1365-B Clifton Road, NE, Atlanta, Georgia 30322 USA
François-Xavier Borruat, MD, PD, MER Department of Neuro-Ophthalmology Hôpital Ophtalmique Jules Gonin Avenue de France 15 CH-1004 Lausanne Switzerland Marcus Deschauer, Priv.-Doz. Dr. Neurologische Klinik der Universität Halle-Wittenberg Ernst-Grube-Straße 40 06097 Halle/Saale Germany Marianne Dieterich, Prof. Dr. Neurologische Klinik, Universität Mainz Langenbeckstraße 1 55101 Mainz Germany Marc Dinkin, MD Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 USA Mark W. Greenlee, Prof. Dr. Institut für Experimentelle Psychologie Universität Regensburg Universitätsstraße 31 93053 Regensburg Germany Stephan Grewe, Dr. Institut für Experimentelle Ophthalmologie Klinik und Poliklinik für Augenheilkunde Domagkstraße 15 48149 Münster Germany
XVIII
Contributors
Yan Guex-Crosier, MD, PD, MER Ocular Immunology and Inflammation Unit Jules Gonin Eye Hospital 15 av. de France CH 1004 Lausanne Switzerland Jennifer K. Hall, MD Scheie Eye Institute University of Pennsylvania Department of Ophthalmology 51 North 39th Street Philadelphia, Pennsylvania 19104 USA Michael B. Hoffmann, Dr. Universitäts-Augenklinik Visual Processing Laboratory Leipziger Straße 44 39120 Magdeburg Germany Claudia Karl, Dr. Institut für Neurologie Universität Regensburg Germany Aki Kawasaki, MD, MER Department of Neuro-ophthalmology Hôpital Ophtalmique Jules Gonin Avenue de France 15 1004 Lausanne Switzerland Birgit Lorenz, MD, FEBO, Prof. Klinik und Poliklinik für Augenheilkunde Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen Friedrichstraße 18 35392 Gießen Germany Tim D. Matthews, MBBS, FRCS, FRCOphth Department of Ophthalmology Selly Oak Hospital Raddlebarn Rd Birmingham B29 6 JD UK
Nancy J. Newman, MD, Prof. Departments of Ophthalmology Neurology, and Neurological surgery Emory University, Neuro-ophthalmology Unit Emory Eye Center 1365-B Clifton Road, NE, Atlanta Georgia 30322 USA Charles Pierrot-Deseilligny, MD, Prof. Hôpital La Pitié-Salpêtrière 47-83, Boulevard de l'Hôpital 75651 Paris Cedex 13 France Joseph F. Rizzo III, MD, Prof. Massachussetts Eye and Ear Infirmary Department of Neuro-Ophthalmology 243 Charles Street, 9th FL Boston, MA 02114 USA Tobias Stupp, PD, Dr. Institut für Experimentelle Ophthalmologie Klinik und Poliklinik für Augenheilkunde Domagkstraße 15 48149 Münster Germany Solon Thanos, Prof. Dr. Institut für Experimentelle Ophthalmologie Klinik und Poliklinik für Augenheilkunde Domagkstraße 15 48149 Münster Germany Susanne Trauzettel-Klosinski, Prof. Dr. Augenklinik der Universität Tübingen Schleichstraße 12–16 72076 Tübingen Germany Peter U. Tse. Dr. Institute für Experimentelle Psychologie der Universität Regensburg 93053 Regensburg Germany
Nicholas J. Volpe. MD, Prof. Scheie Eye Institute University of Pennsylvania Department of Ophthalmology 51 North 39th Street Philadelphia, Pennsylvania 19104 USA Marcela Votruba, MA, BM, BCh, FRCOphth, PhD School of Optometry & Vision Science Cardiff University Maindy Road Cathays Cardiff CF24 4LU UK
Contributors
Stephan Zierz, Prof., Dr. Neurologische Universitätsklinik Ernst-Grube-Straße 40 06120 Halle (Saale) Germany
XIX
Part I
Optic Nerve
Chapter 1
Optic Neuritis and Multiple Sclerosis
1
Edward J. Atkins, Valérie Biousse, Nancy J. Newman
Core Messages
■ Idiopathic optic neuritis, an isolated in-
flammatory optic neuropathy secondary to demyelination, is the most common cause of optic neuropathy in the young and is often the first sign of multiple sclerosis (MS). It is now possible to predict the risk of subsequent MS in selected patients with optic neuritis, allowing the anticipatory use of immunomodulatory agents to reduce the risk and severity of MS in those patients. A number of recent studies have clarified the natural history of optic neuritis, the largest being the Optic Neuritis Treatment Trial (ONTT). The ONTT confirmed that spontaneous visual recovery begins rapidly (within 3 weeks) in about 80% of patients and continues for up to 1 year; if at least some improvement does not occur within 5 weeks, the diagnosis of idiopathic optic neuritis should be reconsidered.
■ ■ ■
■ The initial magnetic resonance imaging
(MRI) helps to stratify the risk of MS. In the ONTT, the 10-year risk of MS in patients with at least one MRI T2 lesion was 56%, as compared to 22% in those with a normal baseline MRI. A normal MRI in combination with painless optic neuritis, severe optic nerve head edema, peripapillary hemorrhages, or a macular star defines a very low MS risk subgroup. In the ONTT, treatment with a lower dose of oral corticosteroids (1 mg/kg per day) was associated with an increased risk of recurrent optic neuritis, with a 41% chance of recurrence at 5 years among patients who received oral prednisone, versus 25% for those who received highdose intravenous methylprednisolone (1000 mg/day) or placebo. High-dose steroids hasten the rate, but not the final extent, of visual recovery in optic neuritis, and the decision to use this therapy should be individualized. Interferon beta-1a or beta-1b therapy should be considered in selected highrisk patients.
■
■ ■
1
Optic Neuritis and Multiple Sclerosis
1.1 Idiopathic Optic Neuritis 1.1.1 Clinically Isolated Syndrome Idiopathic optic neuritis is the most common cause of optic neuropathy in the young. It is an isolated inflammatory optic neuropathy secondary to demyelination, and is considered one of the clinically isolated syndromes suggestive of multiple sclerosis (MS) [28, 57]. Indeed, isolated acute optic neuritis is often the first sign of MS, and many patients with MS develop optic neuritis during the course of their disease [41, 42]. For many patients, carrying the diagnosis of “optic neuritis” is equivalent to having a “high risk of MS” [2]. It is therefore essential that the correct diagnosis be made in a young patient presenting with visual loss [59].
– Normal macula and retina (no exudates, no hemorrhages) – Optic disc pallor (at least 4-6 weeks after onset) • Visual field test: variable, but most often central scotoma • MRI: depending on the quality of imaging, 50%–90% of patients with optic neuritis show enhancement of the optic nerve on orbital MRI; however, this finding is nonspecific [28, 57]
Summary for the Clinician
■ Familiarity with both the characteristic
1.1.2 Clinical Features of Acute Idiopathic Optic Neuritis Idiopathic optic neuritis is typically characterized by the following clinical characteristics [28, 57]: • Young women (3-to-1 female-to-male ratio) • Unilateral (rarely bilateral) • Acute to subacute onset (usually rapidly progressive over a few days) • Decreased visual acuity (variable) • Decreased color vision (usually pronounced) • Pain with eye movements (in >90% of cases) • Exacerbation with heat or exercise (Uhthoff phenomenon) • Absence of any systemic or neurologic symptoms
1.1.3 Examination Findings in Acute Idiopathic Optic Neuritis • Relative afferent pupillary defect (if unilateral or asymmetric optic neuropathy) • Funduscopy: – Normal optic nerve in the acute phase (in two-thirds of cases) or swollen optic nerve (in one-third of cases)
■ ■
clinical features as well as the typical examination findings in idiopathic optic neuritis will greatly decrease the chance of misdiagnosing the cause of the visual loss, and overlooking the risk of MS. The optic nerve appears normal in the acute phase in about two-thirds of cases (retrobulbar optic neuritis), and is swollen in about one-third of cases (anterior optic neuritis or papillitis). In all cases, pallor of the disc develops only 4–6 weeks after the onset of visual loss.
1.2 Natural History of Acute Idiopathic Optic Neuritis Some spontaneous visual recovery is a nearly universal feature of idiopathic acute optic neuritis, and the visual prognosis for these patients is usually excellent, regardless of treatment; however, the risk of subsequent development of MS after an isolated attack of idiopathic optic neuritis has been estimated as high as 74% at 15 years [22, 24, 31, 35, 43, 60].
1.2.1 Important Studies The natural history of optic neuritis has been clarified by a number of recent studies, among which
the Optic Neuritis Treatment Trial (ONTT) [6] is the largest. Natural history data have been collected from a long-term prospective study carried out in Boston [12], from a Queens Square study in London [16], from a prospective study performed in Barcelona [71], and from several clinical trials involving immunomodulatory drugs [9, 15, 16, 18, 26, 31, 56]. Data from these studies have contributed to our understanding of the natural history of optic neuritis. The study descriptions and results are summarized in Table 1.1.
1.2 Natural History of Acute Idiopathic Optic Neuritis
Summary for the Clinician
■ Some spontaneous visual recovery is a nearly universal feature of idiopathic acute optic neuritis, and the visual prognosis of these patients is usually excellent, regardless of treatment. Intravenous steroids hasten visual recovery, but have no effect on final visual outcome.
■
1.2.3 Risk of Recurrence of Optic Neuritis
1.2.2 Visual Prognosis The ONTT confirmed that spontaneous visual recovery begins rapidly (within 3 weeks) in about 80% of patients with idiopathic acute optic neuritis, and continues for up to 1 year [50, 52]. The ONTT also emphasized that if at least some improvement does not occur within 5 weeks, the diagnosis of idiopathic optic neuritis should be reconsidered. At 1-year follow-up almost all patients had visual acuity in the affected eye of better than 20/40, and half of patients had visual acuity of at least 20/20 (see Table 1.2). Nevertheless, a majority of patients complained of permanent visual dysfunction including [50, 52]: • Impaired contrast sensitivity • Decreased color vision • Difficulty with motion perception • Diminished intensity of light Following optic neuritis, patients often also experience Uhthoff phenomenon, a transient visual decline following exposure to heat or exertion. Although intravenous corticosteroids hasten visual recovery, visual outcome at 6 months was the same for all treatment groups. Indeed, a meta-analysis of 12 randomized controlled trials of steroid treatment in MS and optic neuritis confirmed that although corticosteroids were effective in improving short-term visual recovery, there was no statistically significant benefit in long-term outcome [14].
In the ONTT, the probability of recurrence of optic neuritis in either eye was 35 % at 10 years [52]. Treatment with oral corticosteroids was associated with an increased risk of recurrent optic neuritis. In fact, as shown in Table 1.2, patients who received low-dose oral prednisone had the highest rate of recurrence at 5 years compared to those who received intravenous methylprednisolone or placebo [50]. At 10 years, the recurrence risk was still higher when compared to the methylprednisolone and placebo groups [52].
Summary for the Clinician
■ Oral
corticosteroids in conventional doses of 1 mg/kg per day may increase the risk of recurrence, and should not be used in the treatment of acute idiopathic optic neuritis.
1.2.4 Risk of Developing Multiple Sclerosis Even prior to the advent of MRI, several studies had emphasized the risk of developing MS following an episode of isolated optic neuritis [22, 24, 35, 40, 59]. Subsequent studies have shown that brain MRI is the most powerful predictor of MS in patients with acute idiopathic optic neuritis [8, 9, 13, 15, 16, 18, 26, 29, 31, 40, 46, 47,
Period of enrolment
Patient number
Boston (Rizzo and Lessell 1988) [60]
1973–1988
Sweden (Söderström et al. 1998) [68]
Type of study
Methods
Follow-up Risk of clinically (years) definite MS
60 (all ON) Observational study; long-term prospective; natural history
Follow-up of a group of patients with isolated optic neuritis. No MRI data
15
74% of women; 34% of men
1990–1995
116 (all ON)
Observational study; short-term prospective; natural history
Follow-up of a group of patients with isolated optic neuritis. A baseline MRI was obtained
2.1
Normal MRI: 6%; abnormal MRI: 34.5%; (≥3 lesions)
Milan (Ghezzi et al. 1999) [29]
1982–1993
102 (all ON)
Observational study; long-term prospective; natural history
Follow-up of a group of patients with isolated optic neuritis in a serial MRI study
8–10
Normal MRI: 0%; abnormal MRI: 52.1%; (≥1 lesion)
Queens Square (Brex et al. 2002) [13]
1988–2002
71 (36 ON) Observational study; long-term prospective; natural history
Follow-up of a group of patients with clinically isolated syndromes in a serial MRI study
14
Normal MRI: 19%; abnormal MRI: 88%; (≥1 lesion)
Barcelona (Tintoré et al. 2005) [71]
1995–2004
320 (123 ON)
Observational study; short-term prospective; natural history
Follow-up of a group of patients with clinically isolated syndromes in a serial MRI study (using MRI component of McDonald criteria)
2–3
Normal MRI: 5.9%; abnormal MRI: 55%
ONTT/LHONS [6, 51, 52, 53, 54]
1988–1991
388 (all ON)
Randomized double-blind
Randomization in 3 arms: (1) IV 10 methylprednisolone (250 mg q 6 h for 3 days), followed by oral prednisone (1 mg/kg per day for 11 days); (2) oral prednisone alone (1 mg/kg per day for 14 days); (3) oral placebo
Adapted from Atkins EJ, Biousse V, Newman NJ (2006) The natural history of optic neuritis. Rev Neurol Dis 3:45–55 [3].
Normal MRI: 22%; abnormal MRI: 56%; (≥1 lesion); no difference between treatment groups
Optic Neuritis and Multiple Sclerosis
Study name
1 Table 1.1. Summary of large studies evaluating the natural history and management of idiopathic acute optic neuritis. (BENEFIT Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment Study, CHAMPS Controlled High Risk Avonex Multiple Sclerosis Study, ETOMS Early Treatment of Multiple Sclerosis Study, LONS Longitudinal Optic Neuritis Study, ON optic neuritis, ONTT Optic Neuritis Treatment Trial)
Period of enrolment
Patient number
Type of study
Methods
Follow-up Risk of clinically (years) definite MS
CHAMPS/CHAMPIONS [15, 16]
1996–1998
383 (192 ON)
Randomized double-blind
Randomization of high-risk patients with a clinically isolated syndrome (≥2 MRI lesions) to (1) interferon beta-la (Avonex®) (30 µg IM) or (2) placebo
3
All with abnormal MRI (≥2 lesions); 35% in interferon group; 50% in placebo group
ETOMS (Comi et al. 2001) [18]
1995–1997
309 (98 ON)
Randomized double-blind
Randomization of high-risk patients 2 with a clinically isolated syndrome (≥2 MRI lesions) to (1) interferon beta-la (Rebif®) (22 µg SC weekly for 2 years) or (2) placebo
All with abnormal MRI (≥4 lesions); 34% in interferon group; 45% in placebo group
BENEFIT( Freedman and colleagues 2006) [26, 56]
2004–2006
487 (80 ON)
Randomized double-blind
Randomization of high-risk patients with a clinically isolated syndrome (≥2 MRI lesions) to (1) interferon beta-lb (Betaseron®) (250 µg SC every other day for 2 years) or (2) placebo
All with abnormal MRI (≥2 lesions); 28% in interferon group; 45% in placebo group
Adapted from Atkins EJ, Biousse V, Newman NJ (2006) The natural history of optic neuritis. Rev Neurol Dis 3:45–55 [3].
2
1.2 Natural History of Acute Idiopathic Optic Neuritis
Study name
Table 1.1. (continued) Summary of large studies evaluating the natural history and management of idiopathic acute optic neuritis. (BENEFIT Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment Study, CHAMPS Controlled High Risk Avonex Multiple Sclerosis Study, ETOMS Early Treatment of Multiple Sclerosis Study, LONS Longitudinal Optic Neuritis Study, ON optic neuritis, ONTT Optic Neuritis Treatment Trial)
1
Optic Neuritis and Multiple Sclerosis Table 1.2. Summary of results from the Optic Neuritis Treatment Trial Visual prognosis [50, 52] Visual acuity (affected eye)
1-year results (%, n=454)
10-year results (%, n=319)
20/40 or better
95
91
20/20 or better
50
69
Risk of recurrence of optic neuritis in either eye [50, 52] Treatment group
5-year follow-up (%)
10-year follow-up (%)
Oral prednisone (1 mg/kg)
41
44
IV methylprednisolone
25
29
Placebo
25
31
Development of multiple sclerosis [49, 51] Treatment group
5-year follow-up (%)
Oral prednisone (1 mg/kg)
32
IV methylprednisolone
27
Placebo
31
Overall
30
Brain MRI at baseline
10-year follow-up (%)
No lesion
22
One lesion
52
> one lesion
56
Overall
38
49, 51, 54, 56, 68]. This is in accordance with the recent modification of MS diagnostic criteria, which now include MRI changes (Table 1.3) [5, 19, 34, 39, 55]. Several important studies have defined the risk of developing MS, and the results are shown in Tables 1.1 and 1.2. The ONTT did not show any demographic or clinical features of optic neuritis predictive of MS development among patients with an abnormal baseline MRI. However, in patients with a normal baseline MRI, the risk of developing MS was 3 times lower for men than for women. The risk was also lower for those who had optic nerve head edema (anterior optic neuritis) (Table 1.4). It has been suggested that patients with MS who initially present with acute optic neuri-
tis have a better long-term prognosis regarding conversion to MS than those who present with another clinically isolated syndrome [41, 42, 71]. Tintoré et al. [71] propose that the reason why isolated optic neuritis patients may have a smaller risk for conversion to MS is because they more often have a normal baseline MRI than patients with other clinically isolated syndromes. They emphasized that if a patient with optic neuritis has abnormal baseline MRI results, his or her prognosis for MS conversion does not differ from that of other patients with different clinically isolated syndromes. Similarly, the CHAMPS [16] and ETOMS [18] trials found no differences in clinical or MRI behavior between their clinically isolated syndrome groups and their placebo groups.
1.2 Natural History of Acute Idiopathic Optic Neuritis
Table 1.3. The 2005 revised McDonald criteria for the diagnosis of multiple sclerosis. (CSF cerebrospinal fluid, MRI magnetic resonance imaging, MS multiple sclerosis) Clinical presentation
Additional data needed for MS diagnosis
Two or more attacks with objective evidence of two or more lesions
None
Two or more attacks with objective evidence of one lesion
Dissemination in space demonstrated by MRIa, or two or more lesions characteristic of MS on MRI with positive CSF (oligoclonal bands or raised IgG index)
One attack with objective clinical evidence of two or more lesions
Dissemination in time demonstrated by MRIb, or await a second clinical attack
One attack with objective clinical evidence of one lesion (clinically isolated syndrome)
Dissemination in space demonstrated by MRI, or two or more lesions characteristic of MS with positive CSF
Insidious neurological progression suggestive of MS
Positive CSF and dissemination in space and time demonstrated by MRI, and continued progression for at least 1 year
MRI lesions disseminated in space: at least three of the following:
a
1. One gadolinium-enhancing lesion or nine T2-hyperintense lesions (see Fig. 1.2). 2. At least one infratentorial lesion (includes brainstem and spinal cord). 3. At least one juxtacortical lesion. 4. At least three periventricular lesions. MRI lesions disseminated in time: at least one of the following:
b
1. If MRI is obtained more than 3 months after the clinical event, then a gadolinium-enhancing lesion at a site different from the original clinical event is sufficient. If there is no gadolinium enhancement, then a follow-up scan must be done more than 3 months later. A new T2 or gadolinium-enhancing lesion on the subsequent MRI fulfills the requirement. 2. If MRI is obtained less than 3 months after the onset of the clinical event, then a second scan more than 3 months later showing a new gadolinium-enhancing lesion fulfills the requirement. If no gadolinium-enhancing lesion is seen on the second scan, a further scan obtained more than 3 months after the first scan that shows a new gadolinium-enhancing lesion, or a new T2 hyperintense lesion, fulfills the requirement Data from Barkhof et al. [5], McDonald et al. [39], Polman et al. [55], and Tintoré et al. [70].
10
1
Optic Neuritis and Multiple Sclerosis Table 1.4. Features associated with subsequent development of MS in the ONTT patients who had a normal baseline MRI (191 patients) N Overall
10-year risk of MS (%) Hazard ratio
191
22
142
25
1.00
49
10
0.35
Normal
110
28
1.00
Edema
81
14
0.41
Yes
173
24
1.00
No
18
0
95% CI
p
0.12–0.98
0.05
0.20–0.84
0.01
Gender Women Men Optic disc appearance
Pain
Data from Optic Neuritis Study Group (2003) High risk and low risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 121:944–949 [51].
Summary for the Clinician
1.2.5 Severity of Multiple Sclerosis in Patients Presenting with Optic Neuritis
■ The risk of subsequent development of
MS after an isolated attack of idiopathic optic neuritis has been estimated to be as high as 74% at 15 years. In the ONTT, the overall risk of development of clinically definite MS was 30% at 5 years, 38% at 10 years, and 40% at 12 years. The ONTT showed no significant difference among treatment groups (low-dose oral steroid versus high-dose intravenous steroid versus placebo) in terms of the eventual development of clinically definite MS. Studies comparing interferon treatment with placebo show a modest but consistent reduction in the risk of developing subsequent MS in high-risk patients with an abnormal MRI. Brain MRI is the most powerful predictor of MS in patients with idiopathic optic neuritis. MRI at baseline, not clinically isolated syndrome topography, is the crucial issue at MS presentation.
■ ■
Studies have garnered some conflicting data regarding this issue. It has been suggested that optic neuritis patients who eventually develop MS have a better neurologic prognosis (less neurologic disability) than those presenting with another clinically isolated syndrome (such as brainstem or spinal cord syndromes) (Table 1.5) [53, 74].
Summary for the Clinician
■ Optic neuritis patients who ultimately
■ ■ ■
develop MS may have a better neurologic prognosis than those who present with other clinically syndromes.
1.3 Management of Acute Idiopathic Optic Neuritis Although guidelines regarding the early management of acute optic neuritis with corticosteroids were published a few years ago [33], controversy
1.3 Management of Acute Idiopathic Optic Neuritis
Table 1.5. Neurologic impairment after optic neuritis. The Expanded Disability Status Scale (EDSS) is used for rating impairment and disability in MS. It is a 20-step ordinal scale that ranges between 0.0 (normal status) and 10.0 (death due to MS). It is graded according to the findings of a standard neurologic examination summarized into several functional systems. It has been widely used in clinical trials of MS as a measure of disease progression Study
Years of follow-up
Percentage of EDSS score (Expanded patients (%) Disability Status Scale)
Comments
ONTT [53]
10
65
<3
All optic neuritis patients
Boston [60]
15
83
<3
All optic neuritis patients
Queen’s Square [13]
14.1
68
>3
Includes optic neuritis patients and spinal cord/brainstem syndromes
London, ON [74]
12
57
>3
Includes optic neuritis patients and spinal cord/brainstem syndromes
remains regarding the optimal long-term treatment and follow-up of patients with acute idiopathic optic neuritis [34]. Careful assessment of the risk for the subsequent development of MS should be individualized using clinical examination (including detailed ophthalmologic examination) and brain MRI (Table 1.3) [2].
Table 1.6. Features not associated with subsequent development of MS in the ONTT patients who had a normal baseline MRI. In the group of 191 patients with optic neuritis and a normal baseline MRI, none of the patients with at least one of the following characteristics subsequently developed clinically definite MS at the 10-year follow-up Number of patients (n=191)
1.3.1 Diagnosis The diagnosis of optic neuritis is mostly clinical. Indeed, the ONTT showed that routine blood tests including antinuclear antibodies, angiotensin-converting enzyme, syphilis testing, and chest X-ray were of no value in typical cases [7]. Visual-evoked potentials are only useful when the diagnosis of optic neuritis is uncertain [57]. A more aggressive assessment should be considered when atypical features of optic neuritis are present. Interestingly, in the ONTT, some specific ocular findings were associated with a 0% chance of developing MS within 10 years in the patients with a normal baseline MRI, including absence of light perception in the affected eye, absence of pain, severe optic disc edema, peripapillary hemorrhage, and retinal exudates (Table 1.6; Fig. 1.1). These findings emphasize the importance of a dilated funduscopic examination by an ophthalmologist for all patients with
Absence of light perception in the affected eye
6
Absence of periocular pain
18
Severe optic disc edema
22
Peripapillary hemorrhage
16
Retinal exudates
8
acute optic neuritis, as these findings should help identify a group of patients with very low risk of MS [49, 51, 54]. Brain MRI (including fluid attenuated inversion recovery or FLAIR images and administration of contrast) is essential to evaluate the risk of MS, and it may be repeated over time [55] (Fig. 1.2). Spinal cord imaging is usually not helpful in patients with clinically isolated optic neuritis [20]. Dedicated orbital views (thin sec-
11
12
Optic Neuritis and Multiple Sclerosis
Summary for the Clinician
1
■ Laboratory tests are usually only ob-
tained to rule out an underlying disorder when the clinical presentation is not typical of acute idiopathic optic neuritis. Dilated funduscopic examination of all optic neuritis patients is essential to identify features that would place certain patients with a normal baseline MRI in a low-risk subgroup for development of subsequent MS (Table 1.6). Follow-up should demonstrate spontaneous improvement of visual function within a few weeks in >90% of cases and the absence of improvement should raise concern about another diagnosis. Lumbar puncture should only be performed in select atypical cases of optic neuritis, especially in bilateral cases, in childhood, or when an infectious or systemic inflammatory disorder is suspected [57]. Brain MRI is essential for all optic neuritis patients, and this has become the standard of care to evaluate the risk of MS.
■ ■ ■
Fig. 1.1. Funduscopic examination of a patient with acute painful visual loss related to an optic neuropathy. The optic nerve is very swollen and there are peripapillary hemorrhages. The optic neuritis was related to syphilis
■ tions with fat suppression, and administration of contrast) are only necessary in atypical optic neuritis, as the documentation of optic nerve enhancement, although very common, is not necessary in most cases of typical acute optic neuritis [28, 57]. Lumbar puncture for cerebrospinal fluid (CSF) analysis is usually not necessary in patients with typical acute optic neuritis. Although CSF oligoclonal IgG bands, IgG index, and intrathecal IgG synthesis are included in the diagnostic criteria of MS, they are not specific for MS [25]. In the ONTT, CSF studies showed that only the presence of oligoclonal bands (in 50% of patients) correlated with later development of MS, but these patients also had abnormal baseline MRI, already predicting a higher risk of MS. There was no additional value of CSF evaluation [17, 30, 65, 66]. A recent study suggested that the presence of oligoclonal bands in the CSF of patients with a clinically isolated syndrome and abnormal MRI was highly specific and sensitive for early prediction of conversion to MS; however, very few patients had isolated optic neuritis in the study [38].
1.3.2 Acute Therapeutic Options Acute treatment options for acute idiopathic optic neuritis include intravenous methylprednisolone or observation alone. Intravenous methylprednisolone hastens visual recovery, but has no effect on the final visual outcome. In patients with abnormal baseline MRI, treatment with intravenous steroids may delay the onset of MS within the first 2 years following an episode of optic neuritis [7]. Intravenous methylprednisolone as used in the ONTT is generally well tolerated, but mild steroid-related side-effects are common, including insomnia, weight gain, and mood alteration [7]. As emphasized by the American Academy of Neurology (AAN) practice parameter statement [33], oral prednisone in conventional doses of 1 mg/kg per day should not be used in the treatment of idiopathic acute
1.3 Management of Acute Idiopathic Optic Neuritis
Summary for the Clinician
■ Oral
corticosteroids in conventional doses of 1 mg/kg per day may increase the risk of recurrence, and should not be used in the treatment of acute idiopathic optic neuritis. Intravenous methylprednisolone hastens visual recovery, but has no effect on the final visual outcome. The decision to use intravenous methylprednisolone should be individualized and should be made after discussing the risks and benefits of this therapy with the patient. No treatment is a reasonable alternative, as steroids do not change the long-term prognosis of patients with optic neuritis.
■ ■ ■
Fig. 1.2. Axial brain MRI (FLAIR sequence) demonstrating hypersignals in the periventricular white matter
optic neuritis. It is unclear whether high-dose oral corticosteroids would also increase the risk of recurrent optic neuritis [33]. A small prospective controlled clinical trial of oral methylprednisolone (500 mg every day for 5 days) showed no increased rate of demyelinating attacks [67]. Some centers now routinely use high-dose oral prednisone (1250 mg) once daily for 3–5 days; however, supportive evidence is lacking, and no trial comparing intravenous high-dose (1000 mg per day) to oral high-dose (1250 mg per day) has been done. Intravenous immunoglobulin (IVIG) may attenuate clinical and MRI-identified disease activity in patients with relapsing–remitting MS [1, 36, 69]; however, a randomized trial of IVIG treatment in acute optic neuritis concluded that there was no effect of IVIG on long-term visual function or preservation of optic nerve axonal function [64].
1.3.3 Chronic Therapeutic Options Recent pathological and MRI studies have suggested that axonal damage occurs early during the course of MS [2, 10, 21, 23, 41, 44, 58]. It has been emphasized that, once axonal damage occurs, it may result in permanent neurological deficits. The issue of axonal damage and gray matter atrophy is at the center of the ongoing debate over whether to intervene early with immunomodulatory agents in patients with clinically isolated syndromes [4, 27], especially those predicted to be at high risk for the subsequent development of MS. Results of the CHAMPS [16] ETOMS [18], and BENEFIT [26, 56] studies suggest that patients with optic neuritis and abnormal baseline MRI (“high-risk patients”) should be considered for interferon beta therapy. The CHAMPIONS study [15] even suggested that such treatment should be initiated early after the first occurrence of optic neuritis. A trial to assess the effect of glatiramer acetate in monosymptomatic patients has been initiated. Some authors advocate immediate treatment to avoid any further axonal injury, while others suggest delaying long-term treatment, and repeating the MRI to prove the dissemination of lesions in space and time prior to initiating such a
13
14
1
Optic Neuritis and Multiple Sclerosis
serious and costly treatment. This topic remains debated and recommendations vary among countries [44]. IVIG has also been suggested to facilitate recovery in chronic optic neuritis [61, 62, 63, 72, 73]; however, IVIG administration does not significantly reverse persistent visual loss [48].
Summary for the Clinician
■ In children, data are lacking regarding
both the effects of intravenous methylprednisolone on visual recovery and the effects of immunomodulatory agents on the subsequent development of MS. Based on the studies done in adults, it would seem reasonable to offer IV steroids in cases with severe visual loss (especially when bilateral), and to consider immunomodulatory agents when the brain MRI is abnormal [4].
■
Summary for the Clinician
■ Evidence from recent randomized, pla-
cebo-controlled trials supports early intervention with immunomodulatory agents in high-risk patients with clinically isolated syndromes to decrease the risk of subsequent development of MS [4, 28]. The decision to treat high-risk optic neuritis patients with immunomodulatory agents should be individualized.
■
References 1.
2.
1.4 Pediatric Optic Neuritis The natural history and management of optic neuritis in children is different than in adults [11]. The data on pediatric optic neuritis are scarce and controversial, and are primarily based on small retrospective chart reviews [12, 45], and on one longitudinal study [37]. These limited studies suggest: • Mean age of onset: around 10 years • 2/3 female • 2/3 have disc edema (compared to 1/3 of adults) • 2/3 have bilateral involvement • 2/3 have a history of a preceding febrile illness within 2 weeks of onset • Those with unilateral involvement may have a greater tendency to develop subsequent MS, but also carry a better visual prognosis than those with bilateral involvement • Subsequent development of MS is less than in adults, and those who do develop MS are older (mean age 12 years) at the onset of optic neuritis
3.
4. 5.
6.
7.
8.
Achiron A, Kishner I, Sarova-Pinhas I et al (2004) Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Arch Neurol 61:1515–1520 Arnold AC (2005) Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol 139:1101–1108 Atkins EJ, Biousse V, Newman NJ (2006) The natural history of optic neuritis. Rev Neurol Dis 3:45–55 Balcer L (2006) Optic neuritis. New Engl J Med 354:1273–1280 Barkhof F, Filippi M, Miller DH et al (1997) Isolated demyelinating syndromes: comparison of different magnetic resonance imaging criteria to predict conversion to clinically definite multiple sclerosis. Brain 120:2059–2069 Beck RW, Cleary PA, Anderson MM Jr. et al (1992) A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 326:581–588 Beck RW, Cleary PA, Trobe JD et al (1993) The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 329:1764–1769 Beck RW, Arrington J, Murtagh FR et al (1993) Brain MRI in acute optic neuritis: experience of the Optic Neuritis Study Group. Arch Neurol 8:841–846
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
References Beck RW, Chandler DL, Cole SR et al (2002) Interferon β-1a for early multiple sclerosis: CHAMPS trial subgroup analyses. Ann Neurol 51:481–490 Bermel R, Puli S, Rudick R et al (2005) Gray mater MRI T2 hypointensity predicts longitudinal atrophy in multiple sclerosis. Arch Neurol 62:1371–1376 Boomer JA, Siatkowski RM (2003) Optic neuritis in adults and children. Semin Ophthalmol 18:174–180 Brady KM, Brar AS, Lee AG et al (1999) Optic neuritis in children: clinical features and visual outcome. J AAPOS 3:98–103 Brex P, Ciccarelli O, O’Riordan J et al (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:156–164 Brusaferri F, Candelise F (2000) Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials. J Neurol 247:435–442 CHAMPIONS Study Group (2006) IM interferon β-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 66:678–684 CHAMPS Study Group (2001) Interferon β-1a for optic neuritis patients at high-risk for multiple sclerosis. Am J Ophthalmol 132:463–471 Cole SR, Beck RW, Moke PS et al (1998) The predictive value of CSF oligoclonal banding for MS 5 years after optic neuritis. Neurology 51:885–887 Comi C, Filippi M, Barkhof F et al (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study (ETOMS). Lancet 358:1586–1582 Dalton CM, Brex PA, Miszkiel KA et al (2003) New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes. Ann Neurol 53:673–676 Dalton CM, Brex PA, Miszkiel KA et al (2003) Spinal cord MRI in clinically isolated optic neuritis. J Neurol Neurosurg Psychiatry 74:1587–1580 De Stefano N, Narayanan S, Francis GS et al (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65–70 Ebers GC (1985) Optic neuritis and multiple sclerosis. Arch Neurol 42:702–704
23. Filippi M, Tortorella C, Rovaris M et al (2000) Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry 68:156–161 24. Francis DA, Compston DA, Batchelor JR, McDonald WI (1987) A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up. J Neurol Neurosurg Psychiatry 50:758–765 25. Frederiksen JL (1998) Can CSF predict the course of optic neuritis? Mult Scler 4:132–135 26. Freedman M, Kappos L, Polman C et al (2006) Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT): clinical outcomes. Neurology 66:S02.001 27. Frohman E, Racke M (2000) To treat or not to treat? The therapeutic dilemma of idiopathic monosymptomatic demyelinating syndromes. Arch Neurol 58:930–932 28. Frohman E, Frohman T, Zee D et al (2005) The neuro-ophthalmology of multiple sclerosis. Lancet Neurol 4:111–121 29. Ghezzi A, Martinelli V, Torri V et al (1999) Longterm follow-up of isolated optic neuritis: the risk of developing multiple sclerosis, its outcome, and the prognostic role of paraclinical tests. J Neurol 246:770–775 30. Jacobs LD, Kaba SE, Miller CM et al (1997) Correlation of clinical, MRI and CSF findings in optic neuritis. Ann Neurol 41:392–398 31. Jacobs LD, Beck RW, Simon JH et al (2000) The effect of intramuscular interferon beta 1a treatment initiated at the time of a first acute clinical demyelinating event on the rate of development of clinically definite multiple sclerosis. N Engl J Med 343:898–904 32. Jin YP, de Pedro-Cuesta J, Huang YH, Söderström M (2003) Predicting multiple sclerosis at optic neuritis onset. Mult Scler 9:135–141 33. Kaufman DI, Trobe JD, Eggenberger ER et al (2000) Practice parameter: the role of corticosteroids in the management of acute monosymptomatic optic neuritis. Neurology 54:2039–2044 34. Korteweg T, Tintoré M, Uidehaag B et al (2006) MRI criteria for dissemination in space in patients with clinically isolated syndromes: a multicentre follow-up study. Lancet Neurol 5:221–227 35. Kurtzke JF (1985) Optic neuritis or multiple sclerosis. Arch Neurol 42:704–710
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Optic Neuritis and Multiple Sclerosis 36. Lewanska M, Siger-Zajdel M, Selmaj K (2002) No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. Eur J Neurol 9:565–582 37. Lucchinetti CF, Kiers L, O’Duffy A et al (1997) Risk factors for developing multiple sclerosis after childhood optic neuritis. Neurology 49:1413–1418 38. Masjuan J, Alvarez-Cermeno JC, Garcia-Barragan N et al (2006) Clinically isolated syndromes. A new oligoclonal band test accurately predicts conversion to MS. Neurology 66:586–588 39. McDonald W, Compston A, Edam G et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127 40. Miller DH, Ormerod IEC, McDonald WI et al (1988) The early risk of multiple sclerosis after optic neuritis. J Neurol Neurosurg Psychiatry 51:1569–1581 41. Miller D, Barkhof F, Montalban X et al (2005) Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 4:281–288 42. Miller D, Barkhof F, Montalban X et al (2005) Clinically isolated syndromes suggestive of multiple sclerosis, part II: non-conventional MRI, recovery processes, and management. Lancet Neurol 4:341–348 43. Minneboo A, Barkhof F, Polman CH et al (2004) Infratentorial lesions predict long-term disability in patients with initial findings suggestive of multiple sclerosis. Arch Neurol 61:217–221 44. Montalban X (2004) The pros and cons of early treatment of relapsing forms of multiple sclerosis. J Neurol 251 [Suppl. 4]: IV/30–IV/34 45. Morales DS, Siatkowski RM, Howard CW, Warman R (2000) Optic neuritis in children. J Pediatr Ophthalmol Strabismus 37:254–259 46. Morrissey SP, Miller DH, Kendall BE et al (1993) The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study. Brain 116:135–146 47. Nillson P, Larsson EM, Maly-Sundgren P et al (2005) Predicting the outcome of optic neuritis – evaluation of risk factors after 30 years of follow-up. J Neurol 252:396–402
48. Noseworthy JH, O’Brien PC, Petterson TM et al (2001) A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 56:1514–1522 49. Optic Neuritis Study Group (1997) The 5 year risk of MS after optic neuritis: experience of the optic neuritis treatment trial. Neurology 49:1404–1413 50. Optic Neuritis Study Group (1997) Visual function 5 years after optic neuritis. Arch Ophthalmol 115:1545–1552 51. Optic Neuritis Study Group (2003) High risk and low risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 121:944–949 52. Optic Neuritis Study Group (2004) Visual function more than 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Am J Ophthalmol 137:77–83 53. Optic Neuritis Study Group (2004) Neurologic impairment after optic neuritis. Arch Neurol 61:1386–1389 54. Optic Neuritis Study Group (2004) Long-term magnetic resonance imaging changes after optic neuritis in patients without clinically definite multiple sclerosis. Arch Neurol 61:1538–1541 55. Polman CH, Reinglod SC, Edan G et al (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald” criteria. Ann Neurol 58:840–846 56. Polman C, Kappos L, Freedman M et al (2006) Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT): subgroup analyses. Neurology 66:S02.002 57. Purvin V (2000) Optic neuropathies for the neurologist. Semin Neurol 20:97–110 58. Revesz T (2000) Axonal lesions in MS: an old story revisited. Brain 123:203–204 59. Rizzo JF, Lessell S (1991) Optic neuritis and ischemic optic neuropathy. Overlapping clinical profiles. Arch Ophthalmol 109:1668–1672 60. Rizzo J, Lessell S (1998) Risk of developing multiple sclerosis after uncomplicated optic neuritis: a long term prospective study. Neurology 38:185–190 61. Rodriguez M, Lennon VA (1990) Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 27:12–17
62. Rodriguez M, Miller DJ (1994) Immune promotion of central nervous system remyelination. Prog Brain Res 103:343–355 63. Rodriguez M, Miller DJ, Lennon VA (1996) Immunoglobulins reactive with myelin basic protein promote CNS remyelination. Neurology 46:538–545 64. Roed HG, Langkilde A, Sellebjerg F et al (2005) A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology 65:804–810 65. Rolak LA, Beck RW, Paty DW et al (1996) Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial. Neurology 46:368–372 66. Sandberg-Wolheim M, Bynke H, Cronqvist S et al (1990) A long term prospective study of optic neuritis: evaluation of risk factors. Ann Neurol 27:386–393 67. Sellebjerg F, Nielsen HS, Frederiksen JL et al (1999) A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 52:1479–1484 68. Söderström M, Jin YP, Hillert J, Link H (1998) Optic neuritis, prognosis for multiple sclerosis from MRI, CSF, and HLA findings. Neurology 50:708–714
References 69. Sorensen PS, Wanscher B, Jensen CV et al (1998) Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 50:1273–1281 70. Tintoré M, Rovira A, Martinez MJ et al (2000) Isolated demyelinating syndromes: comparison of different diagnostic MRI criteria to predict conversion to clinically definite multiple sclerosis. Am J Neuroradiol 21:702–706 71. Tintoré M, Rovira A, Rio J et al (2005) Is optic neuritis more benign than other first attacks in multiple sclerosis? Ann Neurol 57:210–215 72. Van Engelen BG, Hommes OR, Pinckers A et al (1992) Improved vision after intravenous immunoglobulin in stable demyelinating optic neuritis. Ann Neurol 32:834–835 73. Van Engelen BG, Miller DJ, Pavelko KD et al (1994) Promotion of remyelination by polyclonal immunoglobulin and IVIg in Theiler’s virus induced demyelination and in MS. J Neurol Neurosurg Psychiatry 58 [Suppl. 1]:65–68 74. Weinshenker BG, Bass B, Rice GP et al (1989) The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 112:133–146
17
Chapter 2
Headline-2
Ischemic Optic Neuropathies Anthony C. Arnold
Core Messages
■ Ischemic optic neuropathy is classified
■ The primary purpose of therapy in GCA
■
■
by location as anterior or posterior and by etiology as arteritic or nonarteritic. Anterior ischemic optic neuropathy (AION) presents with rapid, usually painless, monocular visual field loss in the presence of optic disc edema. Arteritic AION is typically more severe and more frequently bilateral than nonarteritic AION, and is associated with severe headache and other systemic symptoms. Arteritic AION is usually associated with a markedly elevated erythrocyte sedimentation rate and C-reactive protein; these studies should always be performed if there is suspicion of giant cell arteritis (GCA). Temporal artery biopsy should be performed if there is suspicion of GCA; the false-negative rate for biopsy is in the range of 3%–5%. High-dose systemic corticosteroids should be administered immediately if GCA is suspected; biopsy may be delayed 7–10 days after institution of therapy.
■ ■ ■ ■
2
is to prevent fellow eye involvement, which occurs in up to 95% if untreated. Nonarteritic AION most often presents with less severe visual loss and an inferior altitudinal visual field defect. Nonarteritic AION is often associated with vasculopathic risk factors such as hypertension, diabetes, hyperlipidemia, and smoking. In nonarteritic AION, disc edema typically is replaced by optic atrophy in 6– 8 weeks, and vision remains stable afterward. There is no proven effective therapy for nonarteritic AION. Low-dose aspirin may play a role in reducing the risk of fellow eye involvement in nonarteritic AION. Posterior ION occurs most commonly in GCA and in acute hypotension with blood loss, but may be idiopathic.
■ ■ ■ ■ ■
2.1 Introduction Ischemic syndromes of the optic nerve (ischemic optic neuropathy, ION) are classified according to: (1) the location of the ischemic damage to the nerve and (2) the etiologic factor, if known, for the ischemia. Anterior ischemic optic neuropathy (AION) includes syndromes involving the optic nerve head, with visible optic disc
edema. Posterior ischemic optic neuropathy (PION) incorporates those conditions involving the intraorbital, intracanalicular, or intracranial portions of the optic nerve, with no visible edema of the optic disc. While several specific etiologic factors have been identified in ION, the most critical for initial management is the vasculitis of giant cell, or temporal, arteritis (GCA); therefore, ION is typically classified as either arteritic (usu-
19
20
2
Ischemic Optic Neuropathies
ally due to GCA) or nonarteritic. Nonarteritic ION is most often idiopathic, but specific etiologies such as systemic hypotension are occasionally identified.
2.2 Anterior Ischemic Optic Neuropathy Anterior ischemic optic neuropathy (AION) typically presents with the rapid onset of painless unilateral visual loss developing over hours to days. An altitudinal visual field defect (typically inferior) is the most common pattern of loss (Fig. 2.1), but arcuate scotomas, cecocentral defects, and generalized depression are also frequently seen (Fig. 2.2). Visual acuity is decreased if the field defect involves fixation, but may be normal if an arcuate pattern spares the central region. The pupil in the affected eye demonstrates the presence of a relative afferent pupillary defect (RAPD) unless pre-existing or concurrent optic neuropathy in the fellow eye results in abnormal pupillary reactivity, which obscures the signs of the RAPD. The optic disc is edematous at onset; the edema may be pallid, but it is not uncommon to see disc hyperemia, particularly in the nonarteritic form. The disc most often is diffusely swol-
len, but a segment of more prominent edema is frequently present (Fig. 2.3). Flame hemorrhages are commonly located adjacent to the disc, and peripapillary retinal arteriolar narrowing may occur. Retinal arteriolar emboli are only rarely associated.
2.2.1 Arteritic Anterior Ischemic Optic Neuropathy 2.2.1.1 Clinical Presentation Giant cell arteritis (GCA) is the cause for arteritic anterior ischemic optic neuropathy (AAION) in a relatively small minority (5.7%) of cases [20], with an estimated annual incidence in the United States of 0.57 per 100,000 over the age of 60 [33]. The mean age of onset for AAION is 70 years, with only rare occurrence under the age of 60. Giant cell arteritis occurs more frequently in women and with increasing age. It is most common in Caucasians and is unusual in African American and Hispanic patients [33]. Arteritic AION usually occurs in association with other systemic symptoms of the disease. Headache (most common), jaw claudication, and temporal artery or scalp tenderness are most
Fig. 2.1. Quantitative perimetry in anterior ischemic optic neuropathy (AION). Grayscale images show inferior altitudinal visual field loss in the left eye
2.2 Anterior Ischemic Optic Neuropathy
Fig. 2.2. Quantitative perimetry in AION. Grayscale images show cecocentral scotoma and less severe diffuse depression in the left eye
Fig. 2.3. Fundus photograph of optic disc in AION. The disc is edematous, with a segment of more prominent hyperemic edema superiorly, pallor inferiorly
specific for the disorder. The headache is often severe, constant, and disabling. True jaw claudication, with muscular cramping and fatigue progressing with continued chewing activity, has high specificity for temporal arteritis. Claudication may also occur in muscles of the neck or tongue. The syndrome of polymyalgia rheumatica (PMR), including malaise, anorexia, weight loss, fever, proximal joint arthralgia and myalgia, is frequently reported. This constellation of systemic symptoms and hematologic inflammatory markers, but without temporal artery or ocular involvement, may lead to arteritis in some cases. In contrast, so-called occult GCA, without overt systemic symptoms and sometimes without abnormal blood testing, may occur; in Hayreh’s recent report, 21.2% of patients with GCA and visual loss had no systemic symptoms of the disease [26]. In addition to systemic symptoms, certain associated local signs may aid in the diagnosis of AAION, including induration of the tempo-
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ral region, decreased or absent temporal artery pulse, and cord-like firmness or nodularity of the temporal artery. Arteritic AION typically presents with severe visual loss (visual acuity <20/200 in 57.8%–76.5% of cases) [1, 10, 41, 52] developing rapidly over hours to days. In one series 21% of cases had no light perception [41]. While the initial presentation is often unilateral, bilateral simultaneous AION is more commonly arteritic than nonarteritic, and its occurrence raises suspicion for GCA. The persistent visual loss of AAION is preceded in 7%–18% of cases [1, 24, 41] by transient visual loss similar to that of carotid artery disease, although the episodes may be of shorter duration; these are only rarely associated with the nonarteritic form of AION (NAION) and are highly suggestive of arteritis. The pallid type of optic disc edema (Fig. 2.4) is seen more frequently in the arteritic than in the nonarteritic form; chalkwhite pallor with edema is seen in severe cases and is highly unusual in NAION. Cotton wool patches indicative of concurrent retinal ischemia may be seen. Retinal arterial occlusion may occur simultaneously with the optic neuropathy. In Hayreh’s recent series [24], cilioretinal artery occlusion occurred in 21.2%; this is a very unusual occurrence in NAION, and is highly suggestive of GCA. Peripapillary choroidal ischemia may be associated with the optic neuropathy, produc-
Fig. 2.4. Fundus photograph of optic disc in arteritic AION. The disc demonstrates prominently pale edema
ing edema deep to the retina adjacent to the optic disc and exacerbating the visual loss [43]. It may also occur in a more widespread area, with or without optic disc involvement. The optic disc of the fellow eye in AAION most frequently is of normal diameter, with a normal physiologic cup [6, 35], as opposed to that in NAION, which tends to be small in diameter, with little or no physiologic cup.
Summary for the Clinician
■ Arteritic AION presents with severe vi-
sual loss, pale optic disc edema, often with other signs of retinal vasculopathy, and in association with systemic symptoms including headache, jaw claudication, and temporal tenderness.
2.2.1.2 Pathophysiology Histopathologic studies in AAION demonstrate vasculitis of the short posterior ciliary vessels supplying the optic nerve head, in addition to variable involvement of the superficial temporal, ophthalmic, choroidal, and central retinal arteries. Infiltration of the short posterior ciliary arteries by chronic inflammatory cells, with segmental occlusion of multiple vessels by inflammatory thickening and thrombus, has been documented. Autopsy studies have demonstrated ischemic necrosis predominantly involving the laminar and retrolaminar portions of the optic nerve supplied by these vessels and their distal tributaries. Fluorescein angiographic data support involvement of the short posterior ciliary arteries in AAION. Delayed filling of the optic disc and adjacent choroid (Fig. 2.5) is consistently noted [16]. Extremely poor or absent filling of the choroid has been suggested as one useful factor in distinguishing arteritic from nonarteritic AION. Mack et al. [43] reported a mean choroid perfusion time (from first appearance to filling) of 69 s in patients with AAION, compared with 5.5 s in NAION; Siatkowski et al. [57] confirmed this finding with slightly different parameters, mean time from injection to choroid filling measur-
2.2 Anterior Ischemic Optic Neuropathy
in the fellow eye without therapy range from 54% to 95% [8, 41]. The optic disc edema typically resolves over 4–8 weeks, with resultant optic atrophy and generalized attenuation of retinal arterioles. Excavation of the optic disc occurs frequently after AAION, whereas this phenomenon is unusual in NAION. Danesh-Meyer et al. [14] reported optic disc cupping in 92% of 92 patients with AAION versus 2% of 102 patients with NAION. The excavation may be severe, mimicking glaucomatous damage, but the severity of the optic atrophy seen after AAION usually differentiates it from glaucomatous excavation.
2.2.1.5 Diagnostic Confirmation Fig. 2.5. Fluorescein angiography in arteritic AION. Optic disc filling is poor and there is prominent nonperfusion of the nasal choroid
ing 29.7 s in AAION compared with 12.9 s in NAION.
2.2.1.3 Differential Diagnosis The acute onset of severe visual loss in the setting of headache and optic disc edema, particularly when bilateral, requires consideration of alternative diagnoses, including acute optic neuropathy secondary to chronic papilledema (with or without intracranial mass), infiltrative optic neuropathy, and meningeal carcinomatosis involving the optic nerves. In cases of suspected AAION with negative workup or atypical course, neuroimaging should be performed to evaluate for intracranial mass or visible meningeal thickening and enhancement, and lumbar puncture should be considered to assess for evidence of elevated intracranial pressure or malignant cells.
2.2.1.4 Clinical Course If untreated, AAION results in severe damage of the affected optic nerve. Recovery of useful vision after initial involvement is unusual, even with prompt therapy. In cases with unilateral presentation, estimates for development of AAION
The most important initial step in the management of AION is the assessment for evidence of GCA. A tentative diagnosis may be made on the basis of advanced age and typical clinical symptoms in conjunction with elevation of the erythrocyte sedimentation rate (ESR). Most cases of active GCA show markedly elevated ESR (mean 70 mm/h, often >100 mm/h). When the level is not extremely high, however, interpretation of the value becomes more difficult, as normative data are imprecise. As a rule, we recommend the clinically useful guideline that the upper level of normal, in mm/h, is calculated by dividing patient’s age by 2 in males, and the patient’s age plus 10, all divided by 2 in females. However, by these criteria, the level may be normal in up to 22% of patients with GCA. Conversely, the ESR rises with age, and levels above the listed upper limit of normal for the laboratory are common (up to 40% over 60 mm/h) in patients over 70 years without arteritis. In the Ischemic Optic Neuropathy Decompression Trial (IONDT), 9% of patients with NAION had ESR levels greater than 40 mm/h, with a range of 0–115 mm/h [31]. Moreover, the test is nonspecific, elevation confirming only the presence of any active inflammatory process or other disorder affecting red blood cell aggregation. In studies of cases in which biopsy of the temporal artery proved negative but the ESR was elevated, the most commonly associated diseases have been occult malignancy (most frequently lymphoma) in 18%–22%, other inflammatory disease in 17%–21%, and diabetes in 15%–20%. In these cases initially suspected of being GCA,
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internal medicine consultation to rule out other systemic disease is essential. Additional blood abnormalities are common in GCA and may have prognostic value. Measurement of C-reactive protein (CRP), levels of which do not rise with age or anemia, may increase diagnostic accuracy and are currently recommended in conjunction with the ESR. Hayreh et al. [25] reported that a specificity of 97% for GCA was attained for AION patients with an ESR ≥47 mm/h and CRP >2.45 mg/dl (normally ≤0.5 mg/dl) from their laboratory. We currently recommend simultaneous measurement of both parameters in suspected cases of AAION. Fibrinogen is commonly elevated and may supplement CRP levels in increasing accuracy over the use of ESR alone. Thrombocytosis is seen in up to 50% of patients with GCA; its presence has been shown to be a marker for positive temporal artery biopsy and may be a predictor of visual loss. Liozon et al. [40] assessed 174 patients with GCA, correlating thrombocytosis with the development of permanent visual loss. Of 20 patients with permanent visual loss due to AAION, 13 (65%) had thrombocytosis. This feature may have implications for therapy (see below). Giant cell arteritis is confirmed by positive temporal artery biopsy, which is strongly recommended in any case of suspected AAION. The certainty of biopsy-proven GCA provides support for long-term systemic corticosteroid therapy, which often is required for up to a year and may be associated with severe systemic complications. It also makes later decisions regarding the risk-benefit ratio of prolonged therapy more clear-cut. Negative biopsy, however, does not rule out GCA. False-negative biopsy may result from: 1. Discontinuous arterial involvement (“skip lesions”) undetected in 4%–5% due to an insufficient length (minimum 3–6 cm recommended) of specimen or insufficiently detailed step-sectioning. 2. Unilateral involvement with biopsy of the uninvolved temporal artery. 3. Improper handling of specimens. 4. Review by pathologist inexperienced in diagnosis of acute and healed arteritis. The false-negative error rate for unilateral temporal artery biopsy has previously been estimated at
5%–11%. Hayreh et al. [25] more recently prospectively studied 76 patients who underwent contralateral biopsy due to high clinical suspicion after initially negative biopsy; 7 (9.2%) had evidence of active inflammation in the second biopsy. Boyev et al. [11] (3%), Danesh-Meyer et al. [13] (1%), Pless et al. [49] (5%), and Hall et al. [21] (5%) found varying rates of discordance between sides in bilateral biopsies. In the critical subset of patients who undergo contralateral biopsy after initially negative result (a sample biased toward the positive based on clinical parameters raising suspicion for GCA), studies with the greatest number of patients suggest a slightly higher discordance (2.8%–9.2%), but the difference is small. The data all suggest some degree of increased accuracy from bilateral biopsy samples, and considering the severe consequences of missed diagnosis, the relatively low risk of procedural complications, and the benefit of biopsy proof in the long-term management of these patients, we consider bilateral biopsy in all cases. The level of clinical suspicion guides these decisions.
Summary for the Clinician
■ Diagnosis is confirmed by elevated ESR and CRP and by positive temporal artery biopsy.
2.2.1.6 Therapy If GCA is suspected, therapy should be instituted immediately; initial treatment should not await diagnostic confirmation by temporal artery biopsy. Although chronic systemic corticosteroid therapy may reduce positive biopsy results in GCA, a delay of 7–10 days has no significant effect on results, and in some cases active inflammation may be detected after longer therapy. High-dose intravenous methylprednisolone at 1 g per day for the first 3–5 days is most often recommended, particularly when the patient is seen in the acute phase, since this mode of therapy produces higher blood levels of medication more rapidly than oral therapy. As these patients are
often elderly with multiple and complex medical problems, we routinely provide inpatient therapy, under the supervision of an internist. Oral prednisone at doses of at least 1 mg/kg per day is recommended after intravenous therapy (or initially if the intravenous route is not utilized), and is tapered slowly, monitoring for control of systemic symptoms and ESR level; therapy is usually maintained for at least 4–6 months, often up to a year. Systemic symptoms typically subside within a week, a response so characteristic that if it is absent, an alternative disease process should be strongly considered. Alternate-day corticosteroid therapy is inadequate for GCA. Some degree of visual recovery in the affected eye may be obtained on therapy, but is not generally anticipated. Reports of visual improvement on corticosteroids vary widely with regard to delay to therapy, dosage, and parameters for visual recovery. Aiello et al. [1] reported improvement of vision in 5/34 patients (15%), while Liu et al. [41] noted it in 14/41 (34%). Foroozan et al. [17] reported improvement in visual acuity in 5/39 eyes (13%), although visual fields remained severely constricted. Hayreh et al. [29] studied 114 eyes in 84 patients for evidence of visual improvement, finding only 5 eyes (4%) with both improved visual acuity and central visual field after therapy. The major goal of therapy other than prevention of systemic vascular complications is to prevent contralateral visual loss. Untreated, fellow eye involvement occurs in up to 95%, often within weeks. With therapy, Aiello et al. [1] found that 2/24 (6.3%) patients with AAION developed such involvement; Liu et al. [41] detected fellow eye AAION on therapy in 3 cases. While corticosteroid therapy reduces risk of further visual loss, it is not uniformly effective; breakthrough involvement of an affected eye while on therapy occurred in 9%–17% [1, 41]. Liu et al. [41] found 6 cases developing AAION while on systemic corticosteroid therapy for systemic symptoms alone, without previous visual loss. The risk of recurrent or contralateral optic nerve involvement with tapering of medications has been reported to be 7% [41]. Thrombocytosis in GCA and its possible predisposition to visual loss suggests the possibility that antiplatelet therapy may be of benefit in con-
2.2 Anterior Ischemic Optic Neuropathy
junction with corticosteroids. Nesher et al. [46] reviewed 175 cases with GCA for evidence of cranial ischemic complications (predominantly AION and stroke), comparing those with and without low-dose aspirin therapy for other conditions. At presentation, 3 (8%) of aspirin-treated cases had cranial ischemic complications, compared with 40 (29%) of non-aspirin-treated cases (p=0.01). During follow-up of at least 3 months on steroid therapy, cranial ischemic complications developed in 3% of aspirin-treated cases versus 13% on steroids alone (p=0.02). Further study may confirm a benefit for low-dose aspirin or other antiplatelet therapy in GCA.
Summary for the Clinician
■ Therapy of AAION should be institut-
ed immediately upon suspicion of the disease, before biopsy, and consists of high-dose systemic corticosteroids; the primary goal is protection of the fellow eye.
2.2.2 Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) 2.2.2.1 Clinical Presentation The majority (94.7%) of cases of AION are nonarteritic [20]; NAION is the most common acute optic neuropathy in patients over 50 years of age, with an estimated annual incidence in the United States of 2.3–10.2 per 100,000 population [22, 33] accounting for at least 6000 new cases annually. The prevalence of NAION in the Medicare Database has been reported at 0.30% [19]. The disease occurs with significantly higher frequency in the white population than in black or Hispanic individuals [33]. There is no gender predisposition [10, 20, 31, 52]. The mean age at onset in most studies ranges from 57 to 65 years [10, 20, 52]; in the IONDT, mean age was 66 years [31]. Nonarteritic AION presents with loss of vision occurring over hours to days, often described as blurring, dimness, or cloudiness in the affected region of the visual field, most often infe-
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riorly. Although Hayreh et al. [27] reported that visual loss was most frequently reported upon awakening, this feature was not confirmed in the IONDT [31]. Nonarteritic AION typically presents without pain, although some form of periocular discomfort has been reported in 8%–12%. In contrast to patients with optic neuritis, those with NAION usually do not report pain with eye movement. Headache and other symptoms associated with GCA are absent. Episodes of transient visual loss as seen in GCA are rare, but vague intermittent symptoms of blurring, shadows, or spots were reported in 5% of patients in the IONDT [31]. The initial course may be static, with little or no fluctuation of visual level after initial loss, or progressive, with either episodic, stepwise decrements or a steady decline of vision over weeks to months prior to eventual stabilization; the progressive form has been reported in 22%–37% of nonarteritic cases [2, 10], and in 29% in a limited group of patients with visual acuity of >20/64 in the IONDT [31]. Nonarteritic AION usually presents with a less severe visual loss than in AAION, with visual acuity >20/200 in 58%–61.2% [10, 52]. In the IONDT, 49% had initial visual acuity of at least 20/64; 66%, better than 20/200 [31]. Color vision loss in NAION tends to parallel visual acuity loss, as opposed to that in optic neuritis, in which color loss is often disproportionately greater than visual acuity loss. Visual field defects in NAION may follow any pattern related to optic nerve damage, but altitudinal loss, usually inferior, occurs in the majority, ranging from 55% to 80% of reported cases [10, 52]. The optic disc edema in NAION may be diffuse or segmental, hyperemic or pale, but pallor occurs less frequently than in the arteritic form. A focal region of more severe swelling is often seen and may display an altitudinal distribution, but it does not consistently correlate with the sector of visual field loss [3]. Diffuse or focal telangiectasia of the edematous disc may be present, occasionally prominent enough to resemble a vascular mass (pseudohemangioma). Peripapillary retinal hemorrhages are common, seen in 72% in the IONDT [31]. Retinal exudates are unusual, but both soft and hard exudates may occur (7% in the IONDT) [31]; a partial or complete macular star pattern of exudate, as seen in neu-
roretinitis, is occasionally seen. The retinal arterioles are focally narrowed in the peripapillary region in up to 68% of cases. The optic disc in the contralateral eye is typically small in diameter and demonstrates a small or absent physiologic cup [6]. The disc appearance in such fellow eyes has been described as the “disc at risk,” with postulated structural crowding of the axons at the level of the cribriform plate, associated mild disc elevation, and disc margin blurring without overt edema.
Summary for the Clinician
■ NAION presents as less severe, painless, ■ ■
unilateral visual field loss, most often altitudinal. Optic disc edema is present, usually less pale than in AAION, with associated flame hemorrhages. Vasculopathic risk factors are often present.
2.2.2.2 Pathophysiology Nonarteritic AION is presumed to result from circulatory insufficiency within the optic nerve head, but the specific location of the vasculopathy and its pathogenic mechanism remain unproven. There are few histopathologically studied cases of typical NAION, the majority of which were atypical. Tesser et al. [59] indicated that the optic disc infarct studied in their case did not follow a specific vascular territory and may have represented a compartment syndrome. Knox et al. [37] reported a series of 193 eyes with a histopathologic diagnosis of ischemic optic neuropathy, but those with typical NAION were not identifiable due to lack of clinical information. No confirmation of lipohyalinosis or other occlusive process or inflammation within the disc’s vascular supply has been documented in these or other cases. The available evidence does, however, highlight one important fact: the infarctions were predominantly located in the retrolaminar region of the optic nerve head, with extension to
the lamina and prelaminar layer in some. This pattern suggests that the vasculopathy responsible for NAION does not lie within the choroidal circulation, since the contribution of the choroid to the optic nerve head vascular supply is to the more anterior laminar and prelaminar layers. In the acute phase of NAION, fluorescein angiography studies show delayed filling of the prelaminar layers of the edematous optic disc; this is the most compelling in vivo evidence to date of optic disc circulatory impairment in NAION [3, 16]. In studies by Arnold and Hepler [3], delayed prelaminar optic disc filling (≥5 s later than choroid and retinal vasculature) was demonstrable in 76% of subjects with acute NAION (Fig. 2.6). This feature was not seen in normal controls or in subjects with nonischemic optic disc edema [4], suggesting that the delayed filling represents a primary ischemic process rather than a mechanical process secondary to obstruction from the disc edema itself. Arnold and Hepler [3] and Siatkowski et al. [57] both found that segmental parapapillary choroidal filling delay (≥5 s) was not a consistent feature in NAION (Fig. 2.6) (46% versus 58% in normal controls). These data speak against a
Fig. 2.6. Fluorescein angiography in nonarteritic AION. There is significant filling delay of the optic disc after choroidal and retinal arteries have filled. The peripapillary choroid fills normally adjacent to the optic disc which fills poorly
2.2 Anterior Ischemic Optic Neuropathy
proximal vascular occlusion in the short posterior ciliary arteries, which would produce a delay in both optic disc and choroidal filling, and against a choroidal origin, which would produce consistently delayed choroidal filling. They are consistent with flow impairment at the level of the paraoptic branches of the short posterior ciliary arteries described by Olver et al. [47].
2.2.2.3 Risk Factors Although carotid occlusive disease may occasionally result in optic nerve ischemia, most often in the setting of more general ocular ischemia and occasionally with associated cerebral ischemia, the vast majority of cases are unrelated to carotid disease. Neither Fry et al. [18] nor Muller et al. [45] found hemodynamically significant stenosis in their series of subjects with NAION. It is clear that acute severe systemic hypotension, particularly associated with anemia, can produce optic nerve ischemia (see below). Hayreh et al. [27] have proposed that less severe nocturnal systemic hypotension may play a role in the development of NAION, suggesting that the relative hypotension which normally occurs with sleep may chronically compromise optic disc circulation, particularly in those patients with an exaggerated nocturnal “dip,” or in patients, such as those with systemic hypertension, whose optic disc circulation autoregulatory mechanisms are impaired. This effect might be worsened with aggressive antihypertensive therapy, particularly if administered at night, by further exacerbating the nocturnal pressure drop. Hayreh et al [27] performed 24-h ambulatory blood pressure monitoring in a total of 114 NAION, 131 normal tension glaucoma (NTG), and 30 primary open angle glaucoma (POAG) subjects, implying that nocturnal systemic hypotension played a significant role in the development of NAION in certain susceptible subjects. No control subjects were studied. In contrast, Landau et al. [39] performed 24-h ambulatory blood pressure monitoring in 24 subjects with NAION and 24 age-, disease-, and medication-matched controls. Mean decreases of 11% systolic and 18% diastolic were measured in NAION, compared with 13% and 18% respectively in controls, showing
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no significant difference. The conflicting data from these two groups leave the role of nocturnal hypotension in NAION unresolved. We do, however, discuss with our patients and their physicians the possible accentuation of nocturnal hypotension by nighttime use of antihypertension medications; consideration of dosing other than at bedtime is recommended. The sleep apnea syndrome (SAS) has been associated in some cases with optic disc edema, presumed to be the result of occult elevations in intracranial pressure. Occasional optic nerve damage was documented, but whether it resulted from chronic papilledema, the hypoxemia of SAS, or both has been unclear. In 2002, Mojon et al. [44] compared 17 consecutively seen NAION patients to 17 age- and sex-matched controls for evidence of SAS. Diagnostic criteria for SAS were met in 71% of the NAION patients versus 18% of controls. These studies are preliminary and involve small patient numbers, insufficient data from which to draw conclusions. Nonarteritic AION has been reported in association with many conditions which may predispose to decreased optic nerve head perfusion via microvascular occlusion. Several cross-sectional case series have estimated the prevalence of systemic diseases which might predispose to vasculopathy in patients with NAION [10, 20, 31, 52]. Systemic hypertension was documented in 34%–49.4% of patients (47% in the IONDT) [31]; however, in several of the studies which compared these figures to matched population data from the National Health Survey, statistical significance was reached only in the younger age group, 45–64 years [20, 52]. Diabetes was reported in 5%–25.3% (24% in the IONDT) [31], with statistically significant increased prevalence in all ages in all but one study. Diabetes was associated with the development of NAION at a younger age in most series as well. In these series, the association of NAION with other cardiovascular events such as stroke and myocardial infarction was inconsistent. Recent studies have addressed additional vasculopathic risk factors. Jacobson et al. [32] performed a case–control study in NAION, addressing hypertension and diabetes, along with smoking and hypercholesterolemia in 51
patients compared with two separate control groups. While hypertension was found in 57% of patients, it was not found to be significantly more prevalent than in controls in any age group; however, diabetes, found in 34%, was a significant risk factor in all age groups. Neither hypercholesterolemia nor smoking demonstrated significant risk. The 61-patient case–control study of Salomon et al. [55] also confirmed diabetes but not hypertension as a risk factor; hypercholesterolemia was found to be significant, while smoking was not. A large-scale (137 cases) but uncontrolled study by Chung et al. [12] concluded that smoking was a significant risk factor on the basis that smokers developed NAION at a significantly younger age than nonsmokers. Deramo and associates [15] reported 37 patients with NAION presenting before the age of 50, in which mean serum cholesterol was significantly elevated when compared with age-and gender-matched controls. Elevated plasma homocysteine levels have been associated with an increased risk of premature ischemic events (peripheral vascular disease, stroke, myocardial infarction) in patients under 50, but the relation to NAION remains unclear. Kawasaki et al. [36] reported hyperhomocysteinemia in 2/17 cases of NAION under the age of 50, while Biousse et al. [9] reported normal values in 14/14 patients with a mean age of 43 years. Pianka et al. [48] reported elevated levels in 45% of 40 NAION patients (mean age 66 years) versus 9.8% of controls, and Weger et al. [60] also reported mean elevation (11.8 versus 9.8 µmol/l) in 59 NAION patients versus controls. The clinical significance of these statistically significant findings is uncertain, limited by small patient numbers and widely varying results. Isolated reports have documented prothrombotic risk factors in patients with NAION, but a larger-scale recent study by Salomon et al. [55] has not confirmed an association with lupus anticoagulants, anticardiolipin antibodies, prothrombotic polymorphisms (factor V Leiden), or deficiencies of protein C, S and antithrombin III in a series of 61 patients with NAION versus 90 controls. However, they recently compared 92 consecutive patients with NAION to 145
controls for evidence of platelet glycoprotein polymorphisms [56]. They found a statistically significant association with the VNTR B allele in NAION versus controls; second eye involvement was more frequent and earlier in onset in those with the polymorphism. Further investigation is required to definitively establish these and other associations.
2.2.2.4 Medications Two medications have been associated with the development of NAION (interferon-alpha and sildenafil), although the number of cases is insufficient to confirm a definite causative effect. A third, amiodarone, has been linked to NAION but probably produces a toxic optic neuropathy which mimics it.
2.2.2.4.1 Interferon-alpha This glycoprotein with antiviral, antitumor, and antiangiogenic effects is in use as adjuvant therapy for malignancies, including melanoma, leukemia, and lymphoma, and for chronic hepatitis C. Several reports [51] confirm the development of NAION, usually bilateral, sequential, and temporally associated with the institution of interferon therapy; recurrences with re-starting the medication have also been described. The clinical course is variable, with some cases showing improvement with discontinuance of therapy. Possible pathogenic mechanisms include interferon-induced systemic hypotension or immune complex deposition within the optic disc circulation.
2.2.2.4.2 Sildenafil This commonly used therapy for erectile dysfunction may produce systemic hypotension; the therapeutic dose may reduce systemic BP by at least 10 mmHg. Pomeranz and Bhavsar [50] reviewed 14 cases of NAION reported in association with the use of sildenafil through 2005. The patients ranged in age from 42 to 69 years; 12 had known vascu-
2.2 Anterior Ischemic Optic Neuropathy
lopathic risk factors. The optic discs in each case with available data showed the typical “crowded” configuration commonly seen in NAION; one patient had prior NAION in the fellow eye. The onset of visual loss was within 3 h of medication use in five cases. The postulated mechanism in these cases has been systemic hypotension in patients with structurally predisposed optic discs, possibly complicated by an exaggerated nocturnal dip in blood pressure. While the number of cases is extremely small, particularly considering the widespread use of the drug, the authors suggest that the drug may be contraindicated in patients with prior NAION, and that this group of patients should be counseled regarding the risk of developing NAION with further use. Additional data are required for definitive recommendations in this regard.
2.2.2.4.3 Amiodarone Amiodarone is in widespread use as a cardiac anti-arrhythmic agent and has been associated with the development of optic neuropathy. Macaluso et al. [42] summarized the data from 73 patients, including 16 published case reports and 57 patients with information recorded in the National Registry of Drug-Induced Ocular Side Effects, with optic neuropathy associated with amiodarone use. They emphasized that these patients with significant cardiovascular disease have risk factors for NAION and that many cases of optic neuropathy with amiodarone use may be typical NAION unrelated to the drug. A syndrome more consistent with medication toxicity, including insidious bilateral onset, generalized rather than altitudinal visual field loss, and chronic optic disc edema persisting months after onset of visual loss, was suggested as the more likely optic neuropathy related to amiodarone use. Limited visual recovery occurred in most cases after discontinuance of medication. The small number of cases precludes definitive conclusions; it remains to be seen whether, as in the case of certain antineoplastic agents such as cisplatin and BCNU [1,3-bis(2-chloroethyl)1-nitroso-urea], there may be a medication-induced microvasculopathy.
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Summary for the Clinician
■ Risk factors for NAION may include
hypertension, diabetes, hyperlipidemia, smoking, sleep apnea syndrome, and medications such as interferon-alpha, sildenafil, and amiodarone.
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2.2.2.5 Clinical Course Untreated, NAION generally remains stable, the majority of cases showing no significant improvement or deterioration over time [2, 10, 52]. Recent studies, however, indicate that spontaneous improvement of visual acuity occurs in a minority of patients. Recovery of at least three Snellen acuity lines has been reported in up to 42.7% (in the IONDT) [30] of patients. After stabilization of vision, usually within 2 months, recurrent or progressive visual loss in an affected eye is extremely unusual and should prompt evaluation for another cause of optic neuropathy. Repka et al. [52] reported recurrent episodes in only 3 of 83 (3.6%) patients. Hayreh et al. [28] reported recurrence more than 2 months after the initial episode in 53 of 829 eyes (6.4%). The optic disc becomes visibly atrophic, in a sectoral or diffuse pattern, usually within 4– 6 weeks; persistence of edema past this point should prompt consideration of an alternative diagnosis. Eventual involvement of the contralateral eye has been reported in 24%–39% with varying follow-up. Beck et al. [7], however, reviewed 431 patients with NAION, finding a substantially lower 5-year risk of 12%–19%; in the IONDT, fellow eye involvement at 5 years was estimated at 14.7%. Occurrence in the second eye produces the clinical appearance of the “pseudoFoster Kennedy syndrome,” in which the previously affected disc is atrophic and the currently involved nerve head is edematous. Significantly impaired visual field in the eye with disc edema distinguishes this condition from the true Foster Kennedy syndrome, in which disc edema is due to elevated intracranial pressure caused by a mass and does not produce visual loss acutely.
2.2.2.6 Differential Diagnosis Nonarteritic AION must be differentiated from idiopathic optic neuritis, syphilitic or sarcoidrelated optic nerve inflammation, particularly in patients under 50 years of age; infiltrative optic neuropathies, anterior orbital lesions producing optic nerve compression, and idiopathic forms of optic disc edema, including diabetic papillopathy, are also considerations. Optic neuritis may resemble ischemia with regard to rate of onset, pattern of visual field loss, and optic disc appearance; however, in most cases, the patient’s younger age, pain with eye movement, and character of the disc edema (diffuse and hyperemic rather than pale or segmental) make distinction clear. Occasionally, ancillary testing such as fluorescein angiography, ultrasonography, or magnetic resonance (MR) imaging of the optic nerve may be helpful in differentiation. Fluorescein angiography often shows delayed optic disc filling in optic disc ischemia, whereas filling is normal in papillitis [4]. Ultrasonography and MR imaging are typically normal in NAION, while increased optic nerve diameter and a positive 30 degree test for perineural fluid may be seen on ultrasound in optic nerve inflammation. Intraorbital optic nerve swelling and enhancement are frequently seen on MR with inflammation and infiltration. Optic nerve inflammation associated with syphilis or sarcoidosis often is associated with other intraocular inflammatory signs, which should prompt further testing. Orbital lesions producing disc edema usually are associated with gradually progressive visual loss, but occasionally onset is more rapid. The detection of subtle signs of orbital disease, including mild proptosis, lid or eye movement abnormalities, or the persistence of optic disc edema past the usual 4–6 weeks in NAION, may indicate the need to perform neuroimaging to detect orbital inflammation or a tumor such as optic nerve sheath meningioma. In the great majority of cases, however, such testing is not required. Diabetic papillopathy typically does not produce significant afferent pupillary defect or visual field loss (see below). In cases with typical presentation, without symptoms or signs to suggest GCA and with normal ESR and CRP, we do not routinely per-
form additional testing. Evaluation by a primary care physician for evidence and control of risk factors such as hypertension, diabetes, and hyperlipidemia is essential. Neuroimaging is not performed unless the patient follows an atypical course, such as prolonged optic disc edema, or continued progressive or recurrent visual loss more than 2 months after initial presentation.
2.2.2.7 Therapy There is no proven effective therapy for NAION. Early medical therapies attempted included anticoagulants, diphenylhydantoin for its effect in improving conduction in hypoxic neurons, subtenons injections of vasodilators, intravenous intraocular-pressure-lowering agents and vasopressor agents (norepinephrine) to improve the gradient of nerve head perfusion pressure to intraocular pressure, thrombolytic agents and stellate ganglion block, oral corticosteroids in an attempt to decrease neuronal edema and any secondary damage related to it, aspirin, and heparin-induced low-density lipoprotein/fibrinogen precipitation or hemodilution. None has been proven effective. More recently applied nonsurgical modalities include hyperbaric oxygen and levodopa/carbidopa. Arnold et al. [5] treated 22 eyes in 20 patients with acute NAION, using hyperbaric oxygen at 2.0 atm (202,650 Pa) twice a day for 10 days, comparing visual outcome to 27 untreated acute NAION controls; no beneficial effect was found. Johnson et al. [34] reported 18 patients with NAION treated with a 3-week course of levodopa/carbidopa within 45 days of visual loss, compared with 19 historical untreated controls. At 6 months, 10/13 (76.9%) treated versus 3/10 (30%) controls improved at least three lines in Snellen visual acuity testing. The study was limited by small numbers and possible confounding factors, and results have not been corroborated by other investigators. This therapeutic modality remains unproven. The Ischemic Optic Neuropathy Decompression Trial (IONDT) of optic nerve sheath decompression surgery for NAION was based on the beneficial effect of the surgery in the optic
2.2 Anterior Ischemic Optic Neuropathy
neuropathy of elevated intracranial pressure and the postulate that reduction of perineural subarachnoid cerebrospinal fluid pressure could improve local vascular flow or axoplasmic transport within the optic nerve head, thus reducing tissue injury in reversibly damaged axons. Recruitment for the study was ceased after 2 years, with 119 treated versus 125 controls, when data analysis revealed no significant benefit for treatment (improvement in visual acuity by at least three lines in 32.6% treated versus 42.7% control) [30]. Moreover, the treatment group showed a statistically significantly greater risk for worsening by three lines or more (23.9% treated versus 12.4% control). The 24-month follow-up data from the study confirmed the initial 6 months report. This technique is not currently recommended for the treatment of NAION. Transvitreal radial optic neurotomy has been proposed as a therapy for both central retinal vein occlusion (CRVO) and NAION [58]. The procedure involves a pars plana vitrectomy and induced posterior vitreous detachment, associated with a stab incision at the nasal margin of the optic disc, with the purpose of opening the scleral canal and relieving compression of an edematous optic nerve. If a compartment syndrome is at least a component of the pathophysiology of NAION, then such a procedure in theory could break the cycle of edema and vascular compression. Soheilian et al. [58] reported the results of transvitreal neurotomy performed in seven cases of NAION with severe visual loss (visual acuity range CF-20/800) and onset prior to surgery ranging 15–90 days. Improvement of visual acuity was noted in six patients with a final range of CF-20/60. This study was limited by several factors, including small patient numbers, sample bias (i.e., severe visual loss with difficulty accurately measuring pre- and postoperative visual levels), and delayed onset of therapy. The authors emphasized the experimental nature of this procedure and recommended a randomized clinical trial prior to considering this approach.
2.2.2.8 Prevention There is no proven prophylactic measure for NAION. Although aspirin has a proven effect in
31
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Ischemic Optic Neuropathies
reducing stroke and myocardial infarction (MI) in patients at risk, published data regarding its role in decreasing the incidence of fellow-eye involvement after the initial episode have been controversial. Both Kupersmith et al. [38] and Salomon et al. [54] found a significant beneficial effect, while a larger retrospective review by Beck et al. [7] studied 431 patients with NAION for second-eye involvement with and without aspirin use. The 5-year risk for fellow-eye involvement was calculated at 12%–19%, and no long-term benefit for aspirin use was found [7]. Although beneficial long-term effects remain unproven for NAION, many experts recommend the use of aspirin after an initial episode, if only for its role in decreasing risk for stroke and MI in this vasculopathic population group.
Summary for the Clinician
■ There is no proven effective therapy for NAION. ■ Low-dose aspirin may reduce the risk of fellow-eye involvement.
2.3 Posterior Ischemic Optic Neuropathy Although the anterior form of ION is far more common than the posterior variety, ischemia of the retrobulbar portions of the optic nerve occurs in many settings, both arteritic and nonarteritic. Posterior ischemic optic neuropathy (PION) is a syndrome of acute visual loss with characteristics of optic neuropathy without disc edema and is marked by the subsequent development of optic atrophy. The diagnosis of PION is most often made in one of two settings [23]: 1. Giant cell arteritis (GCA) or, rarely, other vasculitides such as herpes zoster, polyarteritis nodosa, or lupus erythematosus. Evaluation for GCA is essential in cases without other apparent cause, and should be the primary consideration with this presentation in the elderly, with urgent ancillary testing as described earlier for AION. 2. The combination of systemic hypotension and anemia, usually related to blood loss either from surgery (coronary artery bypass and lumbar spine procedures most frequently reported), gastrointestinal bleed, or trauma.
Table 2.1. Ischemic optic neuropathies Anterior
Posterior
Arteritic
Nonarteritic
Age
Mean 70 years
Mean 60 years
Variable
Sex
F>M
F=M
F=M
Associated symptoms
Headache, jaw claudication, transient visual loss
Usually none
None unless arteritic or postoperative
Visual acuity
<20/200 in >60%
>20/200 in >60%
Usually poor
Disc
Pale swelling common cup normal plus choroid ischemia
Pale or hyperemic Cup small
Normal, variable
ESR
Mean 70 mm/h
Mean 20–40 mm/h
Elevated if arteritic
FA
Disc delay; choroid delay
Disc delay
Not studied
Natural history
Rarely improves Fellow eye 54%–95%
16%–42.7% improve Rarely improves Fellow eye 12%-19% Bilateral >60%
Treatment
Systemic steroids
None proven
Steroids if arteritis
References
The differential diagnosis includes compressive and infiltrative optic neuropathies, although the onset in PION is typically more abrupt. In most cases, neuroimaging is indicated to rule out these possibilities. While NAION typically shows no enhancement of the optic nerves on MR, presumably due to limitation to the optic nerve head, in PION enhancement has been demonstrated and must be differentiated from other causes, such as inflammation and infiltration. Recently, Sadda et al. [53] reported a multicenter, retrospective review covering 22 years, revealing 72 patients with PION, classifying them in three groups: 1. Perioperative 2. Arteritic 3. Nonarteritic The nonarteritic group accounted for 38 of the 72 patients, exhibited similar risk factors, and followed a clinical course precisely like that of NAION. In contrast to perioperative and arteritic PION, which were characterized by severe visual loss with little or no recovery, nonarteritic PION was less severe and showed improvement in 34% of patients. It is important to recognize this nonarteritic form in patients with acute optic neuropathy but no optic disc edema, a scenario that may be mistaken for optic neuritis. Such patients, as in some patients with AION and disc edema, particularly those with ischemic white-matter lesions on MRI, might be incorrectly begun on immunomodulatory therapy to reduce the risk of multiple sclerosis. PION differs from optic neuritis by its occurrence in older age groups, with lack of pain on eye movements. Table 2.1 summarizes the clinical and paraclinical characteristics of AION and PION.
References 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Summary for the Clinician
■ PION occurs most frequently in GCA
and acute hypotension with blood loss, but occasionally is present in an idiopathic form. There is no proven effective therapy.
■
13.
Aiello PD, Trautmann JC, McPhee TJ et al (1993) Visual prognosis in giant cell arteritis. Ophthalmology 100:550–555 Arnold AC, Hepler RS (1994) Natural history of nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol 14:66–69 Arnold AC, Hepler RS (1994) Fluorescein angiography in acute anterior ischemic optic neuropathy. Am J Ophthalmol 117:222–230 Arnold AC, Badr M, Hepler RS (1996) Fluorescein angiography in nonischemic optic disc edema. Arch Ophthalmol 114:293–298 Arnold AC, Hepler RS, Lieber M, Alexander JM (1996) Hyperbaric oxygen therapy for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 122:535–541 Beck RW, Servais GE, Hayreh SS (1997) Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology 94:1503–1508 Beck RW, Hayreh SS, Podhajsky PA et al (1997) Aspirin therapy in nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 123:212–217 Beri M, Klugman MR, Kohler JA et al (1987) Anterior ischemic optic neuropathy. VII. Incidence of bilaterality and various influencing factors. Ophthalmology 94:1020–1028 Biousse V, Kerrison JB, Newman NJ (2000) Is non-arteritic anterior ischaemic optic neuropathy related to homocysteine? Br J Ophthalmol 84:554 Boghen DR, Glaser JS (1975) Ischaemic optic neuropathy. The clinical profile and natural history. Brain 98:689–708 Boyev LR, Miller NR, Gree WR (1999) Efficacy of unilateral versus bilateral temporal artery biopsies for the diagnosis of giant cell arteritis. Am J Ophthalmol 128:211–215 Chung SM, Gay CA, McCrary JA (1994) Nonarteritic anterior ischemic optic neuropathy. The impact of tobacco use. Ophthalmology 101:779–782 Danesh-Meyer HV, Savino PJ, Eagle RC Jr. et al (2000) Low diagnostic yield with second biopsies in suspected giant cell arteritis. J Neuroophthalmol 20:213–215
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Ischemic Optic Neuropathies 14. Danesh-Meyer HV, Savino PJ, Sergott RC (2001) The prevalence of cupping in end-stage arteritic and nonarteritic anterior ischemic optic neuropathy. Ophthalmology 108(3):593–598 15. Deramo VA, Sergott RC, Augsburger JJ et al (2003) Ischemic optic neuropathy as the first manifestation of elevated cholesterol levels in young patients. Ophthalmology 110:1041–1045 16. Eagling EM, Sanders MD, Miller SJH (1974) Ischaemic papillopathy: clinical and fluorescein angiographic review of forty cases. Br J Ophthalmol 58:990–1008 17. Foroozan R, Deramo VA, Buono LM (2003) Recovery of visual function in patients with biopsy-proven giant cell arteritis. Ophthalmology 110:539–542 18. Fry CL, Carter JE, Kanter MC et al (1993) Anterior ischemic optic neuropathy is not associated with carotid artery atherosclerosis. Stroke 24:539–542 19. Gordon LK, Yu F, Coleman AL et al (2003) Medicare database analysis of prevalence and risk factors for ischemic optic neuropathy. Ophthalmology Suppl 110:238 20. Guyer DR, Miller NR, Auer CL et al (1985) The risk of cerebrovascular and cardiovascular disease in patients with anterior ischemic optic neuropathy. Arch Ophthalmol 103:1136–1142 21. Hall JK, Volpe NJ, Galetta SL et al (2003) The role of unilateral temporal artery biopsy. Ophthalmology 110:543–554 22. Hattenhauer MG, Leavitt JA, Hodge DO et al (1997) Incidence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 123:103–107 23. Hayreh SS (1981) Posterior ischemic optic neuropathy. Ophthalmologica 182:29–41 24. Hayreh SS, Podhajsky PA, Zimmerman B (1988) Ocular manifestations of giant cell arteritis. Am J Ophthalmol 125:509–520 25. Hayreh SS, Podhajsky PA, Raman R et al (1997) Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 123:285–296 26. Hayreh SS, Podhajsky PA, Zimmerman B (1998) Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 125:521–526 27. Hayreh SS, Podhajsky P, Zimmerman MB (1999) Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica 213:76–96
28. Hayreh SS, Podhajsky PA, Zimmerman B (2001) Ipsilateral recurrence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 132:734–742 29. Hayreh SS, Zimmerman B, Kardon RH (2002) Visual improvement with corticosteroid therapy in giant cell arteritis. Report of a large study and review of literature. Acta Ophthalmol Scand 80:355–367 30. Ischemic Optic Neuropathy Decompression Trial Research Group (1995) Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. J Am Med Assoc 273:625–632 31. Ischemic Optic Neuropathy Decompression Trial Research Group (1996) Characteristics of patients with nonarteritic anterior ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol 114:1366–1374 32. Jacobson DM, Vierkant RA, Belongia EA (1997) Nonarteritic anterior ischemic optic neuropathy. A case-control study of potential risk factors. Arch Ophthalmol 115:1403–1407 33. Johnson LN, Arnold AC (1994) Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy: population-based study in the State of Missouri and Los Angeles County, California. J Neuroophthalmol 14:38–44 34. Johnson LN, Guy ME, Krohel GB et al (2000) Levodopa may improve vision loss in recent-onset, nonarteritic anterior ischemic optic neuropathy. Ophthalmology 107:521–526 35. Jonas JB, Gabriele GC, Naumann GOH (1988) Anterior ischemic optic neuropathy: nonarteritic form in small and giant cell arteritis in normal sized optic discs. Int Ophthalmol 12:119–125 36. Kawasaki A, Purvin VA, Burgett RA (1999) Hyperhomocysteinaemia in young patients with non-arteritic anterior ischaemic optic neuropathy. Br J Ophthalmol 83:1287–1290 37. Knox DL, Kerrison JB, Green WR (2000) Histopathologic studies of ischemic optic neuropathy. Trans Am Ophthalmol Soc 98:203–222 38. Kupersmith MJ, Frohman L, Sanderson M et al (1997) Aspirin reduces the incidence of second eye NAION: a retrospective study. J Neuroophthalmol 17:250–253
39. Landau K, Winterkorn JMS, Mailloux LU et al (1996) 24-hour blood pressure monitoring in patients with anterior ischemic optic neuropathy. Arch Ophthalmol 114:570–575 40. Liozon E, Herrmann F, Ly K et al (2001) Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients. Am J Med 111:211–217 41. Liu GT, Glaser JS, Schatz NJ et al (1994) Visual morbidity in giant cell arteritis. Ophthalmology 101:1779–1785 42. Macaluso DC, Shults WT, Fraunfelder FT (1999) Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 127:610–612 43. Mack HG, O’Day J, Currie JN (1991) Delayed choroidal perfusion in giant cell arteritis. J Clin Neuroophthalmol 11:221–227 44. Mojon DS, Hedges TR 3rd, Ehrenberg B et al (2002) Association between sleep apnea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 120:601–605 45. Muller M, Kessler C, Wessel K et al (1993) Lowtension glaucoma: a comparative study with retinal ischemic syndromes and anterior ischemic optic neuropathy. Ophthalmic Surg 24:835–838 46. Nesher G, Berkun Y, Mates M et al (2004) Lowdose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 50:1332–1337 47. Olver JM, Spalton DJ, McCartney ACE (1990) Microvascular study of the retrolaminar optic nerve in man: the possible significance in anterior ischemic optic neuropathy. Eye 4:7–24 48. Pianka P, Almog Y, Man O et al (2000) Hyperhomocystinemia in patients with nonarteritic anterior ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion. Ophthalmology 107:1588–1592 49. Pless M, Rizzo JF, Lamkin JC et al (2000) Concordance of bilateral temporal artery biopsy in giant cell arteritis. J Neuroophthalmol 20:216–218
References 50. Pomeranz HD, Bhavsar AR (2005) Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol 25:9–13 51. Purvin VA (1995) Anterior ischemic optic neuropathy secondary to interferon alfa. Arch Ophthalmol 113:1041–1044 52. Repka MX, Savino PJ, Schatz NJ et al (1983) Clinical profile and long-term implications of anterior ischemic optic neuropathy. Am J Ophthalmol 96:478–483 54. Sadda SR, Nee M, Miller NR et al (2001) Clinical spectrum of posterior ischemic optic neuropathy. Am J Ophthalmol 132:743–750 55. Salomon O, Huna-Baron R, Steinberg DM et al (1999) Role of aspirin in reducing the frequency of second eye involvement in patients with nonarteritic anterior ischaemic optic neuropathy. Eye 13:357–359 56. Salomon O, Huna-Baron R, Kurtz S et al (1999) Analysis of prothrombotic and vascular risk factors in patients with nonarteritic anterior ischemic optic neuropathy. Ophthalmology 106:739–742 57. Salomon O, Rosenberg N, Steinberg DM et al (2004) Nonarteritic anterior ischemic optic neuropathy is associated with a specific platelet polymorphism located on the glycoprotein Ibalpha gene. Ophthalmology 111:184–188 58. Siatkowski RM, Gass JDM, Glaser JS et al (1993) Fluorescein angiography in the diagnosis of giant cell arteritis. Am J Ophthalmol 115:57–63 59. Soheilian M, Koochek A, Yazdani S et al (2003) Transvitreal optic neurotomy for nonarteritic anterior ischemic optic neuropathy. Retina 23:692–697 60. Tesser RA, Niendorf ER, Levin LA (2003) The morphology of an infarct in nonarteritic anterior ischemic optic neuropathy. Ophthalmology 110:2031–2035 61. Weger M, Stanger O, Deutschmann H et al (2001) Hyperhomocysteinaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic anterior ischaemic optic neuropathy. Br J Ophthalmol 85:803–806
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Chapter 3
3
Optic Disc Drusen François-Xavier Borruat
Core Messages
■ Optic disc drusen (ODD) represent a
frequent cause of slowly progressive optic neuropathy. ODD result probably from an abnormal axonal metabolism, leading to mitochondrial calcification at the level of the lamina cribrosa. Axons rupture and extracellular mitochondria further calcify. Buried (deep) ODD are more commonly seen in younger patients and exposed (superficial) ODD in older patients. Visual field defects are a frequent finding in ODD patients, more so when ODD are exposed. Visual acuity is usually preserved even in advanced but uncomplicated ODD. Visual acuity loss can result from vascular complications such as: anterior ischemic optic neuropathy, central/branch retinal artery or vein occlusion. The most sensitive diagnostic test for ODD is B-scan ultrasound. There is currently no therapy for ODD.
■ ■ ■ ■ ■
lenge, related to the patient’s symptoms, the fundus appearance, or to vision complications. In general, exposed (superficial) ODD represent no diagnostic problem, whereas buried (deep) ODD are more difficult to diagnose (Fig. 3.1). Buried drusen are thought to represent an earlier stage in the formation of ODD, when the lesions are relatively small and located deep within the prelaminar optic nerve head. Exposed drusen are generally found in older patients, when the lesions are of bigger size, calcified, and located more anteriorly. Exposed drusen are also associated with a thinner nerve fiber layer. Further, evolution from buried to exposed drusen has been demonstrated on several occasions and was also recently reported by Spencer et al. [52]: a young patient who had normal fundus appearance at age 2 developed elevated discs at age 5 with a negative CT scan, then developed calcification visible on CT scan at age 9, and finally showed exposed ODD at age 12.
■ ■
Summary for the Clinician
■ Buried (deep) drusen most likely repre-
sent an earlier stage of optic disc drusen (ODD), and become exposed (visible) later on. Ongoing calcification of ODD and progressive thinning of the nerve fiber layer contribute to the evolution of buried ODD to exposed (visible) drusen.
3.1 Introduction Optic disc drusen (ODD) represent a frequent cause of optic neuropathy. Despite numerous publications since the first histopathological description of ODD in 1858 [40], followed 10 years later by its clinical description [32], the problem of ODD remains unresolved. Two major reviews were recently published, providing a clear overview of ODD [3, 11]. Most frequently the affected patients are asymptomatic and ODD are incidentally found during ocular fundus examination. However, certain cases can represent a diagnostic chal-
■
3.2 Epidemiology There is no sex predilection for ODD, but there is a racial predilection. Patients of African ancestry rarely present ODD and this may result from the overall larger optic disc size amongst this ethnic
38
Optic Disc Drusen
3
Fig. 3.1. Buried and exposed optic disc drusen. Top row: three examples of optic disc with buried (deep) drusen: mild and located nasally (left), moderate and diffuse (middle), and more pronounced (right). Bottom row: exposed (superficial) drusen. The optic nerve head has an irregular aspect, with a “lumpy bumpy” appearance due to the presence of several whitish calcified nodules of variable size
group. Various studies have previously reported an overall prevalence of ODD varying between 0.4% and 3.7% within a normal population and an autosomal-dominant pattern with variable penetrance has been assumed for years. Recently, a study was conducted to determine the incidence of ODD as well as the incidence of optic disc anomalies amongst seven families of seven unrelated probands. The authors found only 1 of 27 examined relatives to exhibit ODD (incidence 3.7%), whereas 30/53 eyes had anomalous optic disc vasculature (57%) and 26/53 eyes had absent optic disc cupping (49%) [1]. The authors proposed that the primary pathology could be an inherited optic disc dysplasia, predisposing to the formation of ODD in susceptible patients.
3.3 Pathology Optic disc drusen result from a slow degenerative process, and originate from axoplasmic derivatives of disintegrating nerve fibers. This mechanism was proposed more than 40 years ago and remains the accepted physiopathology of ODD [49, 50, 53]. In his Edward Jackson Memorial Lecture, Spencer proposed that a blockade of axoplasmic flow occurs at the lamina cribrosa, initially at the optic disc periphery, and that the Bruch’s membrane might act as a mechanical barrier to axoplasmic flow [53]. A few years later, Tso [56] published an outstanding paper on the histopathology of 18 patients with ODD and presented the only electron microscopy study of OND published
to date. He proposed that an abnormal axonal metabolism leads to mitochondrial calcification. Axons eventually rupture, and calcium is then heavily deposited in the now extracellular mitochondria. They form small calcified microbodies which further calcify and coalesce into ODD. Optic disc drusen are found only in the prelaminar portion of the optic nerve, supporting the proposal that blockade of axoplasmic flow occurs at the lamina cribrosa. Tso [56] also showed that some patients with ODD exhibited vascular alterations within the optic nerve head, in the vicinity of ODD (enlargement of the perivascular space, endothelial cells and pericyte degeneration). A more recent histopathological study reported results from 18 patients with ODD (18/3395 autopsies; 0.5% incidence) [20]. Their results confirmed the prelaminar location of ODD, showed that the papillary arterial and venous vessels are displaced in severe cases of ODD, and also suggested that mechanical constriction by a tight Bruch’s membrane might play a role in the formation of ODD. An interesting study from Germany attempted to correlate visual function with the pattern of retinal ganglion cells [19]. They compared the results from 1 patient with ODD to 10 normal retinae. They found a drastic loss of retinal ganglion cells in the ODD patient: the total retinal ganglion cell count was reduced by 75% in the right eye (RE) and by 58% in the left eye (LE), which correlated grossly with visual dysfunction in both eyes, more pronounced in the right eye. However, there was no correlation between visual field loss and the topography of retinal ganglion cell loss. The greatest loss of retinal ganglion cells occurred in the paracentral and mid-peripheral retinal regions, and the least was found in the far periphery. Small retinal ganglion cells were more susceptible to die in ODD. Counting the central retinal ganglion cells (0.8 mm eccentricity from the foveola) showed that 43% of retinal ganglion cells remained in the right eye while 64% were present in the left eye. Such a loss was compatible with visual acuity reduced to 0.8 RE but maintained at 1.0 LE.
3.4 Optic Canal Size
Summary for the Clinician
■ Mitochondrial
dysfunction at the prelaminar level of the optic nerve head seems to be the primary event in the formation of ODD. Mitochondria calcify, axons rupture and extracellular mitochondria further calcify. Vascular alterations in the vicinity of ODD are also found.
■ ■
3.4 Optic Canal Size Since the first clinical descriptions of ODD, a small crowded optic disc without cupping has been frequently reported. In 1984, a photographic retrospective study was performed, comparing the optic disc size between a group of 13 emmetropic eyes with ODD and 19 normal emmetropic eyes [41]. These authors found that the optic disc size in ODD was statistically significantly smaller than in normal eyes. Also, 10/13 eyes with ODD showed vascular anomalies. They concluded that a mesodermal dysgenesis resulted in a small scleral canal, a prerequisite for developing ODD. This widely accepted point of view was recently challenged by Floyd et al. [18]. These authors designed a prospective study to determine whether patients with ODD presented a smaller optic canal as compared to normal subjects. They used optical coherence tomography (OCT) to determine the size of the scleral canal in 25 ODD patients, 13 unaffected first-degree relatives, and 17 normal subjects. The size of the inner aspect of the scleral canal was measured based on the detection of the retinal pigment epithelium and Bruch’s membrane around the optic disc. They found a statistically significantly larger optic canal size in the ODD group when compared to either the normal or the first-degree relative groups. They mentioned but refuted the possibility that ODD would obscure or displace the retinal pigment epithelium and/or the Bruch’s membrane, therefore providing falsely large numbers in the ODD group. It is nonetheless interesting to
39
40
3
Optic Disc Drusen
mention that, in their results, the buried drusen group exhibited an “intermediate” optic canal size (overall, smaller than the exposed drusen group, but larger than the normal or first-degree relative groups). The question of the real size of the scleral canal in patients with ODD awaits further studies.
Summary for the Clinician
■ Most studies agree that ODD develop
in somehow small, crowded optic nerve heads. This issue was recently challenged but awaits confrontation by further studies.
■
differs between patients with RP versus those without RP. Results of a retrospective study found that ODD or parapapillary drusen occurred in 35% of 43 patients with Type I Usher syndrome, and in only 8% of 108 with Type II Usher syndrome. Drusen were also more often bilateral in Type I Usher syndrome [14]. There is no explanation for these findings. One case of ODD associated with pigmented paravenous retinochoroidal atrophy was reported in an 11-year-old black girl [60]. As ODD are very rare in black patients, this report suggests that the pathogenesis of ODD in this setting might differ from that of common ODD.
3.5 Associations Most of the ODD cases are isolated but an association with a retinal disorder such as retinitis pigmentosa, pseudoxanthoma elasticum, or angioid streaks alone has been reported on several occasions.
3.5.1 Inherited Retinal Degenerations To determine the frequency of optic disc and/ or parapapillary drusen in retinitis pigmentosa (RP), Grover et al. [21] retrospectively studied 262 patients with RP of autosomal-dominant (n=117), autosomal-recessive (n=84), and Xlinked recessive (n=61) inheritance. The overall frequency of ODD or parapapillary drusen was 9.2% in this population, without a significant difference between the genetic sub-groups. The authors cautioned that this number could underestimate the real frequency of drusen in RP as they did not systematically use ultrasound confirmation. Although they did not specifically measure the optic disc size, the authors responded to an interesting comment that they felt confident that the presence of ODD in RP patients was not associated with a small disc size [17, 26]. The presence of a normal optic disc size in RP might imply that the pathogenesis of ODD
3.5.2 Angioid Streaks and Pseudoxanthoma Elasticum A retrospective study of 110 patients with angioid streaks led the author [35] to the conclusion that the presence of angioid streaks per se (i.e., without pseudoxanthoma elasticum) was associated with ODD [35]. The hypothesis was that elastin mineralization and adherence of abnormal glycosaminoglycans to elastin fibers could lead to a marked thickening of the lamina cribrosa, secondarily altering axoplasmic transport. Another study addressed the presence of ODD in angioid streaks [44]. Amongst a total of 116 examined eyes (58 patients), the authors found an overall incidence of 21.6% of ODD; 50 patients (100 eyes) had pseudoxanthoma elasticum and 21.0% had ODD. Optic disc drusen were found in 25% of the 8 patients without pseudoxanthoma elasticum. This high incidence of ODD in this study was thought to have resulted from the systematic use of B-scan ultrasound for the diagnosis of ODD.
3.5.3 Miscellaneous The first case of ODD in association with nanophthalmos and RP was reported in 1998 [7]. The authors proposed that the thickened sclera in nanophthalmos might predispose patients to develop ODD. However, there is no other de-
3.6 Paraclinical Investigations
scription of an association of ODD with nanophthalmos, and the present case might have well resulted from RP alone. One case of ODD in a patient with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) was recently reported [13]. Although there is no explanation for the presence of ODD in POEMS syndrome, one might postulate that the chronic optic disc swelling (present in 50% of POEMS cases) might be the cause of ODD in such cases. Wollenhaupt et al. [59] reported a single case of ODD associated with trisomy 15q. They reported the presence of bilateral hypoplastic but nonelevated optic discs at age 2, with subsequent development of optic disc swelling and ultrasound evidence for ODD at age 5. This association had never been reported before.
Summary for the Clinician
■ The incidence of ODD is higher amongst
patients with retinitis pigmentosa, Usher syndrome, pseudoxanthoma elasticum, or angioid streaks alone. Other associations are anecdotal.
■
3.6 Paraclinical Investigations Diagnosing ODD may be easy when ODD are exposed (superficial). In that situation, ocular fundus examination might be sufficient, and autofluorescence is often present (Fig. 3.2). When ODD are buried (deep), the diagnosis relies more importantly on paraclinical examinations, such as B-scan ultrasound, fluorescein angiography, and CT scan (Figs. 3.2, 3.3). Recently, newer imaging techniques have been used in diagnosing and/or staging the degree of optic nerve dysfunction in ODD.
3.6.1 B-Scan Ultrasound There is no doubt that the most sensitive way to detect ODD, buried or exposed, is B-scan ultra-
sound, as has been demonstrated on several occasions (Fig. 3.2). Most of these studies evaluated various diagnostic procedures. Pierro et al. [44] demonstrated that ultrasound was the most sensitive test to detect the presence of ODD, followed by ophthalmoscopy, and fluorescein angiography in a series of 116 eyes with angioid streaks [44]. Kheterpal et al. [29] studied prospectively four patients with swollen optic discs using CT-scan, magnetic resonance imaging (MRI), fundus autofluorescence, and B-scan ultrasound. Only Bscan ultrasound was able to detect ODD in all four patients, whereas the other techniques correctly diagnosed ODD in only one patient each. MRI is not recommended to investigate potential ODD. A nice study was published by Kurz-Levin and Landau [30]. They performed a retrospective study of 261 eyes (142 patients) referred for suspicion of ODD. Of 261 eyes, 36 were investigated with B-scan ultrasound, CT scan and preinjection control photograph looking for autofluorescence of the optic disc. Only B-scan ultrasound correctly identified all 21 patients with ODD, fewer than 50% of ODD being identified by CT scan or showing autofluorescence. Further, amongst 82 eyes with suspected buried ODD, 39 eyes showed ODD by B-scan ultrasound and only 15 eyes showed optic disc autofluorescence. No diagnosis of ODD was missed by B-scan ultrasound, and 50% of all ODD cases were diagnosed only by B-scan ultrasound. Autofluorescence was positive in 96% of exposed ODD, but in only 27% of buried ODD.
3.6.2 Scanning Laser Ophthalmoscope Haynes et al. [23] performed a prospective study of 12 eyes with swollen optic discs, using scanning laser ophthalmoscope (SLO) and B-scan ultrasound. Both techniques correctly identified ODD in 10/12 eyes. The advantages of SLO over B-scan ultrasound reside in the fact that SLO is able to provide a clear image of the fundus even in the presence of significant lens opacity (Fig. 3.2). However, SLO is not readily available to most ophthalmologists.
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Fig. 3.2a–d. Diagnostic investigations. a Ultrasound results from a patient with optic disc drusen (ODD). A nodule of high intensity is visible in the center of the optic nerve head, both with B-scan (top) and with A-scan (bottom). b CT scan of the orbits reveals a hypersignal (arrow) at the level of the optic nerve head, due to the presence of calcium. c,d Results for the right eye (c) and the left eye (d) of a patient with exposed ODD. On preinjection control photograph (left), diffuse and nodular autofluorescence is obvious in both eyes. With the scanning laser ophthalmoscope (middle), the nodules are more precisely identified. Ocular coherence tomography (right) demonstrates the swelling of the optic nerve head and the intrinsic nodular appearance due to ODD. The right optic nerve is vertically scanned (c, right), whereas the left optic nerve is scanned horizontally (d, right)
3.6 Paraclinical Investigations
Fig. 3.3a–d. Angiography of the optic nerve head. Fluorescein angiography (a,c) and indocyanine green angiography (b,d) from the right eye (RE) and the left eye (LE) of the same patient are shown. With fluorescein, there is no leakage of dye but a slow and irregular staining of the ODD, mostly visible in the late phase of the angiography. This contrasts with the absence of either leakage of dye or staining with indocyanine green
3.6.3 Optical Coherence Tomography Optical coherence tomography (OCT) is a newly developed objective technique allowing the measurement of retinal nerve fiber layer (NFL) thickness. Several studies recently addressed the question of NFL loss in patients with ODD. In a prospective study, Roh et al. [46] concluded that OCT was a sensitive and early indicator of NFL thinning in ODD, when compared
to red-free photography and computerized visual field results. Further they also demonstrated that buried ODD were not as damaging to the optic nerve as exposed ODD, as there was no NFL thinning in the buried ODD group. Another group of authors studied the evolution of NFL thickness in ODD patients over an average of 18 months [43]. In this prospective study of 23 eyes with ODD, mean retinal NFL thickness did not change. The authors stressed the difficulties of obtaining comparable optic
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nerve measurements with OCT and also the follow-up time, which might have been too short. Amongst 58 eyes with buried ODD, Katz and Pomeranz [28] found only 3 eyes (5%) with visual field defects. Twenty one patients with normal visual field underwent OCT, and all eyes showed a normal average NFL thickness. Only 4/21 eyes had some sectorial NFL loss, and 4 others were borderline. Most patients with buried ODD had no visual field defects, and only 20% showed some mild abnormalities of NFL thickness. Optical coherence tomography can also be used to directly image the optic nerve head. In the presence of ODD, the irregular “lumpy bumpy” appearance of the optic nerve head is readily apparent (Fig. 3.2).
3.6.4 Scanning Laser Polarimetry Scanning laser polarimetry (SLP) is also an objective technique recently developed to assess NFL thickness. In a prospective study of 38 eyes with ODD, the authors found a good correlation between SLP and functional loss: the average NFL thickness was decreased in eyes with abnormal visual field results [38]. However, SLP results could not differentiate patients with buried ODD from patients with exposed ODD. Similar results were found amongst 23 eyes with exposed ODD: NFL thickness was decreased in ODD patients as compared to normals [55]. Furthermore, NFL thickness loss was more pronounced when the clinical grading of ODD was higher.
sion, visual field, flash or pattern visual-evoked potentials). Pattern ERG might then be a very sensitive way to detect preclinical dysfunction of the retinal ganglion cells in ODD.
3.6.6 Retinal Angiography Fluorescein angiography (FFA) has been used for several years in investigating ODD. It can prove helpful sometimes, when a differential diagnosis with true papilledema (elevated intracranial pressure) is not clear. In patients with ODD, there is neither dilatation nor leakage from the papillary capillaries. In the late phase of FFA, there is however staining of the drusen by the dye, and frequently hyperfluorescence is more pronounced nasally (Fig. 3.3). In our experience, indocyanine green angiography (ICGA) is not helpful in diagnosing ODD. With ICG, the optic nerve stays hypofluorescent even during the late phases.
Summary for the Clinician
■ B-scan ultrasound is widely accepted as
the most sensitive means to confirm the presence of ODD. Scanning laser ophthalmoscopy was recently reported to be as sensitive as ultrasound, offering also a good direct imaging of the optic nerve head in the presence of opaque media. Fluorescein angiography can be helpful, mostly to distinguish ODD from true papilledema. Indocyanine green angiography and MRI are not helpful for diagnosing ODD, as calcifications do not appear on MRI.
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3.6.5 Electrophysiology Electrophysiology is not really needed to diagnose ODD, but can be helpful to stage the degree of optic neuropathy. In a prospective study of 29 eyes with ODD, the P100 latency of the pattern visual-evoked potentials was prolonged in 12 eyes (41%) whereas a reduced amplitude or the absence of the N95 component of the pattern electroretinogram (pERG) was detected in 79% (19/29 eyes) [48]. The abnormality of the pERG was more frequently found than any other test performed in this group (visual acuity, color vi-
3.7 Complications 3.7.1 Visual Field Defects Visual field defects are a common, frequently incidental, finding amongst patients with ODD (Fig. 3.4). In children, the incidence of visual field defect varies between 11% and 51% [15, 24],
whereas it has been reported to be as high as 87% in the adult population with ODD [34, 47]. The increased frequency of visual field defect with age seems to parallel the evolution of ODD from buried (children) to exposed (adults). It also confirms the slowly progressive nature of the optic neuropathy of ODD. A retrospective study recently addressed the question of the rate of visual field loss in ODD patients [31]. The authors determined that the rate of visual field loss was 1.6% per year, based on Goldmann visual field measurements of 32 patients followed for 36 months. There was no sex difference. Recently, Wilkins and Pomeranz [57] published an interesting paper on the visual manifestations of ODD. They retrospectively compared the results from 33 patients with exposed ODD to those of 46 patients with ultrasonographically proven buried ODD [57]. They found an overall prevalence of 49% of visual field defects, nerve fiber bundle defect being the most frequent (73%, mostly infero-nasally), followed by generalized constriction only (20%), and enlarged blind spot only (7%). There was an obvious increased prevalence of defects within the exposed ODD group (73%) versus the buried ODD (36%). However, the type and severity of visual field defects did not significantly differ between the two groups. They also interestingly noticed that more than half of their patients were symptomatic (decreased visual acuity, blurriness of vision, dim vision). More recently in another study of patients with buried ODD, only 5% of patients (3/51 eyes) presented a visual field defect [28]. Sudden visual field constriction can occur in ODD, as it was reported by Moody et al. [39]. They described two patients who suddenly and painlessly presented permanent monocular peripheral visual loss, with preserved visual acuity and a relative afferent pupillary defect. No definite explanation could be provided. As compared to other optic neuropathies, preservation of visual acuity and central visual field suggests that the small fibers of the papillomacular bundle seem to be relatively resistant in ODD. This conclusion contradicts the only study to examine the regional loss of retinal ganglion cells in a patient with ODD [19].
3.7 Complications
Fig. 3.4a–d. Visual field defects in patients with optic disc drusen (ODD). a Mild asymmetrical visual field defect in an asymptomatic 54-year-old woman with buried ODD. Visual acuity was 10/10 in both eyes. The defect is nasal inferior in both eyes. b Moderate and asymmetrical visual field defect in a 24-year-old man with exposed ODD. Visual acuity was 10/10 in both eyes. The defect was still purely nasal. c Severe visual field defect in a symptomatic 49-year-old woman with exposed ODD. Visual acuity was reduced to 4/10 in the right eye with a mild dyschromatopsia (6/13 Ishihara), whereas the left eye visual acuity and color vision were normal (10/10, 13/13 Ishihara). Dense arcuate scotomata surround the macula. d Very severe visual field defect in a symptomatic 39-year-old man with exposed ODD. Visual acuity was 10/10 in the right eye and 6/10 in the left eye. Only a central island of vision remained in both eyes, more so in the right eye, with a temporal superior island of vision partially remaining in the left eye
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3.7.2 Retinal Vascular Complications
3
Retinal arterial or venous occlusion is fortunately a rare complication of ODD. One isolated case of retinal artery occlusion has been reported and a review of the literature revealed only nine other cases up until 1998 [16]. Central vein occlusion was also reported as a single case report [9]. Incidental asymptomatic vascular anomalies at the optic nerve head are not rare in ODD [4]. In this retrospective study, 13.8% of 116 eyes with ODD showed the presence of hemorrhages, mostly in patients with buried ODD, where they were located deeply around the optic nerve. In exposed ODD, the hemorrhages were flameshaped and superficial (Fig. 3.5). Vascular shunts were found in 6.9% (8/116 cases), mostly in patients with exposed ODD. Another paper reported a 16-year-old girl with complete blockade of both central retinal artery and vein, with papillary arterial and venous shunts [2].
personal experience, and availability of the aforementioned treatments.
3.7.4 Anterior Ischemic Optic Neuropathy In a study addressing the rate of visual field loss in ODD, Lee and Zimmerman [31] found that 10/292 patients with ODD suffered from anterior ischemic optic neuropathy (AION) (3% incidence), but details were lacking [31]. Anterior ischemic optic neuropathy has been reported by several authors as a single case report [10, 27, 33, 42]. However, Purvin et al. [45] reported 20 patients with ODD who suffered from AION. Overall patients with AION and ODD are younger than the usual AION patients, more frequently have preceding symptoms of transient visual loss and seem to have a better visual prognosis. Bilateral simultaneous or bilateral sequential AION also seem to be more frequently reported amongst patients with ODD (Fig. 3.6).
3.7.3 Peripapillary Choroidal Neovascularization Several publications addressed the diagnosis and treatment modalities of peripapillary choroidal neovascularization (PCN) (Fig. 3.5). Peripapillary choroidal neovascularization can happen in ODD, but ODD is not a frequent cause of PCN, as reported recently [6]. These authors retrospectively reviewed 115 eyes of 96 patients with PCN and found only one case with ODD (0.9% incidence). Children with ODD are not immune to PCN and four such patients (age 5, 6, 9, and 13 years) were reported in two papers [5, 58]. Treatment options vary and several reports claimed the successful use of argon laser photocoagulation [12], photodynamic therapy with verteporfin [8, 51], or surgical removal [36, 37, 54] in the treatment of PCN complicating ODD. These were mostly single case reports, except for one series of two patients [12] and another of four patients [36]. They all claimed partial or total restoration of vision without recurrences. The choice of therapy for patients with PCN will vary according to the clinical presentation,
Summary for the Clinician
■ Visual field abnormalities are common but frequently asymptomatic in ODD. ■ Exposed drusen are more frequently associated with visual field abnormalities, but the degree of visual field loss is equal between exposed and buried ODD. The types of visual field defect include: nasal step, arcuate, sectorial, or concentric defects. Vascular complications of ODD are not rare and include hemorrhages, occlusions, and anterior ischemic optic neuropathy.
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3.8 Therapy There is no specific therapy recommended for ODD. In the presence of a slowly progressive visual field loss, the use of intraocular-pressure-lowering medications is generally accepted. When choroidal neovascularization occurs, ar-
3.8 Therapy
Fig. 3.5. Vascular complications of optic disc drusen (ODD). Top left: a macular scar resulting from spontaneous involution of a macular choroidal neovascularization was present in the right eye of this 10-year-old girl. Visual acuity was limited to 1/10 with a central scotoma. Bottom left: a parapapillary scar was found in this 45-year-old man in the presence of exposed ODD. Top right: myiodesopsia (the appearance of floaters) was the complaint of this 12-year-old girl, resulting from the extension of a papillary hemorrhage into the vitreous. The hemorrhage cleared spontaneously. No visual field defect developed thereafter. Bottom right: a subtle parapapillary hemorrhage, deeply located, was insidiously found upon routine examination in this 14-year-old asymptomatic boy with buried ODD
gon laser therapy, photodynamic therapy, or surgical ablation is available. However, two specific surgical maneuvers have recently been used in order to treat patients with ODD. In the past few years, radial optic neurotomy has been proposed to treat a subset of patients with central retinal vein occlusion. A few patients with the progressive form of nonarteritic anterior
ischemic optic neuropathy have also been treated with radial optic neurotomy. Radial optic neurotomy has been successfully used in one patient with ODD who acutely lost vision, resulting in a drastic recovery of visual function in the treated eye [22]. However, this is the only patient reported in the literature, and such an outcome is still anecdotal.
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Fig. 3.6. Sequential bilateral anterior ischemic optic neuropathy. Top: initially, at age 10 this young boy with buried ODD had no complaints. Visual acuity was 10/10 in both eyes and his visual fields were normal. Middle: at age 27, he noticed sudden painless and irreversible loss of visual acuity and field in his right eye. Visual acuity of the right eye was 5/10 and paracentral scotoma and nasal field defects were present. The right optic nerve showed increased swelling. Lumbar puncture, MRI and search for other etiologies were negative. Ischemic optic neuropathy was diagnosed. A progressive sectoral temporal inferior atrophy developed (bottom left) and the field defect of the right eye remained unchanged (bottom right). Bottom: 6 months later, he noticed a sudden and painless loss of visual field in his left eye. Visual acuity was 5/10 in the right eye and 10/10 in the left eye. Visual field of the left eye now showed a superior arcuate scotoma and an inferior nasal defect. Swelling of the left optic disc was more pronounced with some discrete hemorrhages inferiorly. Repeat MRI, lumbar puncture, search for a mitochondrial DNA point mutation and other investigations were negative. No recovery of vision occurred in either eye
Optic nerve sheath fenestration (ONSF) is aimed at decompressing the retrolaminar optic nerve when excessive fluid is present within the optic nerve sheath. Thus far, the only recommended use of ONSF is in progressive optic neuropathy resulting from increased intracranial pressure. Optic nerve sheath fenestration has been demonstrated to be harmful in treating nonarteritic anterior ischemic optic neuropathy. One group from Slovenia claimed a successful outcome after ONSF in 62 patients with disorders as diverse as idiopathic intracranial hypertension,
anterior ischemic optic neuropathy, low-tension glaucoma, central retinal vein occlusion, amiodarone neuropathy and ODD [25]. In total, 19 eyes with ODD were treated and improved visual acuity was noted in 10/19 eyes and improved computerized visual field in 13/19 eyes, with a median follow-up of 12 months (2 weeks to 2 years). However, details of this study were scarce and no other study has ever examined this therapeutic option in ODD. More studies by other groups are needed to confirm these results.
References
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15. Erkkilä H (1975) Clinical appearance of optic disc drusen in childhood. Graefes Arch Klin Exp Ophthalmol 193:1–18 16. Farah SG, Mansour AM (1998) Central retinal artery occlusion and optic disc drusen. Eye 12:480–482 17. Fishman GA, Grover S (1997) Author’s reply. Arch Ophthalmol 104:1532 18. Floyd MS, Katz BJ, Digre KB (2005) Measurement of the scleral canal using optical coherence tomography in patients with optic nerve drusen. Am J Ophthalmol 139:664–669 19. Gellrich MM, Neumaier S, Auw-Hädrich C et al (1998) Retinal ganglion cell layer and visual function in a patient with optic disc drusen. Graefes Arch Klin Exp Ophthalmol 236:904–915 20. Giarelli L, Ravalico G, Saviano S et al (1990) Optic nerve head drusen: histopathological considerations – clinical features. Metab Pediatr Syst Ophthalmol 13:88–91 21. Grover S, Fishman GA, Brown J (1997) Frequency of optic disc or parapapillary nerve fiber layer drusen in retinitis pigmentosa. Ophthalmology 104:295–298 22. Haritoglou C, Prieglinger SG, Grueterich M et al (2005) Radial optic neurotomy for the treatment of acute functional impairment associated with optic nerve drusen. Br J Ophthalmol 89:779–780 23. Haynes RJ, Manivannan A, Walker S et al (1997) Imaging of the optic nerve head drusen with the scanning laser ophthalmoscope. Br J Ophthalmol 81:654–657 24. Hoover DL, Robb RM, Petersen RA (1988) Optic disc drusen in children. J Pediatr Ophthalmol Strabismus 25:191–195 25. Jirásková N, Rozival P (1999) Results of 62 optic nerve sheath decompressions. Ceska Slov Oftalmol 55:136–144 26. Jonas JB (1997) Frequency of optic disc drusen and size of the optic disc. Arch Ophthalmol 104:1531–1532 27. Kamath GG, Prasad S, Phillips RP (2000) Bilateral anterior ischaemic optic neuropathy due to optic disc drusen. Eur J Ophthalmol 10:341–343 28. Katz BJ, Pomeranz HD (2006) Visual field defects and retinal nerve fiber layer defects in eyes with buried optic nerve drusen. Am J Ophthalmol 141:248–253 29. Kheterpal S, Good PA, Beale DJ et al (1995) Imaging of optic disc drusen: a comparative study. Eye 9:67–69
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Optic Disc Drusen 30. Kurz-Levin MM, Landau K (1999) A comparison of imaging techniques for diagnosing drusen of the optic nerve head. Arch Ophthalmol 117:1045–1049 31. Lee AG, Zimmerman MB (2005) The rate of visual field loss in optic nerve head drusen. Am J Ophthalmol 139:1062–1066 32. Liebrich R (1868) Contribution to discussion on Iwanoff A Ueber neuritis optica. Klin Monatsbl Augenheilkd 6:426–427 33. Liew SCK, Mitchell P (1999) Anterior ischaemic optic neuropathy in a patient with optic disc drusen. Aust N Z J Ophthalmol 27:157–160 34. Lorentzen SE (1966) Drusen of the optic disk: a clinical and genetic study. Acta Ophthalmol Suppl 90:1–80 35. Mansour AM (1992) Is there an association between optic disc drusen and angioid streaks? Graefes Arch Klin Exp Ophthalmol 230:595–596 36. Mateo C, Moreno JG, Lechuga M et al (2004) Surgical removal of peripapillary choroidal neovascularisation associated with optic nerve drusen. Retina 24:739–745 37. McDonald HR. Diagnostic and therapeutic challenges. Retina 19:336–341 38. Mistlberger A, Sitte S, Hommer A et al (2001) Scanning laser polarimetry (SLP) for optic nerve head drusen. Int Ophthalmol 23:233–237 39. Moody TA, Irvine AR, Cahn PH et al (1993) Sudden visual field constriction associated with optic disc drusen. J Clin Neuroophthalmol 13:8–13 40. Müller H (1858) Anatomische Beiträge zur Ophthalmologie. Albrecht Von Graefes Arch Klin Ophthalmol 4:1–40 41. Mullie MA, Sanders MD (1984) Scleral canal size and optic nerve head drusen. Am J Ophthalmol 99:356–359 42. Newman WD, Dorrell ED (1996) Anterior ischemic optic neuropathy associated with disc drusen. J Neuroophthalmol 16:7–8 43. Ocakoglu O, Ustundag C, Koyluoglu N et al (2003) Long term follow-up of retinal nerve fiber layer thickness in eyes with optic nerve head drusen. Curr Eye Res 26:277–280 44. Pierro L, Brancato R, Minicucci M et al (1994) Echographic diagnosis of drusen of the optic nerve head in patients with angioid streaks. Ophthalmologica 208:239–242 45. Purvin V, King R, Kawasaki A et al (2004) Anterior ischemic optic neuropathy in eyes with optic disc drusen. Arch Ophthalmol 122:48–53
46. Roh S, Noecker RJ, Schuman JS et al (1998) Effect of optic nerve head drusen on nerve fiber layer thickness. Ophthalmology 105:878–885 47. Savino PJ, Glaser JS, Rosenberg MA (1979) A clinical analysis of pseudopapilledema, II: visual field defects. Arch Ophthalmol 97:71–75 48. Scholl GB, Song HS, Winkler DE et al (1992) The pattern visual evoked potential and pattern electroretinogram in drusen-associated optic neuropathy. Arch Ophthalmol 110:75–81 49. Seitz R (1968) Die intraokularen Drusen. Klin Monatsbl Augenheilk 152:203–211 50. Seitz R, Kersting G (1962) Die Drusen der Sehnervenpapille und des Pigmentepithesis. Klin Monatsbl Augenheilk 140:75–88 51. Silva R, Torrent T, Loureiro R et al (2004) Bilateral CNV associated with optic nerve drusen treated with photodynamic therapy with verteporfin. Eur J Ophthalmol 14:434–437 52. Spencer TS, Katz BJ, Weber SW et al (2004) Progression from anomalous optic discs to visible optic disc drusen. J Neuroophthalmol 24:297–298 53. Spencer WH (1978) Drusen of the optic disk and aberrant axoplasmic transport. Am J Ophthalmol 85:1–12 54. Sullu Y, Yildiz L, Erkan D (2003) Submacular surgery for choroidal neovascularisation secondary to optic nerve drusen. Am J Ophthalmol 136:367–370 55. Tatlipinar S, Kadayifçilar S, Bozkurt B et al (2001) Polarimetric nerve fiber analysis in patients with visible optic nerve head drusen. J Neuroophthalmol 21:245–249 56. Tso MOM (1981) Pathology and pathogenesis of drusen of the optic nervehead. Ophthalmology 88:1066–1080 57. Wilkins JM, Pomeranz HD (2004) Visual manifestations of visible and buried optic disc drusen. J Neuroophthalmol 24:125–129 58. Wilson GA, Lloyd C, Moore AT (2002) Optic disc drusen and peripapillary subretinal neovascular membranes in children. J Pediatr Ophthalmol Strabismus 39:351–354 59. Wollenhaupt M, Palmer EA, Magenis E et al (2002) Optic disc drusen associated with Trisomy 15q. J AAPOS 6:49–50 60. Young WO, Small KW (1992) Pigmented paravenous retinochoroidal atrophy (PPRCA) with optic disc drusen. Ophthalmic Paediatr Genet 14:23–27
Chapter 4
Inherited Optic Neuropathies Marcela Votruba
Core Messages
■ Inherited optic neuropathies are a di-
■ ADOA typically presents in mid to late
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verse group of conditions presenting with mild to severe visual loss, colour vision deficits, central/paracentral visual field defects, optic disc pallor and in many cases a positive family history. Modes of inheritance are dominant, recessive, X-linked and mitochondrial. The absence of a family history does not exclude this diagnosis as there are many apparently new mutations and sporadic cases. Examination of first-degree relatives may be essential if family history is in doubt. All of these conditions are untreatable but referral for genetic counselling, molecular diagnosis, low vision aids, school assistance and blindness registration may be of benefit to the patient and their family. Autosomal dominant optic atrophy (ADOA) and Leber’s hereditary optic neuropathy (LHON) are the most common of these conditions.
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4.1 Introduction Inherited optic neuropathies are a diverse group of conditions in which optic nerve dysfunction and optic atrophy arise as a result of loss of retinal ganglion cells. They are inherited in a Mendelian fashion, as autosomal-dominant, autosomalrecessive or X-linked recessive diseases, or in a non-Mendelian pattern, so-called maternal or
childhood, with an insidious bilateral, symmetrical mild to moderate visual acuity loss, accompanied by dyschromatopsia, central/centro-caecal field defect and optic disc pallor. It is only slowly progressive. LHON typically presents in early adult life with a sudden, asynchronous, consecutive, catastrophic loss of central vision progressing rapidly to profound visual loss. Visual recovery is most unusual. A range of dominant, recessive, mitochondrial and possibly X-linked optic neuropathies are associated with neurological features and multi-systemic presentation. In the large majority of these the underlying genetic aetiology remains obscure.
mitochondrial inheritance. They share common clinical features, which comprise a bilateral, symmetrical, painless, reduced visual acuity, colour vision defects, central or centro-caecal visual field loss and pallor of the optic disc. This pattern suggests that papillomacular bundle involvement is also a common feature. Electroretinography shows a normal flash electroretinogram, suggesting normal outer retinal and photore-
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ceptor function. An absent or delayed pattern visually evoked potentials and a reduction of the N95 waveform on the pattern electroretinogram are consistent with a primary ganglion cell dysfunction. The optic neuropathy is generally permanent, may be progressive and is currently irreversible. The underlying pathophysiology remains a subject for considerable research and remains largely unknown in many of these conditions. However, independent of mode of inheritance, there is tremendous phenotypic variability both within and between families, affecting age and mode of onset, severity of the visual loss, colour deficit and overall prognosis. A number of different genes in both nuclear and mitochondrial genomes underlie these disorders. Some manifest with disease restricted to the eye, whilst others have more widespread systemic associated features, many of which are neurological. In this chapter the inherited optic neuropathies are classified as follows: • Primary inherited optic neuropathies with ocular manifestations • Primary inherited optic neuropathies with significant systemic features • Optic neuropathies secondary to hereditary degenerative disease. Discussion will focus on the primary inherited optic neuropathies.
4.2 Primary Inherited Optic Neuropathies with Ocular Manifestations In the primary hereditary optic neuropathies cell death is confined to the retinal ganglion cells (RGCs) of the inner retina. These inherited optic neuropathies comprise autosomal-dominant, autosomal-recessive and X-linked recessive optic atrophy, and the maternally inherited Leber’s hereditary optic neuropathy (Table 4.1). However, some individuals presenting with optic neuropathy may have no family history, in which case it is important to exclude an acquired cause and examine related family members, who may be sub-clinically affected.
4.2.1 Autosomal-Dominant Optic Atrophy 4.2.1.1 Clinical Features Autosomal-dominant optic atrophy (ADOA, OMIM 165500, [26]) is the commonest hereditary optic neuropathy, with an estimated disease prevalence of 1:12,000 to 1:50,000 [28]. The disease presents in childhood, often insidiously making an exact age of onset hard to establish, typically between 4 and 6 years of age. In mild cases it may remain sub-clinical until early adult life and rarely severe cases have been diagnosed as early as 1 year of age. It presents with bilateral, symmetrical visual loss and temporal disc pallor. Investigation may reveal a central or centro-caecal visual field defect and colour vision abnormality. Visual acuity ranges from 6/6 (1.0) to perception of light (which, however, is rare), with a median acuity of 6/36 (0.16). Visual acuity equal to or better than 6/12 (0.5) is seen in about 15% of patients [48]. Nystagmus is uncommon and is seen only if there is severe visual impairment from infancy. There is considerable variability both within and between families. Visual acuity may decline slowly with age, but rarely is this dramatic [28, 48], and vision does not recover spontaneously. The optic nerve appearances range from subtle temporal pallor to complete atrophy (Fig. 4.1). About 55% of patients may be expected to have subtle or temporal pallor and 44% may have total atrophy [48]. Very rarely the nerve may appear normal. Whilst the intra-ocular pressure is normal and optic disc cupping is not typical, some patients may have a degree of atypical cupping, making the exclusion of normal tension glaucoma all the more difficult [18, 49]. Magnetic resonance imaging of the optic nerve in affected patients reveals a reduced optic nerve-sheath complex throughout the length of the intra-orbital optic nerve with no signal abnormality and a clearly visible cerebrospinal fluid space. Perimetry shows a central, paracentral or centro-caecal defect, with a reported predominance of defects in the superotemporal visual field. The peripheral fields are usually full, but there may be an inversion of red and blue isopters [26]. The dyschromatopsia may be an acquired tritanopia, but is often a generalized dyschromatopsia [44], and even a
Inheritance and phenotype
Locus and gene
Age of onset
Prognosis
Visual acuity
Colour vision deficits
Visual field defects
Disc appearance
Nystagmus
165500
ADOA
OPA1: 3q28qter (OPA1)
Early childhood or congenital
Slow deterioration
6/6–6/120
Tritan or mixed, leading to achromatopsia
Centro-caecal scotoma
Rare Temporal pallor to total atrophy
605293
ADOA
OPA4: 18q12.2.12.3 (OPA4)
Childhood to Similar rate of adolescence visual decline to above
6/6–6/120
Similar to above
Centro-caecal scotoma
Temporal Not repallor to total ported atrophy
165300
ADOAC
OPA3: First decade 19q13.2-q13.3 (OPA3)
AROA
-
258501
AROA: type III methylglutaconic aciduria
OPA3: 19q13.2-q13.3 (OPA3)
258500
AROA- chromosome 8
OPA5: 8q21q22 (OPA5)
No
Congenital
static
6/24–6/120
Achromatopsia
2–6 years
Severe
1/10–2/10
Red-green
Central scotoma/ generalized constriction
Probably similar
Yes
no
4.2 Primary Inherited Optic Neuropathies with Ocular Manifestations
OMIM number
Table 4.1. Genetics of primary inherited optic neuropathies. (ADOA Autosomal-dominant optic atrophy, ADOAC autosomal-dominant optic atrophy and cataract, AROA autosomal-recessive optic atrophy, LHON Leber hereditary optic neuropathy, OMIM Online Mendelian Inheritance in Man, X-LOA X-linked optic atrophy)
53
4
Inheritance and phenotype
X-LOA
Mitochondrial- LHON
OMIM number
311050
535000
Age of onset
Mt: point mutations 11778, 3460, 14484
Early adulthood, 18–35 years
OPA2: Early childXp11.4-Xp11.2 hood (OPA2)
Locus and gene
Visual acuity 6/24–6/120
6/36–6/120
Prognosis Very slow deterioration
Asynchronous onset, deterioration over weeks, may improve
Red-green or generalized dyschromatopsia
“Strong defects”: no blue-yellow defect
Colour vision deficits Probably similar
Disc appearance
Centro-caecal Acute-swolprogressing len disc. to absolute Chronic- total pallor
Paracentral scotoma
Visual field defects
No
None
Nystagmus
Table 4.1. (continued) Genetics of primary inherited optic neuropathies. (ADOA Autosomal-dominant optic atrophy, ADOAC autosomal-dominant optic atrophy and cataract, AROA autosomal-recessive optic atrophy, LHON Leber hereditary optic neuropathy, OMIM Online Mendelian Inheritance in Man, X-LOA X-linked optic atrophy)
54 Inherited Optic Neuropathies
Fig. 4.1a,b. Autosomal-dominant optic atrophy. a Fundus photograph of a right eye showing temporal disc pallor in a patient with dominant optic atrophy. b Fundus photograph of a left eye showing temporal disc pallor in a patient with dominant optic atrophy
4.2 Primary Inherited Optic Neuropathies with Ocular Manifestations
red-green defect may be seen. Best preserved colour vision and least field loss have been noted in patients with the least degree of clinical optic atrophy. Many of these features are suggestive of preferential involvement of the papillomacular bundle. In this context current evidence suggests that neither the parvocellular nor the magnocellular pathway is preferentially involved [48].
important to exclude other causes of optic neuropathy before making the diagnosis.
4.2.1.4 Molecular Genetics and the Genetic Heterogeneity of ADOA Currently, ADOA is associated with three mapped genetic loci: OPA1, OPA3 and OPA4.
4.2.1.2 Electrophysiology Pattern visually evoked cortical potentials are absent or delayed, consistent with a conduction defect in the optic nerve. The pattern electroretinogram shows an abnormal N95:P50 ratio, with a reduction in the amplitude of the N95 waveform [20], supporting a ganglion cell defect. A small number of families with ADOA have been reported to have a negative electroretinogram.
4.2.1.3 Histopathology Histopathology reports of human eyes suggest a primary retinal ganglion cell loss [22, 27] with an ascending optic atrophy and a preserved outer retina.
Summary for the Clinician
■ Inherited optic neuropathies share many
common clinical features, such as optic atrophy, dyschromatopsia, central or centro-caecal field defect. There is considerable phenotypic variation both within and between families. A detailed history of onset of visual loss and family history can be essential in making a diagnosis. In many cases it may be highly informative to examine parents and relatives in order to confirm the mode of inheritance.
■ ■ ■
Sporadic cases of inherited optic neuropathy arise frequently. In such cases it is particularly
4.2.1.4.1 OPA1 Locus Families with dominant optic atrophy were mapped by linkage analysis to a large interval on chromosome 3q28-qter [17] in 1994, subsequently refined to 1.4 cM [47]. A large number of dominant families have been reported to map to the locus on chromosome 3q28-qter, suggesting that it may be the predominant locus for dominant optic atrophy. The former estimated penetrance figure of 98% in dominant optic atrophy has been revised recently in the light of molecular studies, and recent estimates of penetrance vary from family to family and mutation to mutation, being as high as 100% [45], and as low as 43% [46].
4.2.1.4.2 OPA1 Gene and Mutations The OPA1 gene [2, 15] (GenBank Acc. No. AB011139, OMIM 605290) is 6031 nucleotides long and is composed of 31 exons spanning >114 kb of genomic DNA. OPA1 is ubiquitously expressed on Northern blot analysis of RNA from human tissue, with most abundant expression in retina and brain. Alternative splicing gives rise to eight splice variants [16]. Two splice variants are particularly highly expressed in fetal brain, retina and heart. There is a wide spectrum of mutations described to date, with over 110 of them reported (http://lbbma.univ-angers.fr). Mutations are dispersed throughout the gene, but there is a concentration of mutations in the GTPase and dynamin central regions, coded for by exons 8–16, and in the C-terminal coding region by exons 27–28. No mutations have been found in exons 4, 4b and 5b, which are alternately spliced. Mutations
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Inherited Optic Neuropathies
4
include missense and nonsense substitutions, deletions, insertions and complex rearrangements. The majority of these result in protein truncation and the functional loss of one allele, suggesting that they may give rise to haploinsufficiency of OPA1. The identification of a 560- to 860-kb microdeletion on chromosome 3q28 that results in the complete loss of one copy of the OPA1 gene [33] would support haploinsufficiency as an important likely disease mechanism. Missense mutations are less common and may cause disease by a dominant-negative mechanism. Unusually, one family has been reported demonstrating apparent semi-dominance [38], with heterozygous mutations in OPA1.
4.2.1.4.3 OPA1 Protein The OPA1 gene encodes a 960-amino-acid mitochondrial, dynamin-related, guanosine triphosphatase (GTPase) protein (SwissProt 060313). The protein comprises a mitochondrial leader sequence within the highly basic amino-terminal, a GTPase domain, a central dynamin domain that is conserved across all dynamins, and a carboxy terminus of unknown function. The carboxy terminus differs from that of other dynamin family members in lacking a proline-rich region, a GTPase effector domain and a pleckstrin homology domain. OPA1 protein is widely expressed throughout the body: in heart, skeletal muscle, liver, testis, and most abundantly in brain and retina. In the eye, OPA1 is present in the cells of the retinal ganglion cell layer, inner and outer plexiform layers and inner nuclear layer [1]. Although the precise function of the OPA1 protein is unknown, current evidence points to a role in the maintenance of mitochondrial morphology. Functional insights are being gained from studies of homologous proteins, patient mutation data, the cellular sub-localization of OPA1 and in vitro expression and knockdown studies.
4.2.1.4.4 Functional Studies of OPA1 OPA1 is the human homologue (33% homology) of the yeast dynamin-related GTP-bind-
ing protein Mgm1, which is involved in mitochondrial genome maintenance. Mitochondrial morphology is maintained through a balance of fusion and fission [12]. Mutations in Mgm1 have been shown to disrupt mitochondrial fusion, and overexpression of mutant or wild-type Mgm1 causes the mitochondria to become fragmented within the cell. Data from ADOA patients with OPA1 mutations has shown that in some the mitochondrial DNA content is lower and oxidative phosphorylation in the calf muscle is defective [30]. The structure of the mitochondrial network in monocytes is reportedly altered compared to normal control subjects, although this is still controversial [2, 15]. Opa1 localization to mitochondria has been experimentally confirmed by co-localization with Hsp60 in HeLa cells [15]. The subcellular distribution of Opa1 overexpressed in COS-7 cells largely overlaps that of endogenous cytochrome c, a mitochondrial marker. Subcellular localization of Opa1 has also been investigated in primary culture of dissociated rat cerebellar cells, where it shows labelling, distributed in a vesicular pattern in the somas of MAP-2-positive neurons and a weaker signal in the dendrites. However, in these cells the authors observed that the Opa1 signal did not completely overlap with that of cytochrome c, suggesting that the distribution of endogenous Opa1 in the brain might not be confined to mitochondria [34]. Furthermore, Opa1 is an intermembrane space protein, closely associated with the inner mitochondrial membrane, although it has been reported that different isoforms of Opa1 (produced by alternative splicing) may be sublocalized to the inner and outer mitochondrial membranes of HeLa cells [42]. Opa1 protein undergoes processing by mitochondrial endopeptidases, which recognize their cleavage motifs at the amino-terminus of Opa1 [34]. Western blot analysis of Opa1 in mouse brain and HEK 293 cells detected the presence of various sized proteins, with a major band at ~ 90 kDa isolated from the mouse brain, which is estimated to be a product of processing of the unprocessed 100-kDa protein. A major band of approximately 90 kDa was also detected in total protein extracts from human tissues (heart, lung, kidney, spinal cord, skeletal muscle, retina, cer-
4.2 Primary Inherited Optic Neuropathies with Ocular Manifestations
ebellum and testes). The enzyme PARL (presenilin-associated rhomboid-like protease), which is located in the mitochondrial inner membrane, may cleave and activate Opa1. Since a number of Opa1 isoforms have been identified, Opa1 may be bi- or multi-functional, and its activity may depend on which isoform predominates. Experiments carried out in HeLa cells have shown that downregulation of Opa1 by small interfering RNAs (siRNA) results in mitochondrial fragmentation and dispersion throughout the cytosol, dissipation of the mitochondrial membrane potential, disorganization of the cristae and release of cytochrome c followed by caspasedependent apoptotic nuclear events [35]. Following an initial leak of Opa1, a consequence of mitochondrial outer membrane permeabilization, there is re-structuring of the mitochondrial cristae, exposing and releasing the sequestered pools of Opa1 and cytochrome c. The loss of Opa1 then causes a block in mitochondrial fusion, providing an explanation for the observed mitochondrial fragmented phenotype. In retinal ganglion cells Opa1 knockdown results in mitochondrial network aggregation and occurs at a higher rate than in cerebellar ganglion cells [23]. Overexpression of wild-type or mutant forms of Opa1 protein (in particular mutations affecting GTPase activity) causes mitochondria to fragment and accumulate to various extents in the cells near the nucleus [34]. However, mitochondrial fragmentation due to Opa1 overexpression is blocked by downregulation of the fission molecule Drp1 [12]. It is increasingly apparent that a collection of mitochondrial shaping proteins function together with Opa1 to maintain the dynamic control of mitochondrial morphology. Such proteins include pro-fusion GTPases, such as mitofusin (Mfn) 1 and 2, and pro-fission GTPases, such as dynamin-related protein 1 (Drp1) and Fis 1. Opa1 and Mfn1 work synergistically to regulate mitochondrial fusion [13]. Opa1 is unable to promote mitochondrial fusion in the absence of Mfn1, and Mfn1 cannot induce mitochondrial elongation in the absence of Opa1. Opa1 and Mfn1 may have a protective role within the cell. Acting as anti-apoptotic GTPases, they may protect the cell from spontaneous apoptosis and the detrimental effects and consequences of apoptotic stimuli.
4.2.1.4.5 Pathophysiology OPA1 is the first dynamin-related protein implicated in human disease. It remains unclear why ADOA manifests with a restricted ocular phenotype, particularly since it is ubiquitously expressed throughout the body, albeit most abundantly in the retina and brain. It may be that the loss of one allele decreases the amount of OPA1 protein below a critical threshold for normal mitochondrial function, and this may compromise retinal ganglion cell survival. Neurons in particular, owing to their high energy demands, may be particularly susceptible to changes in mitochondrial function. OPA1 protein may have different functions in the mitochondria of different tissues, particularly as the eight mRNA splice forms are differentially expressed. Haploinsufficiency may increase tissue susceptibility to apoptotic stimuli, in particular those stimuli that are especially relevant to the retinal ganglion cell, such as exposure to UV light and reactive oxygen species. There are no reported therapeutic interventions for ADOA and supportive intervention and genetic counselling are important in patient management. The development of an animal model for OPA1 ADOA may lead the way to a fuller understanding of the pathophysiology [50].
Summary for the Clinician
■ Over 100 mutations in the OPA1 gene
have been reported and genotype–phenotype correlations are not marked, with the exception of deafness associated with the R455H OPA1 mutation. OPA1 is a nuclear gene targeted to the inner mitochondrial membrane, where it appears to have a role in mitochondrial fusion. Evidence suggests that retinal ganglion cells are lost by apoptosis in OPA1 ADOA. Mitochondrial shaping proteins, such as OPA1, are a newly discovered and important group of proteins, increasingly being associated with human inherited eye disease.
■ ■ ■
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Inherited Optic Neuropathies
4.2.1.4.6 The Wider Role of OPA1 in Optic Neuropathy?
4
Polymorphisms in the OPA1 gene have been associated with normal-tension glaucoma in a British population [6], although no role for OPA1 has been identified in primary open-angle glaucoma. This has led to the hypothesis that normal-tension glaucoma may be an unrecognized hereditary optic neuropathy of mitochondrial aetiology. However, research in geographically distinct populations has produced conflicting results and the role of OPA1 in normal-tension glaucoma is far from clear.
4.2.1.5 OPA4 Locus A second dominant optic atrophy locus, OPA4, has been mapped on chromosome 18q12.2-q12 [25]. The gene has not been identified yet. The phenotype has many similarities to that of OPA1 (see Table 4.1).
4.2.1.6 OPA3 Locus: AutosomalDominant Optic Atrophy and Cataract (ADOAC) 4.2.1.6.1 Clinical Features Cataract has recently been described in association with dominantly inherited optic atrophy in two families, which maps to the OPA3 locus on chromosome 19q13.2-q13.3 (ADOAC, OMIM 165300) [39] (Table 4.1). The reported age at diagnosis of OPA3 cataract is from 4 years up to 56 years of age, with varied cataract morphologies (predominantly blue-dot/cerulean, but also anterior and posterior cortical, anterior and posterior sub-capsular).
4.2.1.6.2 OPA3 Gene and Mutations Associated with ADOAC The OPA3 gene (MIM 606580) consists of a 5´-UTR of 150 bp, an open reading frame of 179 amino acids and >970 nucleotides of 3´ untranslated sequence. Northern blot analysis
demonstrates a primary transcript of approximately 5.0 kb that is ubiquitously expressed, most prominently in skeletal muscle, kidney and brain [4]. Two heterozygous missense mutations in OPA3 have been reported in these patients: 277G>A (G93S) and 313C>G (Q105E) [39] (Table 4.2).
4.2.1.6.3 The OPA3 Protein and Mitochondria The OPA3 protein is predicted to be a 20-kDa peptide. The sequence contains a mitochondrial targeting peptide, NRIKE, at amino acid residues 25–29 and a carboxy-terminal coiled-coil domain of unknown function. The protein is predicted, with a probability of 0.87, to be exported to the mitochondrion. Whilst the function of the protein remains unknown, it may have a significant role in mitochondrial processes. OPA3 protein is located on the inner mitochondrial membrane in mouse liver [14]. OPA3 is speculated to have an anti-apoptotic role. Although no abnormalities were found in the respiratory chain, in the mitochondrial membrane potential or in the organization of the mitochondrial network of fibroblasts in ADOAC patients, an increased susceptibility to staurosporine-induced apoptosis has been demonstrated [39].
4.2.2 Recessive Optic Atrophy 4.2.2.1 Clinical Features Recessive optic atrophy (OMIM 258500) presents at birth or by the age of 3 or 4 years with profound visual deficit, sensory nystagmus and marked optic nerve pallor. There may be parental consanguinity. Visual field assessment shows variable constriction and a paracentral scotoma. There are very few reports of isolated primary recessive optic atrophy and some authors believe that many cases are a variant of dominant optic atrophy with partial penetrance. In general, recessive optic neuropathies are seen much more commonly in association with multisystem diseases.
4.2 Primary Inherited Optic Neuropathies with Ocular Manifestations
Table 4.2. OPA3 mutations associated with autosomal-recessive Costeff ’s syndrome (type III methylglutaconic aciduria, MGA) and autosomal-dominant optic atrophy and cataract (ADOAC) Phenotype
Pattern of inheritance
Mutations reported
Type of mutation
Type III MGA
Recessive
IVS1+1G-C 11; 320-337del 12
Truncating
ADOAC
Dominant
G93S; Q105E
Missense
4.2.2.2 OPA5 Locus The first recessive optic atrophy locus OPA5 (OMIM 258500) has been mapped to chromosome 8q21-q22 in a French consanguineous family [7]. The optic atrophy is of very early onset in childhood and is slowly progressive, but nystagmus is not a feature. Colour vision testing revealed red-green colour loss.
4.2.3 X-Linked Optic Atrophy 4.2.3.1 Clinical Features Isolated X-linked optic atrophy (OMIM 311050) is extremely rare. Affected males my have mental retardation and neurological abnormalities, including dysarthria, tremor, dysdiadochokinesia and abnormal reflexes. The female carriers are normal. The age of onset of optic atrophy has been reported to be early childhood, and there may be a slow loss of visual acuity with age. Defects may be seen on colour vision testing.
4.2.3.2 OPA2 Locus X-linked optic atrophy (OPA2) has been linked to Xp11.4-p11.2 [5].
4.2.4 Mitochondrial Disease: Leber’s Hereditary Optic Neuropathy 4.2.4.1 Clinical Features Leber’s hereditary optic neuropathy (LHON, OMIM 535000) is the most common mito-
chondrial optic neuropathy and it is also the first disease to have been linked to mitochondrial DNA [51]. The minimum prevalence of visual loss due to LHON has been estimated in the UK as 3.22:100,000 [32]. Visual loss occurs most frequently in the second to third decades, with a mean age of 27 years and a reported range of 1–70 years. The initial symptom is acutely blurred central vision in one eye or noticeable colour desaturation. The two eyes are affected sequentially in 75% of cases and simultaneously in 25%. The progression of visual loss for the first eye appears longer than for the second eye and the two eyes are separated by a mean of 2 months (range 6–22 weeks) [41], although the interval has been reported to be as long as 8 years. The visual loss develops over a matter of weeks and is severe, dropping to 6/60, counting fingers or occasionally even no perception of light by 4–6 weeks. Only 5% of patients have vision better than 6/60 [41]. The onset of visual loss may occasionally be accompanied by headache or ocular discomfort (24% of patients) [40] and an Uhthoff ’s phenomenon (worsening of vision with exercise, hot baths, or hot drinks) may be reported. There is variability in expression even within families [31]. The visual field loss, which is initially central, rapidly becomes centro-caecal and results in a large scotoma. In the acute stages 30%–60% of eyes show circumpapillary telangiectatic microangiopathy, or swelling of the nerve fibre layer around the disc with microvascular anomalies, but there is absence of leakage from the disc and aberrant vessels on fluorescein angiography (Fig. 4.2). Increased tortuosity of capillaries, medium-sized arteries and venules, with arterio-venous shunting in the peripapillary vasculature, is observed. Over the next few months the swelling typically resolves, the telangiectasia
59
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Inherited Optic Neuropathies
4
Fig. 4.2a–d. Clinical features of Leber’s hereditary optic neuropathy (LHON). a Right and left optic nerves in a patient with recent onset of LHON, showing swelling. b Right and left fundi in acute LHON. c,d see next page
disappears and optic atrophy develops (with loss of the nerve fibre layer). Microangiopathy is uncommon after 6 months. Optic atrophy has been noted as early as 1 month from the onset of visual symptoms. It is universal after 6 months [41]. Visually evoked responses are delayed and the flash electroretinogram is normal. MRI in the acute phase may show enhancement and magnetic resonance spectroscopy with phosphorous-31 shows impaired metabolism in muscle and brain [29].
4.2.4.2 Findings in Unaffected Relatives Abnormal findings are reported in the eyes of unaffected relatives who carry primary pathogenic mitochondrial mutations. These findings include swelling in the peripapillary nerve fibre
layer, increased tortuosity of capillaries, medium arteries and venules and arterio-venous shunting. Such individuals may also show colour perception abnormalities and mild abnormalities of pattern-reversal visual-evoked responses. The long-term significance of such findings is uncertain, since the presence of telangiectatic vessels is not universal even in affected individuals, with only 58% of patients with the bp 11778 mutation, and 33% with the bp 14484 mutation manifesting this “typical” phenotype.
4.2.4.3 Systemic Manifestations In most patients with LHON the visual loss is the only manifestation of the disease. However, cardiac pre-excitation syndromes have also been reported in up to 9% of patients, including those with Wolff-Parkinson-White syndrome and long
4.2 Primary Inherited Optic Neuropathies with Ocular Manifestations
Fig. 4.2a–d. (continued) Clinical features of Leber’s hereditary optic neuropathy (LHON). c Fundus fluorescein angiogram in patient shown in b. d Right and left discs in the same patient after 3 months
Q-T interval. Systemic neurological abnormalities, including multiple-sclerosis-like symptoms, have also been reported in patients with LHON, particularly with the bp 11778 mutation [36]. MRI of these patients shows appearances typical of multiple sclerosis. Other neurological findings, including spastic paraparesis, dementia, deafness, dorsal column dysfunction and heredofamilial ataxias, have been reported in LHON patients and their families.
4.2.4.4 Molecular Genetics The maternal inheritance pattern of LHON is nonMendelian, and the disease is due to point mutations in mitochondrial DNA (mtDNA). Since mitochondria are maternally inherited this means that there can be no male-to-male transmission in a LHON pedigree – a point that may be use-
ful in assessing families with inherited optic neuropathy. Human mtDNA is a closed, circular molecule of 16,569 bp and there are thousands of copies per cell. The mitochondrial genome is essential for aerobic metabolism, as the vast majority of cellular adenosine triphosphate is generated by the proteins of the oxidative phosphorylation cascade, of which complexes I–V reside in the mitochondrial inner membrane. Complexes I–IV are key components of the electron transport chain. The respiratory chain is, however, assembled from both mitochondrial and nuclear gene products, thus the generation of ATP depends on the coordination of two physically distinct genomes. The first mtDNA mutation in LHON at nucleotide position (np) 11,778 was demonstrated in 1988 by Wallace et al. [51]. Three “primary” mtDNA mutations account for 90%–95% of
61
62
Inherited Optic Neuropathies Table 4.3. Primary mitochondrial mutations associated with Leber’s hereditary optic neuropathy (LHON) 3460
11778
14484
LHON mutation
4
Mitochondrial gene
ND1
ND4
ND6
Amino acid position
52 A to T
340 R to H
64 M to V
Prevalence, %
10–15
60–70
15–20
Males affected, %
~70
70–85
70–85
Mean age onset, years
~29
~28
25–27
Visual recovery , %
22–29
2–4
36–50
Time to nadir, months
2–3
2–4
2–4
LHON cases worldwide: these are G3460A (13% of cases), G11778A (69% of cases) and T14484C (14% of cases) (Table 4.3).
4.2.4.5 LHON-Associated Mitochondrial Mutations LHON-associated mutations can be classified as “primary” or “secondary” pathogenic mutations. Primary mutations (above) are found almost exclusively in multiple LHON families and alter evolutionarily conserved amino acids. There may be other, rarer primary mutations, but their significance has not been established in the population, and they may only occur in a few pedigrees worldwide. (These mutations include T14596A, C14498T, G13730A, G14459A, C14482G and A14495G.) The majority of genes believed to cause LHON encode subunits of complex I. Arguably, a group of so-called secondary mutations may also be involved in the pathogenesis of LHON, but they also occur at a lower prevalence in control populations, and may represent polymorphisms. The secondary mutations usually occur in association with a primary mutation or other secondary mutations. They generally cause the mutation of a less highly conserved amino acid. (Secondary pathogenic mutations may include np G13708A, G15812A, A4917G, T4216C, G9804A, G9438A and G15257A.)
4.2.4.6 Genotype–Phenotype Correlation It is difficult to draw conclusions concerning putative genotype–phenotype correlation in LHON as the three primary mutations have a remarkably similar phenotype. The T14484C mutation is associated with the best visual outcome (6/24 or better in 71% of patients). Some 50%–60% of reported patients with the T14484C mutation have some recovery of vision. A younger age of onset of visual loss with this mutation and other mutations is also associated with a better visual outcome, especially if the onset is before the age of 20 years. Visual recovery can occur more than a year later [40]. Mutation at position G11778A is associated with the lowest chance of recovery (5%). The genetic defect is necessary but not sufficient to explain the expression of the disease, and a number of other factors have been investigated. Heteroplasmy (the presence of both mutant and normal mtDNA) may be a factor, but there is contradictory evidence on its role, as some individuals with 100% mutant mtDNA never suffer loss of vision. The role of the haplotype J (G15812A, G15257A, G13708A and T4216C) has been implicated in disease expression in European kindred. There is likely to be an interplay between mitochondrial and nuclear genetic factors as well as environmental factors. Environmental triggers, which have been investigated, include tobacco,
4.2 Primary Inherited Optic Neuropathies with Ocular Manifestations
alcohol, systemic illness, nutrition and head trauma. Even here there is still some controversy, with one case–control study [24] suggesting no role for tobacco or alcohol.
tive phosphorylation and deficient generation of ATP may have a direct or indirect role, involving generation of free radicals and toxicity. The respiratory dysfunction may lead to axoplasmic stasis and swelling.
Summary for the Clinician
Summary for the Clinician
■ The T14484C mutation is associated with the best visual outcome. ■ Mutation at positions G11778A is associ-
■ LHON is attributable to one of three
common mutations in mitochondrial DNA in 95% of European pedigrees: 11778 (69% of cases), 3460 (13% of cases) and 14484 (14% of cases).
ated with the lowest chance of recovery.
4.2.4.7 Evidence for an X-Linked Susceptibility Factor There has been considerable debate as to why more men than women are clinically affected by LHON. Mutation type does not predict male-tofemale ratio of affected patients. Estimated maleto-female ratio is between 3:1 and 5.6:1, and up to 80%–90% of cases in some series are male. Hudson et al. (2005) [21] recently defined an Xchromosomal haplotype bounded by markers in the proximal half of the short arm of the X chromosome (Xp11) that appears to have a modulating effect on expression. The effect of the modulating haplotype was independent of the mtDNA genetic background and appeared to explain the variable penetrance and sex bias that characterizes LHON.
Therapeutic intervention in LHON has so far been disappointing, with a variety of agents having been tried on empirical grounds, including, co-enzyme Q, idebenone, succinate, l-carnitine, vitamin B2, thiamine, vitamin C and vitamin E. It is important to offer genetic counselling and a range of support to affected individuals and their families. The development of mouse models of complex I deficiency will further help our understanding of the pathophysiology of LHON [9] and may assist the development of therapies tailored to address the metabolic or genetic defect. Gene therapy by allotypic expression may have a role in future treatment strategies [19].
Summary for the Clinician
■ No therapeutic intervention to date has been shown to be effective. ■ The role of accurate clinical and molecu-
4.2.4.8 The Pathophysiology of LHON The pathophysiology of LHON is still not fully understood. The clinical picture points to retinal ganglion cell loss and there is evidence that the small axons of the papillomacular bundle, found centrally in the optic nerve, are particularly vulnerable [11]. Why this should be is not entirely clear, but histochemical studies of optic nerve show that this region has a high requirement for mitochondrial function [10]. Histopathological reports from patients with visual loss with LHON show axonal degeneration in the optic nerve. Abnormal oxida-
lar diagnosis and genetic counselling should not be underestimated. Patients with ADOA may have only moderate visual loss and some functional vision. Patients with LHON are likely to have very significant visual loss. Despite the lack of firm conclusive supportive evidence patients with LHON are well advised to avoid excess alcohol, tobacco and environmental toxins.
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Inherited Optic Neuropathies
4.3 Primary Inherited Optic Neuropathies with Significant Systemic Features
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4.3.1 Autosomal-Dominant Optic Atrophy and Neurological Defects There are a number of pedigrees described in the literature with dominant optic atrophy and other neurological abnormalities, such as sensorineural deafness, ataxia, ophthalmoplegia, polyneuropathy or myopathy. Of these myriad of associations the aetiology is unknown for the vast majority, which are isolated families, and in many the mode of inheritance may even be mitochondrial. Three syndromes stand out: (1) dominant optic atrophy, deafness, ophthalmoplegia and myopathy, (2) autosomal-dominant progressive optic atrophy and deafness, and (3) autosomal-dominant progressive optic atrophy with progressive hearing loss and ataxia. The constellation of dominant optic atrophy and deafness has been associated with the R445H mutation in the OPA1 gene by a number of groups [3, 43]. The hearing loss in these pedigrees is severe and may occur at birth. Many of the patients have optic atrophy with reduced vision by the first decade. Optic atrophy, deafness, ophthalmoplegia and myopathy have been associated with the same OPA1 mutation [37]. The hearing loss is moderate with onset in the first or second decades and the onset of visual loss is between 2 and 9 years of age. Ophthalmoplegia and myopathy occur in midlife.
4.3.2 Autosomal-Recessive Optic Atrophy “Plus” As with syndromic dominant optic atrophies, pedigrees have been reported with recessive or putative X-linked optic atrophy and a variety of syndromes with features including progressive hearing loss, spastic quadriplegia, ataxia, tetraplegia, areflexia, polyneuropathy, mental deterioration and dementia. In some cases it is also possible that they represent mitochondrial diseases.
4.3.3 Costeff’s Syndrome The OPA3 gene (MIM 606580; chromosome 19q13.2-q13.3) has recently been found to be mutated in patients of Jewish Iraqi extraction with type III 3-methylglutaconic aciduria (MGA, MIM 258501): optic atrophy plus syndrome or Costeff ’s syndrome [4]. MGA is a recessive neuro-ophthalmological syndrome that consists of early-onset bilateral optic atrophy and lateronset spasticity, extrapyramidal dysfunction and cognitive deficit. Two homozygous mutations in OPA3 are reported: IVS1+1G-C 11 and 320337del 12, both causing “loss of function”.
4.3.4 Behr’s Syndrome Optic atrophy in Behr’s syndrome (OMIM 210000) is associated with pyramidal tract signs, ataxia, mental retardation, urinary incontinence and pes cavus. Visual loss is moderate or severe, often with nystagmus, with onset before the age of 10- years. Children often also have a spastic ataxic gait.
4.3.5 Wolfram Syndrome, DIDMOAD Optic atrophy in Wolfram Syndrome (Fig. 4.3) is associated with juvenile diabetes mellitus and diabetes insipidus and neurosensory hearing loss [8]. (DIDMOAD stands for diabetes insipidus, diabetes mellitus, optic atrophy and deafness.) Diabetes mellitus develops in the first decade and precedes the optic atrophy, which may cause only mild visual loss to begin with but later leads to profound field constriction and acuity loss. The deafness is severe. A wide range of degenerative neuroendocrine abnormalities has been reported, suggesting widespread central nervous system involvement. The WFS1 gene is on chromosome 4p16.1; 90% of patients with Wolfram syndrome have mutations in WFS1. A second locus on chromosome 4q22-q24 has been identified by linkage. In some pedigrees there also appears to be a mitochondrial factor.
References
Fig. 4.3. Fundus photograph of a left eye showing the optic atrophy in a patient with DIDMOAD
Summary for the Clinician
■ Inherited optic neuropathy can be inher-
ited in a dominant, recessive, mitochondrial or X-linked fashion. There is considerable overlap between the clinical phenotypes and modes of inheritance. Three genetic loci are mapped currently for autosomal-dominant optic atrophy (ADOA): OPA1, OPA4 and OPA3. Of these the OPA1 gene is likely to account for the majority of ADOA. Over 100 mutations have been reported to date in the OPA1 gene. In OPA3 optic atrophy has been associated with cataract. Recessive and X-linked optic atrophies are very rare. Leber’s hereditary optic neuropathy is inherited in a maternal fashion and is due to mutation in mitochondrial DNA.
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4.4 Conclusions The optic neuropathies are revealing new insights into a possible central role for mitochondrial dysfunction in optic nerve disease. It is still
unclear why mutations in ubiquitously expressed proteins should give rise to such a restricted phenotype. The elucidation of the role of the encoded proteins will improve our understanding of basic mechanisms of ganglion cell development, physiology and metabolism and further our understanding of the pathophysiology of optic nerve disease. It will also improve diagnosis, counselling and management of patients, and eventually lead to the development of new therapeutic modalities.
References 1.
Aijaz SS, Erskine L, Jeffery G et al (2004) Developmental expression profile of the optic atrophy gene product: OPA1 is not localised exclusively in the mammalian retinal ganglion cell layer. Invest Ophthalmol Vis Sci 45:1667–1673 2. Alexander C, Votruba M, Pesch U et al (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genet 26:211–215 3. Amati-Bonneau P, Guichet A, Olichon A et al (2005) OPA1 R445H mutation in optic atrophy associated with sensorineural deafness. Ann Neurol 58:958–963
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Inherited Optic Neuropathies 4. Anikster Y, Kleta R, Shaag A et al (2001) Type III 3-methylglutaconic aciduria (ptic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi jews. Am J Hum Genet 69:1218–1224 5. Assink JJM, Tijmes NT, tenBrink JB et al (1997) A gene for X-linked optic atrophy is closely linked to the Xp11.4-Xp11.2 region of the X chromosome. Am J Hum Genet 61:934–939 6. Aung T, Ocaka L, Ebeneezer N et al (2002) A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum Genet 110:52–56 7. Barbet F, Gerber S, Hakiki S et al (2003) A first locus for isolated autosomal recessive optic atrophy (ROA1) maps to chromosome 8q. Eur J Hum Genet 11:966–971 8. Barrett TG, Bundey SE, Macleod AF (1995) Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet 346:1458–1463 9. Biousse V, Pardue MT, Wallace DC et al (2002) The eyes of mito-mouse: mouse models of mitochondrial disease. J Neuroophthamol 22:279–285 10. Bristow EA, Griffiths PG, Andrews RM et al (2002) The distribution of mitochondrial activity in relation to optic nerve structure. Arch Ophthalmol 120:791–796 11. Carelli V, Ross-Cisneros FN, Sadun AA (2002) Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int 40:673–584 12. Chen H, Chomyn A, Chan D (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–26192 13. Cipolat S, Rudka T, Hartman D et al (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodelling. Cell 126:163–175 14. Cruz SD, Xenarios I, Langridge J et al (2003) Proteomic analysis of the mouse liver mitochondrial inner membrane. J Biol Chem 278:41566–41571 15. Delettre C, Lenaers G, Griffoin J et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nature Genet 26:207–210 16. Delettre C, Griffoin J-M, Kaplan J et al (2001) Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet 109:584–591
17. Eiberg H, Kjer B, Kjer P et al (1994) Dominant optic atrophy (OPA1) mapped to chromosome 3q region. I. Linkage analysis. Hum Mol Genet 3:977–980 18. Fournier AV, Damj KF, Epstein DL et al (2001) Disc excavation in dominant optic atrophy: differentiation from normal tension glaucoma. Ophthalmology 108:1595–1602 19. Guy J, Qi X, Pallotti F et al (2003) Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy. Ann Neurol 52:534–542 20. Holder GE, Votruba M, Carter AC et al (1998) Electrophysiological findings in dominant optic atrophy (DOA) linking to the OPA1 locus on chromosome 3q 28-qter. Doc Ophthalmol 95:217–228 21. Hudson G, Keers S, Man PYW et al (2005) Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet 77:1086–1091, 1086–1091 22. Johnston PB, Gaster RN, Smith VC et al (1979) A clinicopathological study of autosomal dominant optic atrophy. Am J Ophthalmol 88:868–875 23. Kamei S, Chen-Kuo-Chang M, Cazevieille C et al (2005) Expression of the Opa1 mitochondrial protein in retina ganglion cells: its downregulation causes aggregation of the mitochondrial network. Invest Ophthalmol Vis Sci 46:4288–4294 24. Kerrison JB, Miller NR, Hsu F et al (2000) A casecontrol study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 130:803–812 25. Kerrison JB, Arnould VJ, Sallum JMF et al (1999) Genetic heterogeneity of dominant optic atrophy, Kjer type – identification of a second locus on chromosome 18q12.2-12.3. Arch Ophthalmol 117:805–810 26. Kjer P (1959) Infantile optic atrophy with dominant mode of inheritance: a clinical and genetic study of 19 Danish families. Acta Ophthalmol Scand 37 [Suppl. 54]:1–146 27. Kjer P (1983) Histopathology of eye, optic nerve and brain in a case of dominant optic atrophy. Acta Ophthalmol Scand 61:300–312 28. Kjer B, Eiberg H, Kjer P et al (1996) Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. Acta Ophthalmol Scand 74:3–7
29. Lodi R, Taylor DJ, Tabrizi SJ et al (1997) In vivo skeletal muscle mitochondrial function in Leber’s hereditary optic neuropathy assessed by 31P magnetic resonance spectroscopy. Ann Neurol 42:573–579 30. Lodi R, Carelli V, Cortelli P et al (2002) Phosphorous MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatr 72:805–807 31. Man PYW, Turnbull DM, Chinnery PF (2002) Leber hereditary optic neuropathy. J Med Genet 39:162–169 32. Man PYW, Griffiths PG, Brown DT et al (2003) The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72:333–339 33. Marchbank NJ, Craig JE, Leek JP et al (2002) Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease. J Med Genet 39:e47 34. Misaka T, Miyashita T, Kubo Y (2002) Primary structure of a dynamin-related mouse mitochondrial GTPase and its distribution in brain, subcellular localization and effect on mitochondrial morphology. J Biol Chem 277:15834–15842 35. Olichon A, Baricault L, Gas N et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746 36. Olsen NK, Hansen AW, Norby S et al (1995) Leber’s hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand 91:326–329 37. Payne M, Yang Z, Katz JB et al (2004) Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a missense mutation in OPA1. Am J Ophthalmol 138:749–755 38. Pesch AEA, Leo-Kottler B, Mayer S et al (2001) OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance. Hum Mol Genet 10:1359–1368 39. Reynier P, Amati-Bonneau P, Verny C et al (2004) OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet 41:e110
References 40. Riordan-Eva P, Harding AE (1995) Leber’s hereditary optic neuropathy: the clinical relevance of different mitochondrial DNA mutations. J Med Genet 32:81–87 41. Riordan-Eva P, Sanders MD, Govan GG et al (1995) The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118:319–337 42. Satoh M, Hamamoto T, Seo N et al (2002) Differential sublocalization of the dynamin-related protein OPA1 isoforms in mitochondria. Biochem Biophys Res Commun 300:482–493 43. Shimizu S, Mori N, Kishi M et al (2003) A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy. Am J Ophthalmol 135:256–257 44. Simunovic M, Votruba M, Regan B et al (1998) Residual colour discrimination in low vision patients: results of a new test in dominant optic atrophy. Vision Res 38:3413–3419 45. Thiselton DL, Alexander C, Taanman J-W et al (2002) A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy (ADOA). Inv Ophthalmol Vis Sci 43:1715–1724 46. Toomes C, Marchbank NJ, Mackey DA et al (2001) Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy. Hum Mol Genet 10:1369–1378 47. Votruba M, Moore AT, Bhattacharya SS (1997) Genetic refinement of dominant optic atrophy (OPA1) locus to within a 2cM interval of chromosome 3q. J Med Genet 34:117–121 48. Votruba M, Fitzke FW, Holder GE et al (1998) Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy. Arch Ophthalmol 116:351–358 49. Votruba M, Thiselton D, Bhattacharya S (2003) Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy. Br J Ophthalmol 87:48–53 50. Votruba M, Smith G, Boulton M et al (2006) Homozygous protein-truncating missense mutation in mouse OPA1 GTPase leads to embryonic lethality. Invest Ophthalmol Vis Sci 46:4590 51. Wallace DC, Singh G, Lott MT et al (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242:1427–1430
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Chapter 5
Optic Nerve Tumours Tim D. Matthews
Core Messages
■ Optic nerve tumours are rare. ■ There is a clear association with neurofibromatosis. ■ Clinical monitoring of children with
optic pathway gliomas may need to continue into adulthood. Appropriate neuroimaging is required to demonstrate these tumours. MRI is preferable to CT. Omission of fat suppression or gadolinium enhancement risks failure to demonstrate the tumour. Masquerade syndromes are usually distinguishable by combining information from the history, examination and special investigations. Observation is an accepted management approach if there is minimal visual dysfunction. Radiotherapy, when used, should be delivered by a modern technique to spare adjacent vital structures and the opposite optic nerve.
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5.1 Introduction Isolated tumours of the optic nerve are a rare occurrence. How rare is a difficult question to answer as most of our epidemiological evidence comes from retrospective reviews of practice in single institutes where patients are referred after the diagnosis of their condition. Despite these deficiencies Dutton has provided us with the best reviews of the available literature on the two most common types of tumour: meningiomas [15] and gliomas [16]. Patients usually present with minimal signs of orbital pathology and subtle changes in visual function
5
in middle age (meningioma) or as children (glioma). If the tumour is present in association with neurofibromatosis type 1 (NF1) the patient may be entirely asymptomatic and the tumour discovered on routine screening. Exact prevalence data are not available for either of these tumours. Wright et al. [65, 66] provided estimates based on the numbers attending his orbital clinic at Moorfields Eye Hospital. Given the inherent bias in this sampling technique we find that gliomas (17/1000) and meningiomas (50/3000) each comprise approximately 1.7% of all orbital tumours. Bias and controversy are rife in the literature of these tumours and consensus has been extremely slow in arriving. The advent of current imaging modalities and the fortitude of individuals to monitor these tumours over many years has led to a better understanding of their indolent natural history. Recently, novel delivery systems for radiotherapy and new modalities including the gamma knife and proton beams have opened up new therapeutic opportunities which spare adjacent vital structures from the damaging effects of conventional external beam radiotherapy. Our understanding of the tolerance of the optic nerve to fractionated radiotherapy has also increased, allowing therapists the possibility to treat the tumours while sparing the visual apparatus. The precise timing of therapeutic intervention is still a subject of debate but guidelines for the overall management of these tumours are emerging. The rarity and natural history of these tumours ensure that true randomized controlled trials are at best unlikely.
5.1.1 Gliomas Optic nerve gliomas are the most common tumour of the optic nerve, but still a very infrequent clinical encounter. Tumours
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restricted to the optic nerve are part of a spectrum of disease involving the visual pathway. It is more useful, therefore, to consider this tumour as a part of the spectrum of optic pathway gliomas (OPG) [34]. Although benign pilocytic astrocytomas that present primarily in the paediatric age group predominate (90% presenting within the first two decades), there is a malignant variant affecting the chiasm which presents in middle age – see Sect. 5.3.1.2. It is essential that this group is considered separately, as this tumour is invariably fatal (usually within months). The presentation, associations, progression and management of these tumours vary depending on the portion of the anterior visual pathway affected [62]. Tow et al. [62] divided their patients into three groups for analysis: (1) tumours restricted to the optic nerve, no chiasmal involvement (optic nerve gliomas or ONG), (2) tumours involving the chiasm (± one or both nerves) but no involvement of the hypothalamus (optic chiasm gliomas or OCG) and (3) tumours additionally involving the hypothalamus (optic chiasm and hypothalamic gliomas or OCHG). This division is largely similar to that used by Grill et al. [21] (suggested by Dodge prior to the advent of CT). The diagnosis of OPG is often incidental. More anterior lesions are likely to be discovered either during screening (in patients with NF1) or due to the presence of signs in asymptomatic individuals. Optic nerve gliomas were discovered incidentally in 50% of patients and OCGs were incidentally discovered in 43% [62]. Optic chiasm and hypothalamic gliomas, however, are much more likely to present symptomatically with visual failure, neurological symptoms or endocrine abnormalities. Only one tumour of this type was discovered incidentally, in a patient with NF1 [62]. Although vision is often decreased even in asymptomatic individuals, patients with incidentally discovered tumours are more likely to have good vision at presentation. Combining the data from the two anterior groups, the Tow et al. [62] paper identifies patients with vision at presentation of less than 6/12 (20/40) in only 4 of 23 affected eyes (17%) in incidentally discovered tumours. In contrast, symptomatic patients
had vision of less than 6/12 in 19 of 26 affected eyes (73%). Other signs in anterior tumours include proptosis, strabismus and swollen or pale optic discs in ONG and strabismus or nystagmus in OCG. Precocious puberty appears to be restricted to the more posterior tumours. The vast majority of the literature concerning these tumours comes from tertiary referral centres. Making things even more difficult is that the majority of these are either surgical practices or oncological institutes. Thus selection bias and the inherent bias of the treating centre make the process of extracting meaningful data applicable to an individual patient almost impossible. Patients with ONG are underrepresented in most series if Tow’s data approximate to the whole population. Most of the patients (78%) in Grill’s series had posterior (OCHG) tumours compared to 31% in Tow’s series. As these tumours are more likely to produce neurological and endocrine abnormalities it is not surprising that a greater number are referred for treatment. Unfortunately we have much less data on the patients who are either asymptomatic or never referred for treatment. A further difficulty with this literature is again due to the rarity of the condition. In order to gather large enough numbers to make statistical analysis valid, most large series report data gathered over decades rather than years [25]. During this time imaging has developed considerably, treatment protocols have changed dramatically and associated conditions have been further characterized. Patients seen at the beginning of some of these series will have been classified quite differently from some seen towards the end of the series.
Summary for the Clinician
■ Gliomas are the most common tumour of the optic nerve. ■ They will often present without symptoms if anterior. ■ Visual, neurologic and endocrine dysfunction maybe presenting features in posterior tumours.
5.1.1.1 NF1 There is a clear association between NF1 and OPGs. Dutton [16] quotes a very wide range of 10%–70% for the frequency of NF1 in this condition. This variation exists for a number of reasons. The literature on OPGs overlaps the recognition of two distinct forms of neurofibromatosis. As the majority of the epidemiological data comes from treatment centres there may be less emphasis placed on establishing the context in which these tumours arise compared to data from referral centres. Between 50% and 75% of patients with OPG in NF1 are asymptomatic [16, 34]. Of those children that have OPG in association with NF1, only a quarter to a third will progress to a point where treatment may be indicated [3]. Our understanding of the nature of NF1 has increased considerably in the last 15 years. The establishment of the nature of the genetic defect in NF1 has led to a better understanding of the pathogenesis of pilocytic astrocytomas in both NF1 and sporadic cases [3]. Optic pathway gliomas in patients with NF1 are more likely to be anteriorly situated [3, 29] although Liu et al. [36] have drawn our attention to a rare manifestation where these tumours are present in the optic radiations as well as the pregeniculate optic pathway. The consensus statement on OPG in NF1 [34] suggests that symptomatic presentation is rare beyond the age of 6. For this reason it was suggested that routine neuroimaging for OPG was unnecessary in asymptomatic patients with a normal ophthalmological examination after the age of 6. Although Massry et al. [39] identifies the fact that negative neuroimaging at a young age does not preclude the appearance of an OPG on imaging at a later stage, both of the patients presented with signs that would have led to imaging at the time the OPGs were detected. Of more concern is the possibility that patients with NF1 may present for the first time with an OPG at a late age. Listernick et al. [35] have recently reported eight such patients. Although these were drawn from regional NF1 centres around the world, indicating the rarity of this presentation, it clearly shows that there is no room for complacency in
5.1 Introduction
the ophthalmic screening of patients with NF1. Screening may need to continue into adulthood. The author has personal experience of a patient with NF1 presenting for the first time aged 24 with a symptomatic OCG and progressive visual loss (Fig. 5.1).
Summary for the Clinician
■ There is a high frequency of asymptomatic tumours in NF1. ■ There is a low frequency of patients requiring treatment. ■ Ophthalmic screening of patients with
NF1 may need to continue into adulthood.
5.1.2 Meningiomas Meningiomas affecting the sheath of the optic nerve may be divided into those which arise in the arachnoid cap cells within the orbit (primary) and those which secondarily involve the optic nerve or orbit, having their origin in the cranial fossa [45]. Irrespective of this distinction, when the tumour has spread beneath the dura of the optic nerve, the neural vascular supply and axonal transport are slowly compromised. This results in the most prevalent clinical symptom of visual loss (present in >90% of patients) and the signs of optic disc swelling or atrophy [15, 40, 44, 45, 60]. Other features of an optic neuropathy are also present with dyschromatopsia and field loss reported in significant numbers. As Miller [45] points out, colour vision deficits are often present in association with a minimal drop in acuity. Colour vision is often not reported upon, but when it is significant numbers of patients have dyschromatopsia. Dutton [15] found 73% and Turbin et al. [63] identified 82% of patients with a colour vision deficit. An afferent pupil defect at presentation is an almost universal finding [45, 63]. Other features are dependent on the anatomical location of the tumour [40, 44, 45]. There is a female preponderance in patients
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Fig. 5.1a,b. Optic nerve and chiasm glioma in a 24-year-old male patient with neurofibromatosis type 1. a The characteristic concentric enlargement and kinking of the optic nerve. b Asymmetric enlargement of the optic chiasm
with optic nerve sheath meningiomas (ONSM) [15, 45, 54, 63]. In the majority of large series women make up approximately three-fifths of patients (F:M = 3:2). The peak incidence is in middle age [15, 54, 63]. Most papers indicating a preponderance of children predate MR imaging and may well have classified gliomas as meningiomas in this group [40]. Patients with neurofibromatosis are represented in disproportionately large numbers in the population of patients with ONSM [15, 45]. Many of the studies that demonstrate this predate the recognition of the two distinct forms of neurofibromatosis. More recently the clear association between NF2 and ONSM [6] and in particular bilateral ONSM has been reported [12]. Although NF2 and ONSM have both been linked to defects on chromosome 22, distinct defects at differing loci seem to be responsible [40].
Summary for the Clinician
■ The most common presentation is with progressive visual loss. ■ Colour vision is affected early. ■ There is a female preponderance. ■ There is an association with NF2. 5.1.2.1 Retino-Choroidal Collaterals
Venous bypass channels connecting the circulation on the surface of the optic disc to the venous network below the retina have been described by many terms in the ophthalmic literature. Unfortunately the most commonly used term (optociliary shunt vessels) is incorrect in every part of its description. There is no optic circulation, the ciliary vessels are not involved and these vessels
do not take blood from an arterial to a venous circulation (a shunt). A more correct term for these connections describes the two circulations that are connected, retinal and choroidal, and the nature of the connection, a bypass channel or collateral circulation. As these connections occur on the venous side of the circulation some authors have added the word vein [19] to an otherwise complete descriptor: retino-choroidal collateral (RCC). Figure 5.2 shows the evolution of these channels in a patient with an ONSM over a period of 7 years. Although these were thought to have pathognomic significance in the presence of painless loss of vision and optic atrophy [18], Miller and Solomon [46] indicated the non-specific nature of this triad 15 years ago. These collateral channels may be congenital [23] and may be differentiated from acquired collaterals by their filling pattern on angiography. As one might expect indocyanine green offers certain advantages in visualizing these vessels [48].
5.1 Introduction
Using fine serial sections through the anterior optic nerve, Schatz et al. [56] demonstrated that the majority of these collaterals pass around the margin of Bruch’s membrane connecting the retinal veins on the surface of the optic disc to the choroidal vascular plexus. Interestingly, the patient also had a juxtapapillary choroidal neovascular membrane and two of the identified six RCCs passed into this membrane to join the choroidal circulation via a break in Bruch’s membrane. These vessels will be present in up to 30% of patients with ONSM but may wax and wane, vessels in one quadrant being more visible at one visit and those in another more visible at a later date (Fig. 5.2). Although Hollenhorst et al. [22] paint a bleak picture for visual prognosis when these collaterals are present (nine eyes in nine patients lost all vision), modern management may mean that RCCs do not have the same prognostic significance today. Indeed following radiotherapy or decompression of the optic nerve there has been apparent resolution of these channels [7, 38, 59].
Fig. 5.2. Evolution of retinochoroidal collateral channels over a 7-year period in a patient with an optic nerve sheath meningioma
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Summary for the Clinician
■ The retino-choroidal collaterals redirect
blood from the retinal to the choroidal circulation. They represent bypass channels (collaterals) between two venous circulations. They may appear and disappear during the disease process and treatment.
■ ■ 5
5.2 Imaging As the presentation of these tumours may be as an acute or chronic optic neuropathy with few other signs, imaging in these patients needs to detect and differentiate between the common causes of this as well as delineate the extent and nature of any compressive or infiltrative pathology. For these reasons the best imaging technique will not only demonstrate these tumours eloquently but also differentiate them from other causes of optic neuropathy. Due to its multiplanar imaging capability, the absence of bone artefact and its excellent contrast sensitivity, magnetic resonance imaging (MRI) is superior to all other imaging modalities when we consider imaging of the anterior visual pathway as a whole [40]. Both of these tumours are best demonstrated with MRI following the injection of a paramagnetic contrast medium. However, when the tumours are confined to the orbit, the signal returned from gadolinium DTPA is almost the same as that returned by orbital fat, unless specific sequences are used to suppress the fat signal. Differentiation from other causes of optic neuropathy may require other specific sequences and often a thorough knowledge of the presenting symptoms and signs.
5.2.1 Gliomas The imaging appearances of gliomas restricted to the optic nerve depend upon the presence of the NF1 gene. Fusiform enlargement of the nerve is more common in the absence of NF1, whereas concentric enlargement of the nerve with elon-
gation and kinking is more common in the presence of NF1 [29, 44] (Fig. 5.1a). Cystic components within the tumour are more common in the absence of NF1 and may account for a large percentage of the tumour mass [29].
5.2.1.1 Typical MRI has supplanted CT and plain imaging as the imaging modality of choice in OPG. As these tumours occur predominantly in the paediatric age group and serial imaging is likely, MRI offers significant advantages over CT scanning due to the absence of ionizing radiation. As gliomas have a normal or slightly prolonged T1 relaxation time, they either appear isointense or slightly hypointense to the optic pathway on T1 images. Gliomas return a hyperintense image on T2-weighted scans due to prolongation of the T2 relaxation time [16, 58]; although, oedema in the optic pathway will also lead to prolongation of the T2 time, making it difficult to correctly identify tumour, particularly in the optic tracts [29]. Mucinous degeneration or areas of necrosis will be apparent as areas of hypointensity relative to normal tissue on T1 imaging. Gadolinium will shorten the T1 relaxation time of the tumour thereby increasing its intensity. Fat suppression techniques are required to delineate the T1 signal of the nerve/tumour from the high T1 signal of orbital fat [58].
5.2.1.2 Masquerade As the arachnoid hyperplasia associated with gliomas does not return a high signal with gadolinium (unlike that associated with meningiomas) MRI is less likely to produce the confusion described by Cooling and Wright [11] in the pre-MRI era; although, due to omission of a T2 sequence, other authors have described mistaking a glioma for a meningioma on MRI in an adult [32]. Thickening of the chiasm may be caused by a variety of pathologies and some of these may mimic the signal pattern one would expect from OPG. Both intrachiasmatic craniopharyngioma and neurosar-
5.2 Imaging
Fig. 5.3. A tubular optic nerve sheath meningioma showing tumour emerging from the intracranial end of the optic foramen
coidosis were mistaken for gliomas in the MRI era [9, 50]. There were clues on the MRI scans, in both cases, to the ultimate pathology. The craniopharyngioma returned a mixed signal, when a reasonably uniform signal would be expected with a glioma. Also there was evidence of leptomeningeal enhancement in the case of neurosarcoidosis, a sign that has not been described in OPG.
5.2.2 Meningiomas Although characteristic signs of ONSM are present on CT scans (calcification, tram tracking, pneumosinus dilatans) [40, 45], MR imaging has largely supplanted CT imaging in this condition. The ability to detect meningioma within the confines of the optic canal and early extension into the intracranial cavity has led to clinicians’ preference for this imaging modality [33].
5.2.2.1 Typical The appearance of ONSM on imaging falls largely into one of three groups: tubular, fusiform or globular [15, 45, 54]. Irrespective of the imaging technique used, the majority of ONSM have a tubular arrangement. These tumours grow to gradually encase the optic nerve and then extend along the nerve sheath. They may be expanded at either the anterior or posterior end of the intraorbital optic nerve [15, 44, 45, 54]. Tubular tumours have a high incidence of involvement of the optic canal and intracranial extension [54]. Indeed the intracranial extension is often only seen on MRI scanning, leading some authors to caution against interpreting this finding on a patient’s first MRI scan as evidence of recent intracranial spread [33]. Indeed when CT scanning and MRI scanning were done in close temporal proximity in four patients in Saaed’s series [54], intracranial extension was visible on the MRI scans but not the CT scans. When MRI is performed, the appearance of a thin line of tumour within the optic canal and a blossom of tumour in the region of
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Optic Nerve Tumours
the anterior clinoid process (Fig. 5.3) is the rule rather than the exception [33]. Even with MRI, tumours restricted to the intracanalicular nerve can be difficult to demonstrate [24]. As meningiomas are generally isointense to brain on both T1- and T2-weighted imaging, it is essential to use gadolinium to detect small tumours. This excellent review highlights the incidence of repeated imaging in the presence of a high index of clinical suspicion and details the importance of fat suppression along with gadolinium enhancement to demonstrate these difficult tumours [24].
al. [57] presented two cases where the imaging was consistent with ONSM but biopsy later demonstrated lymphoma. The visual loss was minimal in one case, despite a large tumour mass and the vision deteriorated rapidly in the second. The authors advocate that this atypical behaviour should warrant review of the diagnosis and suggest the possibility of obtaining a tissue diagnosis, as lymphoma will respond to much lower doses of radiotherapy than ONSM.
Summary for the Clinician
■ The imaging modality of choice is T1 and T2 MRI using fat suppression before and after gadolinium enhancement. Omission of gadolinium significantly increases the risk of misdiagnosis. CT may offer supplementary information but offers less overall in terms of diagnostic information.
5.2.2.2 Masquerade The presence of a meningioma may well be overlooked and an alternate diagnosis entertained particularly if gadolinium has not been given [64]. In addition many disparate conditions have been confused for meningiomas on MR imaging [4, 26, 53, 57, 61]. In the majority of cases clues from the history or examination will have alerted the clinician to the correct diagnosis prior to an imaging report suggesting ONSM. A positive response to steroids and the presence of uveitis may aid the diagnosis of sarcoidosis [53]. But these signs may well be absent and a gradual decline in vision with an isolated optic nerve lesion in the absence of any other systemic features to suggest sarcoidosis may very rarely mimic an ONSM [26]. The very rare occurrence of a metastasis from a breast carcinoma presenting in the optic nerve of an elderly woman was reported recently by Backhouse et al. [4]. Again other features in the history (including presentation with a central retinal vein occlusion and subsequent rubeotic glaucoma) were atypical for an ONSM. Sclerosing orbital inflammation has also presented with imaging findings consistent with ONSM. As in the case of the breast metastasis there was evidence of venous stasis on fundoscopy. The omission of enhanced imaging in this case makes it more difficult to know if the diagnostic dilemma would have persisted in the presence of a complete imaging assessment [61]. Finally, orbital lymphoma has also masqueraded as ONSM on imaging [57]. Selva et
■ ■
5.3 Management Consensus about the management of tumours of the optic nerve has been a long and arduous process. Timing of any intervention is still the subject of some debate as treatment-associated morbidity may take years to develop. For both of these conditions observation is now a recognized treatment option particularly in patients with stable visual function and no signs of progression on serial neuroimaging.
5.3.1 Gliomas There are no randomized controlled trials of treatment for this condition in the literature. Almost all of the papers reporting experience with treatment for OPGs report on a single treatment modality used over decades. The patients were often imaged using CT or plain radiographs and there was not the same degree of diagnostic certainty (particularly regarding intracranial disease) as one would expect today. For those patients treated with conventional radiotherapy, wide safety mar-
gins of up to a number of centimetres were used to ensure that the entire tumour was treated. Not unexpectedly the reports of treatment-associated morbidity are frequent [25, 30]. Due to the tendency to use Kaplan Meier curves to express survival following treatment, readers are presented with a gloomy if not dismal picture from most reports [28, 30]. This is fuelled by the misapprehension that tumourrelated mortality is the inverse of actuarial survival. Most papers do not quote the actual mortality rates and even less frequently the mortality rates directly attributable to the initial tumour. Often death is due to other disease or to second tumours (occasionally induced by radiotherapy). In those papers where it is possible to discern this information, tumour-related deaths are very infrequent. Tow et al. [62] reported that 2/47 (4%) patients died as a direct result of their tumours during a follow-up period of 10–28 years. Khafaga et al. [28] reported 5/50 deaths with a follow-up of 2.4–16.5 years, but only 2 (4%) of these were attributable to the OPGs. Tow et al. [62] do not present their data with Kaplan Meier curves. Khafaga et al. [28] do represent their data in this way and at 10 years the survival is 75%. As the median follow-up was 7 years we know the cohort size has shrunk considerably at 10 years. Thus the five deaths will have a far greater effect on the much reduced cohort size at 10 years, accounting for the 75% survival if the cohort size had reduced to 20 patients. A further difficulty is the selection bias in papers looking at treatment of this condition. By comparing the distribution of the location of tumours in each of the papers we see that posterior tumours are heavily represented in most. This is in stark contrast to Tow et al. [62]. Thus, as Tow et al. [62] and others have shown that posteriorly located tumours have higher intrinsic morbidity and mortality (in the absence of treatment), it is not surprising that overall morbidity and mortality is higher in papers in which this group is over-represented, irrespective of the treatment utilized. The converse is also true: as minimally progressive tumours are under-represented, morbidity and mortality measures will be skewed in an adverse direction irrespective of the treatment modality.
5.3 Management
Summary for the Clinician
■ Bias in the literature produces an unnec-
essarily gloomy picture of the prognosis for these tumours. Tumour-related mortality is likely to be in the region of 4%.
■
5.3.1.1 Paediatric The Consensus Statement from the NF1 optic pathway glioma task force [34] offers clear guidelines for the assessment, surveillance and management of patients with and without OPGs. The recently reported Australian experience [60] supports the stance taken by this task force but emphasizes the need for continued vigilance as many patients developed later progression of their OPG. The management of other patients depends on the site of the tumour. Also, although it was thought to occur infrequently, the very real possibility of spontaneous regression [51] in these tumours may not only have an influence on our management choice but also needs to be taken in to account when considering the response to treatment described in the literature. If Parsa et al. [51] are correct in their assertion that spontaneous tumour regression happens with a high frequency, response to any of these treatment modalities needs to be reassessed. Currently it is not possible to correctly ascertain whether tumour regression is spontaneous or the direct result of therapy.
Summary for the Clinician
■ Spontaneous regression may have occurred in patients who have had “successful treatment” for their tumours.
5.3.1.1.1 Optic Nerve Miller [44] sets out a very pragmatic approach to tumours confined to the orbital optic nerve. If one were to consider survival alone, then sur-
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5
gical removal of these tumours appears to offer good results. Unfortunately there is universal visual morbidity associated with this approach. If surgery is reserved for patients with progressive visual dysfunction, gross cosmetic disfigurement or MRI evidence of extension of the tumour towards the chiasm, then the visual function and survival are maximized [62]. There are insufficient data on the management of tumours in this location with radiotherapy or chemotherapy to make meaningful suggestions about these treatment modalities, due to the under-representation of anterior tumours in treatment papers. This would suggest that large numbers of these patients have been followed-up (or not diagnosed) without referral to a treatment centre over the years. What can be said is that observation, surgical excision and radiotherapy all have equally high survival for tumours restricted to the optic nerve [28, 30, 62].
beams exposing adjacent and sometimes distant structures to high doses of photons. Proton delivery systems now offer the possibility of no exit beam and therefore highly targeted treatment [20].
Summary for the Clinician
■ Anterior tumours – surgery if progres-
sive visual loss, gross cosmetic disfiguration or MRI evidence of extension towards the chiasm. Chiasmal tumours – radiotherapy (or chemotherapy) if progressing. Use 3D conformal or proton beam. Posterior tumours may require surgical debulking.
■
5.3.1.2 Adult 5.3.1.1.2 Optic Chiasm In the literature there is greatest experience with radiotherapy for tumours in this location [10, 14, 20, 21, 25, 28, 30, 62]. In a large number of cases radiotherapy has been used in combination with partial resection as complete resection is not an option in these patients. More posterior tumours (e.g., OCHG versus OCG) are more likely to require surgical debulking. Some authors have advocated early intervention with radiotherapy as in a few cases improved visual function has been demonstrated [14]. Others have adopted a wait and see approach [62] and have demonstrated maintenance of good visual function in the least affected eye for decades. What is clear from the literature is that delivery of radiotherapy has improved dramatically over the last two decades and novel delivery systems have decreased the morbidity (and potentially mortality) associated with radiotherapy [10, 14]. MRI, three-dimensional planning and conformal stereotactic delivery have shrunk the high isodose curves to within a few millimetres of the tumour volume without evidence of marginal recurrence. Conventional external beam radiotherapy was also associated with large exit
OPG presenting as an adult poses a significant management dilemma. If the patient is middleaged or older then biopsy of the lesion is essential. Biopsy-proven OPG in this age group is universally fatal, usually within months. Radiotherapy may increase survival, but the effect is marginal at best and does not improve visual function [13]. The confusion with orbital inflammatory processes at initial presentation, both symptomatically and on imaging, has been highlighted by most authors [8, 41]. This serves as a reminder that typical optic neuritis should only be diagnosed in younger individuals. Although the median age of patients with this malignant subtype is 56 the range of ages in the literature is from 22 to 79 years [13]. Thus patients presenting in their third decade pose a particular diagnostic dilemma. Compare Fig. 5.1b (a 24-year-old man with NF1 and a benign OCG) with Fig. 5.4 (a 72-year-old woman with a biopsy-proven malignant glioma). If stigmata of NF1 are present biopsy is probably avoidable. In all other cases biopsy will be required to (1) accurately assess the non-inflammatory nature of the mass and (2) to determine the degree of differentiation and growth potential.
5.3 Management
Summary for the Clinician
■ Biopsy is required in the absence of stigmata of NF1. ■ If the diagnosis is confirmed on biopsy the prognosis is very poor.
5.3.2 Meningiomas A clear understanding of the natural history of these tumours has long evaded the ophthalmic literature. Data on long-term follow-up of individuals in the absence of surgical intervention have only become available in the last two decades [15, 17, 27, 54, 55, 63]. Prior to this enthusiasm for complete surgical clearance, despite the impossibility of achieving it, was the norm [66]. This resulted in temporary control of the tumour but had immediate and disastrous consequences for vision. This type of intervention also made clear the folly of opening the dural sheath to either decompress the nerve or to attempt partial removal. This approach led to widespread recurrence within adjacent structures, in an unconstrained fashion [66]. The poor visual outcome from this approach has again been recently documented [54]. It is now clear that if a patient presents with good vision they are likely to maintain this for years [16, 54, 63]. It is also clear that earlier con-
cerns about intracranial spread, propensity to affect the opposite optic nerve or chiasm, or other intracranial vital structures were misplaced [17, 44]. Even when these tumours invade the middle cranial fossa they behave in a benign fashion. Al-Mefty [2] points out that they will have an intervening layer of arachnoid between them and other vital structures preventing their envelopment, in effect behaving like type III anterior clinoidal meningiomas. Hormonal and chemotherapeutic manipulation of ONSM have both been reported with poor long-term effects [13, 28]. Many different approaches to the therapeutic delivery of radiation therapy have now been reported. Numerous editorials have indicated the change in approach to treatment that has occurred in the last decade [40, 42, 43]. In an attempt to control the dose of radiotherapy delivered to the opposite optic nerve as well as other adjacent vital structures, stereotactic fractionated radiotherapy [1, 5, 37, 52] or three-dimensional conformal radiotherapy [31, 47, 49] have been employed. Both techniques produce good control of the tumour and limit the deleterious effect of radiation on adjacent and distant structures. In addition a sizable number of patients demonstrate either stability or improvement in their vision (acuity and field) for years after treatment. The only remaining question is at what stage in the disease process to administer radiation therapy [45]. As imaging is now able to detect tumours at an earlier stage and patients are often presenting with excellent visual function, therapeutic intervention is probably best reserved until a demonstrable progressive decline in vision has occurred. At this stage early intervention with conformal or stereotactic radiotherapy offers the best available disease control at present [45].
Summary for the Clinician
■ Observe unilateral tumours even in the presence of intracranial extension. ■ Offer 3D conformal or stereotactic raFig. 5.4. Coronal view of a malignant optic chiasm glioma in a 72-year-old patient
diotherapy if there is progressive visual loss.
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Optic Nerve Tumours Table 5.1. Patient characteristics of benign tumours of the optic nerve
5
Characteristic
Meningioma
Glioma
Age
Middle aged
First two decades
Sex
Female
Either
Neurofibromatosis
Rare – Type 2 > type 1
Common – type 1
Retino-choroidal collaterals
Common
Occasional
Imaging
Calcification on CT; tubular enlargement; isointense on T1; dural tail
Kinking of orbital nerve; fusiform enlargement; hyperintense on T2; whole nerve enhances
5.4 Conclusions Our ability to detect even small tumours affecting the optic pathway has improved tremendously since the introduction of MRI. Although it is still not perfect (intracanalicular meningiomas). Clinical and imaging characteristics are summarized in Table 5.1. Clear guidelines now exist for diagnosing and monitoring patients with both optic pathway gliomas and optic nerve sheath meningiomas. Timing of therapeutic intervention is still a subject of some debate and only long-term well-constructed treatment trials following patients for decades will determine if intervention is more costly in terms of collateral damage than the disease process itself. Whereas preservation of life was the aim of therapy in the pre-MRI era, a clear understanding of the indolent nature of most of these tumours and developments in the field of radiation therapy have led us to a point where preservation of vision is now the primary aim of treatment.
References 1.
2.
Andrews DW, Faroozan R, Yang BP et al (2002) Fractionated stereotactic radiotherapy for the treatment of optic nerve sheath meningiomas: preliminary observations of 33 optic nerves in 30 patients with historical comparison to observation with or without prior surgery. Neurosurgery 51:890–904 Al-Mefty O (1990) Clinoidal meningiomas. J Neurosurg 73:840–849
3. Arun D, Gutmann DH (2004) Recent advances in Neurofibromatosis type 1. Curr Opin Neurol 17:101–105 4. Backhouse O, Simmons I, Frank A et al (1998) Optic nerve breast metastasis mimicking meningioma. Aust NZ J Ophthalmol 26:247–249 5. Becker G, Jeremic B, Pitz S et al (2002) Stereotactic fractionated radiation in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 54:1422–1429 6. Bosch MM, Wichmann WW, Bolthauser E et al (2006) Optic nerve sheath meningiomas in patients with neurofibromatosis type 2. Arch Ophthalmol 124:379–385 7. Brazier DJ, Sanders MD (1996) Disappearance of optociliary shunt vessels after optic nerve sheath decompression. Br J Ophthalmol 80:186–187 8. Brodovsky S, ten Hove MW, Pinkerton RMH et al (1997) An enhancing optic nerve lesion: malignant glioma of adulthood. Can J Ophthalmol 32:409–413 9. Brodsky MC, Hoyt WF, Barnwell SL et al (1988) Intrachiasmatic craniopharyngoima: a rare cause of chiasmal thickening. J Neurosurg 68:300–302 10. Combs SE, Schulz-Ertner D, Moschos D et al (2004) Fractionated stereotactic radiotherapy of optic pathway gliomas: tolerance and longterm outcome. Int J Radiat Oncol Biol Phys 62:814–819 11. Cooling RJ, Wright JE (1979) Arachnoid hyperplasia in optic nerve glioma: confusion with orbital meningioma. Br J Ophthalmol 63:596–599 12. Cunliffe IS, Moffat DA, Hardy DG et al (1992) Bilateral optic nerve sheath meningiomas in a patient with neurofibromatosis type 2. Br J Ophthalmol 76:310–312
13. Dario A, Iadini A, Cerati M et al (1999) Malignant optic glioma of adulthood. Case report and review of the literature. Acta Neurol Scand 100:350–353 14. Debus J, Kocagöncü O, Höss A et al (1999) Fractionated stereotactic radiotherapy (FSRT) for optic glioma. Int J Radiat Oncol Biol Phys 44:243–248 15. Dutton JJ (1992) Optic nerve sheath meningiomas. Surv Ophthalmol 37:167–183 16. Dutton JJ (1994) Gliomas of the anterior visual pathway. Surv Ophthalmol 38:427–452 17. Egan RA, Lessell S (2002) A contribution to the natural history of optic nerve sheath meningiomas. Arch Ophthalmol 120:1505–1508 18. Frisen L, HoytWF, Tengroth BM (1973) Optociliary veins, disc pallor and visual loss: a triad of signs indicating spheno-orbital meningioma. Acta Ophthalmol 57:241–249 19. Fuller JJ, Mason JO, White MF et al (2003) Retinochoroidal collateral veins protect against anterior segment neovascularization after central retinal vein occlusion. Arch Ophthalmol 121:332–336 20. Fuss M, Hug EB, Schaefer RA et al (1999) Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique. Int J Radiat Oncol Biol Phys 45:1117–1126 21. Grill J, Laithier V, Rodriguez D et al (2000) When do children with optic pathway gliomas need treatment: an oncological perspective in 106 patients treated in a single centre. Eur J Paediatr 159:692–696 22. Hollenhorst RW Jr., Hollenhorst RW Sr., MacCarty CS (1977) Visual prognosis of optic nerve sheath meningiomas producing shunt vessels on the optic disk: the Hoyt-Spencer syndrome. Trans Am Ophthalmol Soc 75:141–163 23. Irvine AR, Shorb SR, Morris BW (1977) Optociliary veins. Trans Am Acad Ophthalmol Otolaryngol 83:541–546 24. Jackson A, Patankar T, Laitt RD (2003) Intracanalicular optic nerve meningioma: a serious diagnostic pitfall. Am J Neuroradiol 24:1167–1170 25. Jenkin D, Angyalfi S, Becker L et al (1993) Optic glioma in children: surveillance, resection or irradiation? Int J Radiat Oncol Biol Phys 25:215–225 26. Jennings JW, Rojiani AM, Brem SS et al (2002) Necrotizing neurosarcoidosis masquerading as a left optic nerve meningioma: case report. Am J Neuroradiol 23:660–662
References 27. Kennerdell JS, Maroon JC Malton M et al (1988) The management of optic nerve sheath meningiomas. Am J Ophthalmol 106:450–457 28. Khafaga Y, Hassounah M, Kandil A et al (2003) Optic gliomas: a retrospective analysis of 50 cases. Int J Radiat Oncol Biol Phys 56:807–812 29. Kornreich L, Blaser S, Schwarz M et al (2001) Optic pathway glioma: correlation of imaging findings to the presence of neurofibromatosis. AJNR Am J Neuroradiol 22:1963–1969 30. Kovalic JJ, Grigsby PW, Shepard MJ et al (1990) Radiation therapy for gliomas of the optic nerve and chiasm. Int J Radiat Oncol Biol Phys 18:927–932 31. Lee AG, Woo SY, Miller NR et al (1996) Improvement in visual function in an eye with a presumed optic nerve sheath meningioma after treatment with three-dimensional conformal radiation therapy. J Neuroophthalmol 16:247–251 32. Liauw L, Vielvoye GJ, de Keizer RJW et al (1996) Optic nerve glioma mimicking an optic nerve meningioma. Clin Neurol Neurosurg 98:258–261 33. Lindblom B, Truwit CL, Hoyt WF (1992) Optic nerve sheath meningioma: definition of intraorbital, intracanalicular and intracranial components with magnetic resonance imaging. Ophthalmology 99:560–566 34. Listernick R, Louis DN, Packer RJ et al (1997) Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 optic pathway glioma taskforce. Ann Neurol 41:143–149 35. Listernick R, Ferner RE, Piersall L et al (2004) Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology 63:1944–1946 36. Liu GT, Brodsky MC, Phillips PC et al (2004) Optic radiation involvement in optic pathway gliomas in neurofibromatosis. Am J Ophthalmol 137:407–414 37. Liu JK, Forman S, Hershewe GL et al (2002) Optic nerve sheath meningiomas: visual improvement after stereotactic radiotherapy. Neurosurgery 50:950–957 38. Mashayekhi A, Sheilds JA Sheilds CL (2004) Involution of retinochoroidal shunt vessel after radiotherapy of optic nerve sheath meningioma. Eur J Ophthalmol 14:61–64 39. Massry GG, Morgan CF, Chung SM (1997) Evidence of optic pathway gliomas after previously negative neuroimaging. Ophthalmology 104:930–935
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Optic Nerve Tumours 40. Matthews TD, Anderson IRC (2002) Meningiomas: the anterior visual pathway. Curr Med Lit Ophthalmol 12(4):77–83 41. Millar WS, Tartaglino LM, Sergott RC et al (1995) MR of malignant glioma of adulthood. AJNR Am J Neuroradiol 16:1673–1676 42. Miller NR (2002) The evolving management of optic nerve sheath meningiomas. Br J Ophthalmol 86:1198 43. Miller NR (2002) Radiation for optic nerve meningiomas: Is this the answer? Ophthalmology 109:833–834 44. Miller NR (2004) Primary tumours of the optic nerve and its sheath. Eye 18:1026–1037 45. Miller NR (2006) New concepts in the diagnosis and management of optic nerve sheath meningioma. J Neuroophthalmol 26:200–208 46. Miller NR, Solomon S (1991) Retinochoroidal (optociliary) shunt veins, blindness and optic atrophy: a non-specific sign of chronic optic nerve compression. Aust NZ J Ophthalmol 19:105–109 47. Moyer PD, Golnik KC, Breneman J (2000) Treatment of optic nerve sheath meningioma with three-dimensional conformal radiation. Am J Ophthalmol 129:694–696 48. Muci-Mendoza R, Arevalo JF, Ramella M et al (1999) Optociliary veins in optic nerve sheath meningioma; indocyanine green videoangiography findings. Ophthalmology 106:311–318 49. Narayan S, Cornblath WT, Sandler HM et al (2003) Preliminary visual outcomes after threedimensional conformal radiation therapy for optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 56:537–543 50. Ng KL, McDermott N, Romanowski CA et al (1995) Neurosarcoidosis masquerading as glioma of the optic chiasm in a child. Postgrad Med J 71:265–268 51. Parsa CF, Hoyt CS Lesser RL et al (2001) Spontaneous regression of optic gliomas: thirteen cases documented by serial imaging. Arch Ophthalmol 119:516–529 52. Pitz S, Becker G, Schiefer U et al (2002) Stereotactic fractionated irradiation of optic nerve sheath meningioma: a new treatment alternative. Br J Ophthalmol 86:1265–1268 53. Roberti F, Lee HH, Caputy AJ et al (2005) “Shave” biopsy of the optic nerve in isolated neurosarcoidosis. J Neurosurg Sci 49:59–63
54. Saaed P, Rootman J, Nugent RA et al (2003) Optic nerve sheath meningiomas. Ophthalmology 110:2019–2030 55. Sarkies NJC (1987) Optic nerve sheath meningioma: diagnostic features and therapeutic alternatives. Eye 1:597–602 56. Schatz H, Green WR, Talamo JH et al (1991) Clinicopathologic correlation of retinal to choroidal venous collaterals of the optic nerve head. Ophthalmology 98:1287–1293 57. Selva D, Rootman J, Crompton J (2004) Orbital lymphoma mimicking optic nerve meningioma. Orbit 23:115–120 58. Shen TT, SakaiO, Curtin HD et al (2001) Magnetic resonance imaging of primary anterior visual pathway tumours. Int Ophthalmol Clin 41:171–180 59. Smith JL, Vuksanovic MM, Yates BM et al (1981) Radiation therapy for primary optic nerve meningiomas. J Clin Neuroophthalmol 1:85–99 60. Thiagalingam S, Flaherty M, Billson F et al (2004) Neurofibromatosis type 1 and optic pathway glioma: follow-up of 54 patients. Ophthalmology 111: 568–577 61. Thorne JE, Volpe NJ, Wulc AE et al (2002) Caught by a masquerade: sclerosing orbital inflammation. Surv Ophthalmol 47:50–54 62. Tow SL, Chandela S, Miller NR et al (2003) Longterm outcome in children with gliomas of the anterior visual pathway. Pediatr Neurol 28:262–270 63. Turbin RE, Thompson CR, Kennerdell JS et al (2002) A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy. Ophthalmology 109:890–900 64. Vaphiades MS (2001) Disk edema and cranial MRI optic nerve enhancement: how long is too long? Surv Ophthalmol 46:56–58 65. Wright JE, McDonald WI, Call NB (1980) Management of optic nerve gliomas. Br J Ophthamol 64:545–552 66. Wright JE, McNab AA, McDonald WI (1989) Primary optic nerve sheath meningioma. Br J Ophthalmol 73:960–966
Chapter 6
Traumatic Optic Neuropathy: Recommendations and Neuroprotection
6
Solon Thanos, Stephan Grewe, Tobias Stupp
Core Messages
■ Traumatic optic neuropathy (TON) may result from either direct or indirect injury. TON can be classified into transection and compressive forms of neuropathy. Both forms of TON may result in acute loss of vision. Transection of the optic nerve is rare and currently untreatable. Compressive TON can be treated with steroids, surgery, or both. Conservative treatment has been performed with prednisolone at widely varying doses. Surgical treatment has been performed with transsphenoid and endoscopic decompression of the optic canal.
■ ■ ■ ■ ■ ■
■ However, none of the current treatments
has been tested in a prospective, controlled, and randomized multicentric study, and the available reported results are no better than those when TON remains untreated. None of the treatments can be recommended until evidence-based data are available, and any decision on treatment should be made on an individual basis. Neuroprotection is still in the experimental phase, and cannot be yet recommended in the treatment of TON. Regeneration of the optic nerve is still in the experimental phase but may become available in the future. A complete ophthalmic examination should precede any treatment or the inclusion in a prospective treatment trial.
■ ■ ■ ■
6.1 Introduction 6.1.1 Optic Nerve Anatomy The mature optic nerve consists of about one million retinal ganglion cell axons, all of which are ensheathed by oligodendrocytes, plus astrocytes, capillaries, microglial cells, and extracellular matrix. The cellular organization of the optic nerve is similar to that of the cerebral white matter and the long intraspinal tracts of fibers. The optic nerve differs from peripheral nerves, in that the
latter contain Schwann cells, and are therefore considered as central tracts that project outside the confines of the cranial grooves. Beginning at the optic nerve head, the optic nerve travels within the muscle conus formed by the extraocular muscles, and after about 30 mm passes into the optic canal (which is a 5- to 12-mm-long boney canal superonasally to the superior orbital fissure) and enters the cranium. Some sympathetic axons destined for the orbit and the dura-covered ophthalmic artery located at the inferolateral aspect of the optic nerve lie
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Traumatic Optic Neuropathy: Recommendations and Neuroprotection
within the optic canal close to the nerve. Within the canal and posterior to it, meningeal tissue is tethered to the optic nerve with very little free space. This tight packing of tissue within the optic canal may explain why some traumatic optic and compressive neuropathies may occur without radiographically detectable boney changes. Ganglion cell axons segregate retinotopically at the level of optic nerve head. This retinotopic segregation of axons arising from particular retinal regions changes near the chiasm [9]. Nasal axons (~52%) cross to the contralateral side and temporal axons (~48%) remain ipsilateral [32].
6.1.2 Traumatic Optic Neuropathy Traumatic optic neuropathy (TON) is the sudden loss of vision that occurs after direct or indirect injury along the ascending optic pathway, with an incidence of 2%–5% after facial injury. Direct injuries result from either section or compression (edema, hemorrhages), and are caused by penetrating stab wounds, and orbit-penetrating foreign bodies such as bullets, knives, and sharp bone fragments derived from periorbital bone fractures [13]. Indirect injuries result from shearing forces transmitted through the bones and from inadequate eye movement in relation to the nerve or blood vessels [19], and from secondary vasospasm and swelling within the rigid optic canal. The confines of the optic canal may result in a compartment syndrome that accounts for most of the indirect optic neuropathies, because the nerve is tethered to the dural sheath and hence has a higher sensitivity to shearing. At the cellular level, the damage resulting from either class of injury consists of bidirectional (anterograde/ascending and retrograde/descending) degeneration of axons and retinal ganglion cells, followed by glial scarring. Traumatic optic neuropathies exhibit substantial variations in their clinical outcome. Clear transections of optic nerve axons are relatively rare in the human optic nerve, even during accidental penetrations by bullets or knives, or iatrogenic cuts during the removal of neighboring infiltrating tumors; compressive TONs are more common and result from hematomas and ede-
mas. Although TONs resulting from acute transections and compression share common clinical implications, the former typically result in immediate complete or incomplete loss of vision, whereas the latter may also result in delayed and slower visual impairment. At the initial examination, the ophthalmologist should evaluate the patient as completely as possible, including visual acuity, visual fields, pupillary reflexes, funduscopy (special focus on the optic nerve head and the retinal vessels), and oculomotility. Depending on the patient’s medical condition and the circumstances of examination, the evaluation may be restricted to some basic procedures but should always comprise an assessment of pupillary reflexes to disclose an afferent papillary defect. An incomplete TON is characterized by a moderate-to-severe reduction of visual acuity (1/15 in the case shown in Fig. 6.1) with clear visual field defects (Fig. 6.1b). The corresponding atrophy of the optic nerve is not an early finding and becomes evident a few weeks after the traumatism (Fig. 6.1a).
Summary for the Clinician
■ The optic nerve is a central nerve. ■ Traumatic optic neuropathies (TONs) ■
can result from either a direct or an indirect mechanism. TONs result in immediate visual impairment or blindness.
6.2 Review of Previous Studies on TONs The current body of literature on case series relating to TON includes 745 eyes. Most of the data relate to small and mostly retrospective studies performed within different types of centers of medical treatment, including neuroophthalmologic service centers and departments of plastic and reconstructive surgery, orbital surgery, neurologic surgery, otorhinolaryngology, neurosurgery, and general ophthalmology. Moreover, some of the prospective studies are nonrandom-
6.2 Review of Previous Studies on TONs
Fig. 6.1a,b. a Fundus photography of the left eye of a 63-year-old male. Sectorial temporal superior optic disc pallor was present, 3 months after traumatic optic neuropathy (TON). Visual acuity was limited to 1/15. b Corresponding inferior visual field loss
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ized and lack control groups. It is therefore difficult to compare the studies, even qualitatively, due to the relatively isolated information provided by each study on the spontaneous visual recovery that appears with a relatively high frequency after TON. Indeed, Yu Wai Man and Griffiths [45] reviewed the effects and safety of surgical interventions in the management of TON by searching the Cochrane Central Register of Controlled Trials (CENTRAL) between 1966 and August 2005, and found no evidence that surgical decompression of the optic nerve is beneficial. Moreover, surgery is associated with a risk of defined complications such as leakage of cerebrospinal fluid and meningitis. They suggested that it is necessary to perform a controlled and randomized trial of surgical interventions in TON. The largest group of patients was included in the International Optic Nerve Trauma Study (IONTS), which was designed as a comparative and nonrandomized interventional study with concurrent treatment groups involving a total of 133 TON cases [19] whose visual function was assessed within 3 days of injury. On the basis of treatment received within 7 days of trauma, the authors concluded that there was no indication that either the dosage or the timing of corticosteroid treatment, or the timing of surgery was associated with an increased probability of visual improvement. The study found that visual acuity recovered in 57% of the untreated group, 32% of the surgery group, and 52% of the steroid group, and found no clear benefit for either steroid therapy or decompression surgery [19]. The authors recommended that it is clinically reasonable to decide upon treatment on an individual-case basis. In a recently published epidemiologic study in adolescence, Goldenberg-Cohen et al. [11] presented 40 patients younger than 19 years, with blunt trauma being the reason for loss of vision in 78% of the cases. After treatment with steroids (n=18), decompression of the optic canal (n=3), or optic sheath fenestration (n=1), the vision was better than 20/80 in only four patients, with the rate or degree of improvement not differing between treated and untreated patients. The studies of Yang et al. [43] (n=42) and Ra-
jiniganth et al. [28] (n=44) combined high-dosage intravenous steroids with optic canal decompression. Although both studies found that combination treatment results in a better visual outcome, in neither study were the investigators blinded or the subjects randomized. However, the results do suggest that the outcome is better when decisions are made on an individual patient basis. A further retrospective case series presented by Jiang et al. (n=17) [15] included patients with TON who presented after failure of initial medical treatment. The authors performed endoscopic optic nerve decompression (EOND), and observed an improvement of vision in nine cases with a follow-up of more than 6 months. A similar study with a larger number of patients (n=72) with TON resistant to high-dose steroids was performed by Li et al. [20]. The authors reported that EOND improved visual recovery in 46 eyes followed-up for more than 3 months. The visual acuity improved in 31 out of 55 cases with no preoperative light perception, with even delayed EOND resulting in a pronounced visual improvement. The efficacy of delayed optic nerve decompression in TON was addressed in a prospective study involving 35 cases with a median injury-to-surgery interval of 56 days [36]. That study included only cases with poor vision after treatment with steroid (1 mg/kg prednisolone). Delayed surgery was found to be useful only in patients who were not completely blind (20 of 26 cases improved). A prognostic factor for whether surgical treatment results in a positive outcome is whether the eyes are completely blind [36]. Other studies include that of Hsieh et al. [13], which involved 45 cases of TON complicated with periorbital facial bone fractures. The authors found that there was no significant difference between treatment with megadose steroids and no treatment. Slightly different conclusions were drawn by Acarturk et al. [1], who reported on 11 patients with orbital fissure and orbital apex syndromes. In their cases the neuropathy caused by edema, contusion, and compression was reversible with very high doses of corticosteroids. A meta-analysis of the literature on TON published up to 1996 revealed that the recovery of vision was significantly better in patients who
received any treatment than in those who were not treated [6]. Recovery was also related to the severity of the initial lesion, e.g., better initial visual acuity was associated with better recovery, but did not differ significantly between corticosteroid and surgical treatments [6]. Similar findings were obtained in 113 eyes with indirect TON in which the initial posttraumatic vision was better than light perception [10]. The authors concluded that conservative treatment must first be given, with surgery being indicated when the vision does not improve to 0.5 or better within 3 weeks. The authors recommended the earliest possible surgical intervention when complete visual loss is evident after injury [10]. Endoscopic decompression of the optic canal combined with steroids appeared to be a successful approach in cases of total blindness due to TON, as revealed by the visual acuity returning to preinjury levels in four blind patients (i.e., no light perception) [16]. On the other hand, Wohlrab et al. [42] reported also on visual improvement in 8 out of 20 eyes, 5 of which had no light perception preoperatively. The primary treatment was transsphenoid decompression. Based on a retrospective analysis of 65 primarily decompressed optic nerves of conscious (n=52) and comatose (n=13) patients, Lubben et al. [21] reported a success rate (improvement in visual acuity of at least three lines on an eye chart) of about 60%, and confirmed the efficacy of early decompression in both groups. Notably, 5 of the 13 comatose patients improved completely, 3 improved partially, whereas 3 remained amaurotic [21]. Mine et al. [23] reported that neither the age nor the occurrence of optic canal fracture influenced the visual improvement in 34 patients with indirect TON. When comparing the efficacy of surgery (n=12) with nonsurgery (n=24), a significant improvement was found in eyes that had an initial visual acuity better than hand movements. The above studies together provide no compelling evidence that either type of treatment provides statistically significant advantages over the other or over nontreatment [2, 4, 19, 33, 41]. Also, one of the difficulties in managing patients
6.3 Histopathology of TON
with TON is to determine the exact mechanism of optic nerve injury.
Summary for the Clinician
■ According
to the International Optic Nerve Trauma Study (IONTS) no treatment procedure has statistically improved the visual outcome of TON. Treatment of TON should be done on individual basis.
■
6.3 Histopathology of TON The onset of cellular changes following various types of injury to the optic nerve may be influenced by both the severity of the lesion and its distance from the ganglion cell bodies. It has been suggested that the responses are more rapid for transection of the optic nerve at the globe than for those at a more posterior location involving the intracranial optic tract or the chiasm. Radius and Anderson [27] found that disc pallor developed as early as 2 weeks after a proximal photocoagulation-induced injury in the monkey. However, the ganglion cells and the intraretinal axon segments survived for longer. By 3 weeks there were perceptible changes in the ganglion cells and the nerve fiber layer, leading to a decrease in ganglion cell population, with this becoming significant after 4 weeks. The time of onset and the progression of the ganglion cell atrophy were similar after optic nerve transection in the posterior orbit in owl monkeys [26]. Both of these studies showed that the timing of the atrophy of the ganglion cell bodies is independent of the location of injury along the optic nerve. Apoptosis of ganglion cells and atrophy occur as early as 2 weeks after injury, whereas adjacent cells such as astroglial and microglial cells respond earlier. Very early changes were demonstrated in an eye enucleated 30 h following optic nerve transaction, 24 mm behind the globe (Fig. 6.2). Immunohistologic changes culminated in responses of astrocytes, macrophages and microglial cells. However, no apoptotic profiles or
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6
Fig. 6.2 Transection of the retrobulbar optic nerve. This eye was enucleated 30 h after TON and transection at the optic canal level. Immunohistochemistry results are detailed in Table 6.1
Table 6.1. Early cellular changes associated with optic nerve cut (30 h) 1. Activation of microglial cells and macrophages (NDPase, OX-42, ED-1 immunostaining 2. Onset of astrocyte activation (GFAP staining) 3. Stainable ganglion cell axons (neurofilament, GAP-43 staining) 4. Stainable microvessels and capillaries (endothelin staining) 5. Necrotic zone and myelin disarrangement at the site of necrosis 6. Normal cytoarchitecture of retina 7. No apoptosis within the retina (TUNEL)
disruption of the retinal layers occurred (Table 6.1). As expected, a necrotic zone was present in the vicinity of the optic nerve transection, with accumulation of macrophages and axonal debris, and disruption of myelin (Table 6.1). The optic atrophy of the later stages of TON is characterized by loss of axons in both directions from the site of injury, and by gradual loss of oligodendrocytes includ-
ing their myelin sheaths. The typical organization of glial columns between the parallel nerve fascicles is disrupted, and the astrocytes begin to proliferate (gliosis) together with a profound thickening of interseptal pial membranes. In spite of gliotic proliferation and meningeal thickening, the optic nerve diameter decreases and the subarachnoid space is widened. The ramified resident microglial cells phagocytose
degenerating neuronal debris as well as myelin, thereby transforming into lipid-loaded amebashaped macrophages.
6.4 Mechanisms of TON-Induced Ganglion Cell Death Retrograde degeneration of the retinal ganglion cells is the final common outcome underlying TON, wherever the initial site or mechanism of injury. The axon injury (either compressed or sectioned) initiates ganglion cell disease and death. The molecular responses at the site of axon injury involve interruption of axonal transport, local excitotoxicity from physiologic or pathologic levels of glutamate, the formation of free radicals, a decrease in the flow of neurotrophic factors from targets to the ganglion cells, leakage of potentially toxic constituents at the axonal stump, activation of microglial cells, proliferation of astrocytes, accumulation of retrogradely transportable molecules, and local breakdown of the blood–brain barrier. It is certain that multiple mechanisms account for the axonal response, and an influence of different factors can also be assumed. Further, the presence and posttraumatic expression of receptors to neurite inhibitors such as Nogos (NogoR) [40], which are myelin-associated glycoproteins, may be seen as an additional mechanism leading to the death of ganglion cells. These inhibitors prevent the successful formation of axonal growth cones at the tips of cut axons, and thereby convert a primarily anabolic response (e.g., chromatolysis [7]) into a suicide response. This may occur in conjunction with deprivation of neurotrophic factors, which are blocked by the injury, and by additional factors that are normally retrogradely transported to the ganglion cell body. Apoptosis of the ganglion cell body seems to be the final fate. While proteases are activated in typical cascades to allow clearance of cytoplasmic proteins, DNases are activated within the nucleus to prevent further translation and transcription. At the same time calcium homeostasis is disturbed both intracellularly and extracellularly [12]. Neighboring
6.5 Diagnosis of TON
microglial cells are activated to become phagocytic, ingesting disintegrating ganglion cells [37]. There is actually no possible replacement of dying ganglion cells, despite the recent hopes that intraretinal or other intraocular stem cells may be used to substitute the ganglion cell layer.
Summary for the Clinician
■ TON results in ganglion cell death, which is irreversible. ■ No replacement of ganglion cells is yet possible.
6.5 Diagnosis of TON Advanced TON is visible ophthalmoscopically at the optic nerve head, which shows a differential pattern of pallor depending on the location and severity of the injury. Although loss of vision may occur immediately after injury, pallor of the optic nerve head occurs with a delay of weeks (Fig. 6.3). Ophthalmoscopy is therefore not the diagnostic tool of first choice, although
Fig. 6.3. Fundus photography of a left eye showing complete atrophy of the optic nerve head 3 months after TON
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6 Fig. 6.4. Fundus photography showing bilateral severe optic nerve atrophy. Despite a history of unilateral injury, bilateral total blindness was present
it is recommendable for examining the status immediately after injury. Assessments of the visual acuity, visual field (in conscious and cooperative patients), and pupillary reflexes are essential for determining further management. Examination of both eyes with comparative evaluations of visual acuity, visual field, and fundoscopic status are necessary to exclude the bilateral TON (Fig. 6.4) that results from injury to both optic nerves at the optic canal level. Intraorbital injuries close to the optic nerve head result in a descending atrophy of the ganglion cells within 2–4 weeks and ascending atrophy within 4–6 weeks. Ophthalmoscopically visible atrophy of the nerve head becomes apparent at a few weeks after injury proximal to the optic canal, and is clearly visible 3 months later even in the case of a partial lesion (Fig. 6.1). Examination of experimentally induced TON in monkeys showed a similar chronologic sequence of cellular responses, with the ganglion cells degenerating by 4–5 weeks after optic nerve section and the intraretinal glial cells proliferating over the same period [3]. Optic nerve myelin degenerates more slowly, some remnants of myelin being still detectable 6 months after injury [17]. Although these changes may also occur in the human TON, diagnosis of TON should be based on various grounds, including the trauma history, assessment of visual function, ultraso-
nography, magnetic resonance imaging (MRI), and computed tomography (CT). High-resolution MRI is the preferred imaging technique for evaluating soft-tissue lesions, in particular those within the orbital apex and intracranially. CT is necessary to search for bone fractures around the orbit [18, 38], in the optic canal, at the orbital apex [44], and intracranially, to plan surgical intervention, or when MRI is contraindicated. Ultrasonography can assess anterior orbital fractures including rim and zygoma injuries, in particular when combined with ocular trauma. A complete ophthalmic examination is essential, including slit-lamp microscopy, fundoscopy, and the pupillary reflexes to light, the latter being especially useful in assessing an unconscious patient. Measuring visually evoked potentials is recommended for functionality assessments in conscious and motile patients, in particular if remnant potentials can be detected. Recently introduced methods of scanning laser polarimetry may be helpful in assessing the optic nerve fiber layer after TON. Miyahara et al. [24] described a case in which the retinal nerve fiber thickened immediately after a trauma that resulted in acute visual loss, and then progressively thinned until disappearing altogether after 3 months Whenever possible, measurement of the nerve fiber layer is a reliable and specific
parameter for detecting intraretinal changes after TON.
6.6 Therapeutic Concepts of TON 6.6.1 Steroids Steroids have often been cited as effective in treating central nervous system (CNS) trauma including spinal cord injuries, head trauma, and TON, by inhibiting lipid peroxidation induced by oxygen free radicals. Papers published in the 1990s and thereafter often cite the National Acute Spinal Cord Injury Study (NASCIS) 2 and 3 trials as evidence that high-dose methylprednisolone is an effective therapy in acute spinal cord injury. However, these trials are questionable from various points of view [25], and the evidence from them is now insufficient to support the use of prednisolone in the standard treatment of acute spinal cord injury [31]. Steroids continue to be given to individuals suffering of acute spinal cord injury, and some adverse effects have been reported [14]. Steroids are given to TON patients, even though a critical review of their effects by the IONTS [19] found no significant visual acuity improvement compared to either spontaneous recovery or surgical treatment. Further, Steinsapir et al. [34] found that high-dose methylprednisolone exacerbated axonal loss following optic nerve trauma in animals. The concept of using high-dose steroids must then be reconsidered until a prospective, controlled, and randomized trial delivers decisive evidence.
6.6.2 Neuroprotection Neuroprotectants form a heterogeneous group of substances derived from a wealth of studies involving experimental models on ganglion cell death under different circumstances, including glaucoma, ischemia, and crush and transection of the optic nerve. Neurotrophic factors have been used to enhance survival of axotomized retinal ganglion cells in rats [22]. However, none of these agents has successfully entered the
6.6 Therapeutic Concepts of TON
clinical phase of testing, although some are still considered to have positive effects in glaucoma. In our opinion, the potential of neurotrophic therapy is limited to its use as a complementary therapy.
6.6.3 Surgical Decompression Surgical decompression at the optic canal has been recommended as having beneficial effects on visual acuity and is considered by some authors to be the therapy of choice after initial, unsuccessful use of steroids either alone or in combination with decompression. However, a critical evaluation of retrospective case series revealed that most of the studies were nonrandomized and lacked reliable control groups, such as an untreated group. Such inclusions are mandatory, since there is a high incidence of spontaneous recovery of visual acuity in untreated TON. New approaches may be developed as new surgical techniques evolve and research into the pathophysiology of TON progresses. Endoscopic optic nerve decompression has been considered a minimally invasive procedure with no adverse cosmetic effects, but this remains to be verified given that nonrandomized studies have been used to demonstrate its efficacy [28]. Specifically, any new therapy has to be assessed in prospective and randomized clinical trials in order to avoid ill-founded recommendations with a potential risk of deleterious effects.
6.6.4 The Role of Ophthalmologists Both conservative and surgical treatments of TON remain controversial despite numerous reports in favor of either approach, and hence a prospective, randomized, and multicentric study appears mandatory for drawing definite conclusions. Prompt and accurate ophthalmic diagnosis is essential. Results of initial ophthalmic examination (visual acuity, ophthalmoscopy, and visual field defects) might influence the choice of therapy and are necessary for inclusion/exclusion of the patient in a prospective and randomized study. The necessity for
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further research into the pathophysiology of both ganglion cell death and TON, as well as the development of low-risk surgical techniques and neuroprotection are obvious in the current state of controversies.
Summary for the Clinician
■ There is no sufficient evidence that ste-
roids improve the outcome of either spinal cord or optic nerve injuries. Decompression surgery of TON has also not been proven to result in a better outcome than steroids or no treatment.
6
■
6.7 Outlook on Regeneration of the Optic Nerve One of the most accurate descriptions on how the optic nerve responds to injuries was given by Ramón y Cajal [29], who examined various regions of the peripheral and central nervous system including the injured optic nerve: “It is to be assumed that the retina and optic nerve will react to violence not like peripheral nerves but like the brain on spinal cord … that is with small frustrated acts of growth … because of the absence of cells of Schwann which emit powerful neurotrophic agents…” Retinal ganglion cells exhibit only a limited and transient sprouting reaction after transection, and they fail to regrow axons through the interior of the optic nerve [29]. This failure of regeneration has been attributed to inhibitory factors associated with optic nerve myelin (Nogos) and/or glial scar, which also produces growth-inhospitable extracellular matrix proteins [5]. There are, however, several experimental conditions that permit regrowth of ganglion cell axons. Complete replacement of the sectioned optic nerve with an autologous sciatic nerve segment reconnecting the retina with central targets has been successfully established. This model has been applied to the rat, hamster, mouse and cat optic nerve and shows the intrinsic ability of ganglion cells to regenerate axons and rebuild synaptic contacts with functional significance [39].
Section of the optic nerve in rats and simultaneous injury to the intraocular lens stimulates ganglion cell axons to grow within their own distal optic nerve and reach central targets, thus eliciting positive visual evoked potential responses [8]. It has also been shown that both inflammatory responses involving macrophages and direct lentogenic factors facilitate axonal regeneration [35]. These experiments showed that the intrinsic ganglion cell’s ability to regrow an axon can be supported by external substitution of neurotrophic agents. Further, in vitro models of retinal regeneration have also been developed [35]. They allow for exploration of the mechanisms of axonal growth on various substrates, for testing of neurotrophins and for examining the effects of lens injury, as revealed by co-culture experiments [35]. Moreover, primate tissue could be examined in vitro as well, and recent experiments have indeed revealed that monkey retinal ganglion cells also have a reasonable potential to regrow their axons. Although the rate of axonal regeneration declines physiologically with increasing age, axonal regeneration is still possible, even in adulthood [30]. Consequently, axonal regeneration of retinal ganglion cells may require multiple approaches, such as (1) inactivation of growth-inhibiting signals; (2) activation of the intrinsic growth state of neurons; and (3) adjusting the microenvironment to permit the formation of growth cones at the site of optic nerve transection. Although the aspect of optic nerve regeneration has been addressed only in experimental models, valuable lines of evidence have been collected to encourage further research on the mechanisms initiating and maintaining axonal growth after TON. To this end, the challenge is to transfer such studies into a preclinical or clinical application, for instance by using autologous peripheral nerve grafts in very severe cases of optic nerve transections as shown in Fig. 6.2. Apposition of such a peripheral nerve graft at the site of injury may result in ingrowth of the sectioned optic nerve axons and retrograde stabilization of the ganglion cell bodies, which otherwise are inevitably lost. Stabilized and regenerating ganglion cells may then be surgically reconnected with the lateral geniculate body to rebuild synaptic contacts.
References
Summary for the Clinician
5.
■ All efforts to protect ganglion cells from
death or force them to regenerate are experimental studies with no clinical application as yet.
6.
6.8 Current Clinical Practice and Recommendations The following recommendations can be made based on the above review of the literature: • Examine the patient as accurately as possible (visual acuity, visual field, pupil, and fundus) before making any decision regarding treatment. • Consult additional diagnostic procedures as necessary (MRI, CT, radiography, ultrasonography, otorhinolaryngologic, and neurologic status). • Determine whether (rare) transection or compression of the optic nerve has occurred. • Be aware that neither steroid treatment nor surgical decompression has shown better visual acuity recovery compared with no treatment in TON. • Considering the lack of recommendable procedures, any choice of treatment must be performed on an individual basis. • Neuroprotective strategies are not yet available for TON.
References 1.
2.
3.
4.
Acarturk S, Sekucoglu T, Kesiktas E (2004) Mega dose corticosteroid treatment for traumatic superior orbital fissure and orbital apex syndromes. Ann Plast Surg 53:60–64 Acheson JF (2004) Optic nerve disorders: role of canal and nerve sheath decompression surgery. Eye 18:1169–1174 Anderson DR (1973) Ascending and descending optic atrophy produced experimentally in squirrel monkeys. Am J Ophthalmol 76:693–711 Chang EL, Bernardino CR (2004) Update on orbital trauma. Curr Opin Ophthalmol 15:411–415
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Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403:434–439 Cook MW, Levin LA, Joseph MP, Pinczower EF (1996) Traumatic optic neuropathy. A metaanalysis. Arch Otolaryngol Head Neck Surg 122:389–392 Cragg BG (1970) What is the signal for chromatolysis? Brain Res 23:1–21 Fischer D, Heiduschka P, Thanos S (2001) Lensinjury stimulated axonal regeneration throughout the optic pathway of adult rats. Exp Neurol 172:257–272 Fitzgibbon T, Taylor SF (1996) Retinotopy of the human retinal nerve fibre layer and optic nerve head. J Comp Neurol 375:238–251 Fujitani T, Inoue K, Takahashi T, Ikushima K, Asai T (1986) Indirect traumatic optic neuropathy – visual outcome of operative and nonoperative cases. Jpn J Ophthalmol 30:125–134 Goldenberg-Cohen N, Miller NR, Repka MX (2004) Traumatic optic neuropathy in children and adolescents. J AAPOS 8:20–27 Heiduschka P, Fischer D, Thanos S (2004) Neuroprotection and regeneration after traumatic lesion of the optic nerve. Klin Monatsbl Augenheilkd 221:684–701 Hsieh CH, Kuo YR, Hung HC, Tsai HH, Jeng SF (2004) Indirect traumatic optic neuropathy complicated with periorbital facial bone fracture. J Trauma 56:795–801 Hurlbert RJ (2006) Strategies of medical intervention in the management of acute spinal cord injury. Spine 31:S16–S21 Jiang RS, Hsu CY, Shen BH (2001) Endoscopic optic nerve decompression for the treatment of traumatic optic neuropathy. Rhinology 39:71–74 Kountakis SE, Maillard AA, Urso R, Stiernberg CM (1997) Endoscopic approach to traumatic visual loss. Otolaryngol Head Neck Surg 116:652–655 Kupfer C (1963) Retinal ganglion cell degeneration following chiasmal lesions in man. Arch Ophthalmol 70:256–260
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Traumatic Optic Neuropathy: Recommendations and Neuroprotection 18. Leung DY, Kwong YY, Lam DS (2006) The outcome of 48 eyes with indirect traumatic optic neuropathy and periorbital facial bone fracture. J Trauma 60:685 19. Levin LA, Beck RW, Joseph MP, Seiff S, Kraker R (1999) The treatment of traumatic optic neuropathy: the International Optic Nerve Trauma Study. Ophthalmology 106:1268–1277 20. Li N, Zhang NK, Tian Y, Chen M (2006) Endoscopic optic nerve decompression in traumatic optic neuropathy: analysis of 72 cases. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 41:181–183 21. Lubben B, Stoll W, Grenzebach U (2001) Optic nerve decompression in the comatose and conscious patients after trauma. Laryngoscope 111:320–328 22. Mey J, Thanos S (1993) Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res 602:304–317 23. Mine S, Yamakami I, Yamaura A, Hanawa K, Ikejiri M, Mizota A, Adachi-Usami E (1999) Outcome of traumatic optic neuropathy. Comparison between surgical and nonsurgical treatment. Acta Neurochir (Wien) 141:27–30 24. Miyahara T, Kurimoto Y, Kurokawa T, Kuroda T, Yoshimura N (2003) Alterations in retinal nerve fiber layer thickness following indirect traumatic optic neuropathy detected by nerve fiber analyzer, GDx-N. Am J Ophthalmol 136:361–364 25. Nesathurai S (1998) Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS 3 trials. J Trauma 45:1088–1093 26. Quiqley HA, Davis EB, Anderson DR (1977) Descending optic atrophy in primates. Invest Ophthalmol Vis Sci 16:841–849 27. Radius RL, Anderson DR (1978) Retinal ganglion cell degeneration in experimental optic atrophy. Am J Ophthalmol 86:673–679 28. Rajiniganth MG, Gupta AK, Gupta A, Bapuraj JR (2003) Traumatic optic neuropathy: visual outcome following combined therapy protocol. Arch Otolaryngol Head Neck Surg 129:1203–1206 29. Ramón y Cajal S (1928) Degeneration and regeneration of the nervous system. [Translated by R. M. May] Oxford University Press, Oxford
30. Liedtke T, Naskar R, Eisenacher M, Thanos S (2007) Transformation of adult retina from the regenerative to the axonogenesis state activates specific genes in various subsets of neurons and glial cells. Glia 55:189–201 31. Sayer FT, Kronvall E, Nilsson OG (2006) Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structural analysis of published literature. Spine J 6:335–343 32. Schmid R, Wilhelm B, Wilhelm H (2000) Nasotemporal asymmetry and contraction on anisocoria in the pupillomotor system. Graefes Arch Clin Exp Ophthalmol 238:123–128 33. Steinsapir KD (2006) Treatment of traumatic optic neuropathy with high-dose corticosteroid. J Neuroophthalmol 26:65–67 34. Steinsapir KD, Goldberg RA, Sinha S, Hovda DA (2000) Methylprednisolone exacerbates axonal loss following optic nerve trauma in rats. Restor Neurol Neurosci 17:157–163 35. Stupp T, Pavlidis M, Busse H, Thanos S (2005) Lens epithelium supports axonal regeneration of retinal ganglion cells in a coculture. Exp Eye Res 81(5):530–538 36. Thakar A, Mahapatra AK, Tandon DA (2003) Delayed optic nerve decompression for indirect optic nerve injury. Laryngoscope 113:112–119 37. Thanos S, Pavlidis C, Mey J, Thiel HJ (1992) Specific transcellular staining of microglia in the adult rat after traumatic degeneration of carbocyanine-filled retinal ganglion cells. Exp Eye Res 55:101–117 38. Tsai HH, Jeng SF, Lin TS, Kueh NS, Hsieh CH (2005) Predictive value of computed tomography in visual outcome in indirect traumatic optic neuropathy complicated with periorbital facial bone fracture. Clin Neurol Neurosurg 107:200–206 39. Vidal-Sanz M, Bray GM, Villegas-Perez MP, Thanos S, Aguayo AJ (1987) Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in adult rat. J Neurosci 7:2894–2909 40. Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z (2002) Oligodendrocytemyelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941–944 41. Wilhelm H (2004) Traumatic optic neuropathy – the present state. Klin Monatsbl Augenheilkd 221:702–705
42. Wohlrab TM, Maas S, de Carpentier JP (2002) Surgical decompression in traumatic optic neuropathy. Acta Ophthalmol Scand 80:287–293 43. Yang WG, Chen CT, Tsay PK, de Villa GH, Tsai YJ, Chen YR (2004) Outcome for traumatic optic neuropathy – surgical versus nonsurgical treatment. Ann Plast Surg 52:36–42
References 44. Yeh S, Foroozan R (2004) Orbital apex syndrome. Curr Opin Ophthalmol 15:490–498 45. Yu Wai Man P, Griffiths PG (2005) Surgery for traumatic optic neuropathy. Cochrane Database Syst Rev (4):CD005024
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Part II
Investigations
Chapter 7
Imaging the Nerve Fiber Layer and Optic Disc
7
Marc Dinkin, Michelle Banks, Joseph F. Rizzo III
Core Messages
■ Imaging of the optic nerve head and
■ The Scanning Laser Polarimeter (GDx)
■
■
retinal nerve fiber layer (RNFL) can be a useful adjunct to the clinical evaluation of patients with neuroophthalmologic disease. Techniques for visualizing these structures have progressed over the last century and a half, from illustrations based on ophthalmoscopy to newer technologies whose resolution can provide a nearly cellular level of detail. Stereo photography is a widely used, albeit subjective, means of assessing optic nerve head topography. Optic nerve head analyzers were the first instruments to use computers to assess the optic nerve head, by analyzing either stereoscopic photographs or the deflection of parallel lines of light. Scanning laser ophthalmoscopy uses a diode laser to provide a three-dimensional image of the fundus. The confocal system helps remove stray light, increasing image quality. The Heidelberg Retinal Tomograph II is a scanning laser ophthalmoscope that scans along multiple planes of depth, creating a three-dimensional image. This scan can provide quantitative topographic detail of the optic nerve head, which calculates optic nerve head parameters that may be useful in the clinical assessment of glaucoma.
■ ■ ■ ■
analyzes the “retardation” of polarized light to calculate the RNFL thickness, which makes it a useful test to assess nerve fiber layer defects in glaucoma. Optical coherence tomography (OCT) uses low-coherence reflectometry to produce high-resolution, two-dimensional, cross-sectional images of the optic disc, retinal nerve fiber layer and macula. RNFL thickness measured with OCT has been shown to have good correlation with visual field defects in glaucoma. OCT has been used to study RNFL thickness in many other conditions, but its clinical utility in these settings is not yet established. Enhancement of the optic nerve on MRI helps to identify inflammatory optic neuropathies. Ultra high resolution MRI may one day be available for extremely high resolution optic nerve images. New imaging technologies can provide objective measurements that aid in the detection and evaluation of neuroophthalmic disease, especially optic nerve cupping associated with glaucoma, but they should only be used in conjunction with the clinical exam. Ocular imaging technologies can be useful for the neuro-ophthalmologist, especially in identifying retinal pathology in cases of otherwise unexplained visual loss. Neuroimaging (i.e., MRI) of the optic nerve however, is an integral part of the evaluation of most patients with neurogenic visual loss.
■ ■
■
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7.1 Introduction
7
The introduction of the ophthalmoscope by von Helmholtz in 1851 allowed physicians to view the fundus for the first time. Since then, drawings, photography and more recently computerized imagery have been used to document the appearance of the fundus. Advanced technology has provided reliable tools for recording anatomical details of the optic nerve and nerve fiber layer, which can assist in the management of patients with optic nerve disease, especially glaucoma. Scanning laser polarimetry, confocal scanning laser tomography and optical coherence tomography are being used clinically in many centers, sometimes as part of routine evaluations of patients with glaucoma. This review will provide a brief historical perspective of the advantages and disadvantages of these and other methods used to record the appearance of the optic nerve head.
7.2 Overview of Early Imaging Techniques 7.2.1 Optic Nerve Head Drawings Drawings of the optic nerve head, especially with regard to the cup-to-disc ratio, remain the most routinely used clinical method for documenting the appearance of the optic nerve head. However, there can be disagreement even among skilled glaucoma specialists in the interpretation of the appearance of the optic disc [41]. Inconsistencies may exist even for a single observer [73], which is not surprising given that this method is entirely subjective. This variability limits the value of drawings in the management of patients. The need for more advanced techniques of documenting and analyzing the optic nerve head has resulted in the emergence of objective means to measure and display the topography of the optic nerve head.
7.2.2 Direct Ophthalmoscopy of the Nerve Fiber Layer A high-quality image of the retinal nerve fiber layer (RNFL) can be obtained simply by using the red-free (i.e., green) light source on a standard ophthalmoscope. The nerve fiber layer,
which is composed solely of axons of the retinal ganglion cells, appears as striations with a characteristic “rice grain” texture that are brightest at the superior and inferior poles, where the concentration of nerve fibers is the greatest. With this method, “slit” nerve fiber layer defects, which can be a subtle sign of optic nerve disease, can be detected [32]. Photographic images of the RNFL can be obtained by using a fundus camera with the appropriate filter. Disadvantages of ophthalmoscopy include: (1) the need for subjective interpretation; (2) potentially misleading appearances of the nerve fiber layer due to optical variations among individuals (especially related to the degree of fundus pigmentation); and (3) the difficulty in detecting subtle but diffuse (versus focal slit defects) optic nerve atrophy.
7.2.3 Retinal Nerve Fiber Layer Photography Photography can provide a high-resolution image of the RNFL as well. The RNFL substantially reflects bright, short-wavelength light (i.e., 490 nm blue light, produced with the excitation filter used for fluorescein angiography), while longer wavelengths pass through the retina and are absorbed by the retinal pigment epithelium. Media opacities such as cataracts decrease the penetration of blue light, and conditions associated with generalized fundus hypopigmentation (i.e., myopia) limit the visibility of the nerve fiber layer because of increased reflection by the sclera [34]. Photography can reveal localized or diffuse defects in the nerve fiber layer. Assessment of red-free RNFL photography has an average sensitivity and specificity of 80%–94% in differentiating between normal and glaucomatous eyes, with variation attributed to the observer, and to the patient’s age, ethnicity, and severity of field loss [67]. Sensitivity appears to vary especially with the severity of visual field loss, while ethnicity has been shown to have more of an influence on specificity. As a screening method for glaucoma in large populations, the sensitivity and specificity of red-free photography decrease to 64% and 84%, respectively [78]. A photographic grading system reflecting various nerve fiber layer appearances ranging from normal (i.e., broad, clearly striated nerve fiber bundles) to advanced diffuse atrophy
7.2 Overview of Early Imaging Techniques
(i.e., no nerve fibers visible) has been proposed. This more detailed method of assessment provides improved inter- and intra-observer reliability, with intra-class correlation coefficients of 0.81–0.98 [47]. However, this method provides references only for grades of diffuse atrophy and thus excludes wedge-shaped defects, which are relatively common.
7.2.4 Stereoscopic Optic Nerve Head Photography With improved optics and methods of illumination, optic nerve head photography became the “gold standard” for documentation of the appearance of the optic nerve head. Typically, stereoscopic photographs are obtained from sequential exposures of the optic nerve head, one taken just nasal and another just temporal its central axis. The simultaneous method provides two stereoscopic images with a single exposure. This technique reduces the variability in stereoscopic quality often encountered with sequential photographs that require making alterations in the position of the patient’s head. Fundus photography is widely used because it requires only relatively simple and inexpensive technology, and because of physicians’ experience and comfort in interpreting photographs. Photographs can be interpreted without contending with the vagaries and uncertainties of readings from devices that use newer and more unfamiliar technology. With this method, the sensitivity (94%) and specificity (87%) for experienced observers discriminating between normal and glaucomatous optic nerves [26] are fairly good,
but not at a level that is acceptable for patient management; hence the need for more objective and potentially more reliable means to assess the optic nerve head. Newer technologies that have emerged have the additional notable advantage of being able to image specific structures, such as microtubules, or assess the thickness of the cellular, plexiform or nerve fiber layer of the retina, which might prove to be clinically valuable (Table 7.1). A review of the more widely used of these technologies is presented below.
Summary for the Clinician
■ Optic nerve head drawings are common
in clinical practice, but their value is limited because they are purely a subjective means of documentation. Direct ophthalmoscopy using the redfree filter is a useful means of observing the retinal nerve fiber layer (RNFL), but requires subjective interpretation, and is affected by optical variations among individuals. High-resolution images of the RNFL are possible with photography, but the quality of these images may be affected by media opacities and variable retinal pigmentation. Using two offset images, stereoscopic optic nerve head photography offers improved discrimination between normal and glaucomatous optic nerve heads.
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Table 7.1. Comparison of commonly used nerve fiber layer and optic nerve imaging devices Proprietary name
Principle
Advantages
Disadvantages
GDx (for “glaucoma diagnosis”)
Scanning laser polarimetry
Widely available
Anterior segment birefringence
Heidelberg retinal tomography
Confocal scanning laser ophthalmoscopy/tomography
Three-dimensional image
Reference plane dependent
Optical coherence tomography
Low-coherence reflectometry
High-resolution crosssectional images
Depends on transparent media
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7.2.5 Optic Nerve Head Analyzers
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A group of instruments, collectively referred to as optic nerve head analyzers, were the earliest methods that applied computerized technology to optic nerve head imaging. These instruments were the first to provide objective information about optic nerve head structure, specifically the neuro-retinal rim and the topography of the cup of the optic nerve head. The most significant “analyzers” are the Topcon IMAGEnet, the Humphrey Retinal Analyzer, the Rodenstock Optic Nerve Head Analyzer, and the Glaucoma-Scope. Though rarely used today, these devices formed the basis for the evolution of the more advanced technologies that are now routinely used.
7.2.5.1 The Topcon IMAGEnet The first commercially available system was the Topcon IMAGEnet (Topcon Instruments, Paramus, N.J., USA). Standard fundus camera optics is used to produce stereoscopic images that are digitized. The user marks four points that are then taken to be the optic disc margin on each of the two photographs. Then 36 points 10º apart are automatically placed around the circumference of an ellipse created from the user-defined marks. The margin of the cup is defined at points 125 µm posterior to the four user-defined points on the disc margin. The angular relationship between two horizontally displaced points (i.e., the two photographic images) required to achieve focus on a point in space can be used to calculate depth. A three-dimensional map of the optic nerve head is then constructed.
7.2.5.2 The Humphrey Retinal Analyzer The Humphrey Retinal Analyzer (Humphrey, San Leandro, Calif., USA) obtains input from a redfree simultaneous stereoscopic camera, which produces two images that have slightly disparate levels of brightness in corresponding regions [17]. Three-dimensional images are generated from an algorithm that compares the brightness of corresponding points. The user stipulates eight
points on the margin of the optic nerve head (disc margin) that the analyzer uses as a reference plane, from which the depth of 400–650 points is computed. The edge of the cup corresponds to those points that are 120 µm beneath the user-defined disc margin. The use of subjective margins contributes to variability in results from this system [17].
7.2.5.3 The Rodenstock Optic Nerve Head Analyzer The Rodenstock Optic Nerve Head Analyzer (Rodenstock Instruments, Danbury, Conn., USA) projects two sets of seven lines on the optic nerve head while a stereoscopic video camera obtains a digital image. The computer creates a contour map from the displacement of stripes as they cross the optic nerve head. The user must define the edge of the optic nerve head with four cardinal points. Depth values are calculated at 140 points along each of the 14 stripes. Points that meet or exceed a 150 µm drop in depth correspond to the area of the cup. Values for cupto-disc ratio, disc rim area, cup volume, disc elevation, and total disc area are provided [5]. Reproducibility is better for cup-to-disc ratio and neural rim area than for cup volume, which becomes less reproducible with increasing cup size [65]. The Rodenstock Analyzer has shown promise in detecting changes that may predate clinical changes in optic nerve head anatomy. Significant differences were demonstrated in the neuroretinal rim area of affected and unaffected eyes of patients with unilateral glaucoma compared to eyes of normal subjects [9]. Also, the variability of topographic measurements obtained with the Rodenstock Analyzer is similar within normal and glaucomatous groups of patients [5], which simplifies attempts to use this device for comparative studies. There is a moderate degree of inter-image (i.e., different images on the same eye obtained at different times) variability with the Rodenstock Analyzer, which is believed to be secondary to variability inherent in the instrumentation and measurement. Compared to the Humphrey Analyzer, however, there is less intraobserver (i.e., same observer marks the same disc
7.3 Modern Techniques for Optic Nerve and Retinal Nerve Fiber Layer Imaging
margin repeatedly) variability with the Rodenstock device, which probably relates to the fact that only four (versus eight) user-defined points are required for the Rodenstock technique [17].
tions in which the contour line was drawn at each examination [16]. Although the Glaucoma-Scope is a relatively simple and reliable tool in some settings, it suffers from dependence on images that can be degraded by cataract, aphakia, pseudophakia, myopia and hyperpigmented fundi [16].
7.2.5.4 The Glaucoma-Scope The Glaucoma-Scope (Ophthalmic Imaging Systems, Sacramento, Calif., USA) utilizes the technique of computed raster stereography, in which a series of parallel lines of light are projected onto the optic disc at an oblique angle. The GlaucomaScope requires a minimum pupil diameter of 4.5 mm, through which a series of 25 horizontal lines generated from a halogen lamp illumination system are projected across the optic nerve head at an angle of 9º using a near-infrared light (750 nm). The depth and volume of the cup are proportional to the amount of deflection of the lines. Shallow depths have small deflections while large deflections reflect deep excavations. A three-dimensional anatomical image is reconstructed from the deviation of the projected lines and the image can be stored in digital form. The operator identifies margins of the optic disc with at least eight points. Points on the nerve head 350 µm from the nasal and temporal margins are used as a reference plane to calculate the depth of the cup. A depression ≥140 µm below the reference plane is defined as the optic nerve head cup. Approximately 9100 real data points in an area containing 350 by 280 pixels are converted into depth values, providing a relatively high-resolution image. At the time of the initial evaluation a reference point is selected, which is used to realign the nerve head on subsequent tests. Changes in depth values greater than or equal to 75 µm are reported as a change-from-baseline analysis. The Glaucoma-Scope provides reproducible depth measurements in both healthy and glaucomatous subjects. From a 25 cell “sample,” the mean standard deviation in a single pixel has been reported to be 15.42 µm for the population as a whole, 15.11 µm for healthy discs, and 15.57 µm for glaucomatous discs [30]. A report of inter- and intra-observer variability indicates that there is significant inter-observer agreement and moderate intra-observer agreement even under condi-
Summary for the Clinician
■ Computer-based analytical imaging of
the optic nerve head and RNFL began with the optic nerve head analyzers. The Topcon IMAGEnet and Humphrey Retinal Analyzer use digitized stereoscopic photography from which depth measurements are obtained and threedimensional images are constructed. The Rodenstock Optic Nerve Head Analyzer and the Glaucoma-Scope use the deflection of parallel lines of light to determine depth and create a three-dimensional image. These techniques require user-defined margins, and are subject to inter-observer variability and obscuration by media opacities.
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7.3 Modern Techniques for Optic Nerve and Retinal Nerve Fiber Layer Imaging 7.3.1 Scanning Laser Ophthalmoscopy and Tomography The scanning laser ophthalmoscope illuminates a small spot to produce a high-contrast image. Reflected energy is detected and formed into an image. Scanning laser ophthalmoscopes are constructed as either a nonconfocal or confocal device, depending upon the optics used to detect the reflected light. In the nonconfocal system, two separate apertures are used – a central aperture for illumination of the eye, and a paracentral for light reflected from the eye. This optical arrangement suppresses corneal reflections that can substantially degrade image quality. The
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minimum spot size of illuminated retina (approximately 10–15 µm) is determined by the optical properties of the eye, specifically the clarity of the media and the focusing capabilities of the cornea and lens. The small-diameter laser beam can be delivered to a wide area of the retina by use of a rotating polygon, which provides horizontal scanning, and a galvanometer, which provides slower vertical scanning [51].
The confocal scanning laser ophthalmoscope employs a variation on the scanning device that more substantially removes out-of-focus, scattered light reflected from the retina. This improved optical quality is accomplished by permitting only the best -focused reflected light to reach the detector (Fig. 7.1). Elimination of the stray light (Fig. 7.2) yields a higher contrast image with a reduced depth of field relative to the
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Fig. 7.1. Schematic of the design of a confocal ophthalmic imaging system (Rodenstock SLO 101) (modified from Plesch et al. [51]). The schematic below shows the light sources (laser 1 and 2, upper left) which produce a beam that is projected to desired points on the retina (lower right). The light passes through attenuators that reduce its intensity, followed by a shutter, an optically clear zone in a partially reflective mirror and a convex lens which focuses the light onto a mirror. Light reflected off the mirror hits a rotating polygon, which causes to and fro movement of the beam, which is eventually projected as a fast horizontal scanning movement on the retina. On the way to the eye, the light also strikes the surface of a slowly oscillating mirror controlled by a galvanometer, which produces slow, vertical scanning of the light on the retina. Light reflected from the patient’s eye travels back along the same path until it reaches the partially reflective mirror, which deflects it downward through lenses and a selectable aperture, and finally to the detector. The diameter of the aperture permits control over the depth of field of the image. The essence of the confocal system is the aperture-controlled entry into the detector, which substantially reduces stray, defocused light and thus produces a higher resolution image (Modified from Plesch et al. [51])
7.3 Modern Techniques for Optic Nerve and Retinal Nerve Fiber Layer Imaging
size of the aperture. The reduced depth of field permits high-resolution, layer-by-layer imaging of the retina [51, 56]. Five confocal scanning systems are available.
7.3.1.1 The Rodenstock System The Rodenstock System uses a helium-neon or argon laser with a power of less than 0.1 mW to illuminate the retina. Approximately 10 J of energy is delivered during an interval of about 100 ns at a rate of 30 Hz. Analysis of differences in reflected wavelength is performed and a threedimensional image is constructed.
7.3.1.2 The Heidelberg Laser Tomographic Scanner The Heidelberg Laser Tomographic Scanner (LTS) (Heidelberg Instruments, Heidelberg, Germany) uses a Helium neon laser beam (632 nm). The user determines the range of depth over which images are detected. Most typically images are acquired from just in front of the blood vessels to a level posterior to the lamina [20]. Thirty-two consecutive focal planes beginning at the first reflections of the retina to the bottom of the excavation are automatically scanned. An algorithm is used to calculate the height at each of the pixels to produce a topographic map [20].
Fig. 7.2. Optical benefit of confocal imaging: suppression of out-of-focus reflections and suppression of scattered light (figure modified from Plesch et al. [51]). The schematic provides a magnified view of the confocal detection unit shown in Fig. 7.1. The shaded area represents the path of light rays reflecting off the desired imaging spot on the retina. The dotted lines show the path of scattered light rays that have reflected off slightly more peripheral retinal locations, which are not of interest. Both paths of light emerge from the scanning unit and pass through a focusing lens. The non-desired path of light from the undesired areas of retina is not aligned with the confocal aperture, and hence is not seen by the detector. Only light from the desired, single illuminated point on the retina enters the aperture and reaches the detector
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7.3.1.3 The Zeiss Confocal Scanning Laser Ophthalmoscope and TopSS™ Topographic Scanning System The Zeiss Confocal Scanning Laser Ophthalmoscope (CSLO, Zeiss Instruments, Thornwood, N.J., USA), which uses a red helium laser, and the Topographic Scanning System (TopSS™, Laser Diagnostic Technologies, San Diego, Calif., USA), which uses a diode laser of 780 nm, are similar to the LTS in the method of operation.
7
Summary for the Clinician
■ Scanning
laser ophthalmoscopy uses a diode laser to detect depths at points along the retina by analyzing the reflected wavelength at each point. The nonconfocal system has one aperture for illumination and one for the reflected light, and is therefore to subject to degradation of the image by light scatter. The confocal system offers higher quality images with a reduced depth of field by preventing out-of-focus reflected light from entering the detector with a reduced depth of field.
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7.3.2 The Heidelberg Retinal Tomograph II The Heidelberg Retinal Tomograph II (HRT II, Heidelberg Engineering, Heidelberg, Germany) uses a diode laser (670 nm) to scan the surface in x and y planes. The level of depth (z) is determined after adjusting the position of the objective lens. The image obtained consists of 256 by 256 pixel elements, or 65,000 height measurements, in each focal plane. A three-dimensional image is constructed from scans performed in a series of up to 32 consecutive focal planes that are equidistant and extend from the preretinal plane to the bottom of the excavation. A reference plane, determined automatically by the software as being parallel to the peripapillary retinal surface and 50 µm beneath the level of the papillo-macular
bundle, is used to differentiate between the cup and rim. Structures beneath the reference plane are defined as the cup, and structures above the reference plane are defined as the rim. The HRT II requires the placement of a contour line around the margin of the optic disc by an operator. The instrument automatically places the contour line in the same location at each subsequent examination. Values for the parameters of disc and cup area, cup-to-disc area ratio, rim area, height variation contour, cup and rim volume, mean and maximal cup depth, cup shape measure, mean retinal nerve fiber layer thickness, and retinal nerve fiber layer cross-sectional area are generated. The role of the reference plane and the potential for variation due to the user-stipulated contour line has generated debate on the utility of HRT II in clinical applications. The mean coefficient of variation of HRT topographic parameters ranged from 2.9% to 5.2% in eyes of glaucoma patients, suspects and controls [56]. Reliability coefficients of early HRT topographic parameters ranged from 73.7% to 99.4% both in normal and glaucomatous eyes [44]. Height variation along the contour line, which is affected by a single pixel measurement, has only 60% reliability. Furthermore, measurements of certain regions of the optic nerve have differing degrees of reliability. The greatest variability occurs around blood vessels, while the highest reproducibility is in the peripapillary area [14]. In detecting patients with early glaucomatous visual field loss, a single HRT image is 87%–89% sensitive and 78%–84% specific [43]. Sequential HRT imaging improves reproducibility, from an average standard deviation of 35.5 µm on the first examination to 25.7 µm with three measurements during a single evaluation [82]. In normal and glaucomatous eyes, HRT measurement of cup-to-disc ratio is in agreement with the horizontal and vertical estimates of experienced clinicians evaluating stereoscopic optic disc photos [85]. Compared to clinical assessment of stereoscopic optic disc photographs, confocal scanning ophthalmoscopy with HRT II provides a sensitivity of 84.3% and a specificity of 95.8% in identifying early glaucomatous changes [84]. Neuroretinal rim thinning seen with HRT II can be used to predict development of glaucomatous visual field loss in the unaffected eye of patients
7.3 Modern Techniques for Optic Nerve and Retinal Nerve Fiber Layer Imaging
with strictly unilateral normal-tension glaucoma [84]. There is some evidence that HRT II may be a useful tool to screen high-risk populations for glaucoma. In one study that used HRT II to predict glaucoma, the negative predictive value was very high (0.84–0.99), although the positive predictive value was much lower. (0.31–0.68) [28]. It has not yet been shown that the use of HRT II to predict glaucoma is superior to the clinical exam alone. The HRT II has been used to investigate the anatomical correlates of various pathological states of the optic nerve head and nerve fiber layer. One study found a reduction of the disc edge RNFL thickness, and the neuroretinal rim volume and an increase in the three-dimensional optic cup measurement in eyes with optic neuritis when compared to the fellow eye or eyes from normal controls [75]. In another study, HRT II assessments of the optic disc in nonarteritic ischemic optic neuropathy did not correlate with visual field defects, while RNFL measurements made with the GDx device did provide a reasonably good correlation [61]. The HRT II has also been used to demonstrate a decrease in optic disc size in women on short-term tamoxifen therapy [21].
Summary for the Clinician
■ The HRT II uses confocal scanning laser
ophthalmoscopy to scan the surface of the retina in up to 32 different planes, thereby creating a topographic map of the optic nerve head and surrounding retina. The HRT II can calculate optic nerve disc, cup and rim volumes and areas; cup-to-disc ratio; mean cup depth; cupshape measure; difference in height of the nerve fiber layer (height variation contour of the RNFL); and overall mean retinal nerve fiber layer thickness. Sources of variability with the HRT II include the computer-generated reference plane and the user-stipulated disc margins. HRT II may be a useful ancillary test in the assessment of glaucoma.
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7.3.3 Scanning Laser Polarimetry (“GDx”) The Scanning Laser Polarimeter (GDx; Laser Diagnostic Technologies, San Diego, Calif., USA) is a confocal scanning laser ophthalmoscope with an integrated polarization modulator, corneal compensator, and polarization detector. The scanning polarimeter directs a polarizationmodulated laser beam (780 nm wavelength) onto the retina, which is partly reflected by subretinal tissue. Birefringence in the nerve fiber layer arises from the parallel arrangement of microtubules and other intermediate filament structures within the RNFL, so that light polarized in one plane travels faster than light polarized in a perpendicular direction. This difference in speed causes a phase shift (“retardation”) between the perpendicular light beams as they travel back to the detector. The amount of retardation can be used to calculate the thickness of the RNFL, although the value is more specifically a reflection of the density of microtubules in the measured tissue. The cornea also demonstrates birefringence because of the parallel arrangement of stromal collagen fibers. The standard laser polarimeter accounts for this with a fixed corneal compensator (FCC) which subtracts the presumed birefringence of the cornea and lens from the calculated value [77]. The resulting number has been shown to correlate with the thickness of the RNFL [81]. The FCC uses a fixed axis (15° nasally downward) and a magnitude of retardation (60 nm) that is based on population norms [19, 83], but does not account for individual variations in corneal birefringence. A new modification uses a variable corneal compensator (VCC), which estimates an individual’s corneal birefringence by subtracting the macular retardation pattern from that of the peripapillary RNFL, using that difference to correct its readings [25, 79]. Discrimination between normal and glaucomatous eyes has been shown to be superior using VCC, especially when evaluating patients with early visual loss [70]. The scanning laser polarimeter performs retardation measurements at 65,536 locations in a 15º×15º field in approximately 0.7 s. This gives a 256×256 pixel image centered on the optic disc. Each pixel has a corresponding retardation value
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expressed in thickness units (TU). The software converts degrees of retardation into micrometers, where 1º of retardation equals 7.4 µm, based upon correlation of histological measurements in monkeys [81]. GDx analyzes subsets of the 65,536 pixels in each quadrant (superior, inferior, temporal, and nasal). The software contains ethnicity- and age-specific normative databases of more than 1100 eyes from patients 18–80 years old. With the GDx, there is good correlation between retardation and histopathological measurements in postmortem human eyes [80] and enucleated monkey eyes [83]. In normal subjects, scanning laser polarimetry reveals the expected high degree of inter-eye symmetry of nerve fiber layer thickness [22]. Therefore, it is reasonable to assume that any significant asymmetry in RNFL thickness is probably pathological. In normal eyes, the superior and inferior arcuate regions demonstrate the highest retardation measures [83], which is consistent with the higher density of nerve fibers in these areas. Retardation is lower over blood vessels where the overlying nerve fiber layer is thinner because the vessels are embedded in the nerve fiber layer [83]. These reproducible results increase the confidence that the GDx provides measurements that are clinically relevant. The ability of the GDx to provide data that correlate with the anatomic status of the nerve fiber layer is perhaps best revealed by observing normal aging. The number of optic nerve axons decreases with age [10], with a loss of around 5000 optic nerve cells per year after the age of 40 years [2]. Linear regression analysis demonstrates decreased retardation measurements in the superior and inferior regions with increasing age in normal eyes [83]. The nerve fiber layer thickness determined by the nerve fiber layer analyzer decreases linearly with age by 0.2 µm per year [11]. Furthermore, the GDx has been shown to distinguish normal subjects from patients with glaucoma and suspected glaucoma (ocular hypertension and normal visual fields or large cup-to-disc ratio) [12]. In comparison to visual field testing, the GDx is a rapid and objective test. There is 96% sensitivity and 93% specificity between hemifield polarimetric RNFL measurements and the visual field mean deviation, which emphasizes the
potential clinical utility of this device [74]. The GDx has a sensitivity of 96% and specificity of 91% in identifying patterns of diffuse and localized nerve fiber layer loss [66]. Contact lenses and ablative corneal refractive surgery (i.e., photorefractive keratectomy) have no significant effect on GDx measurements [13]. However, other possible confounding variables must be taken into account when using the GDx. For example, the RNFL appears to show progressive thinning in relation to the severity of type II diabetic retinopathy [52]. Given the significant prevalence of diabetes in the glaucoma population, this one variable could lead to a “false-positive” interpretation of glaucomatous optic nerve damage. “False-negative” results have also been obtained with scanning laser polarimetry. In particular, the GDx failed to detect axonal loss in the temporal regions of the optic disc, in patients who had compression of the optic chiasm by a tumor, despite the fact that this area was clearly atrophic by funduscopy. The GDx was also poor at detecting nasal atrophy, which reveals the lack of utility for this technique in the evaluation of chiasmal or tract compression [46]. The same authors were able to identify nasal and temporal atrophy using optical coherence tomography, which is discussed below [45].
Summary for the Clinician
■ The Scanning Laser Polarimeter (GDx)
■ ■
is a confocal scanning laser ophthalmoscope that includes a polarization detector that can detect the retardation of polarized light that occurs perpendicularly to the parallel fibers of the nerve fiber layer. The innate difference in polarization at right angles provides “birefringence,” which provides a useful optical means to define retinal anatomy. This retardation is used to calculate the thickness of the RNFL at various points, making the GDx an appropriate test for the detection of RNFL defects in glaucoma.
7.3 Modern Techniques for Optic Nerve and Retinal Nerve Fiber Layer Imaging
Summary for the Clinician
■ Results are more sensitive when the con-
founding effect caused by the normal birefringence of the cornea is removed with the more individually tuned variable corneal compensator (VCC).
7.3.4 Optical Coherence Tomography Optical coherence tomography (OCT) produces high-resolution, two-dimensional, cross-sectional images of posterior segment structures, including the optic disc, retinal nerve fiber layer, and macula. The OCT utilizes the principle of low-coherence reflectometry. The time required for light directed into the eye to be reflected back to a detector is related to the depth of the optical interface. For instance, light reflected from the internal limiting membrane returns to the detector more quickly than light reflected from a deeper structure such as the sclera. The time taken by light to travel to and from the eye is compared to the time of travel to and from a reference mirror by examining optical interference patterns. A larger number of optical interfaces produces a greater degree of variability in the timing of reflected signals and hence less coherence in the reflected light. The concept of optical coherence tomography is analogous to B-scan ultrasonography, except that optical, rather than acoustic, backscattering of light is used to create an image. Cross-sectional images are produced with a longitudinal/axial resolution and transverse resolution of 10–20 µm and 20 µm, respectively. The Humphrey® OCT3-Optical Coherence Tomography Scanner projects an optical near-infrared (diode, 820 nm), low-coherence light with a spot size of 20 µm onto the retina (Fig. 7.3). Low-coherence light passes through a beam splitter that produces two separate light paths. One path travels to a rapidly translating reference mirror and the other travels to the patient’s eye. A detector registers the light backscattered from the reference mirror and the patient’s eye. A comparison of the amplitude and timing of light from the two paths is made by a Michaelson in-
terferometer. An advantage of this technique is the fact that it does not require a user-defined reference plane. Patterns of x-y scanning, which are determined by the operator, include arc, circle, composite circle, concentric rings, line, radial lines, and raster lines. The number of pixels between the anterior and posterior boundaries in which the reflectivities exceed software-determined thresholds defines the thickness of the RNFL [64]. OCT nerve fiber layer measurements can be obtained in the circle scan mode, in which a 3.4-mm-diameter circular scan of the retina centered on the optic nerve is made [64]. The system reports the overall RNFL thickness, the thickness in each of 12 sectors, and the thickness in each quadrant in microns. In addition, results are presented graphically in which retinal position (i.e., temporal, superior, nasal, and inferior) are plotted against RNFL thickness. Disc structure can be assessed by radial line scans. Optic disc structure measurements are expressed as disc area, cup area, rim area, cup-to-disc area ratio, horizontal cup-to-disc ratio and vertical cup-to-disc ratio. Cup-to-disc ratio and rim radius (mm) for each of 12 clock hours is expressed in table form. The OCT provides cross-sectional images of layers of the retina (Fig. 7.4), with a resolution of approximately 10 µm. The OCT depends on the transparency of the optical media. Disease processes which affect the clarity of the optical media (i.e., cornea, lens, vitreous, retina) compromise the quality of the OCT images. The reproducibility of the OCT is approximately 10–20 µm [64]. The overall reproducibility (root mean squared error) of the mean RNFL thickness measured with three scans was 7.0 µm in a sample of both normal and glaucomatous eyes [6]. These good performance values make the OCT well-fitted for clinical use. However, measurements obtained from glaucomatous eyes are more variable than from normal eyes [6]. This variability may be partially attributable to the relatively small number of sampled points acquired by OCT compared to the focal nature of some glaucomatous nerve fiber layer defects [6, 27]. Nonetheless, the OCT has been shown to demonstrate RNFL defects that agree with Humphrey 30-2 visual fields and abnormalities of the nerve
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Fig. 7.3. Schematic of the design of optical coherence tomography (OCT): Low-coherence light originates from a superluminescent diode depicted in the upper left corner of the diagram. The light enters a 50:50 beam splitter and is divided into two beams. The upper beam of light travels to a rapidly translating reference mirror. The lower beam of light travels through two lenses, reflects off a mirror and a beam splitter, and then reaches the eye and a slit-lamp biomicroscope. En route to the eye the beam deflects off a transverse scanning mirror (controlled by a galvanometer) which provides lateral oscillation of the beam that projects to the eye. The second beam splitter (depicted at the bottom of the diagram) places the sample beam in the same plane as the slit lamp image to allow operator viewing. Light from both the reference mirror and patient’s eye is reflected back through the same path to the fiber beam splitter. From here the light reaches the detector which houses a Michelson interferometer. Coherent interference exists when the distance of the reflective path from the reflective mirror is equal to that from the eye. Different reflective properties of the tissue sample, compared to those emerging from the reference mirror, are detected as time delays in the speed of reflected light. These time delays permit construction of a twodimensional map of light reflected from the eye [63]
Fig. 7.4. Photographic output of a cross-section of human retina from the Humphrey® OCT2 – Optical Coherence Tomography Scanner (Courtesy, Zeiss Humphrey Systems). Labeled structures are based on the generally accepted interpretation of the layers observable with OCT
7.3 Modern Techniques for Optic Nerve and Retinal Nerve Fiber Layer Imaging
fiber layer visible in black-and-white fundus photographs [72]. OCT 2000 nerve fiber layer measurements demonstrate quantitative differences in nerve fiber layer between normal eyes and both glaucomatous and ocular hypertensive eyes [7].
7.3.4.1 Using OCT for Glaucoma Evaluation Retinal nerve fiber layer measurements with OCT correlate well with known anatomic variations in the RNFL [29]. In one study, good correlation between visual field loss and decreased RNFL thickness in the superior and inferior quadrants in glaucomatous eyes was demonstrated with the OCT [64]. The study also demonstrated a decrease in RNFL thickness in the inferior quadrant in glaucomatous eyes compared to normal eyes, and an overall decrease in thickness with increasing age in normal subjects and patients with glaucoma [64]. In one study, the presence of one or more quadrants with an area of RNFL thickness in the first percentile was used to predict a glaucomatous visual field on automated perimetry. Sensitivity and specificity for predicting field defects using this criterion were 89% and 92% respectively. [8] Average RNFL thinning has also been shown to correlate with the change in mean deviation (9.3 µm/5 dB) on Humphrey Field visual field testing [36]. Others have measured RNFL
internal reflectivity and correlated this with mean deviation obtained by automated perimetry [52].
7.3.4.2 Other Uses of OCT OCT has been used to elucidate the pathological changes in, and enhance our understanding of, disease states of the optic nerve and RNFL. For example, OCT has recently been used to investigate changes in the nerve fiber layer in Leber’s hereditary optic neuropathy (LHON) patients and asymptomatic carriers of the disease mutations [3]. Eyes with LHON for more than 6 months had severely thinned RNFLs, partially sparing the nasal quadrant, while eyes in patients with early LHON had thicker RNFLs compared to controls in the superior, inferior, and nasal quadrants [3]. In cases where there was late-stage visual recovery, the RNFL was thicker when compared with cases without recovery, except temporally where the papillomacular bundle was equally affected. Interestingly, OCT also detected increased nerve fiber layer thickness in the temporal retina of asymptomatic male and female carriers of Leber’s hereditary optic atrophy mutation 11778, suggesting that OCT could be useful in following patients with pre-clinical LHON [62]. Even when it is not seen on clinical examination, submacular fluid secondary to chronic papilledema may be found with OCT [31] and the elevation of the optic nerve head itself
Fig. 7.5a,b. a Papilledema as visualized with OCT. There is obvious elevation of the optic nerve head. The large areas of echo void within the optic nerve head are predominantly artifactual and do not necessarily represent fluid within the optic nerve head proper. OCT of the fellow optic nerve head was similar. b Optic nerve photograph of the same eye
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can be visualized and measured (Fig. 7.5). In many of these cases, the OCT suggested that the submacular fluid tracked from the optic nerve, rather than leaking from the choroidal circulation. OCT may be of value in characterizing pseudo versus true papilledema. The RNFL was observed to be thickened in superior and inferior quadrants of patients with either papilledema or congenitally crowded optic discs as compared with controls, but this test could not differentiate between the two groups [37]. By measuring the mean circumpapillary RNFL thickness, another group was able to differentiate papilledema from pseudopapilledema [49]. OCT has helped elucidate a variety of other retinal and optic nerve pathologies. Serous retinal detachments that were not observed with ophthalmoscopy, including those seen with Leber’s stellate neuroretinitis and branch retinal vein occlusion, can be easily identified by OCT [68]. Optic disc traction syndrome following ischemic central retinal vein occlusion was observed in three patients by OCT, while evidence for the syndrome was less evident on clinical examination or ultrasound [57]. OCT has also been used to show loss of RNFL thickness in patients with grades I–III optic nerve head drusen versus normal patients [55]. A different study showed that there was no loss in RNFL thickness in 23 patients with drusen over an 18month period [48]. The anatomical relationship between optic pits and associated macular pathology has also been investigated with OCT. In one study, it was shown that schisis-like cavities and areas of edematous retina communicated with the optic disc while associated retinal detachments did not [58]. Using OCT, it has been shown that patients with human immunodeficiency virus (HIV) but without cytomegalovirus retinitis and over 6 months of CD4 counts <100 cells/mm3 of blood were found to have thinner nerve fiber layers than healthy subjects or HIV patients with CD4 counts consistently over 100 cells/mm3 [40]. OCT has been used to confirm the characteristic bow-tie atrophy expected in the optic tract syndrome even when magnetic resonance imaging (MRI) was not able to detect the lesion [71].
The optic nerve atrophy seen after single episodes of optic neuritis has been shown with OCT to correlate with loss of RNFL thickness, confirming the presumption of axonal loss that is inferred by the clinical identification of optic nerve “pallor” [76]. Patients with multiple sclerosis have been observed to have reduced RNFL thickness using OCT, especially in those who have had optic neuritis [23]. Furthermore, the RNFL loss also correlated with a low-contrast measure of visual acuity and contrast sensitivity tests in patients with a history of optic neuritis [23]. Ethambutol-associated optic neuropathy has recently been studied with OCT [86], revealing an average loss of 79% of nerve fiber thickness in the temporal quadrant in patients with near-normal fundus examinations, supporting the notion of injury to the metabolically active fibers of the papillomacular bundle. The application of OCT may further our knowledge of many rare conditions whose pathophysiology is unknown, once enough patients are studied. The cross-sectional depth of the white retinal lesion in the multiple evanescent white dot syndrome (MEWDS) has been shown to be at the level of the retinal pigment epithelium [1]. OCT has also been used to evaluate RNFL changes in methanol toxicity [24].
7.3.4.3 Ultrahigh-Resolution OCT (UHR-OCT) Recently, ultrahigh-resolution OCT has emerged as an experimental technology capable of visualizing tissue in vivo with an axial resolution of approximately 3 µm. This more advanced OCT method has mostly been used to study the retina in patients with age-related macular degeneration [50], macular hole, central serous chorioretinopathy, macular edema, RPE detachments, epiretinal membranes, vitreal macular traction, and retinitis pigmentosa [39]. Few studies have been done looking at the optic nerve head itself, but it is likely that this new technology will allow for much more detailed evaluation in the future. For example, one small study used UHR-OCT to demonstrate the persistence of Cloquet’s canal in 93% of normal healthy eyes [35].
7.5 Comparing Modalities
Summary for the Clinician
■ The OCT utilizes the principle of low-
coherence reflectometry and interferometry to produce high-resolution, twodimensional, cross-sectional images of the optic disc, retinal nerve fiber layer and macula. OCT does not depend upon the vagaries of a user-defined reference plane, although it is affected by media opacities. The clinical utility of OCT is most well established for its ability to provide a full cross-sectional image of the retina as part of the diagnosis of retinal disease. OCT has also been shown to have some utility in the evaluation of nerve fiber layer defects in glaucoma. OCT has been used to evaluate the effect of many conditions that affect the RNFL, including: Leber’s hereditary optic neuropathy, optic neuritis, papilledema, and HIV. Ultrahigh-resolution OCT is an emerging technology that provides even greater spatial resolution in its imaging of the optic nerve head and RNFL.
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7.4 Imaging of the Optic Nerve and Alzheimer Disease Some histological and clinical studies have provided evidence that there is loss of retinal ganglion cells in patients with Alzheimer disease (AD) [59] although this is controversial [54]. Recent studies have now tried to confirm this association with objective, reproducible imaging techniques. In one study, the HRT scanning laser ophthalmoscope was used to assess optic disc parameters in 40 patients with AD and compare them with age-matched control patients [18]. Patients with the highest vertical cup-to-disc ratios measured by HRT were more likely to have AD than patients with the lowest values (odds ratio: 4.7). However, the risk of AD was sufficiently low in both groups so that the best sensitivity and specificity for AD, using 0.42 as a cut-off value
for the cup-to-disc ratio, was only 45% and 84%, respectively. In isolation, therefore, laser imaging of the optic nerve head is unlikely to be a good screening test for AD. Using OCT, the RNFL thickness and macular volume were imaged in 30 eyes of patients with AD and found to be significantly decreased compared to age-matched controls [33]. Total macular volume scores appeared to correlate with mini-mental status examination scores, suggesting that degeneration of retinal ganglion cells occurred in parallel with cortical degeneration. New techniques for imaging the optic nerve and RNFL may help us gain a better understanding of the scope of the pathology in AD and other degenerative diseases, and, in combination with other tests, may one day lead to earlier detection of such diseases. All of these findings must be considered in light of one reasonably large prospective clinical and electrophysiological study of patients with AD [54] in which there was no significant difference between AD and control patients. Furthermore, a study which looked at RNFL thickness with GDx in patients with mild to moderate AD found no difference between them and control patients [38]. If there is degeneration of retinal ganglion cells on the basis of AD, the visual consequences of the degeneration must be relatively slight, especially in comparison to the sometimes prominent cortical visual symptoms experienced by approximately 43% of patients with AD [15, 42].
Summary for the Clinician
■ Some studies using HRT and OCT have
suggested that Alzheimer disease may be accompanied by RNFL degeneration, but other studies did not show this with GDx or electrophysiological testing.
7.5 Comparing Modalities There are few studies that compare these different imaging techniques. Hence, it is not possible
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to provide firm guidelines about which testing method would be consistently the best to evaluate a given pathology. It should be appreciated that the various methods are readily interchangeable. One study in particular compared vertical disc diameter using HRT, OCT, and funduscopy and found poor agreement among the tests (kappa < 0.4) [4].
7.5.1 MRI
7
Conventional magnetic resonance imaging (MRI) is useful in grossly imaging the optic nerve and detecting compression, inflammation, and atrophy. The appearance of the optic nerve can in some cases be used to help differentiate disease processes that might clinically appear similar. In 32 patients with optic neuritis, for example, 31 demonstrated enhancement of the involved nerve, while only 2 out of 32 patients diagnosed with nonarteritic ischemic optic neuropathy (NAION) demon-
strated this finding [53]. MRI is therefore the best objective means to distinguish between these two forms of optic neuropathy that may otherwise be impossible to distinguish clinically [53]. While MRI clearly has a role in imaging the optic nerve as a whole, its resolution has not been sufficient to analyze the optic nerve head or nerve fiber layer. Extremely high-resolution MRI (µMRI) has been used to provide three-dimensional in vitro images of the optic nerve with a resolution of less than 50 µm. Using this approach, Sadun et al. were able to image the lamina cribosa, the central retinal artery and vein, the interfascicular septae and the vascular circle of Zinn-Haller in cadaveric optic nerves [60] (Fig. 7.6). Of greater significance, they identified pathological structures in nerves of patients with LHON, such as atrophic fascicles, fluid-filled sacs, and thickened septae. Eventually, µMRI may emerge as a technology useful in the clinical evaluation of the microscopic properties of the optic nerve head and fiber layer, but at present it remains an experimental technology.
Fig. 7.6a–d. a Extremely high-resolution magnetic resonance imaging (μMRI): sagittal section of normal human optic nerve. The retinal layers are discernible. Note the glial columns and the penetration by bundles of axons through the lamina cribrosa (arrow). The central artery (a) and vein (v) are easily seen. The arachnoid (A) is separated from the dura (D) by a potential space. b μMRI: sagittal section of a normal human optic nerve. This is more central than a. The lamina cribrosa is easily seen to consist of three layers: pars retinalis (PR), pars choroidalis (PC), pars scleralis (PS), and within the optic nerve (ON) (arrows) are fascicles of axons exiting posteriorly with myelin. Note also the folds of the arachnoid around the nerve (FA). c μMRI: in this sagittal section of the normal human optic nerve, all the layers of the retina are seen separately (arrows). The nerve doubles in diameter as the axons become myelinated posterior to the lamina cribrosa. Note the point at which the axons become myelinated (posterior to PS). d μMRI: coronal view. Around the optic nerve, the reticulated cerebrospinal fluid-filled spaces of the arachnoid (A) and subarachnoid space are clearly seen. Axon fascicles run between the connected tissue septae. The central position of the central artery (a) and vein (v) indicates that this cut is just posterior to the globe. A portion of the circle of Zinn-Haller (arrow) is seen. Reprinted by permission from Sadun et al. [60]
References
Summary for the Clinician
4.
■ Enhancement of the optic nerve on MRI
is helpful in distinguishing optic neuritis or other inflammatory optic neuropathies from nonarteritic ischemic optic neuropathy. Extremely high-resolution MRI (µMRI) is an experimental technology that may one day offer extremely high-resolution three-dimensional images of the optic nerve in the clinical setting.
5.
■
6.
7.
7.6 Conclusion Since the introduction of the first ophthalmoscope, many advances have been made in nerve fiber layer and optic disc imaging. The initial group of nerve fiber layer analyzers formed the basis upon which confocal scanning devices, laser polarimetry, and optical coherence tomography were developed. New and improved commercial devices for imaging the optic nerve head and nerve fiber layer continue to emerge, enhancing our ability to study these structures in greater detail, and thereby understand more about their function in the living subject. These devices can provide objective measurements that aid in the detection and prospective evaluation of disease, especially optic nerve cupping associated with glaucoma. Finally, they may also provide us with information about differences in the response of the optic nerve head to various forms of injury, and eventually to treatments as well.
8.
9.
10.
11.
12.
13.
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40. Kozak I, Bartsch DU, Cheng L et al (2005) Objective analysis of retinal damage in HIV-positive patients in the HAART era using OCT. Am J Ophthalmol 139(2):295–301 41. Lichter PR (1976) Variability of expert observers in evaluating the optic disc. Trans Am Ophthalmol Soc 74:532–572 42. Mendez MF, Mendez MA, Martin R et al (1990) Complex visual disturbances in Alzheimer’s disease. Neurology 40(3 Pt 1):439–443 43. Mikelberg FS PC, Swindale NV, Graham SL, Drance SM, Gosine R (1995) Ability of the Heidelberg retina tomograph to detect early glaucomatous visual field loss. J Glaucoma 4(4):242–247 44. Mikelberg FS WK, Schulzer M (1993) Reproducibility of topographic parameters obtained with the Heidelberg Retina Tomograph. J Glaucoma 2:101–103 45. Monteiro ML, Leal BC, Rosa AA et al (2004) Optical coherence tomography analysis of axonal loss in band atrophy of the optic nerve. Br J Ophthalmol 88(7):896–899 46. Monteiro ML, Medeiros FA, Ostroscki MR (2003) Quantitative analysis of axonal loss in band atrophy of the optic nerve using scanning laser polarimetry. Br J Ophthalmol 87(1):32–37 47. Niessen AG, van den Berg TJ, Langerhorst CT et al (1995) Grading of retinal nerve fiber layer with a photographic reference set. Am J Ophthalmol 120(5):577–586 48. Ocakoglu O, Ustundag C, Koyluoglu N et al (2003) Long term follow-up of retinal nerve fiber layer thickness in eyes with optic nerve head drusen. Curr Eye Res 26(5):277–280 49. Ophir A, Karatas M, Ramirez JA et al (2005) OCT and chronic papilledema. Ophthalmology 112(12):2238 50. Pieroni CG, Witkin AJ, Ko TH et al (2006) Ultrahigh resolution optical coherence tomography in non-exudative age related macular degeneration. Br J Ophthalmol 90(2):191–197 51. Plesch UK, Rappl W, Schroedel C (1990) Scanning ophthalmic imaging. In: Nasemann JE, Burk ROW (eds) Laser scanning ophthalmoscopy and tomography. Quintessenz, Munich, pp 109–121 52. Pons ME, Ishikawa H, Gurses-Ozden R et al (2000) Assessment of retinal nerve fiber layer internal reflectivity in eyes with and without glaucoma using optical coherence tomography. Arch Ophthalmol 118(8):1044–1047
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Chapter 8
Functional Neuroanatomy of the Human Visual System: A Review of Functional MRI Studies
8
Mark W. Greenlee, Peter U. Tse
Core Messages
■ This chapter reviews work on the meth-
od of functional magnetic resonance imaging (fMRI), which has been used to describe the structural and functional anatomy of the human visual system. Exploitation of the endogenous paramagnetic contrast agent deoxyhemoglobin has yielded functional maps of: lateral geniculate nucleus of the thalamus the columnar organization of primary visual cortex multiple representations of the visual hemifields in the ventral and dorsal visual pathways the interface between the visual system and cortical networks underlying the control of oculomotor behavior, visual working memory, and higher visual cognition.
■
-
■ In a significant advance beyond the tra-
ditional localistic “one region, one type of processing” paradigm, new methods, such as dynamic causal modeling and discriminant analysis, seek to determine temporal relationships among the fMRI time series of multiple brain regions. Applying these new methods, neuroscientists can discern how spatially distributed brain regions interact via feedforward and feedback signals sent within neural circuits. fMRI promises to contribute more to our understanding of the complex neural circuits that subserve visual perception and visuospatial cognition.
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8.1 Introduction Our visual system is one of the great success stories of evolution. Together with the other sensory systems, its purpose is to provide information about the world so that we can operate within a changing environment to fulfill our goals. The representations that our visual system creates of events and objects within a 3D scene are so accurate and produced so quickly, that most of us op-
erate under the false impression that we perceive the world in a veridical way. Perceived qualities such as redness or brightness do not exist in the world; they are creations of our brain. Of course they generally correspond to properties of energy in the environment, such as spectral composition or luminance, but percepts are not the same as what they represent. This is made obvious by the fact that there is no visible light impinging on the cortex; there are only neurons communicating in
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Functional Neuroanatomy of the Human Visual System: A Review of Functional MRI Studies
total darkness. Moreover, cortical neurons do not respond directly to light at all. They only respond to their particular set of dendritic inputs. The culmination of multiple stages of neuronal processing within the dark space of our skull is our visual experience of an external world. How the highly ambiguous pattern of light that is detected at the retina is transformed into visual consciousness remains one of the greatest unsolved problems of science. In some cases, which we tend to dismiss as mere visual illusions, the visual system makes mistakes. It tells us that a color, shape, motion, or light is present when we know that it is not. Visual illusions testify to the fact that even ordinary visual experiences are constructions of the brain. They occur as a consequence of the way the visual system processes its input. In general, these processing steps lead to veridical information about realworld objects. But in cases where they do not, we can learn something about the steps that the visual systems invokes in creating visual representations. For example, when you see a light jumping back and forth on the top of an ambulance, you know that there is no real motion. You perceive these sequences of lights as motion, even though you know that there is no physical movement present, a phenomenon known as apparent motion. From this mistake we can infer how motion percepts in general are constructed. What we have learned from such instances is that the visual system has prior assumptions concerning the mapping between sensory input and the structure of the world. Indeed, the visual system must have these “priors” because visual input is often ambiguous. For example, countless 3D objects could lead to any given pattern of 2D retinal images. To create veridical 3D representations within a fraction of a second, the visual system must solve this inverse mapping problem on the basis of information processing procedures that also make use of extraretinal signals. The visual system must construct object representations that can only be inferred on the basis of the input. How the visual system accomplishes this is partially understood, but much remains to be explained. Many of the most basic issues remain unexplained, including, for example, the neural code used by neurons to communicate among themselves, and the neural basis of consciousness.
Functional magnetic resonance imaging (fMRI) offers a means by which neuroscientists can determine how the brain constructs visual perception. Visual information can evoke or modify neural activity in a majority of cortical areas. Loss of any single function of the visual system can impair a patient’s ability to efficiently interact with the environment. Thus, our motivation to achieve a scientifically grounded understanding of how the brain realizes visual perception and visual consciousness is correspondingly high. This chapter reviews our current state of knowledge about the systems-level functional anatomy of the human visual system. The emphasis will be placed on the results of fMRI as a noninvasive imaging technique that combines structural information (gray/white matter, fiber tracts) with functional activity (blood-oxygen-level dependent, BOLD) with a spatial resolution of 1 mm (or better) and a temporal resolution of under 1 s. Sparing excessive methodological detail, the techniques used to make retinotopic maps of the human visual cortex and the resultant normalized atlases will be described. Taking advantage of the functional specificity of higher visual areas, topographical representations of image features such as color, form, and motion (speed and direction), among other aspects, will be discussed. Stereopsis, the ability to detect disparity in fused binocular images, is detected by neurons with binocular receptive fields. Functional MRI has revealed neural correlates of disparity detection and clarified its role in the perception of motion-in-depth of looming stimuli. Finally we consider recent work on the interface between the visual system and systems involved in the preparation of oculomotor action. In this context, the neural control of saccadic eye movements has been investigated with fMRI and the functional connectivity between the frontal and parietal eye fields and areas in the visual cortex are now better understood. The analysis of such “micro-behavior” opens a window into the functioning of the human brain with respect to higher cognitive functions such as visual working memory and consciousness.
8.4 Striate and Extrastriate Visual Areas in Human Visual Cortex (V1, V2, V3)
8.2 Imaging the Lateral Geniculate Nucleus With the increase of magnetic field strength from 1.5 to 4 Tesla and greater, it has now become possible to map subcortical structures. The human lateral geniculate nucleus (LGN) is estimated to have a volume that varies from 91 mm3 to 157 mm3 (Andrews et al. 1997). Using high-field fMRI, Kastner et al. (2004) and Schneider et al. (2004) mapped the human LGN using hemifield checkerboard stimuli. They showed that the amplitude of the BOLD response in LGN depends on the attentional state of the observer, suggesting a functional role for the massive cortico-thalamic feedback projections to the LGN that have been observed anatomically. That is to say, cortico-thalamic projections modify the thalamic input received by the cortex via neural mechanisms that subserve selective attention. Sylvester et al. (2005) acquired BOLD responses from the LGN and V1 while subjects performed saccades in both an illuminated Ganzfeld and in the dark. Interestingly, saccades in the full-field light condition led to a suppression of activity in the LGN and V1, whereas saccades in the dark led to an increase in activity. Their findings suggest that signals from oculomotor centers have a suppressive effect on on-going activity in V1 and the LGN, in line with recent work from our laboratory (Vallines and Greenlee 2006; see below). Saccades in the dark led to an increase in activation in both V1 and LGN, suggesting an excitatory signal in the absence of visual stimulation (Sylvester et al. 2005). These findings and others suggest that the LGN is not a mere relay station between the retina and the cortex, but rather plays an active role in shaping the retinal information that arrives in V1 and other regions in the brain.
8.3 Functional Maps of the Visual Field Regions in the primate visual cortex are said to be retinotopically organized when neighboring locations within a visual quadrant are mapped onto neighboring portions of cortex (Horton and Hoyt 1991; van Essen et al. 1998; van Essen 2004).
Each visual neuron has a receptive field that responds to stimuli falling within a well-defined region of this retinotopic space. Figure 8.1 depicts a schematic illustration of human visual area 1 (V1) and its corresponding retinotopic map of visual space taken from Horton and Hoyt (1991). Neighboring neurons in the cortical sheet exhibit receptive fields that overlap in visual space. Assuming steady fixation, the human visual cortex can be sequentially stimulated using flickering checkerboard wedge or ring stimuli (Engel et al. 1994; Sereno et al. 1995; Dale et al. 1999; Tootell et al. 1995; Brewer et al. 2002) thereby evoking a traveling wave of activation over the cortical surface. To take advantage of computational algorithms such as fast Fourier transform (FFT), this traveling wave of activity can be reduced to a temporal frequency distribution with a maximal amplitude at the stimulation (rotational) frequency (Warnking et al. 2002). The phase of this FFT component thus provides a reliable index of the spatial location of the peak of activity during the stimulation cycle, after correcting for the time lag of the hemodynamic response. Using these methods, accurate and reproducible maps of the human visual cortex have been produced in which the borders between V1, V2 and higher retinotopic areas are revealed by the so-called mirror sign (a reversal of the phase sequence from vertical to horizontal meridian, or the other way round). Examples of retinotopy are shown in Fig. 8.2.
8.4 Striate and Extrastriate Visual Areas in Human Visual Cortex (V1, V2, V3) There are now several reports on the retinotopic organization of primary visual cortex in humans (Engel et al. 1994; Sereno et al. 1995, Tootell et al. 1995; Dale et al. 1999; reviewed in Wandell et al. 2005), most of which rely on the phaseangle method. A step-by-step description of this methodology has been given by Warnking and colleagues (2002). The group of David van Essen has taken information from several studies with different methodologies to produce average maps of the human cortex. This group has also made this software and database available to the com-
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Fig. 8.1. Schematic illustration of the retinotopic organization of the primary visual cortex in the human brain. The upper panels depict the medial view of the left hemisphere with approximate isoeccentric radii marked on the surface of the calcarine sulcus. Note that the central 2.5° of visual angle around the foveal representation of the right visual field (lower panel) activates a much larger region of visual cortex than an equivalently sized portion of the peripheral visual field. This anisotropic mapping is known as cortical magnification and reflects the relative importance given to the central visual field in cortical processing. The black spot in the lower panel represents the location and extent of the blind spot (lower right panel) and its monocular representation on the cortical surface (adapted from Horton and Hoyt 1991, with permission)
munity (http://brainmap.wustl.edu/caret/). Individual differences in the border location, size and shape of human V1 and V2 have been presented recently (Schira et al. 2007). These data suggest significant differences among individuals, in line with the variations noted in post-mortem specimens (Andrews et al. 1997). An example of retinotopic maps obtained from two subjects is shown in Fig. 8.2 (Tse et al. 2005). As is evident in these maps, considerable variability exists between the size and border locations of the primary and extrastriate visual areas across subjects.
8.5 Receptive Field Size as a Function of Retinal Eccentricity Following a similar line of reasoning as that used in phase-encoded flatmaps, the average receptive field size can be estimated as a function of retinal eccentricity (Kastner et al. 2001; Smith et al. 2001). Instead of identifying the phase of the response, the “duty cycle” of the “on” compared to the “off ” periods of the response time course provides an estimate of the average receptive field size: large receptive fields would be associ-
8.5 Receptive Field Size as a Function of Retinal Eccentricity
Fig. 8.2a–c. Retinotopic mappings projected upon inflated cortical meshes and flattened meshes of the occipital cortex. a The areas of cortex responsive to particular regions of the contralateral visual field are indicated by the corresponding color code. Of particular importance is the determination of the boundaries between visual areas corresponding to the lower vertical meridian (blue present at the V1/V2d and V3/V3A border), upper vertical meridian (red present at the V1/V2v and VP/V4v border), and horizontal meridian (greenish cyan present at the V2d/V3 and V2v/VP border). Note that V3 is also commonly named V3d, and VP is commonly named V3v, representing the dorsal and ventral parts of V3. b The segmented retinotopic areas from one subject on inflated left and right hemispheres as well as corresponding occipital flatmaps. c The same for a different subject. While topological relationships among areas remain generally constant across brains, the particular shape and extent of areas vary a great deal from brain to brain
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ated with a longer “on” period (i.e., with a larger duty cycle) than small receptive fields (Smith et al. 2001). In these experiments, an expanding or contracting ring stimulus was used. The duty cycle of the best-fitting square wave response function is illustrated in Fig. 8.3c–e for each voxel as a color ranging from dark green to bright yellow. The relative size of receptive fields determined using this method, as well as the way receptive field sizes increase with retinal eccentricity, closely resembles the pattern found in nonhuman primates using single-unit recording techniques (see Fig. 8.3; adapted from Smith et al. 2001).
8.6 Alternative Methods of Retinotopic Mapping The phase-encoding method assumes linearity of responses within the cortex. Alternative approaches have employed M-sequences (Hansen et al. 2004; Vanni et al. 2005) to compare the localized responses to individual pixels within the random-dot stimulus sequence. For the most part, the findings from these studies are consistent with the results of earlier studies and thus suggest that the area borders are reasonably robust and do not depend on the exact method used.
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Fig. 8.3a–f. Activation flat maps of human cortex depict the retinotopic organization of the primary visual cortex in the human brain (a). b The encoding of eccentric position with the contralateral visual hemifield demonstrates the preponderance of the foveal representation on the surface of the visual cortex. c–e The colour maps present the results from three subjects with respect to the relative “on” and “off ” components of the cyclic response to the flicking ring stimulus, whereas f presents the findings when the wedge stimulus was used (adapted from Smith et al. 2001, with permission). Area VP is also commonly known as V3v, and V3 as V3d
8.8 Orientation Specificity of BOLD Responses in Visual Cortex
Summary for the Clinician
■ Using high-field fMRI, responses in the human LGN have been mapped using checkerboard stimuli. The BOLD response in LGN depends on the attentional state of the observer, suggesting a functional role for cortico-thalamic feedback projections. The retinotopic organization of the human visual cortex can be determined using fMRI and flickering checkerboard wedge or ring stimuli. Sequential stimulation of sections of the visual field provides information concerning the borders between V1 and V2, V2 and V3 and higher visual areas. Based on phase-encoded flatmaps, the average receptive field size can be estimated as a function of retinal eccentricity.
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8.7 Columnar Structures within Human V1 Thalamic input into layer 4cα of primary visual cortex is characterized by alternating columns of left and right eye input with a period length of about 1 mm (Hubel and Wiesel 1968), which have been referred to as ocular dominance columns (ODC). Optical imaging techniques relying either on intrinsic (oxyhemoglobin and deoxyhemoglobin; Malonek et al. 1997) or extrinsic (voltage-sensitive dyes; Blasdel and Salama 1986; reviewed in Grinvald and Hildesheim 2004) signals have supported the existence of ocular dominance columns in primate V1 and support the idea of a neurovascular coupling between intrinsic (blood oxygenation) and extrinsic (voltage-sensitive) optical signals. Functional MRI studies of the pattern of ocular dominance have compared the relative magnitude of the BOLD response in human V1 during alternating (i.e., left, right, dark) ocular stimulation. Using highfield (4 T) MRI, Menon and Goodyear (Menon and Goodyear 1999; Goodyear and Menon 2001) were first able to track the pattern of ODC in hu-
man V1. In a carefully conducted study with 4-T field strength and a surface coil positioned over the occipital cortex, Cheng et al. (2001) reported a pattern of BOLD responses that correspond to an ODC width of 1.1 mm. The applied imaging technique allowed for an in-plane voxel size of 0.47 mm, which is necessary to resolve the human ODC. The test-retest reliability of the technique conducted in the same subjects within the same recording session or over a time span of 3 months indicates that this method is highly reliable (Fig. 8.4b). Binocular interactions have also been demonstrated with fMRI. Using 1.5-T field strength, Buchert et al. (2002) demonstrated that simultaneous binocular stimulation led to a reduced BOLD response compared to sequential alternating eye stimulation. This pattern of responses was only evident in the central visual field representation of V1 in persons with normal binocular vision and suggests the existence of inhibitory binocular interaction in human visual cortex.
8.8 Orientation Specificity of BOLD Responses in Visual Cortex A hallmark of visual cortical function is the orientation columns in primary visual cortex (Hubel and Wiesel 1968). Optical imaging techniques have revealed a “pinwheel” organization, such that all possible stimulus orientations are represented systemically within columnar structures (Blasdel and Salama 1986). Kamitani and Tong (2005) presented fMRI evidence that linear discriminate analysis can be applied to the temporal response patterns of a selected population of individual voxels to predict which of two orientations the observer is currently attending. This method has been applied to predict the perceptual outcome of binocular rivalry, where orthogonal orientations are presented simultaneously to each eye (Haynes and Rees 2006; see below). Using 4-T high-field imaging, Sun and colleagues (2006) have recently described orientational selectivity in individual voxels in V1. The continuous change in orientation preference corresponds well with the orientation specific-
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8 Fig. 8.4a,b. Ocular dominance columns in human primary visual cortex (a) and scatter plots of the results (ocular dominance index: –1 corresponding to right eye dominance, 1 to left eye dominance) from the same subject measured twice during the same session (b) indicating the relatively high test-retest reliability of the method (r=0.627). The blue and yellow colors indicate the extent to which the individual voxel was activated better by stimulation from the right or from the left eye, respectively (adapted from Cheng et al. 2001, with permission). (CS Calcarine sulcus, ILS intralingual sulcus, ISS inferior sagittal sulcus)
ity in macaque V1. Using adaptation techniques, Boynton and Finney (2003) mapped changes in BOLD responses in V1, V2, V3 as well as V4, and compared them to psychophysical changes in sensitivity. The findings indicate that the BOLD response is reduced by adaptation in areas V3 and V4 (similar to psychophysical sensitivity) but not in V1 and V2. Using spectrally broadband checkerboard stimuli with longer periods of adaptation and re-adaptation, Gardner et al. (2005) reported equally sized shifts in the contrast response functions in V1, V2, V3 and V4, and these shifts corresponded well with earlier psychophysical findings (Greenlee and Heitger 1988).
8.9 Visual Maps of Higher Visual Function: V4 Responses to luminance and color stimuli have been compared in the human homolog of V4 in ventral occipital cortex (Engel et al. 1997; Zeki and Bartels 1999; Bartels and Zeki 2000).
Tootell and colleagues suggested the existence of a further visual area involved in the processing of chromatic stimulus information, which they termed V8 (Hadjikhani et al. 1998; Tootell and Hadjikhani 2001). Wandell and colleagues described a hemifield representation in the ventral occipital cortex and this region responded selectively to chromatic information (Wade et al. 2002; Wade and Wandell 2002). The existence of V8 as an independent visual area with a hemifield representation remains unclear.
8.10 Visual Maps of Higher Visual Function: V3A, V3B and KO The identification of area V3A has been debated in the literature. There is a general agreement that V3A has a contralateral hemifield representation. However, there is evidence for a second retinotopic area (V3B) lateral to V3A that shares the same foveal representation (Smith et al. 1998; Press et al. 2001). It has been argued that V3B is
8.11 Segmenting Extrastriate Areas and MT+ into Functional Subregions
actually the same as the “kinetic occipital” area (KO; Smith et al. 1998; Zeki et al. 2003), which is an area particularly responsive to motion-defined borders (Dupont et al. 1997; Van Oostende et al. 1997; Grossman et al. 2000; Kononen et al. 2003). However, it is important to note that the conclusion that V3B and KO are in fact the same was made without employing retinotopic criteria, but rather on the basis of the similarity between normalized Talairach coordinates. Because of individual differences, this conclusion should be regarded with caution. An alternative segmentation of the areas has been put forth, in which all the cortex lateral to V3A has been grouped into a common topographically defined “V4d topology” (Malach et al. 1995; Sereno et al. 1995; Tootell et al. 1995, 1996, 1997, 1998a, 1998b; Hadjikhani et al. 1998; Tsao et al. 2003). V4d is anatomically rather than functionally defined, and encompasses both V3B and KO. It is therefore still a matter of debate whether V3B is distinct from V3A, and whether V3B, if it exists, is the same as KO.
wave gratings, Heeger et al. (1999) suggested the existence of motion opponency in area MT. Here the responses to sine wave gratings drifting in one direction were higher than those for counterphase flickering gratings, suggesting inhibition from neurons tuned to opposite directions. Singh et al. (2000) also reported that MT+ (V5) responded well to low spatial and high temporal frequencies of drifting gratings. In that study, MT+ responded better to drifting gratings and showed a low-pass spatial and band-pass temporal tuning of the response. Huk et al. (2002) were the first to suggest that Human middle superior temporal area (MST) could be delineated from MT by comparing responses to contralateral and ipsilateral visual stimulation. Using a similar design, we recently replicated these findings in a small group of subjects (Rutschmann and Greenlee, unpublished results). The findings are shown in Fig. 8.5 and suggest that MST exhibits an ipsilateral field representation that is not evident in MT, or in earlier visual areas V1 and V2.
8.11 Segmenting Extrastriate Areas and MT+ into Functional Subregions Many studies have indicated that the human homolog of the primate region middle temporal area (MT, also referred to as V5) lies in the ascending part of the inferior temporal gyrus in BA 37 (Dumoulin et al. 2000). In one of the first fMRI studies of the human visual cortex, Tootell et al. (1995) showed how MT responded selectively to the contrast of moving stimuli, showing a saturating response for low contrast levels of around 4% (Tootell et al. 1995). In a further study, Tootell et al. (1997) reported that V3a, a region in extrastriate cortex, responds selectively to moving stimuli. Smith et al. (1998) investigated the response of early visual areas to first- order (luminance modulated) and second-order (contrast-modulated) motion stimuli. They suggested the existence of a novel area, V3b, as one with a retinotopic map of the contralateral visual field and a high sensitivity to second-order motion, and related it to the so-called kinetic occipital area (KO, see above). By comparing responses to combinations of sine
Summary for the Clinician
■ Functional MRI studies of the pattern
of ocular dominance have compared the relative magnitude of the BOLD response in human V1 during alternating (i.e., left, right, dark) ocular stimulation. The reported pattern of BOLD response corresponds to an ODC width of 1.1 mm. The reliability of these results, measured over a time span of 3 months, indicates that this method is reliable. Responses to luminance and color stimuli have been compared in the human homolog of V4 in ventral occipital cortex. There is a general agreement that V3A has a contralateral hemifield representation. Some studies point to a second retinotopic area (V3B) lateral to V3A that shares the same foveal representation.
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8 Fig. 8.5a–f. BOLD responses to lateralized random dot-motion stimuli presented in the left visual field (a–c) or in the right visual field (d–f). a Sagittal view of activation in the MT+ region in the right hemisphere. b Coronal view depicting the activation in both left and right hemispheres. c Zoomed flatmap of the activation in right MT+ when the stimuli were restricted to the left hemifield. d,e. As in a–c except now the activations are shown for motion stimuli restricted to the right (ipsilateral to right hemisphere). The small green marks help compare the locations in the flatmaps in c and f (adapted from Rutschmann and Greenlee, unpublished results)
Summary for the Clinician
■ The human homolog of the primate re-
gion MT (also referred to as V5) lies in the ascending part of the inferior temporal gyrus in BA 37. Responses in MT/ V5 to drifting gratings were higher than those for counterphase flickering gratings, suggesting inhibition from neurons tuned to opposite directions. Human MST can be delineated from MT by comparing responses to contralateral and ipsilateral visual stimulation: MST shows a response to ipsilateral stimuli, whereas MT does not.
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8.12 Responses to Optic Flow Although the size of the visual stimulus is restricted within the MR scanner, some authors have attempted to record the BOLD responses
to optic flow stimuli. Optic flow is defined as the spatiotemporal pattern of stimulation that occurs when the subject moves within an otherwise stationary environment. One of the challenges of visual neuroscience is to understand how local object motion is discriminated from more global patterns of motion evoked by self-motion, navigation or exploratory eye/head movements (Logan and Duffy 2006; Raabe et al. 2006). Rutschmann et al. (2000) studied the effects of presenting optic flow patterns dichoptically to the left and right eye. These dot patterns were presented to create the sense of self motion in a virtual environment (composed only of dots) leading to expansion/ contraction or spiral motion. The results indicate that areas in extrastriate cortex (V3a/V3b), but not MT+, responded selectively to motion-indepth stimuli. Morrone et al. (2000) isolated an area dorsal to MT+ that responded selectively to changes in motion direction. Smith et al. (2006) presented optic flow stimuli to subjects and isolated responses from MT and MST. Their findings suggest that MST, with its larger receptive
8.14 Interface Between Visual and Oculomotor Systems
fields, is more sensitive to changes in the global characteristics of optic flow stimuli.
8.13 Disparity and Motionin-Depth Stimulation The ability to fuse left and right retinal images allows us to extract horizontal disparity in visual stimuli (Parker and Cummings 2001). Backus and colleagues studied the responses associated with binocular disparity and found selective responses that correlated with the disparity level of the stimuli. These responses were most robust in area V3A (Backus et al. 2001). Motion-in-depth stimuli were employed by Rutschmann et al. (2000) to determine the correspondence between responses in motion-sensitive areas to random dots presented dichoptically. Their results point to a region in the extrastriate cortex, probably corresponding to V3a/V3b, which selectively responded to the disparity and optic flow properties of motion displays. The relative disparity of random-dot stimuli indicated activation in dorsal stream areas (Tsao et al. 2003; Rutschmann and Greenlee 2004).
8.14 Interface Between Visual and Oculomotor Systems The role of the visual cortex in the planning, programming and execution of visually guided saccades remains for the most part unknown. Indeed many prominent models of saccade control leave out the visual cortex completely (Leigh and Zee 2006). In several experiments we have studied the neural correlates of saccadic eye movements in fMRI. Kimmig et al. (2001) compared visually guided saccades performed at different rates and revealed a signal that increased with saccade frequency. Cornelissen et al. (2002) compared pro- and anti-saccades in a random eventrelated task. On each task, subjects were cued by a change in the colored fixation mark whether to perform a pro- or anti-saccade (i.e., to shift their gaze toward or away from the peripheral target). The results indicate similar activations in the
frontal eye fields (FEF) and V1 during both tasks with evidence for anticipatory set effects (see also Connolly et al. 2002). Memory-guided saccades led to activation in FEF and additional areas in prefrontal cortex (Brown et al. 2004; Ozyurt et al. 2006). Applying dynamic causal modeling to explore the effective connectivity between regions in visual, parietal and prefrontal cortex, we recently reported evidence for a complex interactive network in the control of saccades and pursuit (Acs and Greenlee 2006). These new forms of data analysis open new insights into the processes occurring in several brain regions simultaneously. Using an event-related design, Vallines and Greenlee (2006) recently determined the level of activation in V1 in the brief moments prior to the onset of the visually guided saccade. Subjects were requested to detect briefly flashed Gaussianenveloped sinusoidal (Gabor) patterns located just above or below a lateral saccade target. By systematically varying the time between the onset of the Gabors and the onset of the saccade to the eccentric target, the authors found a significant reduction in the BOLD signal in V1 evoked by the transient stimuli. The time course of the effect was comparable to the time course of the drop in psychophysically determined contrast sensitivity to the same stimuli, suggesting that the changes in V1 reflect the changes in sensitivity that occur 50 ms prior to the onset of the visually guided (and planned) saccade. These results suggest that neural processes in V1, or prior to V1, are linked to saccadic suppression. In a further study, Tse et al. (2007) compared V1 responses evoked by micro-saccades as well as visually guided saccades with amplitudes comparable to those of micro-saccades (the smallest being 0.13 visual degrees). Their results suggest that V1 activation is excited by small voluntary fixational eye movements that fall in the range of micro-saccades in V1, V2, V3, and MT. Moreover, the magnitude of the BOLD response increases parametrically in V1, V2, and V3 with the size of the small voluntary eye-movements. However, the BOLD signal response in MT remains constant regardless of the magnitude of the small saccade, suggesting that area MT´s response is not driven primarily by changes in the
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image, since there is greater motion magnitude in the image with larger eye-movements. That microsaccades trigger an increase of the BOLD signal in retinotopic cortex suggests that saccadic suppression does not operate for microsaccades, which are involuntary. This makes sense if one accepts the view that micro-saccades occur in order to counteract the loss of signal that accompanies the perceptual fading that would occur upon the maintenance of perfect visual fixation (see Martinez-Conde et al. 2004). The majority of fMRI experiments to date have been carried out without measuring micro-saccades in the scanner. If micro-saccade occurrence or rate is correlated more with one experimental condition than another, there could be a significant difference in the BOLD signal arising from one condition as compared to another, even though this difference arose because of the artifact of micro-saccades, and not as a function of the difference between experimental conditions. These studies reflect the urgent need to monitor eye movements and fixation behavior of subjects while they perform visual tasks.
Summary for the Clinician
■ Optic flow is defined as the spatiotem-
poral pattern of stimulation that occurs when the subject moves within an otherwise stationary environment. Recent studies have tried to better understand how local object motion is discriminated from more global patterns of motion evoked by self-motion, navigation or exploratory eye/head movements. MST has neurons with large receptive fields and these are more sensitive to changes in the global characteristics of optic flow stimuli. The combination of flow field stimuli with binocular disparity creates a sense of motion in depth. Extrastriate areas V3a/V3b respond selectively to the disparity and optic flow properties of these motion displays. Several studies have explored the responses in visual, parietal and prefrontal cortex during the planning, programming and execution of visually guided saccades. Similar activations in FEF and V1 during pro- and anti-saccade tasks were evident, suggesting the existence of anticipatory set effects. Memory-guided saccades lead, on the other hand, to additional activation in prefrontal cortex.
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8.15 Parietal Lobe Maps of Visuotopic Space Sereno et al. (2001) discovered a region in the superior parietal cortex (Taliarach coordinates: X = 32, Y = –68, Z = 46 mm deviation from the anterior-posterior commissure) that showed robust visuotopic mapping of the remembered target angle. These authors suggested that this region contains a representation of the entire contralateral hemifield and, as such, could be a homolog of the lateral intraparietal area in macaque monkeys (Sereno et al. 2001). Figure 8.6 illustrates the main findings of the Sereno et al. (2001) study, which indicates contralateral visuotopic mapping of the target location for the planned saccade. Interestingly, neurons in the intraparietal cortex in monkeys have been shown to fire during the preparation of saccades (Bisley and Goldberg 2003). In a recent set of studies, Schluppeck et al. (2005, 2006) performed similar experiments and found a similar organization in posterior parietal cortex.
8.16 Working Memory for Visual Stimuli Visual working memory is the ability to use information from prior visual stimulation to perform discrimination or recognition tasks. Recent studies suggest that this information may be stored in neural circuits that are also involved in the encoding of the sensory stimuli (Pasternak and Greenlee 2005). A further form of visual working memory is related to the ability to form vivid visual imagery, and these processes may involve early visual cortex (Kosslyn et al. 1999). Although the exact role of early visual cortex in visual imagery remains to be determined (Knauff et al. 2000; Kosslyn and Thompson 2003), more
8.16 Working Memory for Visual Stimuli
Fig. 8.6. Results of the Sereno et al. (2001) study that employed a delayed saccade task to map the retinotopic organization of a small region in the superior parietal cortex of a single subject. The subject was instructed to maintain central fixation while a peripheral target (lower panel) was flashed. The target was followed by a ring of flickering distractor dots. After 3 s the subject was asked to perform a memory-guided saccade to the location where the target dot had been flashed. Using the phase-angle encoding method, Sereno et al. could apply Fourier techniques to extract the relative phase of the T2*-signal at the stimulus frequency, which was assigned one of three colors (see inset, upper panel) corresponding to the relative location in the contralateral visual field (adapted from Sereno et al. 2001 with permission)
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recent work indicates that the precuneus is an important area for visual memory and visual imagery (Cavanna and Trimble 2006). In a delayed orientation discrimination task, we recently tested the theory that the precuneus is involved in the storage and recall of visual information (Rothmayr et al. 2007). Figure 8.7 shows the main findings of this study. Subjects compared two sequentially presented Gabor stimuli that varied randomly in their orientation. To test the so-called dual-coding theory of visual imagery (Paivio 1986), we instructed subjects to use verbal codes (e.g., tilted left) to aid them in the delayed discrimination task. The results under this instruction set were compared to the results when the instructions informed them to use visual imagery to perform the task (activations shown in green and red, respectively, in Fig. 8.7).
target and flanker bar onsets and offsets. Moreover, targets and flankers can be presented to either the same eye or to different eyes. Monoptic visual masking was found in all visual retinotopic areas, whereas dichoptic masking was only found in retinotopic areas beyond V2. This finding represents a lower bound for the neural correlates of visual consciousness of simple stimuli such as bars. Moreover, they found that those neural correlates lie within the occipital lobe, placing a corresponding upper bound on the neural correlates of bar visibility, as indicated in Fig. 8.8.
Summary for the Clinician
■ Recent studies suggest that this informa-
8.17 Role of V1 in Visual Consciousness One of the deepest questions in neuroscience concerns the role of individual cortical areas in the neural processing underlying consciousness. An experimental paradigm used to explore the role of early visual areas in conscious perception is binocular rivalry (Blake and Logothetis 2002). In these experiments the subjects are presented with a different image in the left and right eye, such as a horizontal grating presented solely to the left eye and a vertical one solely to the right eye. The subject typically oscillates between perceiving the image available to the left and that available to the right eye, but not both. During brain imaging, the subject signals when he or she consciously perceives the left- or righteye image. Using statistical methods based on the response distributions in the different visual areas, Haynes et al. (2005) reported that individual voxels within V1 correlated significantly over time with the conscious perception of the subjects, such that the recorded activation could be used to predict which retinal image the subject was perceiving. Tse et al. (2005) used metacontrast masking as a probe to determine neural correlates of the visibility of simple bar stimuli. In metacontrast masking a target bar can be rendered visible or invisible by flanking bar stimuli, depending on the temporal relationships among
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tion may be stored in neural circuits that are also involved in the encoding of the sensory stimuli. During a delayed orientation discrimination task, subjects exhibit significant clusters of BOLD activation in the precuneus and the posterior parietal cortex. Binocular rivalry has been used to study the neural mechanisms underlying visual consciousness. It has been shown that V1 activation correlates significantly over time with the conscious perception. Monoptic and dichoptic visual masking are techniques that reveal how information combined from the two eyes contributes to conscious perception. Using these techniques, the effects of monoptic visual masking was found in all visual retinotopic areas, whereas dichoptic masking was only found in retinotopic areas beyond V2.
8.18 Summary This chapter has reviewed the current literature on brain imaging studies related to the way the visual image is encoded in primary and extrastriate visual cortex. The results from several laboratories converge to form a clear map of human visual cortex consisting of V1, V2, V3, V4, V5 and visual areas in the precuneus
8.18 Summary
Fig. 8.7. Results of the Rothmayr et al. (2007) study that employed a delayed orientation discrimination task to map the cortical activation related to the storage of pattern information. The subjects were instructed to use either a verbal code to aid them in the memory task (green), or visual imagery to store and recall the first pattern (red). Overlap between the activation from these conditions is indicated by yellow. The brain images from left to right illustrate how the activation develops over the 8-s interstimulus interval of the working memory task. The upper row presents posterior views of the brain and the lower row shows a lateral view of the left hemisphere. Although there is considerable overlap in the activations in these two experiments, responses in the imagery condition (red) were more pronounced in the precuneus and lateral parts of the posterior parietal cortex, whereas languagerelated regions in the left hemisphere (green) were more active in the verbal encoding condition (adapted from Rothmayr et al. 2007)
and posterior parietal cortex along the dorsal pathway, as well as – although not discussed here – in the lateral occipital (LO) area and the inferior temporal cortex along the ventral pathway. Damage to these areas leads to selective impairment in visual function (Goodale and Milner 1992). Higher cognitive processes based on visual stimulus input are now becoming better understood. These functions are related to visual imagery, visual working memory and visual consciousness. These higher levels of cognition pose a challenge to modern visual neuroscience, and new research approaches promise to provide novel insights into the neural circuitry underlying these processes. Functional MRI will continue to
provide some of the best information available to neuroscientists in their attempts to understand visual processing in the human brain.
Acknowledgments The authors wish to express their thanks to the Alexander von Humboldt Foundation for their support of author P.U.T. during his sabbatical visit to Regensburg (Bessel Award). Author M.W.G. was supported by a grant from the Bayerische Forschungsstiftung, by a grant from the European Commission (FP6, Cognitive Systems) and by the University of Regensburg.
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Fig. 8.8. Layout of retinotopic areas that potentially maintain awareness of simple targets. An individual brain model from all perspectives, including both hemispheres flat-mapped, overlaid with the functional activation from one typical subject. The yellow-shaded areas are those portions of the brain that did not show significant dichoptic masking and thus are ruled out for maintaining visual awareness of simple targets. The pink-colored voxels represent the cortical areas that exhibited significant dichoptic masking and thus are potential candidates for maintaining awareness of simple targets (adapted from Tse et al. 2005 with permission)
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Chapter 9
Investigating Visual Function with Multifocal Visual Evoked Potentials
9
Michael B. Hoffmann
Core Messages
■ With multifocal visual evoked potentials
(mfVEPs) the visual field can be sampled for response abnormalities. Thus, mfVEPs open the possibility of an objective visual field test. The issue, however, is greatly complicated by the variability of the responses across the visual field and between subjects. Cortical morphology dictates the mfVEP shape and influences mfVEP magnitude; consequently it is one important cause of the variability of mfVEPs. Thus for some visual field locations severe signal loss can occur, which mimics scotomata. The number of these spurious scotomata can be reduced by recording from multiple electrodes. To account for the cortical magnification of the visual field representation specifically scaled circular checkerboard patterns are used for stimulation.
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■ While different strategies proved suc-
cessful for the evaluation of mfVEP magnitude and latency, root-meansquare calculations and correlations of the responses with reference traces have the advantage of being based on a number of points as opposed to single peak values and yield reliable estimates of response magnitude and latency. Estimates of mfVEP magnitude, latency, and cortical topography are valuable tools for the assessment of visual function. Multifocal VEP magnitude is particularly valuable for an objective visual field assessment in glaucoma patients. Multifocal VEP latency measures promise further insight into visual system abnormalities in patients with optic neuritis and multiple sclerosis. Multifocal VEP topography can help to detail malformation of the optic chiasm, e.g., in albinism.
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9.1 Introduction It did not take long after the pioneering work of Sutter [1, 2, 3] that the potential of the multifocal stimulation technique to describe the visual field topography of visual dysfunction was recognized. Clearly, both the electroretinogram (ERG) and the visual evoked cortical potential (VEP) can be combined with the multifocal stimulation technique [3, 4]. This opens the possibility of a spa-
tially resolved identification of (1) dysfunction of the retinal photoreceptors and bipolar cells with multifocal ERG (mfERG) and (2) dysfunction of the visual pathway with the multifocal VEP (mfVEP). However, while mfERGs have quickly proved to be useful for the assessment of many aspects of visual dysfunction [5], mfVEPs have entered the field more slowly. This is primarily due to methodological problems that are intrinsic to mfVEPs. Multifocal potentials recorded from the
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visual cortex display great variability across the visual field within and between subjects. These fluctuations of response sizes make it difficult to assess whether an unresponsive visual field location has a methodological cause or indicates a veridical scotoma. Indeed, Baseler et al. [4], in their pioneering study, attributed mfVEPs only little potential to contribute to clinical visual field testing. Since then, endeavours to utilize mfVEPs for a functional assessment of the activity in the visual cortex have not ceased and substantial improvements of the procedure in the late 1990s, namely multi-electrode recordings and refined analysis strategies, spurred off a steady stream of investigations. These studies finally succeeded in rendering approaches that enable us to conduct an objective visual field test based on mfVEPs [6]. As will be shown below, the assessment of the magnitude, latency, and topography of cortical responses in diseases such as glaucoma, optic neuritis, and albinism are striking examples of the potential of mfVEPs to enhance our understanding of pathologies of the visual system.
9.2 Multifocal Principle and Characteristics of Multifocal VEPs 9.2.1 Basics – Multifocal Stimulation, Firstand Second-Order Kernels The multifocal technique enables one to extract separate responses from a number of
stimulated visual field locations, typically more than 50, within a short recording interval, typically 8 min for one monocular recording. Instead of measuring the response for each location separately, in the multifocal approach the entire array of locations is stimulated quasi-simultaneously, in a manner that allows for the extraction of the responses of each single location from the summed response (Fig. 9.1). The extraction of the responses is possible as the stimulation sequences are known and have been selected to fulfil a number of requirements, particularly mathematical independence. The sequences are termed binary m-sequences, i.e. they determine two stimulus states, e.g. stimulus pulse and no stimulus pulse. They also have the advantage that from one m-sequence other mathematically independent m-sequences can be derived by the selection of a different starting point within the m-sequence. This is illustrated in the schematic of Fig. 9.1a where m-sequences for locations B and C are shifted by one and two elements, respectively, compared to A. Thus, each visual field location will be stimulated with the same sequence, but with a different starting point. Knowledge of both the applied m-sequence and the different starting points enables one to extract the response for one particular visual field location with a crosscorrelation [2]. The basic principle is illustrated in Fig. 9.1a for a or didactive purposes simplified (e.g., only seven stimulus locations, a very short m-sequence of only seven elements, responses in non-overlapping time bins) schematic. For simplicity the extraction of a response to a flash
7 Fig. 9.1a,b. a Schematic illustrating the basic concept of the multifocal principle. A for didactic puposes substantially simplified example of simultaneous stimulation of only seven locations with a very short stimulation sequence of seven elements is used for this illustration (after Sutter [1], details given there). Each location is stimulated with the same binary m-sequence (1: stimulus pulse, 0: no stimulus pulse), but shifted in time (as indicated by the shaded bins for locations b and c, which comprise the end of the first m-sequence for location A). For each location a sequence of responses (blue traces) is elicited by its stimulation sequence; for illustrative purposes each location is given a different response shape. An electrode recording from all locations will yield the summed response (black trace). To extract the response for location c (indicated in red) each bin of the response sequence is assigned the weight –1 or 1, for 0 (no stimulus) or 1 (stimulus) in the m-sequence for c, respectively. The weighted average over the seven time bins yields the response of location C, as the responses from the other locations cancel out, while those from C are extracted (bottom part of a). b Derivation of the weights for location “c” from the stimulation sequences for the extraction of the first-order kernel (response to flash pulses; stimulation results in a positive, no stimulation in a negative weight) as used in a. The bottom row indicates the weights for the second-order kernel responses, i.e., the responses to stimulus changes, derived from the stimulation sequence (change of state results in a positive, no change in a negative weight) as for the extraction of pattern reversal mfVEP responses. It should be noted, however, that this is a schematic and substantially simplified example, and that in fact only longer sequences allow for the accurate extraction of the kernels (see text)
9.2 Multifocal Principle and Characteristics of Multifocal VEPs
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pulse, as used in standard mfERG recordings, is shown. In this case the first-order kernel is extracted, i.e. the response to one of two stimulus states, namely flash on. For the multifocal VEPs the matter is slightly more intricate, as VEPs are usually recorded in response to pattern reversal and not to flash stimuli. During pattern-reversal stimulation, a pattern is permanently present at each visual field location, and the two stimulus states are the two contrast polarities of this pattern. It is the change between the two states of the pattern that evokes the response. To extract the response to this change, the history of the sequence has to be taken into account, which requires the extraction of higher-order kernels. Specifically, to obtain the response to the pattern-reversal stimulation the so-called first slice of the second-order kernel is extracted (see
schematic in Fig. 9.1b for the principle behind the derivation of the weights). It should be noted that much longer m-sequences than for those of the schematic in 9.1 are actually required. In fact it is evident from figure 9.1 that the short sequences used would not even allow for the distinction of first-order and second-order kernel responses: the weights for the second-order kernel for location C are the same as those for the first order kernel for location F. In a standard recording of around 8 min duration, the m-sequences consist of more than 32,000 elements, where the duration of an element equals one monitor frame interval, e.g. 13 ms. Finally, it should be noted that recently an alternative approach to obtaining multifocal responses, which is based on a multiple regression framework, has been put forward [7].
Fig. 9.2. Circular dartboard pattern used for mfVEP recordings. The stimulus comprises 60 4-by-4 checkerboard patches that increase in size with eccentricity. Three individual patches are isolated and the two states of the pattern-reversal stimulus are indicated. For clarity the centre is enlarged by a factor of two in the inset, as indicated by “2 x”
9.2 Multifocal Principle and Characteristics of Multifocal VEPs
Summary for the Clinician
■ With the multifocal technique separate
responses from many visual field locations, e.g. more than 50, can be obtained within a short time interval, e.g. 8 min per recording. Responses to different stimuli, e.g. flash or pattern reversal, can be extracted from summed responses recorded with a single electrode pair.
■
into account when reading the mfVEP displays. Finally, a note on the stimulation mode should be added. While pattern-reversal stimulation is the most commonly used for mfVEP recordings, recent investigations indicate that another stimulation mode, i.e. pattern onset from an equiluminant grey background, is also an effective VEP stimulus, particularly in the central visual field [7, 8, 10, 11, 12, 13].
Summary for the Clinician
■ Scaled
circular checkerboard patterns are used in mfVEP recordings to compensate for the magnification of the cortical representation of the central visual field. For ease of the illustration, however, the responses from different eccentricities are usually depicted in an equidistant manner.
9.2.2 Stimulus Display for mfVEP Recordings Conventional checkerboard patterns are usually not applicable to mfVEP recordings [4, 8] and circular checkerboards are used instead (Fig. 9.2). The reason for this is the way in which the visual field is represented on the visual cortex. Due to the cortical magnification of the centre, the central visual field covers a greater area of visual cortex than the periphery. Consequently, to obtain sizeable mfVEPs from both the centre and the periphery the cortical magnification has to be taken into account, presenting small stimuli in the centre and greater stimuli in the periphery. The standard way to achieve this is to use a scaled circular checkerboard pattern, i.e. a dartboardlike pattern. An example of a typical mfVEP stimulus is depicted in Fig. 9.2. Here, a circular checkerboard subtending 42° of visual angle is subdivided into 60 single sectors. Each sector comprises a 4-by-4 checkerboard pattern, which proved to be an effective stimulus [9]. Responses from 60 visual field locations can be obtained with this stimulus, with the highest spatial resolution, around 1.5° sector width, in the centre and the lowest resolution, around 7° sector width, in the periphery. The responses are usually displayed as a re-projection of the signals to the visual field locations that evoked them (e.g. Fig. 9.3). It should be noted, however, that for ease of the illustration the responses from different eccentricities are usually depicted in an equidistant manner, while the actual stimulus layout is approximately m-scaled. This discrepancy between the mfVEP stimulus and the response display has to be taken
■
9.2.3 Recording mfVEPs and Practical Considerations In general, the same amplifier settings and electrodes as for conventional VEP recordings [14] can be used for mfVEP recordings. However, different recording sites are recommended for the mfVEP. Optimal are occipital recording sites with an occipital reference [4, 15, 16, 17]. As will be detailed below, mfVEPs benefit from the use of additional lateral electrodes. Different arrangements were successful and an example of a multi-channel montage of three physical recording channels [18] is given in Fig. 9.4. As for the conventional VEP, the quality of the retinal image is of major relevance for mfVEP recordings. Optical deficiencies such as refractive error or light scatter reduce responses particularly to the small central checks of the circular checkerboard pattern [19, 20]. Refractive error needs to be corrected carefully and other factors reducing the retinal image quality have to be taken into account for the assessment of the recordings.
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Fig. 9.3a–c. a Example of a pattern-reversal mfVEP recording from 4 cm above the inion referenced to the inion. mfVEPs are depicted as a re-projection to the visual field locations that evoked them. It should be noted that the responses from different eccentricities are arranged in an equidistant manner, while the actual stimulus layout is approximately m-scaled. Response strength and shape vary across the visual field. A typical feature of mfVEP traces, the tendency of a polarity reversal of the traces from the upper compared to the lower horizontal meridian, is evident. b Quantification of a response at a particular visual field location [29]: calculation of the root-mean-square, RMS, in the signal (45–150 ms) and the noise time window (325–430 ms) and of the signal-tonoise-ratio, SNR, from the signal RMS and the mean noise RMS over all 60 stimulus locations (µ=mean; t=time; i=stimulus location; m=number of samples; n=number of stimulus locations, here n=60). c RMS values derived from the traces in a, symbol size indicates the RMS value. The variability of the RMS values across the visual field corresponds to that of the response magnitude of the original traces shown in a
9.2 Multifocal Principle and Characteristics of Multifocal VEPs
Fig. 9.4a,b. a Recording sites as proposed by Hood et al. [18]. b From three recording sites referenced to the inion (D) another three recording pairs can be derived. Thus electrical dipoles of different orientations can be tapped
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During mfVEP-based objective visual field testing, subjects are not required to respond to the stimuli presented and concentration onto the stimulus does not appear to be of major relevance [21]. While this reduces the degree of cooperation that is required from the subjects, steady central fixation is still of essential importance. This is evident from studies with simulated fixation instabilities and with subjects that suffer from nystagmus [8, 20, 22]. During unsteady fixation particularly central responses are reduced; during steady misfixation the response maximum is likely to be shifted away from the stimulus centre. While mfVEP responses do not appear to depend on age and race, there is a small influence of gender on the mfVEP: signal-to-noise ratios are about 10% greater in females than in males [23]. Finally, while recordings from children are always much more demanding than recordings from adults, Balachandran et al. reported mfVEPs from children as young as 5 years in a study investigating 70 children aged between 5 and 16 years [24]. This study suggests that the clinical assessment of visual function in children can be aided by mfVEPs.
Summary for the Clinician
■ The quality of the retinal image is of major relevance for mfVEP recordings. ■ Refractive errors need to be corrected for carefully for a recording. ■ Other factors reducing the retinal image
quality have to be considered for mfVEP assessment.
9.2.4 Dependence of mfVEPs on Visual Cortex Morphology A typical example of mfVEP traces obtained from a single subject with a circular checkerboard pattern is depicted in Fig. 9.3a. Responses within 200 ms after stimulus onset are evident for many visual field locations and two main features of the
mfVEP can be appreciated. Firstly, mfVEPs vary greatly in response magnitude across the visual field and there are occasional localized response reductions and even drop-outs at various locations. These occasional drop-outs are common in normal subjects and bear no relationship to veridical visual field defects, but unfortunately they mimic visual field defects. Secondly, it is evident from Fig. 9.3 that the trace shape varies across the visual field. In particular, there is a strong tendency for the response polarity to be inverted between upper and lower visual field responses. These two features underline that objective visual field testing based on mfVEPs is not trivial. A major source of the inter- and intra-subject variability of the magnitude and shape of the responses is the cortical anatomy. Multifocal VEPs measured at a particular recording site strongly depend on the convolution of the visual cortex. An electrode pair is only able to pick up activity from a cortical generator if the generated electrical dipole projects onto this pair, which depends on the orientation of the dipole. The orientation of the dipole is assumed to be perpendicular to the cortical surface and is therefore closely linked to the cortical morphology, namely the convolution of a particular part of cortex. Thus mfVEP trace shape is tied to the cortical convolution. This has a number of important consequences. Firstly, as the retinotopic representation of the visual field in the visual cortex is laid out onto the convoluted surface of the occipital lobe, the orientation of the activated electrical dipole will depend on the visual field location stimulated. Consequently, some visual field locations will generate cortical activity that does not project onto a particular pair of recording electrodes and will therefore appear “silent”. Secondly, the convolution of the cortex varies between subjects. Therefore, the position of the silent visual field locations is expected to vary between subjects. Thirdly, a particularly striking part of cortical convolution, namely that of the calcarine sulcus, explains the reversal of the response polarity of the upper compared to the lower visual field responses mentioned above. The pattern-reversal mfVEP is generated mainly in the primary visual
9.2 Multifocal Principle and Characteristics of Multifocal VEPs
cortex [25], which is located in the calcarine sulcus of the occipital lobe. Here a retinotopic representation of the contralateral visual field resides, such that the upper part of the visual field is presented in the ventral bank of the calcarine sulcus and the lower part in the dorsal bank (Fig. 9.5). As a consequence of the representation of the upper and lower visual field on opposing banks of the sulcus, upper and lower visual field locations will activate dipoles of opposite polarity in the primary visual cortex. Thus mfVEP traces recorded with a vertical pair of occipital electrodes to stimulation in the upper visual field are polarity inverted compared to those to stimulation in the lower field (Fig. 9.5). Due to the cortical convolution, some visual field locations generate cortical activity that fails
to project signal onto a particular pair of recording electrodes. This activity, however, might project signal onto another electrode pair, which is sensitive to electrical dipoles of a different orientation. Thus additional recording electrodes increase the number of visual field locations from which a signal can be picked up [16, 18]. Therefore, in order to obtain responses from more visual field locations, mfVEPs are recorded from a number of electrodes. For each visual field location the recording pair with the greatest response is taken as an estimate of the response magnitude. Figure 9.4B illustrates an example of a montage resulting in six recording channels [18], namely three physical channels and three derived channels, which is successful in increasing the number of responsive visual field locations.
Fig. 9.5a,b. Relation of the polarity inversion of the mfVEPs to the anatomy of the calcarine sulcus (CS). a Schematic indicating that electrical dipoles, due to stimulation in the upper and lower field (in red and green respectively), have opposite polarity, as the upper and lower visual field are represented on the lower and upper bank of the CS. b mfVEPs recorded from 4 cm above the inion referenced to the inion, i.e. from a vertical pair of occipital electrodes (an epoch of 250 ms after stimulus onset is depicted). For the left hemifield, traces from three patches at the same polar angles are averaged together as indicated in the stimulus schematic on the right. Note that upper field responses are inverted compared to lower field responses (dotted lines at two particular response latencies are included as guides). The colour code indicates the presumed location of the generators of the traces 1 and 4 in the schematic a on opposing banks. As the lower horizontal meridian tends to be represented close to the fundus of the CS [55], it does not project much signal onto the derivation and results in smaller mfVEPS as is evident from trace 3 (see also Fig. 9.3)
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Summary for the Clinician
■ Cortical
convolution dictates mfVEP shape, influences mfVEP magnitude, and is consequently associated with the occasional signal loss common to mfVEP recordings. The number of the resulting spurious scotomata can be reduced with multielectrode recordings.
■
9.3 Assessment of mfVEPs 9.3.1 Response Magnitude
9
Multifocal VEP response magnitude is an important indicator of visual field defects. In some studies the peak-to-trough measure has been used systematically to quantify response magnitudes [16, 26], but there are problems with this mode of measurement. In particular, if responses are small and contaminated with noise, it can be difficult to detect the individual peaks and to decide whether a response was obtained for a particular visual field location or not. A more objective measure to quantify the response magnitude is the mean root-mean-square (RMS) calculated for a particular time window (Fig. 9.3b). The RMS measure has the great advantage that it does not depend on the identification of particular aspects of the response waveform and polarity – only the time window in which a response is expected has to be specified. As an example of this magnitude estimation, RMS values derived from the mfVEPs depicted in Fig. 9.3a are shown in Fig. 9.3c. Response magnitudes can differ greatly between subjects. One way to deal with this problem is the interocular comparison of the responses, as similar response magnitudes are expected for both eyes of the same subject. Further, both eyes project to nearly identical parts of the retinotopic map in the visual cortex. As a consequence, signal drop-out due to cortical convolution should be similar for both eyes. Differences in the visual field maps of the two eyes must therefor be due to true scotomata and thus an objective visual
Fig. 9.6. Interocular comparison of mfVEP responses in a subject with glaucoma-related visual field defects for the right eye (blue traces; normal left eye: red traces). The responses within the ellipse are significantly smaller in the right eye. From Greenstein et al. [43], wich has further details (with permission copyright© 2004, American Medical Association. All rights reserved)
field testing based on the interocular comparison of mfVEP responses can be established. The approach is successful [26, 27] (Fig. 9.6), but unfortunately it is limited to the detection of only a subset of visual field defects, namely those which are not homonymous. To detect homonymous defects a monocular test is necessary and consequently the problem of the interindividual variability of response magnitudes has to be overcome. This can be achieved by normalizing the responses upon an internal reference, e.g. the overall EEG level [28] or the noise level [29]. The latter approach shall be detailed here. Zhang et al. [29] determined two RMS amplitudes, one in a time window in which the signal is expected and one in a time window in which no signal but noise is expected (Fig. 9.3b). The ratio of these two RMS amplitudes can be taken as an estimate of the signal-to-noise ratio, SNR (Fig. 9.3b). Using SNR as a measurement of the response magnitude reduces the interindividual variability. Thus the SNR values obtained from a patient compared to those of a control population can be used to calculate the probability of a true visual field defect. It should be noted, however, that the statistics of the monocular analysis are not sim-
ple and caution has to be exerted in the interpretation of the results. For example in subjects with noisy records more spurious scotomata than expected by chance will occur. One way to increase the specificity of the detection of visual field defects, but at the expense of spatial resolution, is to define a true scotoma as the contiguous expanse of a number of silent visual field locations, e.g. a cluster of two to three silent locations [6, 30]. An example of an estimation of visual field defects from the interocular and monocular analysis is given in Sect. 9.4.1 (Fig. 9.7).
9.3.2 Response Latency Similarly to the estimation of signal magnitude, mfVEP latency can be estimated based on a single peak analysis [9, 31]. As for the magnitude estimation, however, a single peak analysis requires the identification of individual components of the responses, which can be difficult for mfVEPs. Another way to determine whether a response is shifted in time relative to a reference trace is a cross-correlation of the two traces. This approach has two advantages to a single peak analysis: it is based on many data points and it takes the shape of the traces into account. A correlation of two traces yields a correlation coefficient, which can be taken as a measure of the similarity of the two traces. In a cross-correlation, one of the traces will be shifted with respect to the other and the correlation coefficient will be computed for each shift. The amount of shift necessary to obtain the highest correlation coefficient is taken as the latency difference. For the success of the technique it is important to select the appropriate reference trace. Several studies used the response of the fellow eye as a reference trace and thus determined interocular latency differences [18, 32, 33, 34]. Indeed, this way it is possible to pick up and quantify a physiological interocular latency difference, namely the delay of responses of the temporal relative to the nasal retina. Ganglion cell responses in the temporal retina are delayed compared to those of the nasal retina, as the action potentials of the ganglion cells in the temporal retina must travel further along unmyelinated axons to the optic disc than
9.3 Assessment of mfVEPs
those from the corresponding nasal retina. Using mfERG components reflecting ganglion cell activity this delay was estimated to be up to 10 ms at around ±10° eccentricity [35]. The crosscorrelation technique applied to mfVEPs yielded interocular latency differences of a similar magnitude, namely up to 11 ms [32] and 8 ms [34] (Fig. 9.8). This demonstrates the potential of the technique to quantify latency differences. As for the interocular magnitude comparisons, determining interocular response delays does not allow for the detection of abnormal latencies in patients in whom both eyes are affected. In this case a monocular test is required and the reference trace for each visual field location must be derived from a control population [33, 36]. As for the interocular comparisons, this procedure can be tested by the assessment of physiological latency effects, e.g. the well-known increase of VEP latency with age. This tendency is also evident from the monocular assessment of mfVEP traces. While the accuracy of these approaches to determine latency effects critically depends on the SNR of the signals [32, 36], they promise great potential for the assessment of disease-related latency changes.
Summary for the Clinician
■ Due to small amplitudes and the vari-
ability of trace shape, single peak measures are problematic for the evaluation of mfVEP magnitude and latency. Instead, root-mean-square measures can be used to quantify mfVEP magnitude and to determine the signal-to-noise ratio of the responses. Latency deviations can be determined by cross-correlating the mfVEP trace with a reference trace. Interocular comparisons help to address the problem of interindividual mfVEP variability, but also strategies for the monocular assessment of mfVEP magnitude and latency have been developed.
■ ■ ■
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Fig. 9.7a–g. Comparison of visual field sensitivities derived from subjective visual fields (a, b; Humphrey: dark red and light blue squares indicate sensitivities that differ from normal at a significance level of 1% and 5%, respectively), confocal scanning laser ophthalmoscope (c, d; red circles indicate visual field locations corresponding to optic nerve head rim sectors that are abnormal in HRT II examination) and mfVEPs (e, f interocular comparisons; g monocular comparison; dark and light coloured squares indicate a reduction by 2.58 and 1.96 SD below mean values for the left and right eye in red and blue, respectively) in a subject with glaucoma and visual field defects for the left eye. All three techniques indicate similar visual field defects in this patient. From Greenstein et al. [43] (which has further details) with permission (copyright© 2004, American Medical Association. All rights reserved)
9.4 mfVEP Investigations of Diseases
Fig. 9.8a. Example of the physiological interocular latency differences in normal controls. a Original mfVEP traces for the right and left eye in black and grey, respectively. Responses were recorded from an electrode 4 cm above the inion referenced to the inion. The interocular delay, T (ms) (negative and positive values indicate leading of the right or left eye, respectively), and the correspondence of the traces, Corr (%), is given next to each response. Reprinted from Shimada et al. [34] with permission from Elsevier copyright©(2005)
9.4 mfVEP Investigations of Diseases As multifocal techniques allow for the detection of localized damage, they provide a tool for objective visual field testing and thus promise great potential to aid diagnostics in clinical electrophysiology. Multifocal VEPs tap the visual cortex and can therefore be used to assess damage to its input stages, i.e. the outer and inner retina [6, 37], and the visual pathways [38, 39]. As the outer retina is the domain of the standard mfERG [5, 40], most mfVEP studies address changes to
the cortical activity due to damage to the inner retina and upstream. MultifocalVEP studies with a clinical background have been conducted for a few years now. Although still at an initial stage, these studies indicate the potential of mfVEPs to contribute to this field. In this review an overview over three lines of research will be presented. These investigations in: (1) glaucoma, (2) optic neuritis and (3) albinism illustrate how mfVEP magnitude, latency and topography can contribute to our understanding of pathologies of the human visual system.
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Fig. 9.8b. Illustration of the delay of the responses from the temporal retina relative to those from the nasal retina. Reprinted from Shimada et al. [34] with permission from Elsevier copyright©(2005)
9.4.1 mfVEP in Glaucoma The majority of clinical mfVEP investigations were performed in patients suffering from glaucoma. In glaucoma, damage to the retinal ganglion cells causes visual field defects. At present, patients with suspected glaucoma, based on structural optic disc changes or high intraocular pressure, are assessed with static visual field perimetry, which requires the patients to judge the test stimuli subjectively. The possibility of an objective detection of glaucoma-induced visual field defects is opened by mfVEPs. Indeed, for glaucoma patients a great correspondence was demonstrated between subjective visual field
perimetry and the assessment of visual field topography based on mfVEP magnitude [16, 26, 30, 41, 42]. They showed that the reduction of mfVEPs is a reliable indicator of visual field loss. Recently, Greenstein et al. [43] took this approach a step further and assessed in 40 eyes of patients with open-angle glaucoma whether visual field defects determined with automated static perimetry and with mfVEPs correlated with the visual fields defects predicted from anatomical measures of the optic nerve head. Healthy and glaucomatous optic discs were discriminated with confocal scanning laser ophthalmoscopy (Heidelberg retina tomograph II, HRT II) for six different sectors of the optic nerve head. Each of
these sectors was related to corresponding visual field regions. Thus, for six regions, visual fields were predicted from the state of the respective optic nerve head sectors. In 87% of the regions subjective automated static perimetry and objective mfVEP-based visual fields were in agreement. Of these regions, 85% were in agreement with the visual field defects determined from the anatomical measurements acquired with confocal scanning laser ophthalmoscopy of the optic nerve head. Although the three methods do not provide a perfect match, a great degree of correspondence between subjective and objective visual field measurements and anatomical measurements is present, which highlights the potential of mfVEPs to assist visual field perimetry in glaucoma patients (Fig. 9.7). In contrast to mfVEP magnitude, mfVEP latency appears to be only marginally affected by glaucoma. Rodarte et al. [44] demonstrated small mfVEP delays, i.e. of a few milliseconds rarely exceeding 10 ms, which affected only about 40% of the glaucoma patients tested. Interestingly, this contrasts with great latency effects of glaucoma reported in a recent conventional VEP study [45] and we are keen to learn in the future how this discrepancy resolves. In glaucoma, do mfVEPs increase the yield of detecting early glaucoma? Reduced cortical responses might be evident before a visual field defect can be detected with subjective perimetry. As a consequence, mfVEPs might be a more sensitive indicator of localized ganglion cell damage. While there is at present no direct evidence indicating a sensitivity advantage of mfVEPs, there is some circumstantial evidence. Goldberg et al. [30] not only reported that glaucomatous eyes with abnormal subjective visual fields showed defects in the mfVEP assessment, but also that 60% of the fellow eyes with normal subjective visual fields showed defects. As the incidence of glaucoma in the fellow eye of a glaucomatous eye is very high, the authors of this study assumed that the fellow eyes with abnormal mfVEPs were already affected by glaucoma, but to an extent that did not yet influence subjective visual fields. While this interpretation of the results might suggest that mfVEPs might help to detect ganglion cell damage before subjective visual field perimetry, follow-up studies are needed to vali-
9.4 mfVEP Investigations of Diseases
date this presumption. Further it remains to be shown whether mfVEPs are more sensitive than pattern ERG at detecting early glaucoma [46, 47]. At present, evidence that mfVEPs might aid early detection is only indirect and we are eagerly awaiting studies that clarify this issue.
Summary for the Clinician
■ Multifocal VEP magnitude allows for the
objective detection of glaucoma-induced visual field defects. Thus mfVEPs can assist the follow-up of patients with glaucoma and might contribute to a better understanding of the underlying pathophysiological mechanisms.
■
9.4.2 mfVEP in Optic Neuritis Optic neuritis (ON) is a syndrome characterized by an acute, unilateral loss of visual function. After an episode of ON, its diagnosis can be confirmed by the detection of a delay of the conventional VEPs [48]. Multifocal VEPs might aid the description and characterization of ON as it is expected to detect focal changes in the visual system that might not be evidenced by conventional-pattern VEPs, which reflect a summed response dominated by central vision. Furthermore, a more detailed description of the consequences of ON on the visual system with mfVEPs might help to differentiate between cases of ON that are associated with a risk of developing multiple sclerosis and those that are not. There are at present only few studies investigating the association of ON with changes in the mfVEPs. An initial investigation of three patients with ON [49] suggested a correspondence of mfVEP response reductions and delays with defects in subjective visual field perimetry, albeit of variable degree. To minimize the blending of VEP responses from normal and abnormal visual field locations in ON, it appears therefore to be of benefit in ON patients to sample the visual field for VEP abnormalities in a spatially resolved manner with mfVEPs.
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Based on MRI and clinical examinations Fraser et al. [31] subdivided a group of 64 patients with ON (past and acute) into 3 subgroups: no multiple sclerosis (MS), possible MS, and MS group. mfVEP response amplitudes deviated from those of normals in at least three adjacent visual field locations in 70%, 68% and 91% of the “no MS”, “possible MS” and “MS” group, respectively, and response latencies deviated in 33%, 68%, and 100% respectively. An analysis of grouped responses from sectors with similar waveforms, taking responses of the entire visual field into account, indicated little latency deviations in the “no MS” group and substantial deviations in the “MS” group. Remarkably, the distribution of latency deviations in the “possible MS” group resembled a mixture of the other two groups. This suggests that mfVEP latencies might assist the identification of a patient’s risk for future MS. In another study [33] it was investigated whether, in subjects with MS, mfVEP abnormalities are related to a preceding episode of ON. Multifocal VEP abnormalities were compared in subjects with MS that was associated with a history of ON and in those that were not. In both groups reduced amplitudes and delayed responses were reported. Hence, as the mfVEPs abnormalities are not exclusive to MS patients with a history of severe ON, they might also be indicative of other consequences of MS on the neural substrate. In summary, mfVEPs are able to detect VEP abnormalities associated with ON and MS and promise diagnostic value and insight into the underlying pathophysiological mechanisms. As the abnormalities can affect small portions of the visual field, mfVEPs might be more sensitive than conventional-pattern VEPs. Studies that directly compare the sensitivities of VEPs and mfVEPs in the detection of ON and MS are needed to clarify this issue.
Summary for the Clinician
■ Multifocal VEPs are able to detect VEP
abnormalities associated with ON and MS and promise diagnostic value and insight into the underlying pathophysiological mechanisms.
9.4.3 mfVEP in Albinism The investigation of the visual pathways in albinism with mfVEPs is an example that demonstrates how the topographical information of the cortical responses can be used to describe abnormalities. Normally, the nasal retina projects to the contralateral hemisphere, while the temporal retina projects ipsilaterally. This normal projection of visual fibres from the retina is severely altered in albinism, where a great number of fibres from the temporal retina abnormally cross the midline and project contralaterally [50]. Conventional VEPs are an effective tool to demonstrate the misrouting of the optic nerves in albinism [51]. As each eye projects predominantly to its contralateral hemisphere in albinism, monocular stimulation of the central visual field elicits a greater activation in the hemisphere contralateral to the stimulated eye than in the ipsilateral hemisphere. This is evident from the VEP difference between electrodes over opposite hemispheres. Importantly, the polarity of this difference potential depends on the eye stimulated. A polarity inversion after stimulation of the right compared to the left eye indicates with great specificity and sensitivity misrouting of the optic nerves [51] (Fig. 9.9). By stimulating only parts of the visual field this VEP approach can be used to describe the extent of the projection abnormality [52]. Moreover, in combination with mfVEPs this approach opens the possibility of determining the visual field topography of the projection abnormality [22]. The use of multifocal VEPs to describe the visual field topography of the abnormality, however, is restricted to subjects without nystagmus as nystagmus greatly reduces mfVEP responses. An example of the visual field topography in a subject with albinism is given in Fig. 9.10. Here the polarity reversal was quantified by correlating with each other the traces obtained after left and right eye stimulation (Fig. 9.10b). Positive correlations indicate same polarity and normal projection; negative correlations indicate inverted polarity and misrouting. It is evident that the projection abnormality primarily affects a vertical stripe in the visual field centre, while the more peripheral part of the temporal hemiretina appears to revert to a normal projection pattern. This is in agreement with results obtained with conventional VEPs [52, 53] and functional magnetic reso-
9.4 mfVEP Investigations of Diseases
Fig. 9.9a,b. Schematic of misrouting of the optic nerves in albinism (a) and its detection with VEPs for three controls and three subjects with albinism (b). a Projection of the optic nerves of the left eye. Normally, the nasal retina projects to the contralateral and the temporal retina to the ipsilateral hemisphere. In albinism, part of the temporal retina projects erroneously to the contralateral hemisphere. The colour coding indicates on which hemisphere the hemifields are represented. b Detection of misrouting with VEPs. The inter-hemispheric VEP difference is recorded for left and for right eye stimulation. In the controls (C1–C3) no polarity reversal is evident between left and right eye responses. In the subjects with albinism (A1–A3) a polarity reversal between left and right eye responses is evident (see arrows), which is indicative of the misrouting of the optic nerves
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Fig. 9.10a,b. mfVEPs recorded from electrodes over opposing hemispheres (see Fig. 9.9) for a control subject (left) and a subject with albinism (right). a Raw traces from the left (blue) and right (red) eye as a re-projection of the visual field locations that evoked them. Note that the different eccentricities are depicted as equidistant while the actual stimulus layout is approximately m-scaled (applies also to b). Framed traces are enlarged for an easier assessment of the absence and presence of a polarity reversal in the control and the subject with albinism, respectively (note the succession of the peaks: p= positivity; n=negativity). b Quantification of the polarity inversion of the traces from both eyes as determined by correlating the traces with each other: parallel traces, i.e. no polarity inversion, yield positive correlation coefficients (black symbols), while anti-parallel traces, i.e. polarity inversion, yield negative correlation coefficients (open symbols). The latter indicate misrouting, which is evident along a central vertical part of the visual field of the subject with albinism (right panel). Crosses indicate sub-threshold responses, which cannot be assessed
References
nance imaging [54]. This study highlights how mfVEPs can contribute to a detailed analysis of visual pathway abnormalities. As mfVEPs allow for a detailed description of abnormal cortical representations of the visual field, they open the possibility of detecting small visual pathway abnormalities, which might not be uncovered by conventional VEP approaches.
Summary for the Clinician
3.
4.
5.
6.
■ In patients without nystagmus mfVEP
topography allows for the detection of misrouting of the optic nerves and thus opens the possibility of detecting even small visual pathway abnormalities.
9.5 Conclusion The above examples demonstrate how mfVEPs can be used to describe the visual field topography of magnitude, latency and the topography of cortical responses, and how they can contribute to our understanding of diseases that affect the human visual system. Despite this great potential of mfVEPs to aid clinical diagnostic and basic research, they are used routinely in only a few centres. One reason is that the extraction of visual field maps from the mfVEP traces is demanding and that the required software is not readily available. Once this gap is filled the promising and rapidly developing mfVEP technique can be expected to assist clinical routine in the near future.
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Sutter EE, Tran D (1992) The field topography of ERG components in man – I. The photopic luminance response. Vision Res 32:433–446 Baseler HA, Sutter EE, Klein SA, Carney T (1994) The topography of visual evoked response properties across the visual field. Electroencephalogr Clin Neurophysiol 90:65–81 Hood DC (2000) Assessing retinal function with the multifocal technique. Prog Retin Eye Res 19:607–646 Hood DC, Greenstein VC (2003) Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma. Prog Retin Eye Res 22:201–251 James AC (2003) The pattern-pulse multifocal visual evoked potential. Invest Ophthalmol Vis Sci 44:879–890 Hoffmann MB, Seufert PS (2005) Simulated nystagmus reduces pattern-reversal more strongly than pattern-onset multifocal visual evoked potentials. Clin Neurophysiol 116:1723–1732 Balachandran C, Klistorner AI, Graham SL (2003) Effect of stimulus check size on multifocal visual evoked potentials. Doc Ophthalmol 106:183–188 Hoffmann MB, Straube S, Bach B (2003) Patternonset stimulation boosts central multifocal VEP responses. J Vis 3:432–439 James AC, Ruseckaite R, Maddess T (2005) Effect of temporal sparseness and dichoptic presentation on multifocal visual evoked potentials. Vis Neurosci 22:45–54 Maddess T, James AC, Bowman EA (2005) Contrast response of temporally sparse dichoptic multifocal visual evoked potentials. Vis Neurosci 22:153–162 Klistorner AI, Graham SL (2005) Effect of eccentricity on pattern-pulse multifocal VEP. Doc Ophthalmol 110:209–218 Odom JV, Bach M, Barber C, Brigell M, Marmor MF, Tormene AP, Holder G, Vaegan. Visual evoked potentials standard (2004). Doc Ophthalmol 108:115–123 Klistorner AI, Graham SL, Grigg JR, Billson FA (1998) Multifocal topographic visual evoked potential: improving objective detection of local visual field defects. Invest Ophthalmol Vis Sci 39:937–950 Klistorner AI, Graham SL (2000) Objective perimetry in glaucoma. Ophthalmology 107:2283–2299
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Investigating Visual Function with Multifocal Visual Evoked Potentials 17. Hood DC, Zhang X (2000) Multifocal ERG and VEP responses and visual fields: comparing disease-related changes. Doc Ophthalmol 100:115–137 18. Hood DC, Zhang X, Hong JE, Chen CS (2002) Quantifying the benefits of additional channels of multifocal VEP recording. Doc Ophthalmol 104:303–320 19. Pieh C, Hoffmann MB, Bach M (2005) The influence of defocus on multifocal visual evoked potentials. Graefes Arch Clin Exp Ophthalmol 243:38–42 20. Winn BJ, Shin E, Odel JG, Greenstein VC, Hood DC (2005) Interpreting the multifocal visual evoked potential: the effects of refractive errors, cataracts, and fixation errors. Br J Ophthalmol 89:340–344 21. Seiple W, Holopigian K, Clemens C, Greenstein VC, Hood DC (2005) The multifocal visual evoked potential: an objective measure of visual fields? Vision Res 45:1155–1163 22. Hoffmann MB, Lorenz B, Preising M, Seufert PS (2006) Assessment of cortical visual field representations with multifocal VEPs in control subjects, patients with albinism, and female carriers of ocular albinism. Invest Ophthalmol Vis Sci 47:3195–3201 23. Fortune B, Zhang X, Hood DC, Demirel S, Johnson CA (2004) Normative ranges and specificity of the multifocal VEP. Doc Ophthalmol 109:87–100 24. Balachandran C, Klistorner AI, Billson F (2004) Multifocal VEP in children: its maturation and clinical application. Br J Ophthalmol 88:226–232 25. Slotnick SD, Klein SA, Carney T, Sutter EE, Dastamalchi S (1999) Using multi-stimulus VEP source localization to obtain a retinotopic map of human primary visual cortex. Clin Neurophysiol 110:1793–1800 26. Graham SL, Klistorner AI, Grigg JR, Billson FA (2000) Objective VEP perimetry in glaucoma: asymmetry analysis to identify early deficits. J Glaucoma 9:10–19 27. Hood DC, Zhang X, Greenstein VC, Kangovi S, Odel JG, Liebmann JM, Ritch R (2000) An interocular comparison of the multifocal VEP: a possible technique for detecting local damage to the optic nerve. Invest Ophthalmol Vis Sci 41:1580–1587
28. Klistorner AI, Graham SL (2001) Electroencephalogram-based scaling of multifocal visual evoked potentials: effect on intersubject amplitude variability. Invest Ophthalmol Vis Sci 42:2145–2152 29. Zhang X, Hood DC, Chen CS, Hong JE (2002) A signal-to-noise analysis of multifocal VEP responses: an objective definition for poor records. Doc Ophthalmol 104:287–302 30. Goldberg I, Graham SL, Klistorner AI (2002) Multifocal objective perimetry in the detection of glaucomatous field loss. Am J Ophthalmol 133:29–39 31. Fraser CL, Klistorner A, Graham SL, Garrick R, Billson FA, Grigg JR (2006) Multifocal visual evoked potential analysis of inflammatory or demyelinating optic neuritis. Ophthalmology 113:323e1–323e2. 32. Hood DC, Zhang X, Rodarte C, Yang EB, Ohri N, Fortune B, Johnson CA (2004) Determining abnormal interocular latencies of multifocal visual evoked potentials. Doc Ophthalmol 109:177–187 33. Ruseckaite R, Maddess T, Danta G, Lueck CJ, James AC (2005) Sparse multifocal stimuli for the detection of multiple sclerosis. Ann Neurol 57:904–913 34. Shimada Y, Horiguchi M, Nakamura A (2005) Spatial and temporal properties of interocular timing differences in multifocal visual evoked potentials. Vision Res 45:365–371 35. Sutter EE, Bearse MA (1999) The optic nerve head component of the human ERG. Vision Res 39:419–436 36. Hood DC, Ohri N, Yang EB, Rodarte C, Zhang X, Fortune B, Johnson CA (2004) Determining abnormal latencies of multifocal visual evoked potentials: a monocular analysis. Doc Ophthalmol 109:189–199 37. Granse L, Ponjavic V, Andreasson S (2004) Fullfield ERG, multifocal ERG and multifocal VEP in patients with retinitis pigmentosa and residual central visual fields. Acta Ophthalmol Scand 82:701–706 38. Klistorner AI, Graham SL, Grigg J, Balachandran C (2005) Objective perimetry using the multifocal visual evoked potential in central visual pathway lesions. Br J Ophthalmol 89:739–744 39. Miele DL, Odel JG, Behrens MM, Zhang X, Hood DC (2000) Functional bitemporal quadrantopia and the multifocal visual evoked potential. J Neuroophthalmol 20:159–162
40. Hood DC, Odel JG, Chen CS, Winn BJ (2003) The multifocal electroretinogram. J Neuroophthalmol 23:225–235 41. Hood DC, Zhang X, Greenstein VC, Kangovi S, Odel JG (2000) An interocular comparison of the multifocal VEP: a possible technique for detecting local damage to the optic nerve. Invest Ophthalmol Vis Sci 41:1580–1587 42. Hood DC, Thienprasiddhi P, Greenstein VC, Winn BJ, Ohri N, Liebmann JM, Ritch R (2004) Detecting early to mild glaucomatous damage: a comparison of the multifocal VEP and automated perimetry. Invest Ophthalmol Vis Sci 45:492–498 43. Greenstein VC, Thienprasiddhi P, Ritch R, Liebmann JM, Hood DC (2004) A method for comparing electrophysiological, psychophysical, and structural measures of glaucomatous damage. Arch Ophthalmol 122:1276–1284 44. Rodarte C, Hood DC, Yang EB, Grippo T, Greenstein VC, Liebmann JM, Ritch R (2006) The effects of glaucoma on the latency of the multifocal visual evoked potential. Br J Ophthalmol 90:1132–1136 45. Parisi V, Miglior S, Manni G, Centofanti M, Bucci MG (2006) Clinical ability of pattern electroretinograms and visual evoked potentials in detecting visual dysfunction in ocular hypertension and glaucoma. Ophthalmology 113:216–228 46. Hood DC (2003) Objective measurement of visual function in glaucoma. Curr Opin Ophthalmol 14:78–82 47. Bach M, Unsoeld AS, Philippin H, Staubach F, Maier P, Walter HS, Bomer TG, Funk J (2006) Pattern ERG as early glaucoma indicator in ocular hypertension – a long-term prospective study. Invest Ophthalmol Vis Sci 47:4888–4894
References 48. Halliday AM, McDonald WI, Mushin J (1972) Delayed visual evoked response in optic neuritis. Lancet 1:982–985 49. Hood DC, Odel JG, Zhang X (2000) Tracking the recovery of local optic nerve function after optic neuritis: a multifocal VEP study. Invest Ophthalmol Vis Sci 41:4032–4038 50. Guillery RW (1986) Neural abnormalities in albinos. Trends Neurosci 18:364–367 51. Apkarian P, Reits D, Spekreijse H, van Dorp D (1983) A decisive electrophysiological test for human albinism. Electroenceph Clin Neurophysiol 55:513–531 52. Hoffmann MB, Lorenz B, Morland AB, Schmidtborn LC (2005) Misrouting of the optic nerves in albinism: estimation of the extent with visual evoked potentials. Invest Ophthalmol Vis Sci 46:3892–3898 53. Creel D, Spekreijse H, Reits D (1981) Evoked potentials in albinos: efficacy of pattern stimuli in detecting misrouted optic fibers. Electroencephalogr Clin Neurophysiol 52:595–603 54. Hoffmann MB, Tolhurst DJ, Moore AT, Morland AB (2003) Organization of the visual cortex in human albinism. J Neurosci 23:8921–8930 55. Aine CJ, Supek S, George JS, Ranken D, Lewine J, Sanders J, Best E, Tiee W, Flynn ER, Wood CC (1996) Retinotopic organization of human visual cortex: departures from the classical model. Cereb Cortex 6:354–361
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Part III
Retinal Disorders
Chapter 10
Autoimmune Retinopathies Jennifer K. Hall, Nicholas J. Volpe
Core Messages
■ Autoimmune
retinopathies should be included in the neuroophthalmic differential diagnosis for subacute vision loss with minimal fundus changes. Particularly relevant are paraneoplastic retinopathies [cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), bilateral diffuse uveal melanocytic proliferation (BDUMP)], autoimmune-related retinopathy and optic neuropathy (ARRON), and the acute outer retinopathies with blind spot enlargement [acute idiopathic blind spot enlargement (AIBSE), multiple evanescent white dot syndrome (MEWDS), and acute zonal occult outer retinopathy (AZOOR)].
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■ Important historical factors include his-
tory of cancer, particularly small cell lung cancer or cancers of the reproductive tract, presence of photopsias, night blindness, or decreased vision in bright light. Subtle fundus changes may be present, including multiple evanescent white dots or foveal granularity in MEWDS, subtle red retinal pigment epithelium lesions in BDUMP, narrow retinal vessels in CAR or MAR, or mild disc edema in AIBSE or AZOOR. Automated visual fields, electroretinography, fluorescein angiography, and ocular coherence tomography can help to diagnose these retinopathies.
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10.1 Autoimmune Disease Overview Autoimmune diseases occur when the body’s immune response is directed against self antigens. The natural endpoint of a normal immune response (non-autoimmune) to a foreign antigen is to rid the body of the antigen. This cannot be achieved in autoimmunity, and thus the immune response to self antigen results in a sustained process which generally causes chronic inflammation and tissue damage. Specifically, damage can occur through local inflammation, immune complex formation, damage to cells bearing antigen, or stimulation or blockage of cell receptor function. Both antibodies and T-cells play a role in autoimmune disease. There are multiple mechanisms by which autoantibodies can cause
tissue damage. Binding of autoantibody to autoantigens on cell surfaces can trigger complementmediated destruction of the cell. Autoantibodies may also bind to receptors, either blocking or stimulating receptor function. Graves’ disease provides an example of autoantibody stimulation of receptor function. Thyroid hormone production is stimulated by autoantibodies binding to thyroid stimulating hormone receptors on thyroid cells. In myasthenia gravis, receptor function is blocked. Autoantibodies to the acetylcholine receptor in the neuromuscular junction bind to the receptor and block neuromuscular transmission, as well as causing depletion of the receptors. Autoantibodies can less commonly be directed against extracellular matrix molecules, as in Goodpasture’s syndrome, where they are directed against the basement membrane of the
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renal glomeruli. Although it is more difficult to demonstrate T-cell involvement than antibody involvement in the autoimmune response, T-cells have been implicated in the disease processes of Type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. A further distinction among autoimmune processes is whether they are organ specific, i.e., affecting only one organ such as the retina in cancer-associated retinopathy, or whether they affect multiple organ systems, as in systemic lupus erythematosus, sarcoidosis, or Wegener’s granulomatosis. Molecular mimicry is a common mechanism of autoimmune disease. Similarity between a foreign antigen and a self antigen stimulates an immune response against the self antigen (cross-reactivity), which continues to propagate due to the continued presence of the self antigen.
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10.2 Autoimmune Retinopathy Overview Many diseases affecting the retina are postulated or known to have an autoimmune component. The presentation of a subset of these disorders overlaps with the presentation of disorders affecting the optic nerve, such as compressive or inflammatory lesions, toxic, hereditary or nutritional optic neuropathies, and, in the cancer patient, direct spread of the malignancy, toxic effects of the treatment (chemotherapy or radiation), or carcinomatous meningitis. These entities can present with subacute vision loss and little or no findings on fundus examination. Autoimmune retinopathies that can present in a similar fashion include: paraneoplastic retinopathies such as cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and bilateral diffuse uveal melanocytic proliferation (BDUMP); non-paraneoplastic autoimmunerelated retinopathy and optic neuropathy (ARRON); acute outer retinopathies with blind spot enlargement [acute idiopathic blind spot enlargement (AIBSE), multiple evanescent white dot syndrome (MEWDS), and acute zonal occult outer retinopathy (AZOOR)] (Table 10.1). There are multiple other retinal disorders with confirmed or suspected autoimmune etiologies
that generally have a more distinguishing presentation, history, or associated systemic disease making them less likely to find their way into the neuroophthalmic differential diagnosis, including: birdshot retinochoroidopathy; sarcoid panuveitis; Behçet’s syndrome; diabetic retinopathy; retinopathies associated with systemic lupus erythematosus; periphlebitis retinae and pars planitis associated with multiple sclerosis, among others (Table 10.2).
10.3 Paraneoplastic Retinopathies There are multiple ways in which cancer can affect the visual system: directly; through cancer treatments; or remotely. Direct effects include metastasis, or secondary invasion of tumors located in or near the orbit or any part of the visual pathway. Cancer treatments, both chemotherapy and radiation, can cause vision loss. The third way that cancer can have an impact on vision is via a remote, or paraneoplastic, process in which autoimmune or possibly hormonal processes affect the retina or optic nerve secondary to a neoplasm located elsewhere in the body. This is thought to be mediated via molecular mimicry; similarity between a tumor antigen and a component of the target organ results in misplaced, antibody-mediated attack by the immune system on the target organ. Specific paraneoplastic syndromes have been identified in which the target organ is the retina or choroid, including cancerassociated retinopathy (CAR), melanoma-associated retinopathy (MAR) and bilateral diffuse uveal melanocytic proliferation (BDUMP). Although BDUMP is thought to be paraneoplastic, an autoimmune etiology has not been demonstrated.
10.3.1 Cancer-Associated Retinopathy Cancer-associated retinopathy (CAR) is most often associated with small cell lung cancer (twothirds of cases). Multiple other cancers have been associated with CAR including ovarian, cervical, uterine, and breast. Less common associations
10.3 Paraneoplastic Retinopathies
Table 10.1. Autoimmune retinopathies relevant to the neuroophthalmic differential diagnosis Paraneoplastic
Cancer-associated retinopathy (CAR) Melanoma-associated retinopathy (MAR) Bilateral diffuse uveal melanocytic proliferation (BDUMP)
Non-paraneoplastic
Autoimmune-related retinopathy and optic neuropathy (ARRON)
Acute outer retinopathies with blind spot enlargement
Acute idiopathic blind spot enlargement (AIBSE) Multiple evanescent white dot syndrome (MEWDS) Acute zonal occult outer retinopathy (AZOOR)
Table 10.2. Autoimmune retinopathies with distinguishing features Retinopathy
Distinguishing features
Birdshot retinochoroidopathy
Women>men Vitritis, ±disc edema, vascular sheathing, yellow ovoid chorioretinal lesions (esp. nasally), ERG reduced or extinguished 90% HLA-A29
Systemic lupus erythematosus
Multi-system involvement 8–10× more common in women Skin, serosal surfaces, central nervous system, kidneys, blood cells Eye: central serous chorioretinopathy, hypertensive retinopathy, vascular occlusive retinopathy (combined occlusion central retinal artery and vein) Circulating immune complexes and autoantibodies 99% have ANAs
Sarcoidosis
10× more common in African Americans than Caucasians Male=female Multi-system: lung, liver, CNS Eye: panuveitis: Koeppe/Busacca nodules, mutton-fat keratic precipitates, synechiae, secondary glaucoma, cystoid macular edema, clumps of cells in vitreous (snowballs), retinal vasculitis, vitritis, retinal/choroidal granulomas, retinal neovascularization, optic disc edema, optic nerve granulomas
Behçet’s syndrome
Aphthous oral ulcers, genital ulcers, acute iritis (with hypopyon), retinal vasculitis, focal retinal necrosis, intraretinal hemorrhages, vitritis Men>women Associated with HLA-B51
Multiple sclerosis (MS)
Periphlebitis, pars planitis Periphlebitis and sheathing present in up to 20% of MS patients
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include lymphoma, prostate, bladder, laryngeal, colon and hepatocellular cancers [9, 10]. In about half of the cases, CAR is diagnosed prior to the malignancy.
10.3.1.1 Clinical Presentation Cancer-associated retinopathy typically presents with subacute vision loss, photopsias, and night-blindness. The clinical examination may appear normal, or there may be some narrowing of retinal vessels and/or vitritis (Fig. 10.1).
10.3.1.2 Diagnostic Studies 10.3.1.2.1 Visual Field
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Visual field defects associated with CAR usually begin in the mid-periphery, therefore Goldmann kinetic perimetry is the formal visual field modality of choice. Typical mid-peripheral defects tend to progress to ring scotomas (Fig. 10.2).
10.3.1.2.2 Electroretinogram (ERG) The ERG shows diffuse loss, most marked under scotopic conditions.
Fig. 10.1. Attenuated retinal vessels in cancer-associated retinopathy
10.3.1.2.3 Laboratory Testing Cancer-associated retinopathy has been associated with multiple antibodies, but primarily with an autoantibody to a 23-kDa protein identified as recoverin. A commercial test is available for this antibody. The diagnosis of CAR is a clinical one, however, and should not rely on the identification of this antibody.
10.3.1.3 Pathophysiology Keltner and associates [31] first proposed an autoimmune mechanism for paraneoplastic retinopathy in 1983, when they demonstrated that the serum from a patient with cervical cancer and progressive blindness, with ring scotomas and a flat electroretinogram (ERG), contained antibodies that reacted with human retinal photoreceptors [31]. Subsequently, Western blot and enzyme-linked immunosorbent assays identified a 23-kDa antigen that bound to antibodies from serum of patients with CAR [48]. This protein, which became known as the CAR antigen, was further characterized using antibodies from the serum of patients with CAR to identify the gene that encoded it from a cDNA library of human retina. Analysis of the nucleotide sequence revealed 90% homology with a bovine homolog of the protein recoverin, a calcium-binding protein found in photoreceptor cells [50]. Recoverin production has been demonstrated in small cell lung neoplasms, providing a basis for the molecular mimicry mechanism of autoimmunity [36]. Recoverin, a member of the EF-hand superfamily of calcium-binding proteins, plays a role in the visual transduction cycle [46]. Evidence suggests that recoverin functions in the termination of the transduction cascade via regulation of rhodopsin phosphorylation [46]. Its role was previously thought to involve the recovery phase of the cycle via activation of guanylate cyclase in response to declining intracellular calcium levels. This role, however, has recently been attributed not to recoverin, but to a family of guanylate cyclase activating proteins [46]. Recoverin functions in a calcium-dependent manner, to inhibit rhodopsin phosphorylation, which is a step in the termination of the phototransduction cascade. Direct interaction between recoverin and rhodopsin
10.3 Paraneoplastic Retinopathies
Fig. 10.2. Ring scotomas typical of cancer-associated retinopathy
kinase, the molecule that directly regulates rhodopsin phosphorylation, has been demonstrated in vitro [8]. Inhibition of rhodopsin phosphorylation by recoverin has also been demonstrated in vitro [30]. Recoverin antibodies have been shown to cause photoreceptor cell death by apoptosis. The apoptosis occurs in vitro via a mitochondrial pathway mediated by entry of all or part of the antibody into retinal cells [45]. It is coupled to an antibody-mediated increase in intracellular calcium, which is common component of apoptotic pathways. Adamus and associates [2] demonstrated that exposure of retinal cells to the anti-recoverin antibody causes an increase in intracellular calcium in vitro. Other mediators of apoptosis identified via in vitro studies of retinal cells treated with anti-recoverin antibody included bcl-2 family proteins, cytochrome c, caspase 9 and caspase 3 [2]. Caspase enzymes (cysteine-containing aspartate-specific proteases) are commonly involved in apoptotic pathways in general, although of the 14 subtypes found in human cells, select subtypes are involved depending on cell type and inciting event. Elucidating the pathway of recoverin-antibody-induced cell death allows for the potential development of protective agents, such as calcium channel blockers and caspases inhibitors, which are under investigation. Retinal cells exposed to the calcium channel blocker nifedipine and anti-recoverin antibody were found to have a blunted increase in intracellular calcium, modified changes in the mitochondrial pathway, and ultimately decreased
apoptosis [2]. Calcium channel blockers therefore hold promise as therapeutic agents against CAR. Caspase inhibitors, which have been shown to diminish cell death in animal models, are another class of potential therapeutic agents [34]. The recoverin antibody is present in the serum of most patients with CAR, and its pathogenicity has been well characterized. However, additional factors are involved which are not fully understood. While most patients with CAR have autoantibodies to recoverin, other antigens have been identified in these patients, including alpha-enolase and heat shock cognate protein 70 (HSC70), although only the recoverin antibody has been demonstrated to cause photoreceptor cell death [13]. Additionally, tumors can produce recoverin and not cause CAR [40, 44]. An explanation is also needed for how the CAR antibody crosses the blood–retina barrier to reach photoreceptor cells, if the in vitro studies demonstrating endocytosis of the antibody as a prerequisite for apoptosis hold true in vivo. Bazhin and associates [4] have suggested that this issue may explain why CAR is such a rare condition. They conjecture that a second event may be needed to allow access of these molecules beyond the blood–retinal barrier, and this may explain why not all patients with the CAR antibody develop retinopathy, and may also provide a role for the other antibodies identified in CAR patients. Another explanation for the presence of CAR antibodies in patients without CAR may be attributable to the particular epitope to which the antibody is directed.
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10.3.1.4 Treatment
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Currently, the mainstay therapy for CAR, and indeed for all of the paraneoplastic retinopathies, is systemic corticosteroids. Reported cases indicate that steroids may cause a mild transient improvement in visual fields and/or acuities, or arrest further deterioration [9]. Other treatment modalities include intravenous immunoglobulins (IVIg) and plasmapheresis. Scattered case reports are inconclusive as to the effectiveness of these treatments. Treatment of the primary tumor does not appear to alter the course of the retinopathy [9]. Possible future therapies include calcium channel blockers and caspase inhibitors. Patients with CAR should be followed with serial visual fields, acuities, ERG and antibody titers. Unfortunately, the course of CAR, although variable, is generally characterized by rapidly progressive vision loss resulting in severe bilateral vision loss, often within weeks or months of onset.
Summary for the Clinician
■ Most common association: small cell lung cancer. ■ Also associated with cancers of the female reproductive tract. ■ May be diagnosed prior to malignancy. ■ Presents with subacute vision loss, photopsias, night-blindness. ■ May have normal fundus, narrowing of vessels, or vitritis. ■ Visual field: mid-peripheral defects progressing to ring scotoma. ■ ERG: diffuse loss particularly under scotopic conditions. ■ Antibody to photoreceptor cell antigen, recoverin (“CAR antigen”) commonly involved. Commercial test available for “CAR antibody.” Treatment: corticosteroids. Possible future treatments: calcium channel blockers, caspase inhibitors. Course: rapidly progressive bilateral vision loss.
■ ■ ■ ■
10.3.2 Melanoma-Associated Retinopathy Melanoma-associated retinopathy (MAR) is a paraneoplastic retinal degeneration associated with cutaneous melanoma. The diagnosis of melanoma generally occurs months to years prior to the onset of MAR. A series of 62 patients with MAR revealed an average time from diagnosis of melanoma to diagnosis of MAR of 3.6 years [32]. Two of these patients were diagnosed with melanoma subsequent to the onset of MAR. One patient has been reported to develop MAR 19 years after resection of cutaneous melanoma [41]. The average age on onset was 57.5 years, with a range of from 30 to 78 years. Men were affected more than women (33/40 versus 7/40; the gender was not known for 22 of the patients) [32]. Most patients with MAR have metastatic melanoma although in a review of 12 MAR patients, 3 had no evidence of metastasis [32].
10.3.2.1 Clinical Presentation Patients with MAR present with acute onset of night-blindness, photopsias, and floaters. Vision at presentation is usually better than 20/40. In Keltner’s review [32], 82% had presenting visual acuity better than 20/60. Dyschromatopsia, vitritis, retinal vessel attenuation and optic nerve pallor may be apparent.
10.3.2.2 Diagnostic Studies 10.3.2.2.1 Visual Field Visual field testing at presentation can reveal central scotomas, generalized constriction, or arcuate defects.
10.3.2.2.2 ERG/EOG The ERG findings in MAR are highly specific, showing a normal a-wave and the absence of the b-wave under dark-adapted conditions (socalled electronegative ERG). This pattern is suggestive of bipolar cell dysfunction. The pattern is
similar to the ERG pattern seen in patients with congenital stationary night-blindness. A subset of MAR patients show decreased a- and b-wave amplitudes, suggesting photoreceptor dysfunction in addition to bipolar cell dysfunction [32]. Some MAR patients have abnormal EOGs [31].
10.3.2.3 Pathophysiology The mechanism of MAR is largely conjecture at this point. There is compelling evidence that autoimmune attack of retinal bipolar cells plays a central role. Serum from patients with MAR has been shown by immunocytochemical techniques to react with retinal bipolar cells [6, 37]. Histologic examination of the retina in MAR patients demonstrates bipolar cell degeneration [21, 49]. Serum from patients with MAR injected into monkeys induces retinal bipolar cell degeneration [33]. Consistent with these findings is a typical decreased ERG b-wave in MAR patients. Although no MAR-specific antigen has been identified, a mechanism based on molecular mimicry, as in CAR, has been postulated. Decreased ERG a- and b-wave amplitudes and serum reactivity with photoreceptor cells in some MAR patients suggest that a subset of these patients has photoreceptor dysfunction in addition to bipolar cell dysfunction [7, 32].
10.3 Paraneoplastic Retinopathies
antibodies [32]. However, antibody production may persist despite lowering of tumor load due to continued propagation by the self-antigen in the retina, as is frequently the case in autoimmune disease. One concern regarding treatment for MAR, and indeed all of the paraneoplastic retinopathies, with immunomodulatory agents is that although they may decrease circulating antibodies that are harmful to the retina, these same antibodies may be effective tools fighting against the malignancy. It is not clear whether antibodies induced by these tumors are helpful or harmful to the cancer. The course of MAR is generally more moderate than that of CAR. Patients should be followed with serial visual fields, visual acuities and ERGs. Table 10.3 compares characteristics of MAR and CAR.
Summary for the Clinician
10.3.2.4 Treatment As with CAR, the mainstay of treatment is with systemic corticosteroids. Again, while other therapies have been tried, there has been no rigorous evaluation. Keltner and colleagues [32] found 7/62 patients to have visual improvement on a various therapies, including IVIg, cytoreductive surgery, and prednisone. These authors find cytoreductive surgery to be a promising direction for future therapy, citing four patients who had visual improvement following either cytoreductive surgery alone, or cytoreductive surgery in combination with IVIg. Suggesting a theoretical basis for this therapy, they note that decreasing the tumor load, and thereby decreasing tumor production of antigens that may mimic retinal antigens, may decrease serum levels of pathogenic
■ Associated with cutaneous melanoma. ■ Usually diagnosed after malignancy. ■ Presents with acute onset night-blindness, photopsias, floaters. ■ May have normal fundus, narrowing of vessels, vitritis, or optic nerve pallor. ■ Visual field: central, arcuate or generalized constriction. ■ ERG: absence of b-wave under scotopic conditions. ■ Unidentified antibody to bipolar cells. ■ Treatment: corticosteroids. ■ Course: slower progression than CAR. 10.3.3 Bilateral Diffuse Uveal Melanocytic Proliferation
Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic retinopathy with 28 cases reported in the literature [42]. Among these cases, the mean age of diagnosis was 64, ranging from 34 to 89 years [42]. It is most commonly associated with lung and retroperitoneal cancers in men, and cancers of the reproductive tract in women. Diagnosis of BDUMP may occur prior to that of the primary cancer. In
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Autoimmune Retinopathies Table 10.3. Comparison of characteristics of cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR) CAR
MAR
Subacute vision loss
Night-blindness
Photopsias
Photopsias
Night-blindness
Floaters
Signs
May have vitritis, narrow retinal vessels
May have vitritis, narrow retinal vessels, optic disc pallor
Visual field
Mid-peripheral scotoma progressing to ring scotoma
Central scotoma, arcuate or generalized constriction
ERG
Diffuse loss, Rods > cones
Loss of scotopic b-wave
Retinal target
Photoreceptor cells
Bipolar cells
Disease course
Relentless progression to bilateral blindness weeks to months after diagnosis
Slower progression
Presentation
Normal cone amplitudes
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one review, 10/16 cases presented 3–12 months prior to diagnosis of the primary cancer [19]. The pathophysiology of BDUMP is not clearly understood; compelling evidence of an autoimmune etiology is lacking.
10.3.3.1 Clinical Presentation Patients generally present with subacute loss of vision. The classic fundus findings are bilateral subtle red retinal pigment epithelial lesions which often precede development of multiple subretinal pigmented and non-pigmented slightly elevated melanocytic uveal tumors, which may appear similar to choroidal nevi. Serous retinal detachments, uveitis, and rapidly progressing cataracts may develop subsequently [19]. Dilated episcleral vessels, pigmented cells in the anterior chamber and/or vitreous, pigmented keratic precipitates, a shallow anterior chamber and glaucoma may also be apparent [3, 19, 43]. Patients may also develop pigmented lesions of the skin or mucous membranes. Out of the 28 reported
cases of BDUMP, 26% of patients exhibited such lesions [42].
10.3.3.2 Diagnostic Studies 10.3.3.2.1 Fluorescein Angiography Early hyperfluorescence of the subtle, red retinal pigment epithelial lesions is classic, and virtually pathognomonic [19].
10.3.3.3 Pathophysiology The underlying mechanism of BDUMP involves multifocal areas of retinal pigment epithelium (RPE) destruction (red patches) and uveal proliferation of melanocytes (elevated lesions), although the pathogenesis is not clear. The degree of retinal pigment epithelial destruction is out of proportion to the amount of underlying choroidal infiltration. Gass and colleagues [19] suggest that
10.4 Autoimmune-Related Retinopathy and Optic Neuropathy
additional immune or toxic factors may account for the extensive outer retinal and RPE damage. Whether the melanocytic lesions have malignant potential is controversial. In most cases, pathologic specimens reveal a benign-appearing proliferation of spindle-shaped cells. A minority, however, have an appearance suggestive of malignancy [42]. The lack of any reported cases of metastasis supports a benign nature to these proliferations. This could, however, be related to the poor prognosis associated with this disease, and therefore the short time over which metastasis could declare itself. The mean survival time of these patients is 16 months [19]. Additionally, a protein commonly overexpressed in uveal melanomas, p53, does not appear to be associated with BDUMP melanocytic proliferation, as evidenced by lack of staining with antibodies to p53 [35]. Histologic specimens reveal diffuse uveal tract thickening [42]. Neither the stimulus for melanocytic proliferation nor the explanation for retinal pigment epithelial and choroidal destruction out of proportion to the underlying uveal tumor has been determined. Normal uveal melanocytes rarely, if ever, proliferate. However, it is not uncommon to find nevus cells, pigmented or unpigmented, in the uveal tract that do have the capacity to proliferate, often in response to hormonal signals. Gass and colleagues [19] have suggested that BDUMP patients may have congenital, bilateral, non-pigmented, melanocytic uveal nevi that proliferate secondary to hormones secreted by the distant carcinoma. They suggest that the extent of RPE and outer retinal changes needs an explanation in addition to the presence of underlying melanocytic proliferation, and is possibly due to toxic and/or immune factors secondary to interplay between the carcinoma, uveal tumors and outer retinal/RPE elements.
10.3.3.4 Treatment Radiation or systemic steroids may cause transient improvement in the serous retinal detachment. However, no effective treatment has yet been found to halt the characteristic progressive visual loss, which may proceed despite treatment of the primary cancer [19].
Summary for the Clinician
■ Autoimmune? ■ Associated with lung and retroperitoneal
cancers in men, cancers of the reproductive tract in women. Presents with subacute loss of vision. Early: subtle red retinal pigment epithelial lesions. Later: multiple subretinal pigmented and non-pigmented elevated lesions. Serous retinal detachments, uveitis, cataracts may develop. Fluorescein angiography: early hyperfluorescence of red RPE lesions. Treatment: systemic corticosteroids may improve serous retinal detachments. Course: progressive vision loss.
■ ■ ■ ■ ■ ■ ■
10.4 AutoimmuneRelated Retinopathy and Optic Neuropathy The term autoimmune-related retinopathy and optic neuropathy (ARRON) has been used to describe a number of patients with a clinical presentation, ERG findings, and disease course similar to CAR or MAR, but no underlying cancer [23, 34, 38, 52]. Disease progression is generally slower than in CAR [38]. One or multiple anti-retinal antibodies have been identified in these patients, including anti-recoverin antibodies, although their pathogenic significance is in question. One such patient, described by Whitcup et al. [52], was found to have anti-recoverin antibodies and serum which demonstrated immunohistochemical staining of photoreceptor cells, bipolar cells, and the outer plexiform layer. Heckenlively and associates [23] described ten CAR-like patients who carried the diagnosis of retinitis pigmentosa, and demonstrated immunoreactivity against multiple retinal antigens, including recoverin. Mizener and colleagues [38] reported two patients with a CAR-like syndrome whose serum demonstrated antibody staining the retinal inner plexiform layer. While reports of such cases emerge, this syndrome
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is not well understood, and the role of autoimmunity has been challenged [1]. The patients described by Heckenlively et al. [23] possessed serum antibodies against a variety of proteins; Adamus [1] suggests that this differentiates them from typical CAR, and calls into question the pathogenic importance of any particular antibody. She also notes the common correlation between disease activity and autoantibody levels in autoimmune disease in general, and CAR in particular, and contrasts this with the lack thereof demonstrated in the cohort described by Heckenlively et al. [23]. It is also possible that, despite diligent search, a cancer remains undiscovered in these patients. Indeed it would be prudent to search exhaustively for a malignancy in a patient that presents with vision loss, photopsias, visual field defects, and ERG abnormalities, particularly if anti-recoverin antibodies are identified.
Summary for the Clinician
■ Similar to CAR or MAR but no associated malignancy. ■ Multiple antibodies identified, including “CAR antibody.” ■ Generally progresses more slowly than CAR.
10.5 Acute Outer Retinopathies with Blind Spot Enlargement Several disorders of the retina and/or choroid are associated with enlarged blind spots (Table 10.4). While some of these conditions have examination findings sufficient to explain this visual field defect, such as a markedly edematous or optic nerve (displacing peripapillary retina), ophthalmoscopically apparent choroidal or retinal peripapillary abnormalities, some of the outer retinopathies do not [5]. In fact, acute idiopathic blind spot enlargement (AIBSE), multiple evanescent white dot syndrome (MEWDS), and acute zonal occult outer retinopathy (AZOOR) often have minimal fundus findings. These disorders have a place in the neuroophthalmologist’s differential diagnosis of vision loss with a relatively normal fundus exam. There is continued controversy over whether AIBSE, MEWDS, and AZOOR, and indeed several other syndromes including acute macular neuroretinitis (AMN), multifocal choroiditis (MFC), puncatate inner choroidopathy (PIC), and presumed ocular histoplasmosis are part of a spectrum of a single disease or distinct disease entities.
Table 10.4. Inflammatory retinopathies/choroidopathies that may have enlarged blind spot AIBSE
Acute idiopathic blind spot enlargement
MEWDS
Multiple evanescent white dot syndrome
AZOOR
Acute zonal occult outer retinopathy
MFC
Multifocal choroiditis
POHS
Presumed ocular histoplasmosis syndrome
PIC
Punctate inner choroidopathy
Birdshot choroidopathy DUSN Serpiginous choroiditis
Diffuse unilateral subacute neuroretinopathy
10.5 Acute Outer Retinopathies with Blind Spot Enlargement
10.5.1 Acute Idiopathic Blind Spot Enlargement 10.5.1.1 Clinical Presentation In 1988, Fletcher and associates [15] reported seven patients who presented with enlarged blind spots and photopsias with no significant disc swelling. All of these patients had normal fluorescein angiograms, two had abnormal multifocal ERGs, and two had peripapillary pigmentary abnormalities. This constellation of findings became known as AIBSE, and is characterized by acute onset of photopsias and enlarged blind spot without marked disc swelling. The condition tends to be unilateral. The majority of patients are young women. In a review by Volpe and colleagues [51] of 27 patients with AIBSE, all were women, ranging in age from 19 to 53 years. Though decreased vision is a common presenting complaint, 16/27 patients in this review had normal visual acuity. Patients may have dyschromatopsia (9/27), an afferent pupillary defect (APD) (8/27), mild disc edema, hyperemia or peripapillary pigmentary changes, and, occasionally, multiple white lesions similar to those seen in MEWDS (5/27). There is a high rate of misdiagnosis in AIBSE. Other conditions that can be confused with AIBSE, and in fact should be in the differential diagnosis, include: migraine (photopsias); optic neuritis (sudden onset of visual field defect in young woman); papilledema (enlarged blind spot); and chiasmal lesion (temporal field defect).
10.5.1.2 Diagnostic Studies 10.5.1.2.1 Visual Field All patients with AIBSE have enlarged blind spots (Figs. 10.3, 10.4). There is wide variability in the size of the blind spot; however, steep borders of the field defect are characteristic of this disorder. The enlarged blind spot seen in AIBSE can appear similar to a temporal defect seen in chiasmal disease.
10.5.1.2.2 ERG Full-field ERG amplitudes are generally within normal in patients with AIBSE. However, intereye asymmetry has been observed, with the affected eye having lower amplitudes [51] (Fig. 10.5). Focal ERGs directed at the peripapillary retina tend to be abnormal [15, 51]. In the review by Volpe and associates [51], eight out of the nine patients who had focal ERGs showed such abnormalities.
10.5.1.2.3 Fluorescein Angiography Fluorescein angiography may show disc staining, which may not correlate with clinically apparent optic disc edema. Out of 27 patients in the Volpe review [51], 12 had disc staining on fluorescein angiography, while 3 of these 12 and normal appearing discs by ophthalmoscopy. Late-staining retinal pigment lesions may also be seen. These lesions do not correspond to white lesions sometimes seen on examination.
10.5.1.3 Pathophysiology Abnormal ERG results from focal ERGs directed at the peripapillary retina suggest that retinal dysfunction in this region is responsible for the enlarged blind spot. The pathophysiology of AIBSE is poorly understood. It has been known to occur in members of the same family; however, no defined heritable pattern has been identified. The acute presentation and sporadic occurrence of AIBSE have led to speculation of an autoimmune or infectious etiology. The prevalence among young women and occasional recurrence (6 out of 27 patients had recurrences in the review by Volpe and colleagues [51]) fit the profile of autoimmune disease, although perhaps a higher recurrence rate would be expected in an autoimmune condition. No specific antibody or infectious agent has been identified. The common finding of disc staining on fluorescein angiography suggests the possibility of optic nerve inflammation in addition to presumed
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10
Fig. 10.3. Enlarged blind spot – Humphrey visual field – right eye
10.5 Acute Outer Retinopathies with Blind Spot Enlargement
Fig. 10.4. Enlarged blind spot – Goldmann visual field – right eye
Fig. 10.5. Full-field ERG showing inter-eye asymmetry in acute idiopathic blind spot enlargement (AIBSE), with the affected eye having lower amplitudes
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outer retinal dysfunction. This staining, however, may simply represent increased vascularity secondary to contiguous inflammation.
10.5.1.4 Treatment There is no treatment for AIBSE. The photopsias tend to resolve over time. The enlarged blind spot, while occasionally improving, generally persists.
Summary for the Clinician
10
■ Unilateral. ■ Usually affects young women. ■ Presents with photopsias and enlarged blind spot. ■ May have mild disc edema. ■ May have an APD and/or dyschromatopsia. ■ Visual field: enlarged blind spot with steep borders. ■ ERG: abnormal focal ERG directed at peripapillary retina. ■ Etiology: suspected autoimmune/viral/ genetic. ■ Treatment: none. ■ Course: persistence of blind spot. 10.5.2 Multiple Evanescent White Dot Syndrome 10.5.2.1 Clinical Presentation
Multiple evanescent white dot syndrome (MEWDS) was first described in 1984, by two independent research groups: Jampol et al. [28] and Takeda et al. [47]. They reported series of patients presenting with acute unilateral vision loss, scotomas, and multiple, white fundus lesions. The majority of patients were women: 10 of the 11 patients were women in Jampol’s series [28]. A recent review of the literature shows 51 out of 62 reported cases to be women, with an average age of 27 years, ranging from 14 to 47 years [12]. In Jampol et al.’s study, nearly half of 11 patients with MEWDS had had a flu-like ill-
ness prior to developing MEWDS [28]. In addition to complaining of decreased vision and dark spots, most patients describe photopsias (flickering lights). Fundus exam may reveal, often subtle, multiple white lesions, often extending centripetally from the disc, with particular concentration between the arcades, however sparing the fovea. The lesions tend to disappear altogether within 4–6 weeks, and during this time may fade and reappear in other locations. They have been described as “dots and spots” where the dots are smaller, measuring approximately 100 µm, and the spots are larger, at approximately 200 µm in diameter. Clinical examination in conjunction with fluorescein or indocyanin green angiography and ocular coherence tomography (OCT) suggests involvement of the neurosensory retina, RPE, and choroid [22, 26]. Other examination findings include foveal granularity of the RPE, and less commonly mild disc edema, vascular sheathing, or vitritis (Figs. 10.6, 10.7). An afferent papillary defect may be present. Patients may have dyschromatopsia.
10.5.2.2 Diagnostic Studies 10.5.2.2.1 Visual Field Visual field testing may reveal an enlarged blind spot. Other less common defects include central, cecocentral or arcuate scotomas. As with AIBSE, the field defect is generally more extensive than would be expected based on the clinical appearance of the retina or optic nerve.
10.5.2.2.2 Fluorescein Angiography The classic finding on fluorescein angiography is a middle-phase wreath-like pattern of hyperfluorescence surrounding the fovea, corresponding to the white lesions seen on ophthalmoscopy, although more lesions are evident angiographically. Gross and colleagues [22] demonstrated hyperfluorescence of most dots during the choroidal-filling stage, localizing them to the RPE or inner choroid; however, some dots fluoresced during the retinal arteriolar filling stage, suggesting a more anterior location in the retina. The
10.5 Acute Outer Retinopathies with Blind Spot Enlargement
Fig. 10.6. Foveal granularity in multiple evanescent white dot syndrome (MEWDS)
Fig. 10.7. Higher magnification of foveal granularity
angiographic appearance of the larger lesions, “spots,” was variable in this study.
tent deep choroidal reflectivity. Seven weeks after presentation, the subretinal lesion was resolved; however, the choroidal reflectivity remained 5 months after presentation, suggesting greater choroidal involvement in this disorder than previously thought. Kanis and van Norren [29] report evidence of temporary disruption of foveal cones by both OCT and foveal reflection analyzer techniques.
10.5.2.2.3 Indocyanine Green Angiography Indocyanine green (IGC) angiography demonstrates multiple hypofluorescent lesions larger and more numerous than those evident clinically. These may be indicative of inflammatory lesions in the choriocapillaris [24, 39]. Some patients with blind spot enlargement exhibit peripapillary hypofluorescence, the resolution of which corresponds to the resolution of their field defect [12].
10.5.2.2.4 ERG Full-field ERG may show diffuse photoreceptor dysfunction during the acute phase of the illness, implicating involvement of the photoreceptor/ RPE complex in the disease process.
10.5.2.2.5 Ocular Coherence Tomography Jampol [26] reported OCT findings suggestive of transient accumulation of material in the subretinal space corresponding to white lesions (domeshaped reflective lesion), with underlying, persis-
10.5.2.3 Pathophysiology The pathogenesis of MEWDS is incompletely understood. A viral trigger has been postulated based on the acute onset and a frequent preceding viral illness. An autoimmune etiology would fit with this scenario, and is supported further by the tendency to occur in young women, sporadic occurrence, and occasional recurrence. Although elevated levels of immunoglobulins have been detected in the serum of patients with MEWDS, no histochemical evidence of antibody binding to retinal proteins has been demonstrated [11, 25]. Additional pieces of the puzzle that remain to be united include ICG angiography and OCT findings suggestive of choroidal inflammation, and OCT, fluorescein angiography, ERG, and reflection analyzer techniques findings indicative of transient outer retinal disturbances [22, 26, 29]. Additionally, the optic nerve may be involved in MEWDS either via direct inflammation or secondary inflammation. Dyschromatopsia, visual
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field defects, an afferent papillary defect, and optic nerve head staining on fluorescein angiography, which may be present in patients with MEWDS, could be explained by extensive retinal involvement; however, direct inflammation of the nerve/ retinal ganglion cell layer, or secondary inflammation due to adjacent retinal/vascular inflammation could also be responsible.
10.5.2.4 Treatment
10
Most patients with MEWDS recover fully over 3– 10 weeks. Some may experience persistent field defects. MEWDS occasionally recurs: 5 out of 62 patients have been reported to experience recurrences [12]. There is currently no effective treatment; however, in a report of one patient who had multiple recurrences of MEWDS (nine recurrences over 7 years) cyclosporin therapy was found to reduce the recurrence rate. Over a 2year period, recurrences occurred only when the cyclosporin was discontinued or when the dose was decreased [14].
Summary for the Clinician
■ Unilateral. ■ Usually affects young women. ■ Presents with acute unilateral vision loss, scotomas, and photopsias. ■ Subtle, transient white fundus lesions. ■ May have foveal granularity, mild disc edema, vascular sheathing, vitritis. ■ May have an APD and/or dyschromatopsia. ■ Visual field: enlarged blind spot common. May have central, cecocentral or arcuate defect. ERG: full-field ERG may show diffuse photoreceptor dysfunction. Fluorescein angiography: middle-phase wreath pattern surrounding fovea. Etiology: suspected autoimmune/viral/ genetic. Treatment: none. Course: generally full recovery in 3– 10 weeks.
■ ■ ■ ■ ■
10.5.3 Acute Zonal Occult Outer Retinopathy 10.5.3.1 Clinical Presentation Acute zonal occult outer retinopathy (AZOOR) was first described in 1993 by Gass, who reported a series of 13 patients, 10 of whom were young women, who presented with acute loss of peripheral vision in one or both eyes, photopsias, and minimal or no fundus abnormalities. The syndrome was further characterized by recurrences in the same or fellow eye, ERG abnormalities, and persistence of both photopsias and visual field defects, sometimes associated with fundus changes later in the disease course [17, 20]. While the term AZOOR sometimes refers to a complex of diseases including variably MEWDS, AIBSE, multifocal choroiditis, punctuate inner choroidopathy, acute macular neuroretinopathy; and pseudo-presumed ocular histoplasmosis syndrome, Gass and colleagues [20] reviewed 51 patients with AZOOR, in 2002, excluding all of the above conditions excepting AIBSE. 20% of these patients had a preceding viral-like illness days or weeks prior to the onset of the visual symptoms [20]. Vision loss was often described as “dark blind spots.” Other findings include: 88% of the patients described photopsias; 90% of the patients were aware that their vision was worse in the bright light; and 24% had an APD within a few weeks of presentation [20]. While no patients had vitritis within 1 week of onset, vitreous cell was observed in 57% of eyes weeks to months later [20]. No fundus changes related to AZOOR were noted in 91% of eyes in this review [20].
10.5.3.2 Diagnostic Studies 10.5.3.2.1 Visual Field Visual field defects in AZOOR are variable, and include from most frequent to least frequent: blind spot enlargement, ring scotomas, hemianopic scotomas, generalized constriction, arcuate defects, and multiple isolated scotomas. The blind spot was involved in 87% of eyes in the review by Gass et al [20].
10.5 Acute Outer Retinopathies with Blind Spot Enlargement
10.5.3.2.2 ERG In the original cohort described by Gass [17], most eyes showed mild to moderate reduction in rod and cone amplitudes. Out of 13 of these patients, 11 had the ERG more than a month into the disease course [17]. In their review of 51 patients, Gass and colleagues report variable ERG findings with 55/90 eyes showing scotopic and photopic dysfunction, and 16/55 showing photopic dysfunction, and 8/55 eyes showing only scotopic dysfunction [20]. Jacobson et al. [25] reported full-field ERG abnormalities on a cohort of 24 patients with the AZOOR complex of disease, including MEWDS, multifocal choroiditis, acute macular neuroretinopathy, and pseudo-presumed ocular histoplasmosis syndrome [25]. Francis and associates [16] reported an ERG and EOG analysis of 28 patients who fit the criteria for AZOOR originally presented by Gass in 1993. These patients were predominantly young females (86% female), whose condition was characterized by persistent, usually temporal field loss, photopsias, and normal appearing fundus at presentation. Involvement of both eyes occurred in 46%; 4 out of the 15 who presented unilaterally subsequently developed second eye involvement, and 46% of these patients carried a previous diagnosis of a white dot syndrome [16]. ERG findings demonstrated diffuse RPE/photoreceptor dysfunction, and were suggestive of greater cone than rod involvement [16]. Francis et al. [16] additionally postulated inner retinal involvement based on the abnormal 30 Hz flicker ERG results.
10.5.3.2.3 EOG Gass and colleagues [20] report abnormal EOG results in 9/13 eyes tested. Francis et al. [16] found consistently abnormal EOG results, which, they note in the context of their ERG findings, is suggestive of RPE involvement in this disease [16].
10.5.3.3 Pathophysiology The pathogenesis of AZOOR is unknown. As with MEWDS and AIBSE, the predominance among
young women is suggestive of an autoimmune etiology. This is further supported by the presence of at least one autoimmune disease in 28% of the 51 patients reviewed by Gass et al [20]. This is compared to no autoimmune disease noted in an age- and sex-matched control group [20]. No immunocytochemical studies have directly linked AZOOR with an autoimmune etiology. Gass has postulated that AZOOR may be precipitated by a virus infecting photoreceptor cells. Photoreceptor destruction may then be triggered by a delayed host immune response to the virus [18]. It is relevant to this hypothesis that 20% of patients in Gass’s review of 51 patients with AZOOR had an antecedent viral-like illness [20].
10.5.3.4 Treatment As with MEWDS and AIBSE, there is no proven effective treatment for AZOOR. One out of six patients in the original report by Gass showed improvement with corticosteroids. In the review of 51 patients with AZOOR, 39 out of 113 episodes were treated with corticosteroids [20]; 11 episodes were also treated with acyclovir or valacyclovir. Of the 51 patients, 13 showed improvement in vision. Of these, 9 had no treatment, 4 had been treated with steroids, and 2 of the 4 had also been given acyclovir. Visual loss generally stabilizes within 6 months following an episode of AZOOR (77% of 90 eyes in the review by Gass et al [20]). Recurrences may occur in approximately 25% of patients [27]. (See Table 10.5 for a comparison of AIBSE, MEWDS, and AZOOR.)
10.5.3.5 AZOOR Complex of Disease Controversy continues over whether AZOOR, MEWDS, AIBSE, as well as other white dot syndromes, variably including punctuate inner choroidopathy, acute macular neuroretinopathy, multifocal choroiditis, and presumed ocular histoplasmosis, are separate diseases, or comprise one disease with variable presentation. Proponents of one unifying disease cite similar demographics, the overlap of signs and symptoms, and the occurrence of several of
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Autoimmune Retinopathies Table 10.5. Comparison between AIBSE, MEWDS and AZOOR. (B/L Bilateral, U/L unilateral)
AIBSE
10
Gender
Presentation Enlarged Dyschrom- APD Other signs U/L or Recurrences blind spot atopsia B/L
Female
Scotoma, photopsias
Yes
MEWDS Female
Acute vision Common loss, photopsias, scotomas
AZOOR Female
Peripheral vision loss, photopsias
±
±
± Mild disc edema
U/L
Occasional
±
±
White fundus lesions, foveal granularity
U/L
Occasional
±
± Mild disc edema
B/L
Common
Common
these different entities in one person as evidence for a single condition. All of these entities tend to occur in young, otherwise healthy women. Presentation is similar, consisting of an acute onset of photopsias and visual field defects with minimal if any fundus changes, and an abnormal ERG. While these various conditions do have distinguishing features, such as the multiple evanescent dots in MEWDS, Gass has proposed that this could be explained by differences in individuals’ genetic and immune system make-up [18]. On the other hand, these very differences can be considered reason to consider these as separate diseases until a single etiology is determined. Becker has proposed a “genetic hypothesis of autoimmune/inflammatory disease” that could explain the similar demographic and character of these syndromes [27]. His hypothesis proposes a genetic predisposition to autoimmune disease that may develop into specific autoimmune disease depending on environmental triggers such as viral illness. Individuals with this predisposition may be susceptible to multiple autoimmune/ inflammatory diseases, explaining the occurrence of several of these diseases in one person. More investigation is required to further refine this hypothesis; however, there is some evidence to support allelic associations with multiple autoimmune diseases [27].
Summary for the Clinician
■ Unilateral or bilateral. ■ Tends to recur. ■ Usually affects young women. ■ Presents with acute peripheral vision loss in one or both eyes and photopsias. ■ Normal fundus. May have vitritis weeks to months after onset. ■ May have an APD. ■ Visual field: enlarged blind spot com-
mon. May have ring scotoma, hemianopic scotoma, constriction, arcuate, or multiple isolated defects. ERG: may show diffuse reduction of rod and cone amplitudes. Etiology: suspected autoimmune/viral/ genetic. Treatment: none. Course: stabilization of field defect within 6 months of onset. Recurrences in 25% of patients.
■ ■ ■ ■
10.6 Summary Paraneoplastic retinopathies and acute outer retinopathies with blind spot enlargement can present with subacute vision loss, photopsias, visual field defects, and minimal fundus changes. An APD and/or dyschromatopsia may be present.
The nature of the visual field defect, description of photopsias and, in some cases, night-blindness or decreased vision in bright light, history of cancer, subtle fundus changes, ERG and fluorescein angiography can help to differentiate these patients from those with primarily neuroophthalmic problems, and lead to the correct diagnosis.
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Autoimmune Retinopathies 24. Ie D, Glaser BM, Murphy RP et al (1994) Indocyanine green angiography in multiple evanescent white dot syndrome. Am J Ophthalmol 117:7–12 25. Jacobson SG, Morales DS, Sun XK (1995) Pattern of retinal dysfunction in acute zonal outer retinopathy. Ophthalmology 102:1187–1198 26. Jampol LM (2006) Optical coherence tomography findings in multiple evanescent white dot syndrome. Retina 26(4):483–484 27. Jampol LM, Becker KG (2003) White spot syndromes of the retina: a hypothesis based on the common genetic hypothesis of autoimmune/inflammatory disease. Am J Ophthalmol 135:376–379 28. Jampol LM, Sieving PA, Pugh D et al (1984) Multiple evanescent white dot syndrome. 1. Clinical findings. Arch Ophthalmol 102:71–74 29. Kanis MJ, van Norren D (2006) Integrity of foveal cones in multiple evanescent white dot syndrome assessed with OCT and foveal reflection analyzer. Br J Ophthalmol 90:795–796 30. Kawamura JA, Cox P (1994) Inhibition of rhodopsin phosphorylation by non-myristoylated recombinant recoverin. Biochem Biophys Res Commun 203:121–127 31. Keltner JL, Roth AM, Chang RS (1983) Photoreceptor degeneration: possible autoimmune disorder. Arch Ophthalmol 101:564–569 32. Keltner JL, Thirkill CE, Yip PT (2001) Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol 21:173–187 33. Lei B, Bush RA, Milam AH et al (2000) Human melanoma-associated retinopathy (MAR) antibodies alter the retinal ON-response of the monkey ERG in vivo. Invest Ophthalmol Vis Sci 41:262–266 34. Ling C, Pavesio C (2003) Paraneoplastic syndromes associated with visual loss. Curr Opin Ophthalmol 14:426–432 35. Margo CE, Lowery RL, Kerschmann RL (1997) Lack of p53 protein immunoreactivity in bilateral diffuse uveal melanocytic proliferation. Retina 17:434–436 36. Matsubara S, Yamaji Y, Sato M et al (1996) Expression of a photoreceptor protein, recoverin, as a cancer-associated retinopathy autoantigen in human lung cancer cell lines. Br J Cancer 74:1419–1422
37. Milam AH, Saari JC, Jacobson SG et al (1993) Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest Ophthalmol Vis Sci 34:91–100 38. Mizener JB, Kimura AE, Adamus G (1997) Autoimmune retinopathy in the absence of cancer. Am J Ophthalmol 123:607–618 39. Obana A, Kusumi M, Yamaguchi M et al (1995) Two cases of multiple evanescent white dot syndrome examined with indocyanine green antiography. Nippon Ganka Gakkai Zasshi 99:244–251 40. Ohguro H, Ogawa K, Maeda T et al (1999) Cancer-associated retinopathy induced by both antirecoverin and anti-hsc 70 antibodies in vivo. Invest Ophthalmol Vis Sci 40:3160–3167 41. Okel BB, Thirkill CE, Anderson K (1995) An unusual case of melanoma-associated retinopathy. Ocul Immunol Inflamm 3:121–127 42. O’Neal KD, Butnor KJ, Perkinson KR et al (2003) Bilateral diffuse uveal melanocytic proliferation associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic syndrome. Surv Ophthalmol 48:613–625 43. Ritland JS, Eide N, Tausjo J (2000) Bilateral diffuse uveal melanocytic proliferation and uterine cancer. A case report. Acta Ophthalmol Scand 78:366–368 44. Savchenko M, Bazhin A, Shirfrin O et al (2003) Antirecoverin autoantibodies in the patient with non-small cell lung cancer but without cancer-associated retinopathy. Lung Cancer 41:363–367 45. Shiraga S, Adamus G (2002) Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase-9- and caspase-3-dependent pathway. J Neuroimmunol 132:72–82 46. Subramanian L, Polans AS (2004) Cancer-related diseases of the eye: the role of calcium and calcium-binding proteins. Biochem Biophys Res Commun 322(4):1153–1165 47. Takeda M, Kimura S, Tamiya M (1984) Acute disseminated retinal pigment epitheliopathy. Folia Ophthalmol Jpn 35:2613–2620 48. Thirkill CE, Roth AM, Keltner JL (1987) Cancer-associated retinopathy. Arch Ophthalmol 105:372–375
49. Thirkill CE, Roth AM, Takemoto DJ et al (1991) Antibody indications of secondary and superimposed retinal hypersensitivity in retinitis pigmentosa. Am J Ophthalmol 112:132–137 50. Thirkill CE, Tait RC, Tyler NK et al (1992) The cancer-associated retinopathy antigen is a recoverin-like protein. Invest Ophthalmol Vis Sci 33:2768–2772
References 51. Volpe NJ, Rizzo JF, Lessel S (2001) Acute idiopathic blind spot enlargement syndrome: a review of 27 new cases. Arch Ophthalmol 119:59–63 52. Whitcup SM, Vistica BP, Milam AH et al (1998) Recoverin-associated retinopathy; a clinically and immunologically distinctive disease. Am J Ophthalmol 126:230–237
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Chapter 11
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11
Ludwig Aigner, Claudia Karl
Core Messages
■ The existence of many different apoptot-
ic mechanisms presents a current limitation in the identification of anti-apoptotic drug targets and in the development of anti-apoptotic drugs. Neuroprotective strategies are promising at the experimental level, but mostly lack long-term therapeutic effects. Cell transplantation seems to be a promising approach, at least in the preclinical setting. Grafted embryonic and fetal stem and progenitor cells have the potential to replace degenerated retinal tissue in preclinical models. However, major ethical concerns and limited availability seem to make them unlikely for a standard therapy.
■ ■ ■
■ Adult stem cell transplantation might
have clinical relevance in future. However, the growth and differentiation potential of these cells is not sufficient yet. These need further investigation and development. The presence of stem and progenitor cells in the adult retina makes these cells a very promising drug target, which might be stimulated to regenerate the retina. However, the preclinical development is still at a very early step.
■
11.1 Introduction A common hallmark of retinal diseases is the selective loss of retinal neurons, mostly photoreceptor cells or retinal ganglion cells (RGC). Retinal degenerative diseases are classified in three major groups: those affecting primarily photoreceptors [retinitis pigmentosa (RP) and related diseases], those involving the retinal pigment epithelium (RPE) but affecting photoreceptors [e.g. age-related macular degeneration (AMD)], and those affecting RGC (glaucoma).
11.1.1 Retinitis Pigmentosa Most diseases of the RP group are caused by single gene mutations, which contribute to photoreceptor death. Over 100 single gene mutations for RP have been identified, most of them causing decline of rods selectively, while cones often undergo apoptotic cell death secondarily to rods and are seldom directly affected by the mutations. As a consequence, a first symptom in diseases of the RP group is often night-blindness due to destruction of rods, followed by loss of central vision and complete blindness due to dying cones. Approximately 1 in 3000 individuals worldwide
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suffers from RP, which is the leading cause of inherited blindness in the developed world. There is no efficient treatment for this large group of retinal degenerative diseases. Future strategies developed from data collected in animal models comprise the application of neuroprotective factors, transplantation of stem cells, RPE or retinal sheets, gene therapy and others.
the overlying retina. A more gentle approach combines intravenous infusion of the light-sensitive dye verteporfin, which is activated inside the neovascularized area by a low-intensity laser in order to occlude pathologic vessels without touching the overlying retina.
11.1.3 Glaucoma 11.1.2 Age-Related Macular Degeneration
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The AMD group mostly consists of diseases caused by polygenic incidents with a strong environmental influence. It shows a high prevalence in industrialized countries and is expected to increase significantly in the coming decades: between 10% and 20% of people over the age of 65 years suffer from maculopathy, an early stage of AMD or of overt macular degeneration, making AMD the most common cause of blindness in older patients in developed countries. By 2020, the number of AMD patients is expected to increase by 50%. In AMD central visual acuity is lost due to degeneration of photoreceptor cells in the macula. Loss of cone and rod cells in AMD is a secondary effect following the degeneration of the adjacent RPE, which – in its healthy state – is responsible for removal of photoreceptor cell debris generated during the phototransduction cascade. Early AMD is recognized by the presence of yellow deposits beneath the retina called drusen and pigmentary changes following atrophy and/or proliferation/de-differentiation of the RPE. At later stages, often two clinical subtypes can be identified. The most common one is “wet” or exudative AMD. It is associated with abnormal vessels that proliferate from the choroid into the subretinal space and retina resulting in fluid and blood leakage, with secondary damage to the photoreceptive structures. Detachment of the RPE and fibrosis are common symptoms in late AMD. The second clinical subtype is a “dry” retinal atrophy, which often involves spots of the retina responsible for central visual acuity, such as the fovea. Current treatment strategies use thermal laser photocoagulation to stop neovascular growth in the choroid at advanced stages of wet AMD, although this simultaneously destroys
Glaucoma is caused by high intraocular pressure, resulting for example from oxidative stress, deficiency of neurotrophic factors, and various other pathogenic origins, leading to RGC death and optic nerve degeneration. Glaucoma accounts for around 11% of diseases accompanied by low vision. Presently, glaucoma therapy aims at reducing the intraocular pressure, hence protecting the optic nerve function. However, when intraocular pressure is lowered by medication or surgery, progression of disease does not slow down in all patients. Moreover, a substantial number of patients (about one-third) show a form of glaucoma without elevated intraocular tension making it necessary to look for neuroprotective treatments in glaucoma besides pressure-lowering surgery. In all of these diseases the visual system can be severely and irreversibly damaged, resulting in ongoing loss of visual function and often ending in complete blindness. The major goal of all different treatments is to preserve, protect, and rescue the declining cells, and ultimately to prevent blindness. However, proven strategies for prevention and treatment are not numerous. Previous and current research targeting cell loss aims to: (1) protect dying cells from cell death, (2) replace degenerated cells by transplantation, or (3) replace degenerated cells by endogenous cellular sources. This chapter will review current research in this field, summarizing possible future therapeutic approaches.
11.2 Cell Death in the Retina It is well established that apoptosis is the final cell death pathway in RP, AMD and glaucoma. Tissues undergoing programmed cell death in these diseases are photoreceptor layers in the case of RP and the RPE in the case of AMD, whereas in
glaucoma the decline of RGCs provokes similar symptoms such as loss of visual function. However, knowledge about pro-apoptotic cues during retinal dystrophy and degeneration is scarce. Although a great number of gene mutations triggering RP and AMD have been identified, many questions remain as to which molecular mechanisms are accompanied by apoptotic events in this context. Investigating causative signals and resulting mechanisms of apoptosis in these blinding diseases is a major task: better discernment of related events might provide a powerful handle to develop rescue strategies against progressive cell loss in the visual system. This review starts with a summary of what is known on cell death pathways in general, followed by an overview of possible survival-promoting and cell-replacement strategies, including the stimulation of endogenous regeneration.
11.2.1 Major Characteristics and Pathways of Apoptosis The development and maintenance of an organism demand not only cell proliferation, but also the removal of surplus or damaged cells that otherwise might affect the correct functioning of organs or even endanger the survival of the entire system. Controlled execution of cell death, classically referred to as apoptosis, is usually finely tuned during development and in the adult. Histogenesis and tissue homeostasis in mature individuals depend largely on the regulated elimination of individual cells. However, exogenous stimuli or endogenous gene mutations may affect this highly regulated process and lead to neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease in the brain, or RP and AMD in the retina [20]. Apoptotic cells were first identified on the basis of their morphology, characterized by condensation of chromatin, membrane blebbing and disintegration of dying cells into apoptotic bodies, which are then removed by phagocytic cells. In addition, details on physiological changes that correlate with alterations in cell architecture have been observed, such as inter-nucleosomal DNA cleavage and exposure of phosphatidylserine to the outside of cellular membranes. Specific en-
11.2 Cell Death in the Retina
dopeptidases called caspases have been identified as central tools that drive programmed cell death to its endpoint. The classical concept of apoptosis being initiated and executed by caspases has recently been complemented by caspase-independent mechanisms of apoptosis. While the first work through aspartate-specific endopeptidases, the latter can depend on a variety of factors, including proteases, apoptosisinducing factor (AIF), endonuclease G (EndoG), proteasomes and lysosomes. An increasing number of caspase-independent mechanisms are still being explored. While discovering new pathways of apoptosis besides the caspase-dependent mechanisms it became clear that apoptosis might involve various cellular compartments in addition to mitochondria, such as lysosomes, the endoplasmic reticulum, the Golgi apparatus, proteasomes or autophagic vacuoles. The different mechanisms of programmed cell death and apoptosis are summarized in Table 11.1.
11.2.1.1 Caspase-Dependent Apoptosis Caspases are endopeptidases that cleave distinct polypeptides – over 100 different substrates are known – on the carboxyl side of aspartate residues. To enter a caspase-dependent pathway of apoptosis, caspases need to be activated by other enzymes. Caspases are synthesized as zymogens and consist, in their inactivated form, of an N-terminal prodomain, and a large and a small subunit. Upon cleavage by a caspase-dependent process, large and small subunits are released and form the activated caspase comprising two large and two small subunits. Classification of caspases describes two major groups. The first group seems to participate in cytokine cleavage and maturation (caspases-1, -4, -5, -11, -12, and -14), whereas the second group (caspases-2, -3, -6, -7, -8, -9, and -10) acts on apoptosis by cleaving various intracellular proteins. In a mechanistic approach, caspases associated with apoptosis have been divided into upstream or initiator caspases (e.g., caspases-8, -9, and -10) and their downstream targets known as effector or executioner caspases (e.g., caspases3, -6, and -7).
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Caspase-independent apoptosis
Extrinsic pathway: Mechanisms involving non-cas– binding of extracellular ligands to death repase proteases, for example: ceptors (e.g., Fas/CD95 or TNFα) – m- and µ-calpain – cathepsin-B, -L and -D granzymes – activation of procaspase-8 by a death receptor/adaptor molecule complex – proteasomal proteases – direct or cytochrome-c-mediated activation – serine proteases (e.g., Omi/HtrA2) of effector caspases (e.g., caspases-3 and -7) Protease independent mechaIntrinsic pathway: – direct induction of cytochrome-c release from mi- nisms involving, for example: tochondria without involvement of death receptors – increased intracellular Ca2+ levels – mitochondrial death effectors (AIF, EndoG) – cytochrome-c-mediated activation of effector caspases (e.g., caspases-3 and -7) – reactive oxygen species – reactive nitrogen species
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Caspase activation can happen along several pathways, two of which have been characterized extensively that differ in their way of initiation, but converge at some point to one common path: the death receptor-mediated or extrinsic pathway and the mitochondrial-mediated or intrinsic pathway. The extrinsic type starts from binding of extracellular ligands to specific receptors (e.g., Fas/CD95 or tumor necrosis factor alpha, TNFα). Death domains of these receptors subsequently cluster in the plasma membrane and recruit adaptor molecules such as FADD or RAIDD. The latter activate procaspase-8 leading either directly to the activation of effector caspases such as caspase-3 or to the cleavage of Bid, a member of the Bcl-2 family of proteins residing in the outer mitochondrial membrane. Bid cleavage facilitates the release of cytochrome c from mitochondria, thereby converging with the second pathway of caspase activation described below. The intrinsic pathway to caspase activation directly induces the release of cytochrome c from the mitochondrial intermembrane space. Therefore, it relies on mitochondrial membrane permeabilization without involving death receptors. Besides Bid and other members of the Bcl-2 family of proteins, it can be regulated by proteases as well as by agents that increase the permeability of mitochondrial membranes directly (reviewed in [27]). After its release to the cytosol,
cytochrome c combines with dATP, APAF-1 and caspase-9 to form a catalytic complex, the apoptosome. Downstream follows the activation of effector caspases-3 and -7 eliciting ultrastructural features characteristic of the apoptotic process, which is synonymous with entering the degradation phase.
11.2.1.2 Caspase-Independent Apoptosis An overall property of apoptosis is the proteolytic degradation of proteins, but the caspases are not the only executioners of the apoptotic program. It has been shown that inhibition of caspases cannot block apoptosis in cultured cells that had been exposed to toxic stimuli. Moreover, apoptosis reportedly occurs in the absence of caspases in many in vivo cell death models (reviewed by [27]). Non-caspase proteases that have been implicated in apoptotic cell death are cathepsins, calpains, granzymes, serine proteases and proteasomal proteases. From the cathepsin family, cathepsin B and L (both cysteine proteases) as well as cathepsin D (an aspartate protease) have been proven to play a role in apoptosis through their translocation from lysosomes or endosomes to the cytosol. Calpain proteases, a family of cysteine proteases
11.3 Therapeutic Strategies in Degenerative Retinal Diseases
residing in the cytosol, are activated by increased intracellular Ca2+ concentrations. In particular, m-calpain and µ-calpain seem to be linked to apoptotic processes, as has been shown to occur in Alzheimer and Parkinson’s disease. Granzymes specifically cleave proteins on the carboxy side of acidic amino acid residues, most often aspartate. Secretion of granzymes to the extracellular space attracts natural killer cells that consequently induce apoptosis. Omi/HtrA2 is a serine protease sitting in the mitochondrial intermembrane space that is released to the cytosol upon various apoptotic stimuli and can induce apoptosis via its protease activity. Proteasomal proteases can influence the stability of apoptotic regulators from the Bcl-2 and IAP families thereby acting on apoptosis. In addition to proteolysis, more caspase-independent mechanisms have been reported: death effectors such as AIF can be released from the mitochondrial intermembrane space following permeabilization of this membrane in a caspaseindependent manner. AIF translocates to the nucleus where it starts chromatin condensation and DNA fragmentation by recruiting or activating an endonuclease. EndoG, the most abundant endonuclease in mitochondria of eukaryotic cells, follows a similar pathway as AIF and can promote nuclear degradation in apoptosis. In addition to these death effectors, an imbalance in reactive oxygen species (ROS) production can be a powerful pro-apoptotic stimulus. Again, mitochondria are the focus of attention: overproduction of ROS in mitochondria can – via its influence on membrane permeability – provoke osmotic swelling of these organelles and physical rupture, releasing a vast amount of pro-apoptotic factors into the cytosol. Similar effects have been reported for reactive nitrogen species (RNS). Increased levels of intracellular Ca2+, caused for example by instability of the endoplasmic reticulum, and excess calcium can activate Ca2+-dependent enzymes such as calpains and endonucleases. This summary of what is known on apoptosis in general has made clear that there is no real limitation in apoptotic mechanisms but rather a manifold amount of pro-apoptotic stimuli exists. Recent evidence has shown that caspases can no longer be termed sole central effectors of apoptosis. The ever-increasing non-caspase effectors
may represent failsafe mechanisms for apoptotic cell elimination [27]. The great number of possible mechanisms was described almost exclusively in non-ocular tissues and might be true for the retina as well, although there are few data on which apoptotic mechanisms exactly contribute to neurodegenerative diseases in the eye [59].
Summary for the Clinician
■ The existence of very different apoptotic
mechanisms presents a current limitation in the identification of anti-apoptotic drug targets and drugs.
11.3 Therapeutic Strategies in Degenerative Retinal Diseases 11.3.1 Strategies for Neuroprotection 11.3.1.1 Animal Models in Retinal Degeneration Research A promising way of preventing programmed cell death is the application of neuroprotective factors such as cytokines, antioxidants or calcium antagonists. A broad set of substances has been examined with respect to their influence on cell death in all kinds of animal models. While for antioxidants and calcium antagonists the mechanism of cell rescue is quite obvious, for most of the cytokines molecular interactions remain to be elucidated. Studies on apoptosis are performed in animal models that use light-induced retinal degeneration or in animal models for inherited RP. Both models share the mechanism of cell death by apoptosis with corresponding inherited human diseases. Substances that protect neurons from dying in both light damage and animal models of inherited forms of RP are particularly promising. Several aspects need to be taken into account when comparing these two different experimental setups. The number of mice models mimicking human inherited degenerations is constantly growing. Genetically engineered mouse models
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carrying a mutation described in patients are powerful tools with which to connect the failure of specific genes with their molecular outcome in diseased retinal cells. In order to work out preventive strategies for human degenerative diseases, exploring specific cell death mechanisms in this context is especially valuable. However, studying apoptosis in these inherited models needs to overcome several obstacles, as the time course of programmed cell death differs widely between individual models, and the onset of apoptosis is different in individual retinal cells of the same model. It can take a substantial amount of a mouse’s lifetime for symptoms to emerge, and at a given time point only a small number of cells will be at the same stage of decline. For comparison, light damage animal models, where excessive light induces apoptosis in photoreceptor cells, show fast and reproducible retinal degeneration. In these models apoptosis proceeds through its characteristic steps simultaneously in all affected photoreceptors, which is a prerequisite for identifying molecular markers that correlate with distinct steps of programmed cell death. Light-induced and inherited models also differ in another respect: whereas the first sometimes show complete retinal regeneration following a specific treatment, in the latter persistent genetic mutations at best slow degeneration down [59]. However, compounds that are protective in both light-induced damage models and inherited degeneration have proven to be beneficial in several
aspects and therefore seem to be promising candidates for preventing photoreceptor cell death. While many mouse models for RP exist, only a few are suitable for AMD. An exception to this rule are two models showing several morphological features of AMD including drusen, apoptotic cell death and neovascularization: Ccl2(–/–) or Ccr2(–/–) mice show impaired macrophage recruitment which may contribute to AMD pathogenesis. Another model mimicking symptoms of macular degeneration is the abcr–/– knockout mouse model for Stargardt’s disease. This inherited disease is characterized by macular degeneration and accumulation of toxic lipofuscin deposits in the retina similar to pathologic events in AMD. In all of these mouse models for AMD the conversion from non-neovascular to neovascular tissue seems to be accompanied by increased expression of vascular endothelial growth factor (VEGF), probably inducing choroidal vessels to infiltrate retinal structures [40].
11.3.1.2 Strategies for Neuroprotection Interfering with the Induction Phase of Apoptosis Different neuroprotective strategies are summarized in Table 11.2. Correct function of the visual cycle has been shown to be a prerequisite
Table 11.2. Promising neuroprotective strategies in retinal degenerative diseases. (b-FGF Basic fibroblast growth factor, BDNF brain-derived neurotrophic factor, CNTF ciliary neurotrophic factor, LEDGF lens epithelium-derived growth factor, PEDF pigment epithelium-derived factor, VEGF vascular endothelial growth factor) Factors interfering with the induction phase of apoptosis: – antioxidants (e.g., DMTU, PBN) – calcium antagonists (e.g., D-diltiazem) – transgenic expression of Bcl2 for stabilization of mitochondrial membranes Neuroprotective cytokines: – BDNF (brain-derived neurotrophic factor) – CNTF (ciliary neurotrophic factor) – b-FGF (basic fibroblast growth factor) – LEDGF (lens epithelium-derived growth factor) – PEDF (pigment epithelium-derived factor) Antagonists to cytokines: – VEGF antagonists (e.g., pegaptanib, ranibizumab, VEGF trap)
11.3 Therapeutic Strategies in Degenerative Retinal Diseases
for light induced apoptosis in several mouse models. Consequently, inhibiting the visual cycle can protect the retina against light damage. Application of 13-cis-retinoic acid reportedly slows down the visual cycle [52]. This effect is mediated by inhibition of RDH5, which catalyzes oxidation of 11-cis-retinal in the pigment epithelium before the chromophore is delivered back to the photoreceptor [52]. 13-cis-Retinoic acid has been shown to reduce the age-related accumulation of lipofuscin in the abcr–/– mouse model of AMD [43]. Accumulation of lipofuscin seems to contribute substantially to the etiology of Stargardt’s disease as well as of AMD, making application of 13-cis-retinoic acid a possible treatment strategy in these retinal diseases [43].
11.3.1.3 Strategies for Neuroprotection Interfering with the Early Phase of Apoptosis The early phase of apoptosis in acute bright light damage models is in agreement with, for example, with elevated intracellular calcium levels, the induction of oxidative stress, and aberrant mitochondrial function [18]. Several reagents and factors that can counteract these mechanisms had a protective effect in light-induced neurodegenerative animal models as well as in mouse models of inherited RP. The calcium antagonist d-diltiazem is a blocker of calcium channels. It prevents light damage in mice, as revealed by the absence of TUNEL-positive cells in the outer nuclear layer [19]. However, these data could not be reproduced in all studies, including those performed in the rd1-mouse and the P23H transgenic rat (for review see [59]). Exposure to acute bright light is accompanied by changes in mitochondrial membrane integrity, and membrane leakage in these organelles might account for the induction of photoreceptor apoptosis in the respective animal models [18]. There are attempts to stabilize mitochondrial membranes by the over-expression of Bcl2 using a transgenic approach. While transgenic expression of Bcl-2 under the rhodopsin promoter in a study using constant white light had no protective effect, this was the case in a similar experiment performed by another group. How-
ever, in knockout mice with no expression of the Bcl-2 family members Bax and Bak the retina was protected against light damage. Despite these conflicting results, there is good evidence that Bcl-2 influences the cellular calcium homeostasis and modulates the anti-oxidative capacity of cells [17]. Anti-oxidants that showed a reportedly beneficial effect on retinal degeneration are DMTU and PBN, as it was revealed both in light induced apoptosis as well as in models of inherited retinal degeneration, although PBN was not sufficient in all inherited models examined. Taken together, these results indicate that anti-oxidative treatments are able to slow down certain forms of retinal degeneration.
11.3.1.4 Strategies Using Neuroprotective Cytokines that Showed Effects in Other Tissues During application of cytokines in neurodegenerative retinal diseases, several promising candidates emerged, although the mechanism of cell rescue in the retina remains to be elucidated. Lens epithelium derived growth factor (LEDGF) has a general anti-apoptotic effect that is mediated by a higher rate of expression of heat shock proteins and antioxidant proteins. In the eye, LEDGF protected retinal function during exposure to excessive light as well as after its application to the retinas of mice and rats carrying mutations responsible for retinal degeneration [1]. The expression of basic fibroblast growth factor (b-FGF) is endogenously upregulated when mouse retinas are exposed to excessive light, showing a neuroprotective effect if, for example, the retinas had been preconditioned with milder light before application of high doses [37]. Recombinant b-FGF was also injected intravitreally and showed a neuroprotective effect [8]. Successive attempts to preserve retinal morphology were undertaken by expressing b-FGF from virally delivered transgenes, for example in rats carrying a mutated rhodopsin gene (S334ter mutation), although retinal function could not be restored as effectively as retinal morphology in these experiments [35].
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Pigment epithelium-derived factor (PEDF) originates in the eye and is neuroprotective after oxidative stress [55]. It had a robust neuroprotective effect when injected prior to light exposure and in two mouse models of inherited degeneration (rd1 and rd2) (for example see [8]). Ciliary neurotrophic factor (CNTF) is reportedly upregulated after pre-conditioning with milder light in a similar way as b-FGF, and also after injury of ganglion cells [9]. While after light-induced damage the injection of CNTF alone protected the retina, in models of inherited diseases the delivery of a transgene was necessary to provide the long-term elevated levels of CNTF necessary for neuroprotection in these genetic models. Brain-derived neurotrophic factor (BDNF), either applied directly or indirectly through release from transgenic cell transplants, protected the retina from light-induced degeneration [29]. Viral delivery of a BDNF transgene, but not injection of recombinant BDNF, slowed down cell death in several inherited mouse and rat models of retinal diseases [12]. It has been suggested that VEGF induces pathologic symptoms in AMD especially neovascularization of the retina in later stages of the disease. Therefore, several VEGF antagonists have been developed and tested in animals, but also in patients with neovascular AMD. Among those showing modest benefits in clinical trials is pegaptanib, an RNA molecule binding VEGF165 but not other isoforms of VEGF-A. Another VEGF antagonist tested in patients is ranibizumab, a Fab fragment of an antibody that binds all isoforms of VEGF-A. Repeated intraocular injections of ranibizumab resulted in stabilization of vision in the majority of patients, with substantial improvement in vision in about a third of the patients [40]. VEGF Trap is another VEGF antagonist that has been administered in clinical studies intravenously to patients suffering from AMD resulting in significantly reduced retinal thickness [40]. Despite some promising results in cell preservation following the different treatments, several further aspects need to be taken into account. The rescue of neurons by application of neuroprotective factors does not necessarily correlate
with functional rescue of the respective cells in their environment, as researchers often had to admit after taking a closer look at their results. Functional tests as well as effective neuronal signaling are necessary in order to evaluate whether there is satisfactory protection and restoration of retinal function. In addition, the mode of applying a factor seems to influence its effect on neuroprotection: some cytokines were ineffective when injected intravitreally, whereas their transgenic expression achieved a significant cell rescue effect. This is especially true in inherited models of retinal degeneration, where often long-term expression of a factor is essential for its beneficial effect. Moreover, the long-term expression of factors may be important in another respect: considering the relatively rapid turnover of vitreous liquid, a single intra-vitreal injection might not be enough to sufficiently protect photoreceptors and adjacent tissue in the presence of persistent pro-apoptotic stimuli. The majority of data indicate that factors need to be present in the diseased tissue over extended periods of time in order to be protective. Even so, there is no proof that long-term application of factors can be managed in small laboratory animals let alone in the human retina, which is larger and has a substantially longer lifetime.
Summary for the Clinician
■ Neuroprotective strategies are promising at the experimental level, but mostly lack long-term therapeutic effects.
11.3.2 Cell Therapy for the Diseased Retina The replacement of retinal cells lost during the course of a retinal degenerative disease is a strategy that is currently being investigated heavily. In general, one may think of several different approaches. The ex vivo approach uses cultured cells that are expanded and sometimes induced in culture before being transplanted back into the diseased tissue. A further possibility within
11.3 Therapeutic Strategies in Degenerative Retinal Diseases
this approach is to enhance the therapeutic potential of these cells by genetic engineering (ex vivo gene therapy). The in vivo approach, in contrast, tries to stimulate endogenous stem cells within the diseased tissue. Here we review and discuss progress in the retinal transplantation approaches and also in approaches targeted toward endogenous cell replacement.
11.3.2.1 Cell Transplantation in the Retina 11.3.2.1.1 General Considerations Prerequisites to success in the transplantation approach are: (1) establishment of appropriate cellular connections between transplanted cells and the local circuitry inside the visual system, and (2) a significant restoration of eyesight as assessed by behavioral tests. Transplanting retinal layers from healthy individuals to diseased retina aims to replace the injured or degenerated cells with new functional tissue. The first experiments in this field were performed in 1959 using material from fetal eyes injected into the anterior chamber of rat eyes [47]. In the 1980s, similar experiments with pieces of RPE followed [25], and then between 1986 and 1992 the first data on embryonic and neonatal retinal cell aggregates transplanted into lesioned retina were published (reviewed by [4]). Research on improving transplantation techniques focused on the composition of transplants (cell aggregates or pieces of tissue of different size), the cell types transplanted, and the way of delivering them to the graft site. To prove the adequate integration of donor tissue into the host photoreceptor layer one needs to distinguish between the two, which can be achieved by labeling the cells prior to transplantation. In preclinical studies, this was achieved mostly by genetically labeling the cells with cytoplasmic reporters such as green fluorescent protein (GFP) or beta-galactosidase, or by nuclear markers (e.g., 3H-thymidine, bromodeoxyuridine or by detecting Y chromosomes in male tissue transplanted to female recipients). Only with cytoplasmic stains can the cell pro-
cesses of transplanted cells be followed, because cell-to-cell contacts become visible. The GFPmouse – all of its cells show green fluorescence – has been widely used for experiments on retinal transplantation. Another promising attempt is to use transgenic rats expressing human placental alkaline phosphatase (hPAP) in the cytoplasm of all cells. Grafts from these animals can later be detected by histochemistry or immunohistochemistry in the host eye. Immunological rejection of grafted cells or tissue needs to be considered seriously when thinking of future therapeutic concepts for human retinal degenerative diseases and their possible cure by allogeneic transplantation. In principle, the subretinal space has been shown to be rarely accessible to immunogenic elements, similar to the CNS. This “immune privilege” was deduced from data showing that allografts of neonatal retina and also other foreign antigens do not elicit a classic immune response in the subretinal space. A prerequisite for these results was an intact blood–brain barrier [58]. Nevertheless, upregulation of microglia expressing major histocompatibility complex (MHC) class I and II antigen was detected after allogeneic subretinal transplantations in mice and rats. These microglia could be found in the transplant and surrounding host tissue [34]. It is not yet known why this activation of microglia does not elicit rejection of the foreign tissue. Fetal tissue has yet to develop inner retinal vessels and therefore it elicits less of an immune response than postnatal tissue. As a consequence, the number of microglia is less in fetal versus postnatal tissue [4].
11.3.2.1.2 Transplantation of Retinal Sheets Earliest attempts to restore retinal function by transplantation were undertaken using retinal pieces of different size or dissociated cells (reviewed by [4]). However, in nearly 100% of treated rodents the grafted cells formed spherical structures, so-called rosettes, due to mechanical disruption of transplanted material. These roundshaped artifacts have the inner retinal layers on the outside, clasping photoreceptors that point
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with their outer segments towards the lumen of the rosettes [51]. Gouras and Tanabe established a micro-aggregate procedure, in which neonatal retina was cut into pieces small enough to pass through an injection needle without mechanical disruption, e.g. by shearing forces. Sheets integrated randomly at the proper orientation to the host RPE and survived well for at least 9 months [26]. In addition it has been shown that grafting material to the subretinal space was more advantageous to the laminar organization of transplants than grafting it to the epiretinal space [2]. In a different approach, Silverman used vibratome sectioning of postnatal-day-8 rat retinal wholemounts and transplanted the resulting retinal sheets into the subretinal space. In order to avoid rosette formation by the transplanted photoreceptors during these experiments, it was necessary to include the inner retina within sheets, indicating the importance of Müller cells for correct retinal lamination [53]. A similar method using vibratome sectioning was later applied to isolate photoreceptors from human post-mortem eyes [31]. Aramant and Seiler have developed a method to transplant sheets of fetal retinal neuroblastic progenitor cells into the subretinal space of rat eyes (reviewed in [4]). Healthy RPE provided by host or donor tissue was a prerequisite for the successful establishment of lamination resembling a normal retina. Authors saw the repair of degenerated retina after the transplantation of fetal tissue, also proven by visually evoked responses detected in areas of the superior colliculus corresponding to the transplant. These results seem to be especially promising, as not only protection but also repair of damaged tissue could be seen in these experiments. However, it became clear that transplantation cannot reverse all stages of disease to the healthy state: when photoreceptor degeneration in the host has advanced too far, including neovascularization and tight adherence of the retina to its RPE, no restoration of lamination can be achieved, because the force necessary to detach the host retina upon transplantation of donor tissue causes major tissue disruption in the recipient [3]. Clinical trials of retinal transplantation have been performed using adult (allogeneic and autologous) as well as fetal material in order to restore or prevent loss of vision in retinal degen-
erative diseases. When using RPE allografts in AMD patients, long-term beneficial effects were inhibited by inflammatory events and rejection of transplanted cells inside the recipient eye, although this effect could be inhibited using immunosuppressive treatment. Similarly, rejection was not observed in autologous transplantation of adult RPE cells in patients with wet AMD, who reported subjective improvements in vision after the treatment (reviewed in [3]). Another group established the transplantation of fetal retinal sheets together with its RPE in patients with RP or AMD [42]. Vision was not significantly improved by this treatment, although no apparent rejection was observed.
11.3.2.1.3 Transplantation of Stem and Progenitor Cell Populations Stem-cell-based therapies are being introduced to the clinic in a wide range of human illnesses. Regarding neurodegenerative diseases of the eye, the use of stem and progenitor cells has been expected to be a promising tool for the replacement of injured or irreversibly declining tissue. The main focus of present cell therapy development is the replacement of lost photoreceptors by transplantation of suitable cells into the subretinal space between the outer retinal layers and the RPE. The subretinal space was established as preferred location for grafts in retinal damage. Several cell types with stem and progenitor characteristics have been investigated for their potential in retinal transplantation, including transplantation of embryonic stem cells, iris pigment epithelium, Schwann cells, retinal progenitor cells, fetal and adult neural stem cells, and bone marrow mesenchymal cells. The application of a retinal prosthesis was considered as an alternative. More recently, ex vivo genetic modification of transplanted cells has become an interesting modality. This chapter concentrates on stem- and progenitor-cell-based therapy of retinal degenerative diseases. Stem and progenitor cells are defined by unique properties: they proliferate, they self-renew and they give rise to a multitude of differentiated cell types. While embryonic stem cells
11.3 Therapeutic Strategies in Degenerative Retinal Diseases
derived from the inner cell mass of the blastocyst can develop into virtually any type of tissue and are therefore considered pluripotent, fetal or adult stem cells are generally more restricted with regard to their differentiation potential and are considered multipotent. In this context, it is widely accepted that neural stem cells of the developing or adult brain can develop into neurons, astrocytes, and oligodendrocytes (Fig. 11.1), and that retinal progenitors generate all the different retinal cell types, while hematopoietic stem cells give rise to all types of hematopoietic cells. However, some data suggest that in rare events transdifferentiation of hematopoietic or bone-marrow-derived mesenchymal stem cells into cells of neuro-ectodermal phenotype can occur, although these findings are strongly debated.
11.3.2.1.3.2 Fetal Stem and Progenitor Cell Populations from the Retina Fetal stem and progenitor cell populations that might be relevant for cell transplantation strategies for the retina are those derived from the fetal brain or retina. These cells have the potential to differentiate into neurons and, in the case of fetal retinal progenitors, to differentiate into retinal-specific neurons such as photoreceptors. Therefore, we focus here on progenitors from the developing retina and recapitulate retinal development. The mammalian eye is generated during development from bilateral evaginations of the di-
11.3.2.1.3.1 Embryonic Stem Cells Embryonic stem cells are derived from the inner cell mass of very early embryos (blastocysts). Their massive impact on biological and medical sciences derives from two unique characteristics that distinguish them from all other cell types. First, they can indefinitely be maintained as undifferentiated cell populations (self-renewal) and therefore represent an unlimited supply of material for cellular-based replacement therapies. Second, embryonic stem cells are pluripotent, possessing the capacity to create all cell types that constitute an adult organism including the reproductive cells of the germ line. The field of embryonic stem cell research is trying to develop from a basic science discipline to a highly relevant clinical issue for replacement therapy approaches. Very recent data demonstrated that embryonic stem cells can be triggered to differentiate efficiently into retinal neurons indicating their therapeutic potential for retinal diseases [32]. Despite their broad capacity to generate a great multitude of differentiated cells, the use of embryonic stem cells is significantly limited due to ethical issues in humans. Since substantial evidence has emerged that stem cells are present in the adult human eye, more effort has been focused on the development of feasible treatments using these cells.
Fig. 11.1. Neural stem cell tree. Neural stem cells are characterized by their potential to proliferate, self-renew and to generate the three main cell types of the CNS: neurons, astrocytes and oligodendrocytes
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encephalic neuroepithelium forming the optic vesicles. Coordinated invagination of ectodermal tissue results in the lens placode, while the optic vesicles form a bilayered structure, the so-called eyecup. The retinal pigment epithelium (RPE) develops from the outer layer, while the neural retina is derived from the inner layer of this optic cup. During later developmental steps, multipotential retinal stem cells develop from the inner layer, giving rise to the basic cell types of the adult retina. The mammalian retina is populated through proliferation of these stem cells and differentiation of daughter cells. This process happens along a conserved pattern, although there is considerable overlap between the generation of different cell types: the first daughter cells in the retina are the retinal ganglion cells (RGCs), followed by cones and amacrine cells, horizontal cells, rods, bipolar cells and Müller glia. In the mature tissue, RGCs can be found at the inner surface of the retina, and photoreceptors comprising rods and cones form the outer margin next to the RPE. Between these two outermost layers of the retina lie the cells of the inner nuclear layer including bipolar, amacrine, and horizontal cells. The Müller cells span the entire retina and descend from retinal stem cells, while the two other types of glial cells in the eye, the astrocytes of the inner retinal surface and the oligodendrocytes that clasp the optic nerve, migrate to the retina during development. Retinal progenitors can be isolated from the developing retina and expanded in culture [23]. They are restricted to a bipotent fate and give rise to neurons and glia, but not oligodendroglia, suggesting certain molecular differences between retinal progenitors and neural stem cells.
in the adult mammalian retina, a number of different cell types might function as sources for somatic neural stem cells. These cells can be derived from the margin of the ciliary body (CB), the pigment epithelium layer (RPE) and the sensory retina (SR) (Fig. 11.2). In vitro experiments suggest the presence of multipotent neural progenitor cells in the CB or the ciliary marginal zone of the adult mammalian eye [56]. Under the culture conditions used in these studies, pigmented cells from the CB, but not the SR, RPE or other retinal structures, formed neurospheres consisting of pigmented and non-pigmented cells. Several cells in these neurospheres expressed Nestin and Chx10, both markers for somatic neural precursor cells and retinal progenitors. Some CB-derived cells differentiated into retinal neurons and glia. Despite the lack of convincing clonal analysis, pigmented cells in the CB were proposed in these studies to be multipotent neural stem cells [56]. As Müller glia cells are among the last cells in the retina to develop, their ability to generate retinal progenitor cells during development was excluded. However, after injury, Müller glia cells undergo reactive gliosis, a process associated with cell proliferation and the upregulation of glial fibrillary acidic protein (GFAP) [21]. After an N-methyl-d-aspartate lesion in postnatal
11.3.2.1.3.3 Stem Cells from the Adult Retina It was proposed that the adult mammalian retina – unlike its poikilothermic vertebrate analogs in fish, amphibians or reptiles – is devoid of proliferative or regenerative capacity. However, recent data suggest that there is indeed such proliferative capacity, as has been proven during the identification of stem or progenitor cells in the adult mammalian eye. Several studies have shown that
Fig. 11.2. Putative stem and progenitor cells in the adult retina. The adult mammalian retina has putative stem and progenitor cell populations: Müller glial cells, RPE cells, cells from the ciliary body and from the ciliary marginal zone
11.3 Therapeutic Strategies in Degenerative Retinal Diseases
chicken retina, cell proliferation is induced and triggers the expression of the retinal progenitor markers CASH-1, Pax6 and Chx10 in Müller glia. Newly born cells differentiate into retinal neurons, into Müller glia or remain undifferentiated [24], suggesting that Müller glia might be a potential source for de-differentiating cells that acquire a somatic neural stem cell phenotype. The RPE is of neuroectodermal origin as it derives from the neural plate and descends from precursors that later generate neural retina. The mature RPE consists of a mosaic of fully differentiated, polygonal cells between the choroid and the neural retina. This single cell layer is strongly important in processes essential to vision such as the metabolism of intermediates of the visual cycle and the phagocytosis of photoreceptor outer segments (reviewed in [7]). While in birds and amphibians RPE cells are able to either transdifferentiate into retinal neurons and glia or dedifferentiate into multipotential retinal stem or progenitor cells, homeothermic vertebrates have apparently lost this capacity. In mammals, RPE cell proliferation is described as a consequence of retinal detachment surgery. The resulting cells partially trans-differentiate and acquire neural progenitor and neuronal features [22], including expression of β III tubulin and voltage-gated Na+ channels. However, they do not de-differentiate into a multipotent somatic neural stem cell and neither do they trans-differentiate completely to acquire the full phenotypic pattern of a nerve cell or regenerate a retina (reviewed in [14]).
11.3.2.1.3.4 Transplantation of Stem and Progenitor Cells to the Degenerated Retina In the field of retinal degenerative diseases, much hope has been placed on the potential use of stem and progenitor cells to restore vision. Transplantation of tissue or single cells/cell aggregates may be especially useful at stages of disease where the majority of photoreceptors have disappeared and neuroprotective approaches are doomed to failure. However, cell replacement is a challenging task, and several obstacles need to be overcome
in order to develop efficient strategies. First of all, cell delivery techniques need to be improved. Nowadays, retinal sheets can be transplanted to the subretinal space, although single cell transplantations are much more difficult with regard to the formation of a three-dimensional network [61]. The capacity of grafted cells to survive in the host retina is probably limited and needs to be increased in order to establish long-term improvement of vision in retinal diseases. Another hurdle in efficiently applying or inducing stem cells in the eye is the lack of sufficient protocols regarding purposeful differentiation of stem and progenitor cells. Some of the only cell transplants with an established clinical application in diseases of the eye are corneal limbal epithelial stem cells (LESCs) used in corneal defects. These LESCs show characteristics of stem or progenitor cells in having a high capacity for self-renewal and being poorly differentiated. LESCs can be found in the basal layer of the limbus between the cornea and the conjunctiva. Although descending from mesodermal tissue, these cells are being explored with regard to their capacity for the repair of retinal structures (for review see [36]. Additionally, autologous transplantation of RPE cells in AMD has been established [6]. Embryonic stem (ES) cells have been considered a powerful source for ocular regeneration due to their high proliferative capacity and differentiation potential. However, ethical considerations inhibit the widespread use of these cells in most parts of the world. While differentiation protocols for ES cells have recently been improved and established towards retinal cell type differentiation [32], the success of ES cell transplantations in the past was low due to immunological rejection [38]. Neural stem cells, which can be derived from the adult brain and propagated in vitro in the presence of FGF and EGF, have also been transplanted into retinal degeneration models. The grafted cells integrated into the laminar structures of the retina and extended processes into the optic nerve head [50, 54], but no expression of retina-specific markers was observed. When transplanted into the immature retina, neural stem cells adopted expression profiles similar to those of retinal neurons [48].
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Retinal progenitor cells from the fetal retina [60], the postnatal retina [23] and the adult mammalian CB [56] have been characterized in detail. Transplantation studies with these cells indicate that the degree of integration and migration into the host retina depends on the age or stage of the diseased or injured recipient retina. Grafted retinal progenitor cells express the retina-specific marker opsin [11], but their differentiation potential seems to be limited to the glial lineage after transplantation to an adult host with retinal degeneration [60]. Some of the material transplanted into the retina is summarized in Table 11.3.
Summary for the Clinician
■ Cell transplantation seems to be a prom-
ising approach, at least in the preclinical setting. Grafted embryonic and fetal stem and progenitor cells have the potential to replace degenerated retinal tissue. However, major ethical concerns and limited availability seem to make them an unlikely candidate for standard therapy. Adult stem cell transplantation might have some clinical relevance in future. However, the growth and differentiation potential of these cells is yet not sufficient.
■
11
■
11.3.2.2 Application of Transgenes or Genetically Engineered Stem and Progenitor Cells One of the major limitations in successful transplantation strategies is probably the fact that cells are transplanted into a pathological, hostile environment. This environment is unlikely to provide the necessary stimuli for differentiation and integration of grafted cells. Ex vivo gene transfer has been shown to harbor the potential to overcome this barrier. The advantage of these strategies is the inclusion of survival-promoting factors into the grafts. Factors applied in this way could also act in an autocrine manner to simulate a physi-
ological environment for differentiation after transplantation and integration into the retina. Ex vivo gene transfer could facilitate neuroprotection and thereby prevent retinal cell loss in RP, AMD or glaucoma. Several studies have been conducted that address optic nerve degeneration and gene transfer via viral vectors, most of them using recombinant adeno-associated viruses. Gene therapy focuses on: (1) providing growth factors to protect resident neurons or improve graft integration, (2) delivering anti-angiogenic proteins that may help to overcome secondary adverse effects of retinal diseases, and (3) gene replacement strategies for autosomal recessive retinal diseases (reviewed in [46]). Results from the application of survival factors by gene therapy indicated that the delivery of neurotrophins such as nerve growth factor (NGF) [33], ciliary neurotrophic factor (CNTF) [10] or brain-derived neurotrophic factor (BDNF) [16] by viral vectors can rescue photoreceptors and RGC within the optic nerve in degeneration models. Genetically modified human-derived RPE cells, which over-express BDNF, have been shown to promote cell survival [30] and to inhibit aberrant retinal neovascularization [39]. An FGF transgene has also been implemented to endogenously stimulate regeneration in degenerative retinal models, where it provoked axonal outgrowth of adult RGC after optic nerve injury [49]. An approach using small interfering RNA (siRNA), which targeted VEGF, effectively inhibited ocular neovascularization in a mouse model for AMD [45]. This suggests that, besides the viral vectors, siRNA techniques also harbor the potential to address retinal degeneration and neural protection by targeting factors that drive disease mechanisms.
Summary for the Clinician
■ Progress in the development of safer vectors and new technologies such as siRNA make gene therapy a highly promising therapeutic approach.
11.3 Therapeutic Strategies in Degenerative Retinal Diseases
Table 11.3. Selected literature on retinal transplantation experiments in rodents and humans. (AMD Age-related macular degeneration, RP retinitis pigmentosa, RPE retinal pigment epithelium) Transplanted material
Graft site
Retinal cell aggregates
Embryonic and neonatal retinal cell aggregates (rat)
Retinal lesion site, epi- and subretinal space (rat)
Dissociated retinal cells
Retina
[15]
Retinal sheets
Retinal microaggregates (i.e., < 0.2 mm2) (rat and mouse)
Retinal degeneration animal models (rat and mouse)
[26]
Photoreceptor sheets (adult and postnatal day 8 rats)
Subretinal space (rat)
[53]
Fetal retinal neuroblastic progenitor cells with and without the RPE (from rat)
Subretinal space in retinal degeneration models (rat)
Cell transplants in clinical trials
Published/reviewed in [2, 5]
[4]
RPE allografts
AMD patients
[4]
Autologous transplantation of RPE cells
AMD patients
[6]
Fetal retinal sheets including the RPE
Patients with RP or AMD
11.3.2.3 Endogenous Cell Replacement in the Retina One of the most promising ideas for replacement strategies in the retina is the stimulation of endogenously persisting stem or progenitor cell populations. Even though it has been reported that the mammalian retina is devoid of regenerative capacities, numerous studies have indicated that, with appropriate stimuli, regeneration can be induced, especially in chicken and neonatal mammalians (reviewed in [44]). Many attempts have been made to overcome the quiescence that stops endogenous stem and progenitor cell proliferation and differentiation in the diseased retina. With the observation that glial cells of the CNS provide a source of neural regeneration [28], focus has been placed on the glial cell type of the retina, the Müller glia. Fischer and Reh showed that Müller glia cells respond to injury or exogenous growth factors by de-differentiation, proliferation and expression of neuronal and glial markers [24]. First indications for successful endogenous stimulation of Müller glia regeneration
[42]
in the adult mammalian retina were published by Ooto et al. [41]. The authors applied NMDA lesions to the adult rodent retina and demonstrated that Müller glia cells were stimulated to proliferate in response to the toxic injury. Furthermore, the cells produced bipolar cells and rod photoreceptors and their numbers could be promoted by the application of retinoic acid. The authors convincingly showed that they could partially control the fate of the newly generated neurons with extrinsic factors and intrinsic factors. The analysis of the integration of newly generated neurons and their functionality remains to be elucidated. Müller glia cells might be an endogenous source of retinal progenitor cells and may become a target for both drug delivery and gene therapies to effectively treat retinal degenerative diseases. The reasons for the limited or nonexistent proliferation of retinal stem and progenitor cells in the adult retina might be different; for example, the lack of a sufficient amount of mitogens might be a limiting factor. Alternatively, anti–stem-cell proliferative activities might be present in the adult retina. This hypothesis was recently introduced by the work of Close et al. [13], which sug-
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gests that TGF-beta1 might be a paracrine-inhibiting factor derived from mature retinal neurons that limits retinal progenitor cell proliferation [13]. In a similar context, TGF-beta1 has recently been described to be an inhibitor of neurogenesis in the adult brain [57]. Future experimental approaches might be targeted towards the elimination of such activities to restore retinal stem and progenitor proliferation and functional regeneration.
Summary for the Clinician
7.
8.
9.
10.
■ The presence of stem and progenitor cells
in the adult retina makes these cells a very promising drug target, which might be stimulated to regenerate the retina. However, the preclinical development is still at a very early step.
11
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18. Donovan M, Carmody RJ, Cotter TG (2001) Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3-independent. J Biol Chem 276:23000–23008 19. Donovan M, Cotter TG (2002) Caspase-independent photoreceptor apoptosis in vivo and differential expression of apoptotic protease activating factor-1 and caspase-3 during retinal development. Cell Death Differ 9:1220–1231 20. Dunaief JL, Dentchev T, Ying GS, Milam AH (2002) The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120:1435–1442 21. Dyer MA, Cepko CL (2000) Control of Muller glial cell proliferation and activation following retinal injury. Nat Neurosci 3:873–880 22. Engelhardt M, Bogdahn U, Aigner L (2005) Adult retinal pigment epithelium cells express neural progenitor properties and the neuronal precursor protein doublecortin. Brain Res 1040:98–111 23. Engelhardt M, Wachs FP, Couillard-Despres S, Aigner L (2004) The neurogenic competence of progenitors from the postnatal rat retina in vitro. Exp Eye Res 78:1025–1036 24. Fischer AJ, Reh TA (2001) Muller glia are a potential source of neural regeneration in the postnatal chicken retina. Nat Neurosci 4:247–252 25. Gouras P, Flood MT, Kjeldbye H (1984) Transplantation of cultured human retinal cells to monkey retina. An Acad Bras Cienc 56:431–443 26. Gouras P, Tanabe T (2003) Survival and integration of neural retinal transplants in rd mice. Graefes Arch Clin Exp Ophthalmol 241:403–409 27. Hail N Jr., Carter BZ, Konopleva M, Andreeff M (2006) Apoptosis effector mechanisms: a requiem performed in different keys. Apoptosis 11:889–904 28. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Gotz M (2002) Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 5:308–315 29. Kano T, Abe T, Tomita H, Sakata T, Ishiguro S, Tamai M (2002) Protective effect against ischemia and light damage of iris pigment epithelial cells transfected with the BDNF gene. Invest Ophthalmol Vis Sci 43:3744–3753 30. Kanuga N, Winton HL, Beauchene L, Koman A, Zerbib A, Halford S, Couraud PO, Keegan D, Coffey P, Lund RD, Adamson P, Greenwood J (2002)
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52. Sieving PA, Chaudhry P, Kondo M, Provenzano M, Wu D, Carlson TJ, Bush RA, Thompson DA (2001) Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci USA 98:1835–1840 53. Silverman MS, Hughes SE, Valentino TL, Liu Y (1992) Photoreceptor transplantation: anatomic electrophysiologic and behavioral evidence for the functional reconstruction of retinas lacking photoreceptors. Exp Neurol 115:87–94 54. Takahashi M, Palmer TD, Takahashi J, Gage FH (1998) Widespread integration and survival of adult-derived neural progenitor cells in the developing optic retina. Mol Cell Neurosci 12:340–348 55. Tombran-Tink J, Barnstable CJ (2003) PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 4:628–636 56. Tropepe V, Coles BL, Chiasson BJ, Horsford DJ, Elia AJ, McInnes RR, van der Kooy D (2000) Retinal stem cells in the adult mammalian eye. Science 287:2032–2036 57. Wachs FP, Winner B, Couillard-Despres S, Schiller T, Aigner R, Winkler J, Bogdahn U, Aigner L (2006) Transforming growth factor-beta1 is a negative modulator of adult neurogenesis. J Neuropathol Exp Neurol 65:358–370 58. Wenkel H, Streilein JW (1998) Analysis of immune deviation elicited by antigens injected into the subretinal space. Invest Ophthalmol Vis Sci 39:1823–1834 59. Wenzel A, Grimm C, Samardzija M, Reme CE (2005) Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res 24:275–306 60. Yang P, Seiler MJ, Aramant RB, Whittemore SR (2002) Differential lineage restriction of rat retinal progenitor cells in vitro and in vivo. J Neurosci Res 69:466–476 61. Young MJ (2005) Stem cells in the mammalian eye: a tool for retinal repair. Apmis 113:845–857
Part IV
Systemic disease
Chapter 12
Chorioretinal Lesions in Infectious Diseases of Neuroophthalmic Interest
12
Yan Guex-Crosier
Core Messages
■ Ocular toxoplasmosis is the most fre-
quent cause of posterior uveitis. In most cases, ocular toxoplasmosis is not a primary infection but corresponds to a reactivation of retinal cysts. Congenital toxoplasmosis occurs when primary infection is acquired by the mother during pregnancy. Early infection has a worse prognosis than late infection, but transmission of the disease is less frequent in early infection. Ocular toxoplasmosis is less frequent than cerebral toxoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). Toxocara canis is transmitted to children by hand-to-mouth contact when playing in contaminated sand. Toxocara canis can present as leucocoria. Two main diseases are transmitted by tick bites: tick-borne encephalitis and Lyme disease. Tick-borne encephalitis is a flavivirus infection transmitted by ticks (Ixodes ricinus). Lyme disease occurs after bacterial infection with the spirochetes Borrelia burgdorferi, B. garinii or B. afzelii. Clinical manifestations are protean and non-specific. The disease has three clinical stages. Lyme disease is a rare cause of posterior uveitis.
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■ Syphilis has a protean ocular expression
(anterior uveitis, papillitis, chorioretinitis, Argyll Robertson pupils). Ocular syphilis occurs mostly in advanced stage of the disease [positive Treponema pallidum hemagglutination assay (TPHA) and negative VDRL (Venereal Disease Reference Laboratory)]. Indocyanine green angiographic lesions can be observed in syphilitic chorioretinitis. Human immunodeficiency virus (HIV) retinopathy corresponds to the first manifestation of HIV disease. Variant disease of Creutzfeld Jacob (vCJD) corresponds to fewer than 5% of transmissible spongiform encephalopathies. Rare forms of the disease have been described after corneal transplantation. Acute retinal necrosis syndrome corresponds to the onset of peripheral retinal necrotic lesions in herpetic infection. In the presence of a cytomegalovirus (CMV) retinopathy a HIV infection must be ruled out.
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12.1 Introduction
12
Ocular structures as well as the brain can be affected by many infectious diseases. The blood– brain barrier controls the passage of molecules or potential sources of infection from the blood into the brain. In the presence of meningitis the blood–brain barrier is disrupted and allows molecules or infectious agents to penetrate the eyes. Inflammatory processes such as septicemia or viremia trigger the liberation of large amounts of inflammatory molecules within the bloodstream. The upregulation of the inflammatory cascade produces a rupture of the blood–brain or blood– ocular barrier so that infectious agents can then penetrate into the eyes or the brain. Neuroophthalmic examination can reveal the presence of cranial nerve palsies, pupillary reflex anomalies, retinal lesions or optic disc swelling. Cerebrospinal fluid analysis will reveal the presence of concomitant brain infection. Classic infectious agents simultaneously affecting the brain and ocular structures belong to two main groups: those causing zoonotic diseases (i.e., transmitted by animals) and those caused by sexually transmitted diseases. Most of these diseases will be revealed only by a careful ocular or neurological examination. A close collaboration is necessary between ophthalmologists and neurologists. Specific retinal manifestations of infectious disease are helpful for guiding further clinical and laboratory investigations.
12.2 Ocular Zoonosis Zoonosis means a wide group of infectious disea ses that can be transmitted by animals to humans. The incidence of disease in humans is particularly high in areas where animals are infected endemically. A better understanding of the mode of transmission of the disease is an important step in the development of prevention programs.
12.2.1 Ocular Toxoplasmosis Toxoplasmosis has a worldwide distribution and is related to Toxoplasma gondii infection. The prevalence of T. gondii infection varies between
geographic regions and population groups on the basis of numerous factors. According to the Third National Health and Nutrition Examination Survey, the overall age-adjusted seroprevalence was 22.8% (95% confidence interval, CI, 21.1–23.9) [24]. In France about 67.3% of pregnant women have been previously infected. Most primary infections are asymptomatic and the infection then enters a latent phase. Bradyzoites are present, forming cysts in nervous and muscle tissues. Ocular infection is estimated to occur in about 2% of individuals infected with T. gondii. However, the incidence of ocular involvement (retinochoroidal scars) may be much higher: about 17.7% of the population of South Brazil presents with retinal lesions. The infection occurs when raw or partly cooked meat is eaten: pork, lamb and venison are the main sources of infection. Contamination can also occur after contact with contaminated instruments (knives, cutting boards or food that have been in contact with raw meat). Hand-tomouth contact is also a source of infection when a cat’s litter box is cleaned. Ingestion of unpasteurized cow’s or goat’s milk is also a source of contamination. More recently, the ingestion of contaminated water was also mentioned as a potential source of infection [24]. Flu-like symptoms occur during acute infection. Swollen lymph nodes are present and muscle aches and pain can last for more than a month. During the acute phase of the disease a dissemination of trophozoites occurs. The disease remains asymptomatic for years in most cases. Bradyzoites are present and form cysts in nervous and muscle tissues. In about 2% of individuals, eye structures are colonized and reactivation of the disease can occur later in life. The natural history of toxoplasmosis depends on the immune response of the host; three conditions have to be considered: congenital toxoplasmosis, reactivation of ocular toxoplasmosis and toxoplasmosis in patients with acquired immunodeficiency syndrome (AIDS).
12.2.1.1 Congenital Toxoplasmosis When primary infection of the mother occurs during pregnancy, the devastating consequences of congenital toxoplasmosis can be seen. About 0.5%
12.2 Ocular Zoonosis
of pregnant women throughout the world are affected by primary toxoplasmosis infection. The risk of transmission of the disease to the fetus varies from 30% to 60%. During the first trimester of pregnancy transmission occurs in about 10% of cases, 30% in the second trimester and 60% in the third trimester. During the early stage of pregnancy, toxoplasmosis is responsible for spontaneous abortion [19]. Later, congenital infection leads to the development of a cataract or chorioretinitis. Macular scars appeared in 54% of treated patients; 23% were bilateral [38]. In the absence of therapy, historical cases have shown that 82% of congenitally infected individuals will develop ocular lesions by adolescence. The diagnosis of congenital infection is accepted when an infection is confirmed at an age of less than 2.5 months at the time of referral. Systemic manifestations include anemia, petechiae associated with thrombocytopenia, pneumonitis, diarrhea and jaundice (associated with hepato- or splenomegaly). Neurologic manifestations are severe and correspond to hemiparesis, seizure, microcephaly, hydrocephalus, intracranial calcification and encephalomalacia. Psychomotor or mental retardation is frequent [12].
Summary for Clinicians
■ Severe
manifestations of congenital toxoplasmosis are seen when the transmission of the disease occurs at the beginning of pregnancy: microcephaly, hydrocephalus, intracranial calcifications or cataract. When the primary infection occurs in the late stage of pregnancy, chorioretinitis can be observed.
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12.2.1.2 Reactivation of Toxoplasmosis in Immunocompetent Patients Ocular toxoplasmosis is the most frequent cause of posterior uveitis. The aspect of retinitis does not differ between congenital and acquired toxo-
plasmosis. Patients complain of photophobia, blurred vision and decreased visual acuity. Lesions are located mainly in the posterior pole (75% of cases) whereas only 25% are located in the periphery [17]. Slit-lamp examination reveals the presence of granulomatous anterior chamber inflammation with Mutton fat precipitates (Fig. 12.1). During the active phase of the disease, fundus examination reveals the presence of a yellowish focus of inflammation; this lesion corresponds to a focal chorioretinitis (Fig. 12.2). Usually, spontaneous resolution of the disease is seen in about 4–12 weeks. In the presence of posterior uveitis a relapse of disease is observed in 29% of cases during the first year and in 57% of cases within 2 years. Intraocular cysts are not destroyed by anti-toxoplasmic medication. Most current medications are only active against tachyzoites but not against tissular cysts. Recurrence of the disease occurs near old chorioretinal scars (satellite lesion). In immunosuppressed patients, the disease has a more severe evolution. Complications of ocular toxoplasmosis include: macular scar, vascular occlusion, exudative retinal detachment, macular star, subretinal neovascularization, epiretinal membrane formation, and macular edema. Retinal detachment has been correlated to the severity of ocular inflammation. The diagnosis of the disease is mainly clinical. Serological tests are used to confirm previous systemic infection with T. gondii. IgG antibodies usually appear 1–2 weeks after the onset of infection by T. gondii. Titers peak within 1–2 months and remain positive for the rest of that person’s life. IgM antibodies appear earlier and decrease faster than IgG antibodies. IgM antibodies disappear 6 months to 18 weeks after primary infection. Current therapy of ocular toxoplasmosis consists of anti-protozoan therapy of sulfadiazine (3–4 g) and pyrimethamine (50 mg) combined with oral prednisone therapy (1 mg/kg) [21]. Other therapeutic options include atovaquone and spiramycin. Azithromycin was recently proposed as an alternative therapy [47, 63]. The aim of the therapy is to block the multiplication of the parasite during the period of active chorioretinitis. The introduction of therapy during the acute phase does not protect individuals from a
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Fig. 12.1 Mutton fat precipitates characterizing a granulomatous inflammation
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Fig. 12.2. Focus of macular chorioretinitis in acute toxoplasmosis. The destruction of photoreceptors is responsible for a central scotoma and a significant decrease in visual acuity
recurrence of the disease. When the recurrence occurs repetitively near the macula, prophylactic therapy with trimethoprim/sulfamethoxazole has a beneficial effect in the prevention of recurrences when administered intermittently on a long-term basis [51].
Neuroophthalmologic manifestations consist mainly of the presence of arcuate visual field defects that correspond to nerve fiber loss due to juxtapapillary retinochoroiditis [36]. Anterior optic neuritis (papillitis) can be observed when the lesion occurs within the optic disc. The lesion
12.2 Ocular Zoonosis
is associated with an afferent pupillary defect. Neuroretinitis can also be observed.
Summary for Clinicians
■ Toxoplasmosis is a common cause of retinochoroiditis. ■ The disease can result from a primary infection or from a reactivation of dormant intraretinal cysts of Toxoplasmosis. Juxtapapillary toxoplasmosis can be responsible for the development of arcuate scotoma.
■
duction of systemic prophylaxis of toxoplasmosis with trimethoprim/sulfamethoxazole or dapsone and pyrimethamine may decrease the incidence of cerebral toxoplasmosis. The diagnosis of cerebral toxoplasmosis remains difficult in AIDS patients, as false-negative laboratory results can result from a depressed antibody response. Disseminated infections have been rarely observed in immunosuppressed or immunodeficient patients with pneumonitis, myocarditis, pericarditis and lymphadenitis [56].
12.2.1.5 Radiologic Manifestation of Toxoplasmosis in AIDS
12.2.1.3 Ophthalmic Toxoplasmosis in AIDS Patients Ocular toxoplasmosis appears rarely in AIDS patients, but ocular lesions are more extensive than in immunocompetent patients. No spontaneous resolution of chorioretinitis has been reported to occur in AIDS patients. Small hemorrhages can be observed within the lesions. Rare cases of iris infection have also been reported. Neuroophthalmologic manifestations correspond to lesions affecting the visual and ocular motor pathways in the presence of encephalitis or meningoencephalitis [44].
12.2.1.4 Neurologic Manifestation of Toxoplasmosis in AIDS Patients Prophylaxis of cerebral toxoplasmosis is a major concern in the treatment of AIDS patients. The clinical and pathological incidence of cerebral toxoplasmosis in AIDS patients before the era of highly active antiretroviral therapy (HAART) were, respectively, 11.3% and 40%. Central nervous system (CNS) toxoplasmosis develops during the advanced stage of AIDS. Among patients with positive toxoplasma serology one in three will develop cerebral toxoplasmosis when the CD4 count is below 100×106/l. Symptoms of cerebral toxoplasmosis include headache, confusion, fever, lethargy and correspond to the presence of encephalitis or meningoencephalitis. The intro-
Neuroimaging reveals the presence of multiple intraparenchymal lesions that can be localized in the cerebral hemispheres, thalamus, brainstem or cerebellum. Lesions appear hypodense on a computed tomography (CT) scan in the absence of contrast material and are enhanced after injection of contrast material. Hyperdense lesions can be observed in unenhanced CT scans in the presence of hemorrhages. Magnetic resonance (MR) images are helpful in the detection of cerebral lesions that appear hypodense in unenhanced T1weighted images, and cerebral edema surrounding the lesions is seen in T2-weighted images. Neuroradiologic imaging is not specific and the presence of CNS lymphoma, bacterial or fungal abscess must be ruled out. In AIDS, the probability of a solitary mass being CNS toxoplasmosis is 35%, whereas it is 62% in the presence of multiple lesions [7]. Lumbar puncture is performed to exclude the diagnosis of cryptococcosis.
Summary for Clinicians
■ Cerebral toxoplasmosis is the common-
est manifestation of toxoplasmosis in AIDS patients. Primary prophylaxis in patients with positive serology with a CD4+ cell count of less than 200×106/l is therefore recommended: co-trimoxazole or dapsone with pyrimethamine.
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12.2.2 Toxocariasis 12.2.2.1 Introduction Toxocara canis is a parasite responsible for visceral larva migrans or ocular toxocariasis. Dogs are the definitive host of Toxocara canis, with more than 80% of puppies being infected. Humans are infected when ingesting infective-stage eggs of the parasite. Young children are frequently infected when they play in contaminated sand areas. In young children, visceral larva migrans is a common manifestation of the disease, which is characterized by hepatomegaly, pulmonary signs and marked eosinophilia [48]. However, most infected individuals are asymptomatic. Parasitic infection is associated with hypereosinophilia. About 4.5%–31% of children test positive for Toxocara canis [15,46]. Among the 106 patients who tested positive for Toxocara canis, none had ocular infection [15].
12
12.2.2.2 Ocular Manifestations When the parasites migrate towards the eyes, the term ocular toxocariasis is used (less than 1% of uveitis). In young children ocular toxocariasis is a cause of leucocoria which can mimic the presence of a retinoblastoma. According to Zane F. Pollard, titers of 1:8 or greater should be considered as positive for ocular toxocariasis [43]. 17 out of 20 patients [43] . Concomitant visceral larva migrans is rare, as only 5/245 cases of ocular toxocariasis simultaneously had visceral larva migrans [5]. Ocular lesions are usually unilateral, and may present as posterior chorioretinitis, peripheral chorioretinitis, papillitis, neuroretinitis, endophthalmitis, motile chorioretinal nematode or diffuse unilateral subacute neuroretinitis (DUSN) [50]. Keratitis, conjunctivitis and lens involvement have also been described [50]. When the patient is asymptomatic and an ocular lesion is found, no therapy is necessary. The administration of albendazole, an anti-parasitic drug, can be associated with severe ocular inflammation. In the presence of a severe ocular inflammation, an anti-parasitic drug must be used in association with systemic steroid therapy and/or vitrectomy.
12.2.2.3 Neurologic Manifestations Hematogenous dissemination of the larvae to the brain or spinal cord has been observed. In the early stage of the disease, vascular occlusion of the vessels is seen, which can be followed by vessel rupture and intracranial hemorrhages. When the parasite subsequently dies a secondary granuloma develops. The lesions consist of lymphocytes, eosinophils, plasma cells, fibroblasts and epithelioid cells.
Summary for Clinicians
■ Toxocara canis is a rare cause of ocular or cerebral infection. ■ The diagnosis of retinoblastoma must be ruled out in the presence of leucocoria.
12.2.3 Diseases Transmitted by Ticks 12.2.3.1 Introduction Two main diseases can be transmitted by tick bites: tick-borne encephalitis, which is caused by a flavivirus [13], and Lyme disease caused by the bacteria Borrelia burgdorferi. Both are transmitted by Ixodes ricinus ticks. Lyme disease is much more frequent than tick-borne encephalitis. In Switzerland about 1 tick out of 1000 is infected by the flavivirus while about 20% of ticks are infected with B. burgdorferi.
12.2.3.2 Tick-Borne Encephalitis The following diseases are produced by a flavivirus: dengue fever, yellow fever, Japanese encephalitis and tick-borne encephalitis. Tickborne encephalitis is produced by an arbovirus, the flavivirus of the family Flaviviridae and of the genus Flavivirus. Tick-borne encephalitis is an important cause of morbidity and mortality in endemic areas. The disease is endemic in Central and Eastern Europe, Russia and Far East. The disease was first described by Schneider in 1931. The main hosts and reservoirs are small rodents; the
vectors are Ixodes ricinus and Ixodes persulcatus. Two routes of infection are classically admitted: the virus may enter the body through a tick bite or after ingestion of infected unpasteurized milk. The virus initially multiplies at the site of inoculation. Later it spreads through the reticuloendothelial cells of the lymph nodes and eventually it will produce a viremia through the thoracic duct. Clinical manifestations of tick-borne encephalitis occur after a short incubation period of 7–14 days (range 2–28 days). A biphasic rise of fever occurs. The first period of fever is followed by an asymptomatic period of 2–10 days. The second rise of fever is associated with signs of meningitis or meningoencephalitis. During the acute stage of the disease Flavivirus can be responsible for granulomatous inflammation of the eyes but ocular manifestations are much less frequent than encephalitis [13, 54].
12.2.3.3 Lyme Disease 12.2.3.3.1 Introduction Lyme disease is a bacterial infection resulting from tick bite. About 60,000 cases are reported each year in Europe [41], where the disease has a more aggressive neurologic presentation than in USA. In USA, endemic areas for Lyme disease are in the Northeast (from Maine to Maryland), in the Midwest (Wisconsin and Minnesota) and in the West (North California and Oregon). In Europe the disease is mainly present in the middle of Europe and Scandinavia. American neuroborreliosis is caused predominantly by B. burgdorferi sensu stricto, whereas European disease is caused by B. garinii or B. afzelii (B. burgdorferi senso lato). Genetic differences between these subspecies appear considerable. Infection is transmitted by nymphs and adult ticks (Ixodes ricinus). Maturation from larval to nymphal and later adult stages requires the ticks to consume a blood meal. Risk of tick transmission remains low; fewer than 3.2% of patients bitten by ticks in endemic areas develop Lyme disease. The risk increases when ticks feed for 72 h or longer [49]. Borrelia burgdorferi belongs to the spirochetes, and, like syphilis, the disease has three stages. Early infection consists of localized erythema
12.2 Ocular Zoonosis
migrans (stage 1), followed within days or weeks by disseminated infection affecting the nervous system, heart, or joints (stage 2) and, weeks or months later, by the late or persistent stage of infection (stage 3). 1. Stage 1: localized erythema migrans occurs at the site of tick bite. Acute infection is associated with flu-like symptoms such as malaise, fatigue or headaches. In patients infected by B. afzelii a particular skin manifestation called acrodermatitis atrophicans may occur during chronic stage of the disease. 2. Stage 2: corresponds to the dissemination of the infection. It occurs in about 15% of untreated patients in USA [53]. Cardiac manifestations can be seen in 5% of untreated patients. Common manifestations correspond to a fluctuating degree of atrioventricular block, acute myopericarditis or mild left ventricular dysfunction. 3. Stage 3: up to 5% of untreated patients in USA will progress to the third stage of the disease which corresponds mostly to immunologic manifestations of the disease.
12.2.3.3.2 Ophthalmologic and Neuroophthalmologic Manifestations Ocular manifestations can be seen at any stage of the disease. Conjunctivitis appears during Stage 1 in about 10% of patients. The other manifestations are cranial nerve palsies, cortical blindness, optic disc edema, optic neuritis, neuroretinitis and retinitis. Endophthalmitis occurs mostly during Stages 2 and 3. Facial nerve paresis accounts for 80%–90% of all cranial nerve dysfunction of Lyme disease. Borreliosis must always be ruled out in the presence of a facial palsy in children (Fig. 12.3a). In most cases, resolution occurs after therapy (Fig. 12.3b). Abducens nerve paresis is another manifestation of disseminated Lyme disease [30]. Lyme uveitis is a granulomatous uveitis associated with keratic precipitates and posterior synechiae. Intermediate uveitis is a common manifestation in Lyme disease (Fig. 12.4) [61]. A mild to severe vitritis is present, and snowballs or snowbanks can be seen at the pars plana. Stromal keratitis with superficial and deep corneal infiltrates can also be observed in Stage 3 of the disease [33].
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12 Fig. 12.3a,b. Facial palsy in Lyme disease (a). Resolution of the symptoms occurred after anti-infectious therapy (b)
12.2.3.3.3 Neurologic Manifestations Neurologic manifestations of the disease are mostly seen in Stage 3. This stage can produce lymphocytic meningitis and can be responsible for episodic headache, mild neck stiffness, and subtle encephalitis. Neurologic manifestations of the disease occur in 10%–15% of cases of Lyme disease. Cranial neuropathy (such as unilateral or bilateral facial palsy), motor or sensory radiculoneuritis, mononeuritis multiplex, cerebellar ataxia or myelitis can be present. The disease can produce axonal polyneuropathy which manifests primarily as spinal radicular pain or distal paresthesia. The most common syndrome is chronic progressive encephalomyelitis [28]. The major symptoms are difficulties with gait and bladder dysfunction. A large variety of symptoms may occur during the advanced stage of disease. The
cerebrospinal fluid (CSF) presents increased concentration of IgG and, occasionally, both IgM and IgA. Oligoclonal bands are commonly present and myelin basic protein may be present [29]. The late stage of the disease remains difficult to treat: immune-mediated disease can be responsible for symptoms.
12.2.3.3.4 Diagnosis of Lyme Disease Direct isolation of B. burgdorferi remains difficult. The spirochete has been isolated from skin lesions, CSF, blood and affected tissues. A silver staining technique appears suitable for direct demonstration of spirochetes within tissue biopsy samples. In most cases of Lyme disease the diagnosis is suspected on indirect detection of B. burgdorferi antibodies by ELISA tests. The ELISA test can
12.2 Ocular Zoonosis
Fig. 12.4. Vasculitis and papillitis in Lyme disease. Perivascular staining is observed in the late stage in the fluorescein angiogram. Note the asymetric aspect of macular edema (arrows)
be confirmed by a Western blot test. In endemic areas a high prevalence of positive ELISA test is seen in the absence of Lyme disease.
12.2.3.3.5 Treatment and Prevention of Lyme Disease Treatment recommendations for Lyme disease in Stage 1 consist of doxycycline in patients older than 8 years of age, except in pregnant women
[62]. A single dose of 200 mg doxycycline given within 72 h after I. scapularis tick bite was shown to prevent the development of Lyme disease [40]. During the second or third stage of the disease ceftriaxone is considered the therapy of choice [26]. Amoxicillin is the alternative therapy in young children or in pregnant women. The eye structure offers poor permeability to doxycycline or to amoxicillin. Risk of tick transmission remains low: less than 3.2% of patients bitten by ticks in endemic areas develop Lyme disease. The risk increases when ticks feed for 72 h or longer [49].
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Summary for Clinicians
■ Lyme disease is produced by infection with the spirochete Borrelia burgdorferi. ■ Neuroophthalmic manifestations of Lyme disease correspond mainly to the development of uveitis, facial palsy, optic disc edema, although many other manifestations can be observed.
12.2.4 Cat Scratch Disease
Fig. 12.5. Parinaud’s syndrome due to cat scratch disease in a 7-year-old girl
12.2.4.1 Introduction
12
Cat scratch disease was first described in 1889 by Henri Parinaud: he reported three patients with chronic fever, regional lymphadenopathy and follicular conjunctivitis. The disease was later described as Parinaud oculoglandular syndrome. The etiologic agent of the disease was isolated much later: a Gram-negative rod. Serological studies have proven the association between Rochalimaea henselae infection and cat scratch disease. Recently the genera Bartonella and Rochalimaea were united according to 16S rRNA similarities [3]. The disease is transmitted by the bite or scratch of an infected animal. Animal fleas (Ctenocephalides felis) are also suspected to transmit the disease. An erythematous papule or pustule develops at the site of infection and is associated with local lymphadenopathy, fever, malaise and fatigue. Systemic complications such as splenomegaly, splenic abscess, encephalopathy, granulomatous hepatitis, pneumonia, and osteomyelitis occur only rarely.
12.2.4.2 Ocular and Neuroophthalmologic Manifestations Ocular manifestation occurs several weeks after a cat scratch in about 10% of patients and is characterized by local lymphadenopathy and follicular conjunctivitis which was described as Parinaud’s oculoglandular syndrome (Fig. 12.5). Other later manifestations include anterior uveitis, papillitis, neuroretinitis and serous retinal manifestations.
In a recent series of 24 patients with the presumptive diagnosis of cat scratch disease, 27 (83%) of 35 eyes had posterior segment findings [52]. Retinal or choroidal white lesions were found in 83% of cases, disc edema and macular star were found in 46% of eyes, and serous elevation of the neurosensory retina and vitreous inflammation were found in 20% of eyes. Vasoocclusive disease was found in 4 eyes. Severe papillitis can be seen in 9% of patients. Stellate maculopathy was originally used by Leber to describe an idiopathic disease; later the term macular star was used. It corresponds to a leakage of lipid-rich exudates within the outer plexiform layer. Even though a macular star is frequently associated with cat scratch disease, it is not specific as it can be associated with many infectious diseases such as syphilis, salmonella, herpes simplex, mumps, leptospirosis, toxocariasis, toxoplasmosis and non-infectious conditions such as increased intracranial pressure, hypertensive retinopathy, and anterior ischemic optic neuropathy. Bartonella henselae has been also associated with obliterative vasculitis. Bacterial invasion of the vascular endothelium is known to be the origin of the thrombotic mechanism. Optic nerve swelling may also contribute to vascular occlusion. Vascular occlusion can be associated with a local vasoproliferative response, which induces neovascularization [11]. Fluorescein angiography will often reveal late staining of the submacular region and optic disc leakage that is associated with perivenous staining surrounding the disc.
12.3 Sexually Transmitted Diseases
12.2.4.3 Neurologic Manifestations Approximately 2% of patients will develop systemic complications including involvement of CNS, liver, spleen, lung, bone, and skin. Neurologic manifestation usually begin about 1–6 weeks after the onset of lymphadenopathy, and consists mostly of meningitis, encephalitis, radiculitis and myelitis [31, 32].
12.2.4.4 Therapy Many antibiotic therapies, including doxycycline and rifampicin, have been proposed to treat Bartonella henselae infection. More recently, azithromycin has been proposed as an alternative therapeutic agent [10]. However, the efficacy of specific therapies remains to be demonstrated.
Summary for Clinicians
■ Cat scratch disease results from an infection by Bartonella henselae. ■ Parinaud’s oculoglandular syndrome is the commonest ocular manifestation of cat scratch disease and represents a primary infection in the vicinity of the eye. Secondary ocular manifestations include uveitis, papillitis, macular edema, and neuroretinitis. About 2% of systemic complications can be observed.
■ ■
12.3 Sexually Transmitted Diseases 12.3.1 Syphilis 12.3.1.1 Introduction Acquired syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. The clinical course of infection consists of three stages: primary, secondary and tertiary stage or late syphilis [22]. The chancre is the first manifestation of the disease; it consists of a painless indurated ulcer that develops at the site of
inoculation. The incubation period is 2–6 weeks. The chancre heals in the absence of therapy in 3–6 weeks. The primary infection is usually followed by a secondary infection 4–10 weeks later. A latent infection can be present between the secondary and the tertiary stage. Patients with early syphilis (stage I or stage II) are contagious and can sexually transmit the disease. Patients with late syphilis (stage III) are not sexually contagious.
12.3.1.2 Ocular and Neuroophthalmologic Manifestations Protean clinical manifestations of the disease can be observed according to its stage of development. During the primary stage a chancre is rarely observed on the eyelid or on the conjunctiva. Ocular manifestations are mainly seen during the secondary and tertiary stages. During the secondary stage, it can be responsible for vitritis, diffuse or localized choroiditis, neuroretinitis, papillitis, optic neuropathy, exudative retinal detachment associated with choroidal effusion [25], retinal vasculitis and occlusive retinal vasculopathy [55]. Anterior optic neuritis is a frequent complication of neurosyphilis; it occurs mostly during stages II and III of the disease. When hard macular exudates are present, the term of neuroretinitis is used. The Argyll Robertson pupil is a rare but typical sign of mesencephalic involvement in neurosyphilis. Pupils are small, irregular, and react poorly to light but constrict normally during convergence. During initiation of antibiotic therapy a severe ocular inflammation can be observed (Jarisch–Herxheimer reaction) that can be associated with bilateral retinal detachment and giant retinal tears [45]. Ocular syphilis is a rare cause of uveitis occurring in fewer than 2% of cases. The retinopathy of syphilis is usually described as salt and pepper retinopathy. Fluorescein angiography will reveal hypofluorescent zones associated with hyperfluorescent zones (leopard spots). Indocyanine green angiography reveals two type of lesions in patients with syphilitic posterior uveitis: late-phase scattered hyperfluorescent spots and persistent staining of the retinal vessels (Figs. 12.6, 12.7, 12.8) [39].
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12.3.1.3 Diagnostic Tests The Venereal Disease Laboratory Test (VDRL) reflects the activity of the disease: the VDRL test progressively decreases by about one dilution every month after adequate therapy. The VDRL tests can be negative during very early stages of the disease or during late syphilis (about 25% of untreated patients have a VDRL test that becomes non-reactive). The clinical diagnosis of syphilis is confirmed by the presence of specific laboratory tests such as the FTA-ABS test and TPHA, which remain positive throughout life.
12.3.1.4 Therapy
12
Standard therapy of a patient with ocular syphilis consists of 18–24 million units of intravenous aqueous penicillin G given daily for 10–14 days, which is divided into six doses [34]. An alternative therapy to intravenous penicillin is ceftriaxone [35].
Summary for Clinicians
■ Ocular complications of syphilis occur mostly in the advanced stage of the disease and are protean. VDRL is often negative and TPHA positive.
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12.3.2 Human Immunodeficiency Virus (HIV) and Ocular Infection 12.3.2.1 Introduction In the family of retroviridae, the Lentiviruses, are subdivided into two groups: human immunodeficiency virus type 1 and 2 (HIV) and the human T cell leukemia/lymphoma virus type I and type II (HTLV-I and HTLV-II). Early HIV infection is often asymptomatic.
Fig. 12.6. Syphilitic chorioretinitis in a 24-year-old patient. No lesion was visible on fundus examination
HIV viruses are responsible for acquired immunodeficiency syndrome (AIDS) in the late stage of HIV infection. In the absence of therapy, the progression of HIV infection towards immunodeficiency depends on the progressive loss of CD4+ T lymphocytes (about 65×106/l per year). Ocular and neurological manifestations of HIV infection are mostly seen when the CD4+ cell count falls below 50×106/l. Many neurologic complications can be observed during HIV disease. Primary neurologic complications consist mostly of neurocognitive disorders, meningitis and meningo-encephalitis, headaches, vascular myelopathy, neuropathies, and myopathies. Secondary neurologic complications occur only in advanced stages of the disease and consist of opportunistic infections (toxoplasmosis, Cryptococcus neoformans, CMV, JC virus and other opportunistic infections). In AIDS patients, opportunistic infection occurs when the CD4+ cells are not able to control the infection.
12.3 Sexually Transmitted Diseases
The development of highly active antiretroviral therapy (HAART) has changed the evolution of AIDS, drastically decreasing the incidence of opportunistic infections. However, opportunistic infection such as CMV retinitis can be the inaugural manifestation of AIDS in patients unaware of their infection. Ocular manifestations of infectious diseases can be frequently observed in AIDS patients. This chapter focuses mainly on ocular manifestation of CMV retinitis, which remains the major ocular manifestation in AIDS patients in the absence of the introduction of an effective anti-retroviral therapy.
12.3.2.2 HIV Retinopathy HIV retinopathy is observed in any stage of HIV infection and fundus lesions include peripheral hemorrhages and cotton wools spots. It can be seen at any stage of the disease. HIV retinopathy corresponds to an ischaemic microan-
Fig. 12.7. Fluorescein angiography of the same patient (fig. 12.6). Note the absence of vascular leakage, fluorescein angiography appears normal in the presence of ocular syphilis
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12 Fig. 12.8. Indocyanine green angiography (ICGA) of the same patient with ocular syphilis (Fig. 12.6) reveals hyperfluorescent dots in the late stage of angiograms
giopathy. Optical coherence tomography (OCT) images demonstrate the presence of progressive and subtle thinning of the retinal nerve fiber layer.
12.3.2.3 CMV Retinitis The immune status of the host will play a major role in the development of ocular disease. When sufficient CD4+ cells are present, no opportunistic infection will develop in HIV-positive patients. CMV infection is frequent: more than 50% of the general healthy population has a positive serologic test for CMV. CMV retinitis usually occurs at the end stage of the disease or in advanced HIV infection, when the CD4+ cell count is below 50×106/l. Cytomegalovirus infection can be asymptomatic or can manifest as visual loss. Cytomega-
lovirus retinitis has a typical “crumble cheese and ketchup” aspect corresponding to white granulomatous lesions and hemorrhages (Fig. 12.9). Cytomegalovirus infection can be the inaugural symptom of AIDS and HIV infection must always be ruled out in the presence of such lesions. Therapy of CMV retinitis was a major problem for AIDS patients before the advent of HAART therapy. Ocular lesions are associated with systemic CMV infection. Virus can be excreted in the urine. Systemic CMV infections are treated with intravenous antiviral drug therapy: ganciclovir, foscavir or cidofovir (HPMPC). Systemic therapy with antiviral drugs is associated with many side-effects: leukocyte toxicity (ganciclovir); renal insufficiency (foscavir) and ocular hypotony (cidofovir). An induction therapy of 3 weeks or more is used to obtain a cicatrisation of the lesions. This induction therapy is followed
12.3 Sexually Transmitted Diseases
Fig. 12.9. Peripapillary cytomegalovirus retinitis in a patient with human immunodeficiency virus
by a maintenance therapy. Relapse of the disease may occur upon cessation of therapy. The incidence of CMV retinitis has decreased considerably with the use of HAART. Nowadays, CMV retinitis occurs only in HIV-positive patients that are not under HAART therapy or in HIVnegative patients who are treated with systemic immunosuppressive drugs after kidney or bone marrow transplantation. Local therapies have been developed in a compassionate use to avoid the systemic toxicity of drugs. Intraocular ganciclovir injections are successful in controlling the disease. An intraocular drug delivery system was recently developed to produce constant intraocular release of ganciclovir and to allow better control of ocular disease. At the same time, oral drugs, such as oral ganciclovir, were developed but the drug has poor bioavailability and frequent relapses of CMV retinitis are seen. The development of HAART has changed the evolution of AIDS. Before the HAART era, patient death was seen after a mean time of 18 months after the onset of CMV retinitis. For the first time HAART produced an increase in CD4+ cell count. The restoration of immunity is responsible for the onset of an immune recovery vitritis, hypopyon or frosted angiitis
syndrome. The increase in CD4+ cell count over a value of about 180×106/l allows the cessation of anti-CMV therapy without presenting a risk of relapse. The development of an oral prodrug of ganciclovir, valganciclovir, has changed the therapy of CMV retinitis. Oral therapy has a similar efficacy to intravenous therapy. In CMV retinitis, oral valganciclovir is given at a therapeutic dosage of 900 mg twice a day until cicatrisation of the lesions. Maintenance therapy is given until the CD4+ cell count reaches a value over 180×106/l. With the increase in CD4+ cell count, an immune recovery vitritis can be observed and cystoid macular edema may develop. The onset of macular edema parallels a marked decrease in visual acuity. Local therapies with posterior subtenon’s steroid injections (40 mg triamcinolone acetonide) have been proposed to control inflammation and to restore good visual acuity. The injection is performed in the supero-temporal quadrant of the eye. The needle is inserted under the conjunctiva and the subtenon’s capsule. Despite aggressive therapy in AIDS patients with CMV retinitis, long-term follow-up of patients reveals a poor visual outcome in some. Retinal detachment is a classical complication
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of CMV retinitis. Chronic macular edema is associated with loss of photoreceptors or fibrosis of the macula. Optic nerve atrophy is a complication of end-stage HIV infection.
tracranial calcifications, chorioretinitis, cerebral palsy, and mental retardation.
12.4.2 Creutzfeldt–Jakob Disease Summary for Clinicians
■ HIV infection produces primary neuro-
logical complications (meningo-encephalitis). Secondary infectious complications are seen when the CD4+ cell count falls below 200×106/l. CMV retinitis occurs when the CD4+ cell count is <50×106/l.
■ ■
12.4 Encephalopathies Due to Viral and Non-Conventional Agents
12
12.4.1 Lymphocytic Choriomeningitis Virus Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenaviridae family. Virus carriers are chronically infected rodents such as mice and hamsters. The virus is excreted during active infection by saliva, nasal secretions, milk, semen, urine and feces. Contamination occurs either by inhalation of aerosols or by contact with the virus. One-third of the patients remain asymptomatic despite viral infection. Half of the patients develop asymptomatic meningitis or meningoencephalitis. LCMV infection appear biphasic with the following initial symptoms: fever, malaise, myalgia, headache, photophobia, nausea, vomiting, soar throat, cough, and adenopathy. Eye manifestations occur usually in the presence of neurologic symptoms but chorioretinal lesions may be the only manifestation of infection [4]. The following findings are observed in patients with choriomeningitis virus infection: chorioretinitis 71%, chorioretinal scar 36%, optic atrophy 21%, nystagmus 10%, esotropia 4%, microphthalmia 4%, and cataract 4% [2]. Classical neurologic manifestations include unexplained hydrocephalus, micro- or macroencephaly, in-
Creutzfeldt-Jakob disease (CJD) is a neurological disease characterized by rapidly progressive myoclonus, ataxia, and dementia. The term transmissible spongiform encephalopathies (TSEs) was later used to characterize these diseases. Human TSEs are divided by etiology into infectious (5%), sporadic (80%), and inherited diseases (15%). Sporadic CJD occurs at a rate of 0.5 to 1 per million populations per year. Inherited TSEs occur after a mutation of the prion gene, located on chromosome 20p. They include GerstmannStraussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Less than 5% of TSE is secondary to iatrogenic or dietary exposure (infectious TSEs). Variant Creutzfeldt–Jacob (vCJD) disease was first described in 1996 as a new TSE in human beings. This disease has now been causally linked to bovine spongiform encephalopathy (BSE) [8]. The infectious agent involved in the sporadic form of Creutzfeldt–Jacob is a prion protein (PrpSc). This agent has been identified by Western blot in neuronal tissue, in neuronal retina, optic nerve, and in retinal pigment epithelium [58]. The abnormal PrpSc molecule will induce the normal molecule Prpc to undergo a change of conformation into PrpSc. Diagnosis of the sporadic form of Creutzfeldt–Jacob disease (CJD) relies on an appropriate clinical profile supported by the results of EEG (periodic sharp wave complex) and CSF (14-3-3 protein) [27]. Between 1992 and 2002, 2,451 patients were reported with sporadic form of CJD: 136 cases from Australia, 68 from Austria, 146 from Canada, 491 from France, 450 from Germany, 342 from Italy, 100 from the Netherlands, 438 from UK, 18 from Slovakia, 183 from Spain, and 79 from Switzerland. The median age at death was 68 years (range: 20–92). EEG abnormalities, i.e., typical sustained periodic sharp wave complexes (PSWCs), were present in 58.4% of cases. EEG anomalies were higher in the presence of codon 129 genotype. CSF 14-3-3 protein was present in 62.1% of sporadic CJD [9].
12.4 Encephalopathies Due to Viral and Non-Conventional Agents
Presumed iatrogenic Creutzfeldt–Jacob has a very low incidence. In 2000, only 267 cases were reported worldwide: 3 cases were related to corneal grafting (1 confirmed, 1 probable, 1 possible), 114 were related to dura mater grafts, 139 were related to human growth hormone treatment, 4 to human pituitary gonadotrophin therapy and 7 to neurosurgical or stereotactic EEG electrodes [6]. Diagnostic criteria for probable vCJD are summarized by the National CJD Surveillance Unit [60]. Definitive diagnosis can be performed after neuropathological confirmation of brain biopsy samples. Spongiform change and gliosis on histology are still used in diagnosis. Immunohistochemistry became possible with the development of Prp-specific antibodies. More recently a highly sensitive Western blot analysis was developed by Wadsworth et al. [58]. For diagnosis of vCJD, Prp-specific antibodies or Western blot analysis of lymphoid tissue is now available (lymphotropism of the disease). Tonsil biopsy samples associated with MRI can also be helpful. The Heidenhain variant of CJD is of particular concern for the ophthalmologist, as these patients present with visual loss when their cognitive functions are still intact. Visual symptoms result from posterior involvement of the optic radiations, and a rapidly progressive often bilateral homonymous hemianopia is the rule. CJD or vCJD must be suspected in the presence of patients presenting with an unexplained visual loss or in the presence of a homonymous hemianopia in the absence of a proliferative cerebral lesion or ischemic lesion (on brain MRI or CT). In the classical form of CJD a large percentage of patients had visual symptoms. The presence of neurological or psychiatric symptoms in patients of less than 50 years old . When CJD is suspected, disinfection of ophthalmic instruments is critical to prevent transmission of the disease. Each country has recommendations for prevention of the disease. The Swiss CJD Task Force has proposed three alternatives in the population at risk of transmission of CJD: (1) the use of disposable instruments, (2) the use of contact lenses that can be sterilized at 134°C for 18 min and (3)
the disinfection with 2.5% Na hypochlorite, but the corrosive nature of this agent limits its clinical use.
Summary for Clinicians
■ Transmissible spongiform encephalopathies represent a wide group of diseases. ■ According to the mode of transmission they can be subdivided into a sporadic form (80%), inherited disease (15%) or infectious (5%). The infectious agent involved in the sporadic form of Creutzfeldt–Jacob is a prion protein (PrpSc).
■
12.4.3 JC Virus and Progressive Multifocal Leukoencephalopathy JC virus (JCV) is a human polyomavirus. The virus is very common, affecting 70%–90% of the general population [42]. The pathogenesis of the infection remains unclear. Primary infection occurs in childhood. JC virus has been detected in the urinary tract of immunosuppressed individuals and pregnant women. In normal individuals the disease remains asymptomatic. In the presence of severe immunodeficiency unrestricted viral replication can lead to tissue destruction in the urogenital tract, CNS, and lung. Before the AIDS pandemic, progressive multifocal leukoencephalopathy (PML) only occurred as an extremely rare complication of malignant diseases such as lymphoma or leukemia or in association with granulomatous disorders such as tuberculosis and sarcoidosis. The number of PML cases has increased dramatically since the onset of AIDS. For decades the definitive diagnosis of PML was based on a positive brain biopsy, and detection of JCV DNA or viral antigens. More recently polymerase chain reaction (PCR) analysis of CSF has shown high sensitivity for viral detection in 80%–90% of biopsy-confirmed PML patients [37, 59]. JC virus has been detected in 32% of paraffin-embedded eyes of HIV patients whereas
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only 1 out of 21 eyes of patients without AIDS was positive [14]. Rare ocular manifestations of the disease have been described: most patients present with a rapid decline in vision or visual field defects. A favorable outcome was observed after cancellation of immunosuppressive therapy [57]. Patients with PML and AIDS undergoing HAART have a prolonged survival and improved or stabilized neurological conditions. Cidofovir (HPMPC) also has in vitro activity against polyomaviruses but its use in clinical practice awaits more studies [1].
Therapy consists of intravenous foscavir therapy or high-dose intravenous acyclovir to block viral replication. High dose valacyclovir, an oral prodrug of acyclovir, was recently proposed as an alternative therapy in Herpes infection [16, 18].
Summary for Clinicians
■ Acute retinal necrosis syndrome is a se■
12.4.4 Herpetic Encephalopathy and Acute Retinal Necrosis Syndrome
12
Acute retinal necrosis (ARN) syndrome was first described in 1971 by Urayama and is a rare ocular inflammatory condition that results from the reactivation of Herpes simplex, Herpes zoster or CMV infection. Herpes simplex and Herpes zoster virus have been isolated in most cases of ARN syndrome. Some patients have previous history of herpetic encephalopathy. Acute retinal necrosis syndrome consists of: (1) an arteritis and phlebitis of retinal and choroidal vasculature; (2) a confluent necrotizing retinitis; and (3) a moderate to severe vitritis [20]. Anterior segment inflammation, optic neuritis, and retinal detachment are commonly found. The term herpetic retinopathies is used to cover all manifestations of the disease. Prompt treatment with antiviral therapy is necessary to avoid full-thickness necrosis and permanent loss of vision. The spectrum of the disease depends on the immune status of the host. In AIDS patients a more devastating form of necrotizing herpetic retinopathy has been described under the term PORN syndrome, i.e., progressive outer retinal necrosis syndrome [16]. Patients presenting PORN disease present with a unilateral fulminant necrosis involving the outer retinal layers with sparing of the inner retina and retinal vasculature. The diagnosis is based on a positive PCR or after demonstration of intraocular Herpes virus IgG synthesis (Goldmann-Witmer coefficient).
■
vere ocular infection related to Herpes simplex, Herpes zoster or CMV infection. In some patients the disease can be associated with a previous episode of herpetic encephalopathy. Prompt therapy with intravenous antiviral agents is necessary to avoid further progression of ocular necrosis.
12.5 Conclusion Ophthalmic manifestations are frequently observed in association with systemic infectious diseases. The typical pattern of ocular chorioretinitis may be helpful in guiding further bacteriological or viral investigations. A good knowledge of the epidemiology of infectious diseases is necessary to avoid unnecessary tests. Combined neurological investigations and CSF fluid analysis are very helpful in the management of diseases since concomitant ocular and brain infection are frequent. The improvement of diagnostic tools has helped our understanding of new infectious agents. Six factors have recently been identified by Lederberg et al. as factors for emergence of infectious diseases: change in human demographics and behavior, technology and industry, economic development and land use, international travel and commerce, microbial adaptation and change, and breakdown of public health measures [23]. The recent increase in travel around the world has probably contributed to the spread of many infectious diseases.
References
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37. McGuire D, Barhite S, Hollander H, Miles M (1995) JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy. Ann Neurol 37:395–399 38. Mets MB, Holfels E, Boyer KM, Swisher CN, Roizen N, Stein L, Stein M, Hopkins J, Withers S, Mack D, Luciano R, Patel D, Remington JS, Meier P, McLeod R (1996) Eye manifestations of congenital toxoplasmosis. Am J Ophthalmol 122:309–324 39. Mora P, Borruat FX, Guex-Crosier Y (2005) Indocyanine green angiography anomalies in ocular syphilis. Retina 25:171–181 40. Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, Welch P, Marcus R, Aguero-Rosenfeld ME, Dennis DT, Wormser GP (2001) Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 345:79–84 41. O’Connell S, Granstrom M, Gray JS, Stanek G (1998) Epidemiology of European Lyme borreliosis. Zentralbl Bakteriol 287:229–240 42. Padgett BL, Walker DL (1973) Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy. J Infect Dis 127:467–470 43. Pollard ZF (1987) Long-term follow-up in patients with ocular toxocariasis as measured by ELISA titers. Ann Ophthalmol 19:167–169 44. Porter SB, Sande MA (1992) Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med 327:1643–1648 45. Pournaras JA, Laffitte E, Guex-Crosier Y (2006) Bilateral giant retinal tear and retinal detachment in a young emmetropic man after Jarisch-Herxheimer reaction in ocular syphilis. Klin Monatsbl Augenheilkd 223:447–449 46. Raistrick ER, Hart JC (1975) Adult toxocaral infection with focal retinal lesion. Br Med J 3:416 47. Rothova A, Bosch-Driessen LE, van Loon NH, Treffers WF (1998) Azithromycin for ocular toxoplasmosis. Br J Ophthalmol 82:1306–1308 48. Schantz PM, Glickman LT (1978) Toxocaral visceral larva migrans. N Engl J Med 298:436–439 49. Shapiro ED (2001) Doxycycline for tick bites – not for everyone. N Engl J Med 345:133–134 50. Shields JA (1984) Ocular toxocariasis. A review. Surv Ophthalmol 28:361–381
51. Silveira C, Belfort R Jr., Muccioli C, Holland GN, Victora CG, Horta BL, Yu F, Nussenblatt RB (2002) The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis. Am J Ophthalmol 134:41–46 52. Solley WA, Martin DF, Newman NJ, King R, Callanan DG, Zacchei T, Wallace RT, Parks DJ, Bridges W, Sternberg P Jr. (1999) Cat scratch disease: posterior segment manifestations. Ophthalmology 106:1546–1553 53. Steere AC (1989) Lyme disease. N Engl J Med 321:586–596 54. Süss J, Schrader CFW, Wohanka N (2004) Tickborne encephalitis (TbE) in Germany – epidemiological data, development of risk areas and virus prevalence in field-collected ticks and ticks removed from humans. Int J Med Microbiol 293(4):69–79 55. Tamesis RR, Foster CS (1990) Ocular syphilis. Ophthalmology 97:1281–1287 56. Tschirhart D, Klatt EC (1988) Disseminated toxoplasmosis in the acquired immunodeficiency syndrome. Arch Pathol Lab Med 112:1237–1241 57. Vulliemoz S, Lurati-Ruiz F, Borruat FX, Delavelle J, Koralnik IJ, Kuntzer T, Bogousslavsky J, Picard F, Landis T, Du Pasquier RA (2006) Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry 77:1079–1082
References 58. Wadsworth JD, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, Collinge J (2001) Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 358:171–180 59. Weber T, Turner RW, Frye S, Luke W, Kretzschmar HA, Luer W, Hunsmann G (1994) Progressive multifocal leukoencephalopathy diagnosed by amplification of JC virus-specific DNA from cerebrospinal fluid. AIDS 8:49–57 60. Will RG, Zeidler M, Stewart GE, Macleod MA, Ironside JW, Cousens SN, Mackenzie J, Estibeiro K, Green AJ, Knight RS (2000) Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 47:575–582 61. Winward KE, Smith JL, Culbertson WW, ParisHamelin A (1989) Ocular Lyme borreliosis. Am J Ophthalmol 108:651–657 62. Wormser GP, Nadelman RB, Dattwyler RJ, Dennis DT, Shapiro ED, Steere AC, Rush TJ, Rahn DW, Coyle PK, Persing DH, Fish D, Luft BJ (2000) Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis 31 [Suppl. 1]:1–14 63. Wynn RF, Leen CL, Brettle RP (1993) Azithromycin for cerebral toxoplasmosis in AIDS. Lancet 341:243–244
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Chapter 13
13
Giant Cell Arteritis Aki Kawasaki
Core Messages
■ Giant cell arteritis (GCA) is the most
■ Hearing loss and other audiovestibular
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common vasculitis in Caucasian adults older than 50 years. There are three predominant clinical subtypes of GCA: systemic inflammatory syndrome, cranial arteritis, and largevessel vasculitis. Patients with large-vessel vasculitis are likely to have negative temporal artery biopsy results; thus, diagnosis rests on clinical suspicion, corroborative laboratory tests, and imaging. Ischemic visual loss due to GCA is generally severe and cannot be restored with steroid therapy but it can be prevented with steroids. Transient visual loss or amaurosis due to GCA is often a warning symptom of impending blindness and should prompt immediate treatment with high-dose steroids.
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manifestations are common in patients with GCA. A sedimentation rate, C-reactive protein and platelet count are the most useful standard parameters for detecting GCA and following disease activity. In the setting of a high clinical suspicion of GCA and one negative biopsy, biopsy of the contralateral temporal artery is recommended to confirm a diagnosis. In the setting of a low clinical suspicion, a single negative biopsy is sufficient to rule out the diagnosis. Corticosteroids are the mainstay of treatment. However, the appropriate dose, route of administration, duration and tapering regimen remain unsettled due to lack of evidence-based data. Various adjuvant therapies show promise but none has yet shown unequivocal efficacy for controlling disease activity or reducing steroid requirements.
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13.1 Pathophysiology of Giant Cell Arteritis 13.1.1 Epidemiology Giant cell arteritis (GCA) is the most common primary vasculitis of adults in the Western world [57]. The disease is most prevalent in Caucasians, especially those of Northern European descent, and is distinctly rare in African-American and Hispanic populations [33]. There is a gender predilection favoring women. However, the single
greatest risk factor is age. Giant cell arteritis occurs in persons aged 50 years or older with a median age of onset of about 75 years. No convincing cases have been reported in persons younger than 50 years and incidence rates of the disease increase with advancing age [33, 34]. The clinical prevalence of GCA in the adult population aged over 50 years varies with the geographic location. In a recent population-based study from the United Kingdom, the incidence rate of GCA was 6.8 per 100,000 in persons aged between 50 and 59 years and the rate increased
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nearly tenfold to 60 per 100,000 in the over-80 age group [54]. A seasonal clustering with increased incidence in the summer months has been suggested but not wholly substantiated [54]. There is a genetic predisposition for GCA, as suggested by its ethnic and geographic distribution and occasional familial forms [15]. Both GCA and its forme fruste version, polymyalgia rheumatica, are associated with selected human leukocyte antigen haplotypes, particularly HLA-DR4 and HLA-DRB1*04 alleles [9, 58]. Additionally, the presence of immunogenetic polymorphisms may influence individual susceptibility to GCA.
13.1.2 Triggering Event
13
Giant cell arteritis is an antigen-driven, T-cellmediated process but the instigating event remains elusive. Microbial pathogens as the instigating antigen have been a popular hypothesis and a source of widespread research. The DNA of Chlamydia pneumoniae has been found in eight of nine temporal artery biopsy specimens [55]. A recent study determined the presence of parvovirus B19, varicella virus and herpes virus 6 in the temporal artery biopsy specimens of 57 patients with GCA and 56 controls [1]. Although there was a higher prevalence of B19 DNA in GCA biopsy samples (54%) compared to control biopsy samples (38%), the difference was not significant. These investigators proposed that reactivation of B19 latent infection could be a disease trigger, particularly in those patients with a high viral load. Another recent analysis of 24 positive biopsy samples using high-sensitivity polymerase chain reaction for herpes simplex virus found a positive DNA result in 21 (88%) of specimens, although this result conflicts with a previous study that failed to detect herpes simplex virus [46]. All in all, the role of microbial pathogens as the triggering event of GCA remains debated.
13.1.3 Tropism to Certain Vascular Beds Giant cell arteritis is a vasculitis of large- and medium-sized arteries yet it displays a proclivity for
certain vascular beds while rarely affecting other vessels of similar caliber [57, 58]. Commonly affected vessels include the aorta, the extracranial branches of the carotid artery, the subclavian and axillary arteries, and the vertebral arteries. However, involvement of the coronary arteries and femoral arteries is relatively rare in comparison and the intracerebral arteries are spared from the vasculitic attack of GCA. Such a vascular tropism suggests a primary role of the arterial wall itself in the propagation of an immune attack. Recent studies have begun to elucidate this close relationship between the arterial wall and inflammatory cells, a key aspect in the pathogenesis of GCA. As stated earlier, GCA is a T-cell-mediated disease. It preferentially affects arterial walls, which are composed of three well-developed layers separated by an elastic lamina: the outer adventitial layer, the muscular medial layer and the innermost intimal layer (Fig. 13.1). Each layer plays a separate but important role in the development of a transmural vasculitis. The adventitial layer is the site of the primary immunologic injury in GCA [58]. There are two structural reasons for this. In medium- and largesized arteries, only the adventitia is vascularized with a capillary network (called vasa vasorum), in contrast to the media and intima which are avascular. The vasa vasorum are the sole entryway by which T-cells and macrophages can access the arterial wall. Entry into the arterial wall from the luminal side is prohibited by the strong shearing forces of high-velocity blood flow through these large arteries. The second reason is that the adventitia harbors an indigenous population of immunologic surveillance cells, called dendritic cells, which patrol the outer layer of the arterial wall for possible intruders [58, 59]. Under physiologic conditions, these dendritic cells are immature, phagocytic, and relatively quiescent and act to inhibit T-cell activation in the perivascular space. However, once activated, dendritic cells transform into powerful antigen-presenting cells that recruit, prime and activate naïve CD4+ T-cells against invading antigen in the tissue. Dendritic cells are elemental in the induction as well as the maintenance of the inflammatory process of GCA [59].
13.1 Pathophysiology of Giant Cell Arteritis
Fig. 13.1. Schematic diagram of the adaptive immune responses in the arterial wall. The adventitia is the site of the initial immune stimulation. T-cells enter the artery through the vasa vasorum to interact with indigenous dendritic cells which, in turn, regulate T-cell and macrophage recruitment. The T-cell-produced cytokine interferon-gamma, IFN-γ, controls differentiation of infiltrating macrophages. The media is the site of oxidative damage. Medial macrophages, especially multinucleated giant cells, produce growth factors and regulate the mobilization, migration and proliferation of myofibroblasts. This results in rapid intimal hyperplasia and expansion, causing vessel occlusion. Neoangiogenesis, distantly regulated by IFN-γ, is necessary to support the expanding intima. Reprinted from Autoimmunity Review, volume 3, Weyand CM et al. [58] Immunopathways in giant cell arteritis and polymyalgia rheumatica, pp. 46–53, 2004 with permission from Elsevier
13.1.4 Macrophage Recruitment and Vascular Injury Once activated in situ, adventitial T-cells (typically CD4+ subtype) undergo clonal expansion and secrete a potent cytokine called interferon-γ. Interferon-γ is the key regulating cytokine of the arteritic injury in GCA and serves to recruit macrophages and stimulate giant cell formation. Macrophages ultimately cause vessel wall injury and destruction. Macrophages have the capacity
to differentiate into several distinct lines of effector cells and in this way they acquire a broader spectrum of harmful actions. Macrophages in the adventita focus on producing inflammatory cytokines that optimize T-cell stimulation. Macrophages in the media specialize in generating reactive oxygen intermediates that induce lipid peroxidation of smooth muscle cell membranes, and metalloproteinase enzymes that breakdown and digest the internal elastic lamina [58]. Macrophages at the media-intima junction, along
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with multinucleated giant cells, form granulomas in the medial layer and release a variety of growth factors and angiogenic factors, notably plateletderived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Once the internal elastic lamina is fragmented, the intima becomes accessible to invasion by myofibroblasts, which proliferate exuberantly and rapidly under the influence of PDGF, causing intimal hyperplasia and vessel occlusion (Fig. 13.1). This marked expansion of the intima is necessarily accompanied by neoangiogenesis, driven by VEGF, to support this previously avascular layer. The degree of vascular inflammation and intimal hyperplasia is, once again, under control of activated T-cells in the adventitia. If the T-cells produce high concentrations of interferon-γ, there is marked intimal hyperplasia, luminal occlusion and tissue infarction. If the Tcells produce low concentrations of interferon-γ and instead favor production of interleukin-2, then an inflammatory process develops in the vessel wall but without intimal hyperplasia and luminal occlusion [57, 58]. The mechanisms that promote the development of one population of T-cells over another are still unclear but it is obvious that early T-cell differentiation into primarily interferon-producing versus primarily interleukin-producing cells influences and may even pre-determine the clinical course of the disease. Recent years have brought many new and valuable contributions to what we know of the process that ultimately leads to inflammatory infiltrates (CD4+ T cells, macrophages) in the arterial wall. But a complete understanding of the disease pathophysiology, though still emerging, is not fully established. In short, the immune-mediated inflammatory assault on the vessel wall as described in the preceding paragraphs represents an inappropriate or misguided activation of an antigen-specific adaptive immune response that normally serves a protective function. The clinical manifestations are related to the arteries involved and may, in some cases, be limited to a single vessel, e.g., aortitis. A second immunopathogenetic process (activation of the innate immune response) also occurs in GCA and accounts for the systemic inflammatory response and some of
the classic symptoms of GCA, as described in the next section.
Summary for the Clinician
■ The inciting event for the development of GCA is unknown. ■ An early and critical event is inappropriate activation of dendritic cells in the adventitial layer of arterial walls. Interferon-γ is the key cytokine that promotes arterial wall injury. High concentrations of interferon-γ correlated with focal ischemic complications.
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13.1.5 Systemic Inflammation In GCA, a non-specific and systemic inflammatory response (activation of the innate immune response) is typically present and represents, in essence, a hyperactive acute-phase reaction. Activation of the acute-phase reaction involves a cascade of signals, particularly interleukin-6 (IL-6), which derive from circulating monocytes, neutrophils, and macrophages but the mechanisms and site of cell activation have not been elucidated. The intensity of an acute-phase reaction can be partly gauged by the serum level of IL-6 as well as circulating levels of hepatic acute-phase proteins such as C-reactive protein, serum amyloid A, haptoglobin, fibrinogen, and complement [57]. Symptoms related to this systemic inflammatory response are non-specific and non-localizing and include fever, night sweats, anorexia, myalgias, and weight loss. The arterial wall inflammation (called the adaptive immune response) and the systemic inflammation (called the innate immune response) are neither dependent on each other nor mutually exclusive of each other. In the diagnosis and management of patients with GCA, it is helpful to consider that the clinical manifestations are reflective of whichever inflammatory process – vascular or systemic – is predominant at that moment.
13.2 Clinical (Non-Ophthalmic) Manifestations of GCA
Summary for the Clinician
■ In addition to the T-cell-mediated, adap-
tive immune response triggered within arterial walls, there is also activation of a systemic inflammatory reaction (innate immune response) in GCA. The levels of circulating acute-phase reactants and interleukin-6 correlate with the degree of the systemic inflammatory response and the presence of non-focal systemic symptoms.
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13.2 Clinical (Non-Ophthalmic) Manifestations of GCA 13.2.1 Natural History The spectrum of clinical manifestations associated with GCA is broad, ranging from non-specific complaints such as headache and general achiness to specific organ dysfunction such as visual loss, arm claudication, or stroke. The onset of symptoms is rather abrupt in most patients who may even be able to recall the day of onset of a specific symptom. In other patients, symptoms may appear insidiously. Sometimes, there is a migratory and changing nature of symptoms over an extended period of time so that each symptom seems unrelated to the next, and recognition that a single disease entity accounts for the sum complex of signs and symptoms may be overlooked. The frequency of each of the clinical manifestations is variable, but in most series the most commonly reported symptoms are headache, scalp tenderness, arthralgias and jaw claudication. The natural history of GCA in non-fatal cases is spontaneous remission after months or years of disease activity. This is evident from the descriptions of GCA in the medical literature dating from the pre-steroid era. A recent article highlighted the self-limited nature of untreated GCA in two patients with biopsy-positive GCA [29]. One patient was a 90-year-old man with a prior history of leg claudication who developed an enlarged, pulseless temporal artery.
His clinical course remained unchanged until he died of pneumonia 4 years later. The second patient was a 62-year-old man with self-limited episode of jaw pain, malaise, weight loss and elevated sedimentation rate lasting 4 months. Thereafter, he remained asymptomatic without treatment for 10 years.
13.2.2 Systemic Signs and Symptoms At least one symptom or sign of systemic inflammation such as anorexia, asthenia, malaise, myalgia, arthralgia, weight loss, and fever can be found at presentation in the majority of patients. The frequency at which these constitutional signs and symptoms manifest in GCA is variable among different studies, in part from selection bias of patients, accuracy of history-taking, and the use of different criteria to diagnose GCA. In one large series examining the inaugural symptoms of 260 patients with GCA, 65% of patients had an altered sense of well-being (asthenia, weight loss) and 50% had fever [3], compared to estimates of 38%–90% and 19%–80% respectively found in the literature [23, 36]. The myalgia of GCA is typically in the large proximal muscles. Thus, patients may report an achiness and fatigue when raising their arms to reach upper shelves or difficulty getting out of a low chair or car. Some patients have a paucity of symptoms or just an isolated abnormality such as unexplained weight loss or fever. The classic picture of an elderly patient with new headache, jaw claudication, fever, anorexia, polymyalgia rheumatica and a tender temporal artery is only seen in about one-half to two-thirds of patients so the clinician must be able to recognize the less typical presentations of this disorder [36].
13.2.3 Headache and Craniofacial Pain The most common symptom of GCA, related to both systemic inflammation and local vascular injury in the carotid circulation, is headache. Headache occurs in up to 90% of patients, may
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sometimes localize to the temporal and occipital areas, and is very frequently bilateral. A unilateral headache in GCA is uncommon [47, 52]. Scalp tenderness is a more distinctive symptom indicative of tissue ischemia. Patients may report discomfort when brushing or washing their hair; others develop such exquisite sensitivity that even putting their head on a pillow becomes painful. Perhaps the symptom most specific to GCA is jaw claudication but it is present in less than half (30%–48%) of patients at presentation and may be misdiagnosed as temporomandibular joint syndrome [3, 23, 57]. Unlike temporomandibular joint pain, which is immediately present with any jaw movement, claudication pain due to masseter muscle ischemia develops after a few minutes of mastication and then disappears with rest. Patients with jaw claudication often avoid eating chewy foods and meats. Jaw claudication stems from vasculitis and occlusive stenosis in the maxillary artery, a branch of the external carotid artery, and, not surprisingly, correlates highly with positive findings on biopsy of the temporal artery, which is another branch of the external carotid artery [23, 52].
13.2.4 Auditory Manifestations Recently, Amor-Dorado and colleagues [2] reported a high prevalence of audiovestibular manifestations in a cohort of 44 patients with GCA (38 biopsy-positive and 6 biopsy-negative). Symptoms included hearing loss, tinnitus, vertigo, disequilibrium, and dizziness. Remarkably, 39 of 44 (almost 90%) demonstrated abnormal vestibular function on one or more objective tests of audiovestibular function. Symptomatic improvement and reversal of quantitative vestibular dysfunction was observed in most patients (70%) after 3 months of steroid treatment, and after 6 months only one patient had residual vestibular dysfunction. However, hearing loss improved in only 27% of patients and occurred only during the first 3 months of treatment suggesting that early treatment may be important for a more favorable hearing outcome.
13.2.5 Neurologic Manifestations There is a wide range of neurological complications attributed to GCA. The older literature emphasized the central complications such as cerebral and brainstem stroke syndromes, dementia, psychosis and coma related to diffuse cerebral ischemia, spinal cord infarction, seizures, and subarachnoid hemorrhage, and their associated high morbidity and mortality. The more recent literature suggests that peripheral complications, namely neuropathies (14%), are actually the most common neurologic complication of GCA. These may be cranial neuropathy, mononeuropathy multiplex or peripheral polyneuropathy [47]. The clinical message is to consider GCA in an elderly patient who presents with any acute neurologic deficit, even in the absence of headache [18, 47, 52].
13.2.6 Occult GCA Giant cell arteritis has been called the great masquerader because it can take on many clinical forms and when systemic manifestations are minimal or absent, these have been termed the “occult manifestations” of GCA or “occult GCA”. Occult GCA may occur in 5%–38% of cases [9]. Patients with occult GCA typically seek medical attention because of dysfunction with a particular organ system such as acute visual loss, respiratory symptoms such as chronic cough or sore throat, peripheral neuropathy, dementia, stroke, coronary ischemia, pulmonary artery thrombosis, hematuria, renal failure and mesenteric infarction [24, 36]. Giant cell arteritis can even present as a tumor-like lesion of the breast, ovary or uterus. Thus, it is important that nonrheumatologic specialists such as ophthalmologists, neurologists, cardiologists, nephrologists, oncologists and even gynecologists maintain a heightened awareness for these less common manifestations of GCA as they may be the first to evaluate such patients.
13.3 Visual Manifestations of GCA
Summary for the Clinician
■ Giant cell arteritis can cause a variety
of constitutional symptoms as well as symptoms related to focal ischemia. The typical clinical presentation of GCA is easy to recognize (elderly patient with aches and myalgias, anorexia, new headache and jaw claudication) but is absent in as many as half of cases. Elderly patients should be specifically questioned about a pain or ache in their jaw that occurs only after a few minutes of continuous chewing because jaw claudication is the single most specific symptom of GCA.
■ ■
13.3 Visual Manifestations of GCA Visual manifestations are common in patients with GCA, though the exact frequency is variable and ranges from 14% to 70% amongst different studies [47]. In Hayreh’s prospective study [25] of 170 biopsy-positive cases of GCA diagnosed at a single referral center in the midwestern United States, 50% (85/170) of the patients had ocular findings or visual symptoms at their initial visit and in the vast majority (97.7%) of these patients, visual loss in one or both eyes was the most commonly reported symptom [25]. Gonzalez-Gay et al. [20] reported their retrospective series of 161 biopsy-positive patients followed at a single institute in northwestern Spain, and 26% had visual manifestations at diagnosis [20]. HLA phenotyping was performed in 62 of these patients with biopsy-proven GCA and the authors found that the frequency of ischemic visual complications was 3 times higher in the patients carrying the HLA DRB1*04 allele, suggesting that genetic differences may influence the phenotypic profile [20]. Ocular involvement and visual symptoms may be the first or sole manifestation of GCA, emphasizing the importance of maintaining a heightened awareness of this disease in any elderly patient with a new visual disturbance.
13.3.1 Transient Visual Loss Visual loss in GCA can be transient or permanent. Among patients with visual manifestations of GCA, a history of transient visual loss is reported by 30%–54% of patients [17, 20, 25]. In some patients, transient visual loss may be the only visual symptom. Transient monocular blindness, or amaurosis, in GCA is not a trivial symptom but rather should be considered an ominous sign of impending blindness [25, 39]. It occurs as a result of insufficient perfusion of the optic nerve, retina or choroid and precedes the development of permanent visual loss in more than half (50%–64%) of untreated cases [20, 25]. Thus, amaurosis in a patient known or even suspected to have GCA is considered an ophthalmologic emergency and immediate high-dose steroid treatment is recommended in an effort to prevent permanent visual loss which follows in the majority of untreated cases [20, 25]. Additionally, hospitalization and strict bed rest during treatment initiation is advised as even small, posturally mediated decreases in perfusion in already compromised arteries may precipitate an ischemic complication [39]. In a patient who presents with transient monocular blindness with little or no systemic symptoms of GCA, the difficulty lies in distinguishing GCA amaurosis from classical amaurosis fugax due to retinal emboli. Clues that the transient visual loss is due to GCA include a relatively short duration of visual loss (1–2 min or less), multiple recurrences in the same eye over a short period of time and brief episodes of visual dysfunction precipitated by a change in posture such as standing up or bending over. A history of amaurosis alternating between the two eyes is rarely due to retinal emboli and should be considered GCA. Funduscopic examination sometimes demonstrates evidence of retinal or disc ischemia, which further substantiates a diagnosis of GCA in patients with amaurosis. There may be cotton-wool spots (CWS), intraretinal hemorrhages, observable sludging of blood in the retinal arterioles, or optic disc edema. Even in patients with no visual complaints, isolated CWS have been found [17].
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Summary for the Clinician
■ Giant cell arteritis should be in the dif-
ferential diagnosis of transient visual loss in an elderly patient. A history of transient visual loss in a patient suspected to have GCA should prompt immediate treatment with highdose steroids until a diagnosis is confirmed or refuted.
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13.3.2 Anterior Ischemic Optic Neuropathy
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By far the most common cause of permanent visual loss due to GCA is anterior ischemic optic neuropathy (AION). GCA-related AION, also called arteritic AION, is due to inflammatory occlusion of the short posterior ciliary arteries which provide blood flow to the optic disc, the choroid and, in some persons, a small part of the retina supplied by the cilioretinal artery. As such, arteritic AION (infarction of the prelaminar and laminar portion of the optic nerve head) is frequently accompanied by choroidal ischemia or ciliary artery occlusion which may be evident on funduscopic examination or by fluorescein angiography (Fig. 13.2) [25]. The more common form of AION, called non-arteritic AION, is due to insufficient perfusion through the terminal paraoptic branches of the short posterior ciliary artery causing optic disc ischemia. Thus, non-arteritic AION is not accompanied by evidence of choroidal ischemia. A diagnosis of AION is clinically based on acute visual loss accompanied by optic disc edema. The importance in distinguishing between arteritic versus non-arteritic AION in a timely manner lies in the immediate prognosis for the other eye. Among patients with arteritic AION, 25%–50% will suffer a similar event in the other eye, typically within 1–14 days, if left untreated [39]. In this acute setting, the clinician must use clinical indices to determine if the AION is likely to be GCA-related. Certain historical features favor a diagnosis of arteritic AION: age greater than 70 years, preceding amaurosis, very severe visual loss in range of count-
ing fingers or worse, new headache and positive systemic review of systems particularly jaw claudication. On examination, the following features are considered diagnostic for arteritic AION until proven otherwise: severe pallid disc edema or a “chalky white” disc swelling, a normal or large optic cup in the contralateral eye, an associated cilioretinal artery occlusion or the presence of retinal ischemic findings such as CWS or retinal edema (Fig. 13.3) [25, 39]. The presence of retinal ischemic lesions in the presence of AION (optic disc ischemia) is highly suggestive of a systemic inflammatory vasculopathy such as GCA because two different vascular territories of the eye (the central retinal arterial circulation and the posterior ciliary arterial circulation) are implicated. Recurrent episodes of ischemic optic neuropathy are considered rare once the systemic symptoms, sedimentation rate and acute-phase reactants have normalized. A recent report by Chan et al. found an unexpectedly high 10% recurrence rate (7 of 67 patients) [10]. The recurrences were all ipsilateral and occurred 3–36 months (median 8 months) after the initial episode. In six of the seven patients with recurrent ischemic optic neuropathy, recurrent visual loss was associated with a relapse of systemic symptoms or re-elevation of acute-phase reactants.
Fig. 13.2. Fluorescein angiogram in a patient with arteritic anterior ischemic optic neuropathy (AION). There is delayed and patchy choroidal perfusion indicating occlusion of the short posterior ciliary artery supplying the optic disc
13.3 Visual Manifestations of GCA
Fig. 13.3a,b. Two funduscopic signs highly suggestive of giant cell arteritis (GCA) in the setting of acute anterior ischemic optic neuropathy. a Chalky white swelling of the optic disc. b Retinal edema in the distribution of the cilioretinal artery accompanying disc edema and peripapillary hemorrhage
Summary for the Clinician
■ Acute visual loss in a patient with GCA
is most likely due to anterior ischemic optic neuropathy and if the patient is not treated with steroids immediately, bilateral visual loss will occur in up to half of these patients within the next days or weeks. The older the patient, the more likely an episode of AION will be due to GCA. A swollen optic disc plus any retinal ischemic findings in a patient over age 50 years is GCA until proven otherwise.
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13.3.3 Other Types of Ischemic Visual Loss Visual loss in GCA can be due to ischemia affecting any aspect of the anterior visual pathway from retina to occipital lobe. Anterior ischemic optic neuropathy is by far the commonest cause of visual loss (78%–99%) [9, 20, 25]. Central retinal artery occlusion is the second most common cause of visual loss in GCA, affecting about 10%–13% of patients. Other less common causes include posterior ischemic optic neuropathy,
cilioretinal artery occlusion, choroidal infarction and, rarely, ischemia to the chiasm or postchiasmal visual pathway [39]. Occipital lobe infarction due to vertebrobasilar artery involvement occurs in less than 5% of patients with visual loss [20]. In patients with cortical visual loss, visual hallucinations may arise in the area of visual field loss and generally disappear spontaneously after several weeks. They may resolve abruptly with steroid initiation.
13.3.4 Diplopia Diplopia is the second most common visual symptom related to GCA but occurs far less frequently than visual loss. Transient or constant diplopia was reported to occur in 5.9%–21% of patients with visual manifestations [17, 20, 25]. In some patients, the diplopia may be a harbinger of subsequent visual loss [17]. In others, the diplopia is transient and the sole visual manifestation of GCA [25]. Ischemia of the extraocular muscles, of the cranial nerves and of brainstem ocular motor pathways has been implicated as the mechanism of diplopia in GCA. Thus, weakness of a single extraocular muscle, an isolated cranial nerve III, IV or VI palsy (partial or complete), combined cranial nerve palsies, skew de-
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viation, internuclear ophthalmoplegia, one-anda-half syndrome and upgaze palsy have all been described to occur with GCA [39].
13.3.5 Orbital Manifestations
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The more unusual ocular manifestations of GCA include efferent pupil abnormalities (tonic pupil, Horner pupil), acute hypotony, ocular ischemic syndrome, orbital ischemia, and, rarely, orbital infarction syndrome [39]. Signs of orbital inflammation such as red eye, chemosis or proptosis accompanied by pain typically evoke consideration of a more common condition known as orbital pseudotumor, which is also treated with steroids. However, the steroid requirement for orbital pseudotumor is lower in dosage and shorter in duration than that used for GCA, so caution must be taken to exclude GCA in any older patient with an orbital inflammatory syndrome [35]. In a review of 13 cases of GCA-related orbital manifestations, Lee et al. [35] noted that all patients had proptosis and only 2 patients had pain. Chemosis, lid edema, ophthalmoplegia, visual loss and episcleritis were other findings. The outcome was reported as “improved” in 8 of these 13 patients.
13.4 Clinical Subtypes of GCA Patients with GCA can be grouped into three clinical subtypes which are defined by the signs and symptoms that predominate the patient’s clinical picture. These clinical subtypes are probably related to different levels of expression of different cytokines, and, as such, identification of characteristic cytokine patterns in the serum and biopsy specimen is being investigated as a potential means of predicting who might be at risk for ischemic complications and where the complication might occur [7, 36, 57].
13.4.1 Systemic Inflammatory Syndrome This subtype of patients is characterized by non-specific constitutional symptoms related to
systemic inflammation in the absence of focal ischemic symptoms. Such patients have asthenia, arthralgias, myalgias, achiness, anorexia, weight loss, and night sweats. A fever of unknown origin which may be low-grade or spiking up to 40°C is common and often generates concern and investigations for an underlying systemic infection or malignancy. Serologically, these patients typically have high sedimentation rates, elevated acute-phase reactants such as C-reactive protein, haptoglobin and fibrinogen, elevated liver function tests, low albumin levels, thrombocytosis and a normocytic normochromic anemia [37]. The serum level of the inflammatory cytokine interleukin-6, which derives from circulating monocytes, is also a sensitive indicator of active systemic inflammation [47, 57].
13.4.2 Cranial Arteritis This clinical subtype of GCA is dominated by localized vasculitis and focal tissue ischemia. The inflammation primarily involves the branches of the carotid arteries, hence the name “cranial arteritis.” Common symptoms of cranial arteritis include headaches or facial pain, even carotidynia, scalp tenderness, jaw claudication, painful dysphagia, hoarseness, and visual loss. Necrosis of the scalp or tongue necrosis are dramatic but rare manifestations of cranial GCA, inaugural in 1% of cases or fewer (Fig. 13.4) [3, 8]. In the world
Fig. 13.4. Hemorrhagic necrosis of the scalp in GCA. Reprinted from Clinical and Experimental Dermatology, volume 28, Campbell FA et al. [8], Scalp necrosis in temporal arteritis, pp. 488–490, 2003 with permission from Blackwell Publishers
literature, tongue necrosis has been described in 46 cases of GCA since 1959 [49]. Their relative infrequency is related to the abundant vascular supply to these tissues. Scalp necrosis occurs only when all four supplying arteries are occluded, indicating an extensive vasculitis and portending a grim prognosis. In patients with scalp necrosis, the associated mortality rate related to cerebral or coronary artery occlusion is 41% and the incidence of irreversible visual loss is 67% [8].
13.4.3 Large-Vessel Vasculitis The third clinical subtype of GCA is a localized vasculitis that primarily involves the subclavian and axillary arteries and/or the aorta. This form of GCA has been termed “large-vessel arteritis or large-vessel vasculitis.” Because the inflammatory process is localized, the temporal artery biopsy is negative in at least half of these patients with large-vessel vasculitis [7, 36, 57], and the diagnosis requires vascular imaging. In contrast to cranial arteritis which leads to arterial stenosis and obstruction, aortitis leads to dilation and aneurysm formation, most commonly of the thoracic aorta. Local stenosis develops in the superior branches of the aortic arch, particularly the subclavian artery and axillary artery. Involvement of the large arteries to the lower extremities is rare, reported in less than 1% of patients [43]. On angiography, the characteristic finding is bilateral stenosis of large arteries or occlusion of large arteries with a smooth tapering proximal and distal to the occlusive lesion. Compted tomography (CT) scan can demonstrate aortic involvement (thickening of the wall) and aortic aneurysm formation [30]. Magnetic resonance imaging (MRI) findings consistent with aortitis are aortic wall thickening, wall edema, increased mural contrast enhancement, and vascular stenosis of aortic branch points. MRI has the advantage of easily combining angiographic images of the aortic branches to provide a comprehensive evaluation for large-vessel vasculitis (Fig. 13.5) [7, 40]. Positron emission tomography (PET) scanning has shown encouraging results for detecting and monitoring large-vessel vasculitis [6, 38]. However, one important and unresolved issue with PET is ascertaining whether increased
13.4 Clinical Subtypes of GCA
vascular uptake is a finding specific to vasculitis or if it is simply a marker of any type of wall injury [7]. There is no gold standard test for largevessel vasculitis and imaging is selected on individual considerations. Large artery involvement is an under-appreciated aspect of GCA. It may occur as the predominant clinical subtype in which patients chiefly have ischemic symptoms in their arms and shoulders. It may also occur as a subclinical process in patients with a systemic inflammatory syndrome or cranial arteritis. The reported rate of large-vessel arteritis reaches 27% of patients with GCA [14, 43, 52], and even if an aortic aneurysm is not present at the initial presentation, it can develop later. In 94 patients with GCA followed longitudinally at one institution, 9 (9.6%) had a thoracic aneurysm in a median of 5.8 years after diagnosis, raising questions about the need for serial assessments for the development of large-vessel disease [14]. PET scan suggests that subclinical aortitis is even more common than suspected, although the specificity of the PET scan for detecting vasculi-
Fig. 13.5. Magnetic resonance imaging arteriogram of large-vessel vasculitis. Abnormal findings are a proximal high-grade stenosis in the left subclavian artery, stenosis in the region of the left subclavian–axillary junction and mild long segment narrowing of the proximal right subclavian artery. From Current Opinion in Rheumatology, volume 8, Bongartz T, Matteson EL [7] Large-vessel involvement in giant cell arteritis, pp. 10–17, 2006 with permission from Lippincott, Williams and Wilkins
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tis remains in question. One study demonstrated increased uptake in the aorta in more than half of 35 patients tested [6] and an autopsy series suggests that the frequency of aortic involvement during the course of GCA reaches an amazing 70% [44]. Such numbers have led to the speculation that aortitis may be the rule rather than the exception in GCA. Nonetheless, the clinical symptoms of aortitis are rare (3%–11%) [7, 36]. Symptoms related to large-vessel occlusion are limb claudication, peripheral paresthesias, Raynaud phenomenon and rarely tissue gangrene [36, 57]. The limb claudication is frequently bilateral and may have an acute onset. Physical signs include diminished or absent pulses, asymmetric blood pressure readings and bruits over the carotid, axillary, brachial or subclavian arteries. Aortitis with subsequent aneurysm formation is often clinically silent until a complication occurs, i.e., aortic valve insufficiency, aortic rupture or aortic dissection, heralded by symptoms of acute chest pain, shortness of breath, and hypotension [7]. Patients considered high-risk for aortic aneurysm have a murmur of aortic insufficiency, polymyalgia rheumatica plus ESR >100 mm/h, or any two of the following: hypertension, hyperlipidemia, polymyalgia rheumatica, and coronary artery disease [7]. Such patients are recommended to have CT/MR angiography and abdominal ultrasound at the time of their diagnosis of GCA and again 1 year later with an annual chest radiograph and transthoracic echocardiogram thereafter [7]. All other patients are recommended to have at least an annual abdominal ultrasound, chest radiograph, and echocardiogram.
Summary for the Clinician
■ Large-vessel involvement in GCA is often clinically silent at the time of diagnosis and is an underappreciated aspect of the disease. Stenosis of the aortic branches causes claudication and gangrene in the arms whereas aortitis leads to aneurysm formation and dissection years after initial diagnosis.
■
Summary for the Clinician
■ Vascular imaging is necessary to detect
large-vessel vasculitis. Aortitis can be detected with CT, MRI or PET scanning. There is no established protocol for screening patients for large-vessel involvement; some authors recommended annual testing.
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13.5 Laboratory Investigations in GCA 13.5.1 Erythrocyte Sedimentation Rate It is well known that an elevated erythrocyte sedimentation rate (ESR) strongly supports a clinical suspicion of GCA. But it is equally well accepted that a normal ESR does not rule out a diagnosis of GCA. According to the American College of Rheumatology, an ESR by the Westergren method is elevated if it is ≥50 mm/h. Approximately 85% of patients have ESR ≥50 mm/h and almost all patients have an ESR greater than 20 mm/h [53]. Yet, ESRs as low as 4 mm/h have been reported in patients with symptomatic, biopsy-positive disease [23]. In interpreting the significance of a given ESR, it is important to consider other factors which raise or lower the ESR. Conditions known to elevate the ESR are increasing age, female gender, pregnancy, anemia, inflammatory disorders, infection, connective tissue disorders, trauma, hypercholesterolemia and malignancy [23]. Conversely, a very low ESR occurs in polycythemia, hereditary spherocytosis, impaired hepatic protein synthesis, hypofibrinogenemia, congestive heart failure and use of antiinflammatory drugs [23, 47]. Some patients with GCA consistently demonstrate a low or normal ESR despite active disease, and they have no other condition which might lower the ESR. In such patients, a genetically programmed inhibition of the initiation of the cellular and cytokine cascades may be one possible explanation. Despite these shortcomings, the low cost and universal availability of the ESR make it a useful
laboratory test in the diagnosis and management of patients with GCA. Recent studies have focused on the potential prognostic value of the pre-treatment ESR but results have not been wholly consistent. Some investigators have noted that the presence of a strong acute-phase response with fever, weight loss and high ESR >85 mm/h confers a low risk of cranial ischemic complications, but others have not corroborated this relationship [11, 27]. Hernandez-Rodriguez et al. [27] reported that patients with systemic symptoms and a high ESR are more refractory to treatment (requiring higher cumulative steroid doses and longer duration) in contrast to Liozon et al. [37] who noted that such patients have an excellent response to steroids with rapid control of symptoms. In sum, further studies are needed to define if and how the ESR might be used as a prognosticator for risk of ischemic events and response to treatment.
13.5.2 C-Reactive Protein C-reactive protein (CRP) is a single protein quantification whose level rises more rapidly than the ESR in response to inflammatory activity (within 4–6 h). It is not influenced by age, gender, or hematologic factors. Several studies have found the CRP to be a more sensitive indicator (sensitivity generally at 100%) of active GCA compared to the ESR [19, 23]. Like the ESR, an elevated CRP is a non-specific finding but the specificity increases to 97% when both the ESR and CRP are elevated in a patient suspected to have GCA [23]. Its disadvantages include the higher cost of testing compared to ESR and perhaps a relative unfamiliarity amongst clinicians with the test.
13.5 Laboratory Investigations in GCA
lower hemoglobin and albumin. In other studies as well, thrombocytosis appears to correlate well with the ESR, but opinion regarding its predictive value for a diagnosis of GCA remains conflicted. Costello et al. [12] compared the laboratory results between patients with arteritic AION (n=121) and patients with non-arteritic NAION (n=287). The patients with GCA had higher median levels of ESR, CRP, platelets and white blood cells (WBC) with lower levels of hemoglobin and hematocrit. The presence of thrombocytosis did not have a greater predictive ability than either ESR or CRP for diagnosing GCA [12]. Foroozan et al. [16] found differently in their retrospective series of 91 patients suspected of GCA: 47 (52%) patients had positive biopsy results and 27 of these patients had thrombocytosis (defined as platelet count greater than 400×103/µl), yielding a sensitivity of 57%. However, the specificity of thrombocytosis was 91% compared to 27% for an elevated ESR. Furthermore, thrombocytosis had a higher positive predictive value than the ESR (87% compared to 54%) and a relatively high negative predictive value of 67%. These authors concluded that the presence of thrombocytosis is a helpful corroborative finding for GCA in a suspected patient with an elevated ESR [16].
Summary for the Clinician
■ Thrombocytosis is common in active GCA. ■ In a patient with suspicious clinical
symptoms and a high ESR, the presence of thrombocytosis is highly specific for a diagnosis of GCA. However, a normal platelet count is not sufficient to rule out GCA in this setting.
13.5.3 Thrombocytosis An elevated platelet count is a common laboratory finding in GCA. Gonzalez-Gay and colleagues [19] recently reviewed the laboratory findings of 240 patients with biopsy-positive GCA. It was found that 48.8% of patients (most of whom had constitutional symptoms) had thrombocytosis at presentation, and thromobocytosis was associated with a higher ESR and CRP and
13.5.4 Interleukin-6 and Other Cytokines Cytokines are the messenger proteins within the cellular immune system and mediate a variety of functions. In GCA, cytokines play an important role in regulating the intensity of cellular proliferation and the direction of cellular differen-
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tiation, which ultimately determines the nature and magnitude of the inflammatory response. Interleukin-6 (IL-6) is a cytokine found both in inflamed arterial walls and the blood circulation. Interleukin-6 is a chief stimulator of the systemic inflammatory response and the production of most acute-phase proteins. Serum levels of IL-6 are highly elevated in active GCA and respond rapidly to steroid treatment. Weyand et al. [56] prospectively followed the acute-phase markers in 25 patients with biopsy-positive GCA. At the time of diagnosis (before treatment initiation) the ESR was elevated in 76% of patients and plasma IL-6 was elevated in 92%. Within 1 month of steroid treatment, all patients experienced symptomatic resolution and normalization of the ESR. The plasma IL-6 did decrease but did not return to normal levels. During a clinical relapse of disease, the ESR was elevated in 58% of patients whereas the plasma IL-6 was elevated in 89%. Thus, the authors concluded that plasma IL-6 appears to be a more sensitive indicator than ESR for diagnosing and monitoring GCA patients [56]. How does IL-6 compare to CRP? Hayreh et al. [23] found a linear relationship between levels of IL-6 and CRP, suggesting that IL-6 is comparable but not superior to CRP for monitoring the systemic inflammatory response. In addition to being a diagnostic marker for GCA, another proposed usefulness of the cytokines is to serve as a prognostic indicator. As mentioned previously, it has been speculated that the pattern of cytokines in the biopsy specimen and in the blood may be helpful in distinguishing clinical subsets of the disease and predicting disease evolution. Hernandez-Rodriguez et al. [27] noted that patients with an exuberant systemic inflammatory response (measured by high ESR, anemia, presence of fever and weight loss) had elevated levels of circulating IL-6 as well as tumor necrosis factor (TNFα). Such patients required higher steroids doses and longer duration of treatment. In follow-up studies, these authors measured tissue cytokine levels using quantitative polymerase chain reaction (PCR) of mRNA and immunostaining with anti-cytokine antibody. They found that, in general, IL-6 levels in tissue and in serum were lower in patients who suffered ischemic complication. No differences
were found in levels of TNFα or IL-1β expression among patients with and without ischemia. However, there was a correlation between tissue TNFα and IL-1β and longer duration disease, i.e., patients relatively refractive to steroid treatment [28]. Measurement of serum cytokines is a commercial ELISA technique of limited availability and is not widely used of among clinicians who care for patients with GCA.
13.5.5 Anemia A normocytic, normochromic anemia of mildto-moderate degree (< 12 g/dl) is frequently observed in patients with GCA as a result of decreased hematopoiesis related to the acute-phase response. An unexplained anemia may even be the presenting manifestation of GCA. Some recent studies have reported that the presence of anemia at presentation is associated with a reduced incidence of ischemic events [11, 19].
13.5.6 Others Other laboratory tests that may be abnormal in GCA include WBC count, liver enzymes, other acute-phase reactants (fibrinogen, haptoglobin), albumin, gamma globulin, anticardiolipin antibodies, plasma viscosity, and amyloid A apolipoprotein [19, 47].
13.6 Diagnosis of GCA There is no single laboratory value, imaging procedure or even biopsy sample that is positive in all patients and there is no one symptom or sign that is pathognomic of GCA. Giant cell arteritis is a syndrome in which characteristic symptoms accompanied by objective signs of inflammation and vasculopathy are used to define the clinical diagnosis. Histopathologic evidence of inflammation in arterial tissue provides definitive diagnostic evidence and should be sought whenever possible as the commitment to treatment is not a trivial matter, often long in duration and fraught with medication side-effects.
13.6.1 Temporal Artery Biopsy The temporal artery biopsy is the most common method of histopathologic testing for GCA. It is generally agreed that an adequate biopsy specimen should have a minimum length of 2 cm [9]. Longer specimens (3–5 cm) are preferable and multiple fine (0.25–0.5 mm) sections are necessary due to the presence of skip lesions and the potential effect of post-fixation shrinkage [52]. In many situations, a unilateral temporal artery biopsy is performed and the frozen section is immediately examined. If the initial examination is negative and the clinical suspicion is high, then a sequential biopsy is completed during the same procedure. Thereafter, a more critical examination of a paraffin-embedded biopsy specimen should be performed under light and electron microscopy. Reliance on frozen sectioning alone has a high rate of false negatives [42]. If the clinical suspicion for GCA is high and the first biopsy is negative, the chances of a second biopsy demonstrating positive histopathology is rather low, ranging from 5% to 9% [23, 45]. If the clinical suspicion is low, a unilateral biopsy appears to be sufficient to rule out the diagnosis [21, 23]. Findings which should raise clinical suspicion for the diagnosis and which tend to predict a positive biopsy include: presence of jaw claudication, CRP >2.45 mg/l, elevated ESR >47 mm/h, neck pain, white or pale disc edema, systemic symptoms other than headache, temporal artery abnormalities, and elevated platelet count [21, 23]. The chief pathologic finding is a panarteritis consisting mostly of lymphocytes and macrophages. Granuloma formation may be present. The intima is thickened and the internal elastic lamina is fragmented. Infiltration by mononuclear cells and multinucleated giant cells (present in 50% of specimens) is concentrated around the inner half of the media, characteristically along the disrupted internal elastic lamina [42, 57]. The presence of active arteritis remains for up to 6 weeks after initiation of corticosteroids [9]. Fibrinoid necrosis is rarely found in GCA and should raise suspicion of other vasculitides. The healed or chronic phase of GCA is characterized by foci of lymphocytes, fibrosis and vascularization with continued evidence of intimal disruption.
13.6 Diagnosis of GCA
Although the temporal artery biopsy is considered the gold standard test for diagnosis, it is important to remember that a negative biopsy result may be found in up to 10%–15% of cases [53]. Particularly when GCA assumes a localized form, such as large-vessel vasculitis, and the arterial inflammation occurs in the relative absence of systemic inflammation, the gold standard temporal artery biopsy is negative in at least 50% of patients [7, 57]. In such instances, the diagnosis of GCA must be taken from clinical indices, supportive laboratory findings and corroborative imaging. Insistence on positive histopathology in these patients may lead only to multiple negative biopsy specimens (from both temporal arteries, the occipital artery, other extracranial arteries, etc.) and unnecessary delay in treatment.
Summary for the Clinician
■ Histologic confirmation of diagnosis is
recommended in all patients who are treated for GCA. If one temporal artery biopsy is negative but the clinical suspicion for GCA remains high, a second biopsy of the contralateral side is recommended despite the low yield. If the clinical suspicion is low, a single negative biopsy is sufficient to rule out the diagnosis. Steroid treatment should never be delayed in suspected patients as pathologic features of active arteritis can still be detected on biopsy samples for up to 6 weeks after treatment. A biopsy length of 2 cm or more is recommended.
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13.6.2 American College of Rheumatology Criteria In 1990, the American College of Rheumatology (ACR) developed a set of criteria which have been used to diagnose GCA [32]. These are listed in Table 13.1 and, in brief, consist of advanced age, new headache, temporal artery abnormali-
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Giant Cell Arteritis Table 13.1. Criteria of the American College of Rheumatology for the Diagnosis of giant cell arteritis Age at onset ≥50 years New headache Temporal artery abnormalities (either tenderness or reduced pulsation ) Elevated erythrocyte sedimentation rate (≥50 mm/h by Westergren method) Positive temporal artery biopsy (arteritis characterized by a predominance of mononuclear infiltrates or granulomas, usually with multinucleated giant cells)
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Fig. 13.6. Photograph of right temporal artery in a patient with acute visual loss due to GCA. This hard, nodular temporal artery was tender to palpation and pulseless
Fig. 13.7. Color Doppler ultrasonography of temporal arteries. Longitudinal (top) and transverse (bottom) view of superficial temporal artery branch showing the hypoechoic rim (arrows) around the perfused lumen, representative of edematous wall swelling in active arteritis. From Schmidt WA [53], Current diagnosis and treatment of temporal arteritis, in Current Treatment Options in Cardiovascular Medicine 2006; 8, 145–151
ties, high ESR and positive biopsy (Fig. 13.6). The presence of any three of these five criteria permitted a diagnosis of GCA with a sensitivity of 93.5% and a specificity of 91.2% based on a population of patients (n=807) with rheumatologic disease [47]. A note of caution should be taken when applying these ACR criteria to the general clinical population because the criteria were primarily developed to distinguish patients with GCA (n=214) from patients with other vasculitides (n=593) and for classifying patients with rheumatologic disorders for research purposes. It is thus possible that patients who lack typical systemic symptoms and present with an ischemic complication (so-called occult GCA)
may not have been accurately represented in the ACR study as they are more likely to seek the care of a non-rheumatologic specialist. From the ophthalmic perspective, Hayreh et al. [24] found that among 85 patients who presented with ocular symptoms due to biopsy-positive GCA, 21% had no systemic symptoms or signs of GCA. In these patients, the diagnosis was suspected on clinical grounds (AION in a patient aged 50 years or older) and confirmed by histologic findings (biopsy), so strictly speaking this would meet only two of the five ACR criteria. Likewise in the setting of large-vessel arteritis, imaging the vascular territories of interest may prove most fruitful in aiding the diagnosis.
Given the protean manifestations of GCA, it is more important to view the patient’s presentation as a whole and ask “Could this be GCA?” rather than to rely on criteria sets to make a diagnosis of GCA. In this respect, alternative modalities are emerging for imaging the temporal and other cranial arteries to help support a diagnosis of vasculitis. These modalities include ultrasound, MRI, and single photon emission tomography (SPECT) and are discussed in the next sections.
13.6.3 Role of Ultrasound Modern sonography can delineate vascular structures with a resolution of 0.1–0.2 mm [52]. In 1997, Schmidt et al. [51] used high-resolution color Doppler imaging and duplex ultrasonography to examine the superficial temporal arteries in patients with GCA. They described the presence of a hypoechoic (dark) thickening around the lumen of the temporal artery, termed a “halo” sign which represents edema of the vessel wall (Fig. 13.7). This sonographic finding disappears within a few weeks after steroid initiation. Salvarani et al. [50] later commented that only halos having a thickness of 1 mm or more have diagnostic importance. They examined 86 patients clinically suspected to have either GCA or polymyalgia rheumatica. A halo with diameter of 1–3 mm was found in 6 of 15 (40%) patients with positive biopsy findings. A surprising 15 of 71 (21%) of patients with a negative temporal artery biopsy also had a halo sign but only 5 had a halo with diameter of 1 mm or greater. These authors concluded that the sensitivity of the halo sign for detecting GCA is low (40%) and in fact, not superior to careful physical examination assessing for a tender or pulseless temporal artery [50]. On the other hand, if the halo sign is present with a thickness of 1 mm or more, this carries a high specificity (>90%) for a diagnosis of GCA in the appropriate clinical setting. In follow-up to this and other studies examining the utility of sonography, Schmidt and Grominica-Ihle [52] reviewed the literature in 2005 in asking the question “how sensitive and specific is temporal artery sonography with regard to clinical and histologic diagnosis?”. They
13.6 Diagnosis of GCA
found that the halo sign alone had a sensitivity of 40%–100% and a specificity of 68%–100% for a biopsy-positive diagnosis of GCA. The sensitivity of sonography increased if additional features such as stenosis and occlusion of the temporal artery were included in the sonographic criteria for GCA. Despite the generally accepted high specificity of the halo sign, the authors cautioned that it is not a pathognomonic sign of GCA as they have noted the halo sign in rare patients with temporal artery involvement from Wegener’s granulomatosis. Sonography is not a replacement for a temporal artery biopsy in the diagnosis of GCA. It is one of an armamentarium of ancillary tests that can lend support to a clinical diagnosis of GCA and its chief advantage is the ability to examine the entire length of one or both temporal arteries in a non-invasive fashion.
13.6.4 Other Non-Invasive Imaging of the Cranial Arteries MRI is currently under investigation as another means to non-invasively evaluate the superficial temporal arteries of patients with suspected GCA. Multislice contrasted T1-weighted spin echo sequences with a submillimeter spatial resolution on a standard 1.5-Tesla scanner can detect inflammatory vessel wall changes [5]. These changes appear as circumferential thickening of the temporal artery and/or increased contrast enhancement (Fig. 13.8). The sensitivity and specificity of MRI for detecting temporal artery inflammation due to GCA have not yet been determined. However, as MR is a favored imaging procedure for investigating the presence of large-vessel involvement due to GCA, such T1-weighted images can be easily combined with thoracic MR angiography to provide a rapid, single-test assessment of the major cranial, cervical and thoracic vascular beds [4]. Increased 67gallium uptake has been noted in the temporal region of patients with GCA, and SPECT scintigraphy appears to be a promising tool to investigate and monitor patients with GCA [48]. PET scanning, however, should not be used to evaluate for arteritis in medium-sized vessels such as temporal arteries as the vessel resolution with PET is about 5 mm diameter and
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Fig. 13.8a,b. MR images of a 73-year-old man with GCA. a Unenhanced high-resolution coronal T1-weighted 2D spin-echo sequence depicts frontal branch of right temporal artery (arrow). b Contrast-enhanced, fat-saturated T1-weighted 2D spin-echo sequence at the same position as a shows bright contrast enhancement of thickened vessel wall, strongly indicating arteritis (arrow). Concomitant bright signal intensity of lumen of temporal vein (arrowheads) and low signal intensity of lumen of temporal artery are due to flow-void phenomenon (arrow). Reprinted from American Journal of Radiology volume 184, Bley TA, Wieben O, Uhl M et al. [5], High-resolution MRI in giant cell arteritis: imaging of the wall of the superficial temporal artery, pp. 283–287, 2005 with permission from the American Roentgen Ray Society
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there is high background activity related to brain uptake of the radioactive substance.
13.7 Treatment and Prognosis of GCA It was mentioned earlier in this chapter that the natural history of GCA, based on early descriptions of the disease before steroids were available, is spontaneous remission. However, the disease activity may smolder on for months or years before extinguishing. The need-to-treat stems from the high rate of morbidity related to ischemic complications due to GCA, particularly blindness. In the pre-steroid era, the estimated percentage of patients experiencing permanent visual loss due to GCA was 35%–60% and since the advent of corticosteroid treatment, this percentage has dramatically dropped to 7%–14% [20].
13.7.1 Corticosteroids Treatment of GCA is aimed at controlling and arresting the inflammatory process in order to prevent an ischemic complication such as visual loss, neurologic dysfunction or other or-
gan infarction. Corticosteroids remain still the mainstay treatment of GCA. Within the first few days of steroid initiation, systemic symptoms of malaise, myalgia, anorexia and fever begin to subside and within the first week the sedimentation rate begins to normalize. Although there is general consensus about the need to initiate corticosteroids immediately upon diagnosis or even suspicion of GCA, there remains controversy about the dosage, the means of administration and the duration of corticosteroid treatment. To date, there are no randomized, controlled studies which have evaluated the differing steroid regimens used among clinicians and results of treatment reported in the literature are retrospective and anecdotal. Most authors agree that the initial treatment should be a sufficiently high dosage of steroids, equivalent to 60 mg or more of prednisone daily. A daily schedule is recommended over alternate-day dosing which has been associated with higher rates of disease relapse [26, 28]. Although many authors favor intravenous administration in the acute setting, there is no evidence that intravenous is superior to oral steroid. Waiting for home nursing arrangements or hospital admission is never a reason to delay steroid treatment. In such a situation, high-dose oral prednisone is perfectly adequate and can be
started during the office examination. Additionally, the potential adverse effects of high-dose intravenous steroids in the elderly population must always be considered, including sudden death, cardiac arrhythmia, aseptic osteonecrosis, acute psychosis, sepsis, and anaphylaxis. The following paragraphs attempt to provide general guidelines for the steroid treatment of GCA [9, 22].
13.7 Treatment and Prognosis of GCA
when the daily dose reaches 10–15 mg. A patient evaluation and laboratory markers are repeated before each reduction in daily steroid dosage. Any recurrence of symptoms or rise in ESR/CRP should be considered a reactivation of disease activity or, in some cases, the development of a secondary infection, and should prompt a thorough re-evaluation of the steroid dosage needed.
13.7.1.1 Starting Dose At the time of patient presentation and clinical suspicion of diagnosis, patients can be divided in two groups: those without and those with visual or neurologic manifestations. In the patients without visual or neurologic manifestations who have only rheumatic and systemic symptoms, treatment with oral prednisone (in doses ranging from 60 to 120 mg daily, or 1 mg/kg per day) may be used. In patients with any acute visual or neurologic symptom or sign i.e., an ischemic complication of GCA, hospitalization and treatment with intravenous methylprednisolone (1000 mg daily in single or divided doses given for 3 days) is recommended. After the intravenous bolus, oral prednisone is begun, at 80 mg daily or 1–2 mg/kg per day.
13.7.1.4 Duration of Treatment Hayreh and Zimmerman [26] treated and followed 145 patients with biopsy-positive GCA. Their average time to reach a dosage of 40 mg daily was 2 months (range 1–5 months), and the time to reach the lowest maintenance dosage (median 7 mg daily) was 2 years. After 2 years, more than 92% of patients (without and with visual loss at presentation) were still on steroids, emphasizing the long duration of treatment.
Summary for the Clinician
■ Any
patient suspected to have GCA (based on historical symptoms, physical examination and/or laboratory findings) should be started on corticosteroids at a dose equivalent to prednisone 60 mg or more daily. Intravenous administration of methylprednisolone at 1000 mg daily is recommended for patients who have visual or neurologic ischemic symptoms or signs. Steroid tapering is guided at all times by patient evaluation and laboratory markers, typically ESR and/or CRP. Most patients are still on low-dose steroids after 1–2 years of treatment.
13.7.1.2 Maintenance Dose
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High-dose oral prednisone is maintained for at least 4–6 weeks until systemic symptoms have subsided and markers of disease activity (ESR and/or CRP) have normalized. Calcium supplementation, vitamin D, and peptic ulcer prophylaxis should accompany steroid treatment. In patients with or at-risk for osteoporosis, bone densitometry and physical counseling should be considered.
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13.7.1.3 Tapering Regimen Steroid tapering is a slow process and highly individualized. In most patients, the initial reduction in dosage is 5–10 mg per month but later the rate of reduction should proceed more cautiously, even as low as 1 mg per month
13.7.2 Visual Outcome on Corticosteroids Visual loss from GCA is typically profound and permanent. Patients are suddenly rendered severely disabled, often functionally blind for life.
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Yet the literature cites favorable rates of visual recovery in GCA, ranging from 15% to 34% [13]. This discrepancy between what is observed in clinical practice (patients are still blind) and what is reported in studies (vision can recover) is likely related to the means by which vision is assessed. When visual recovery is defined solely as an improvement in visual acuity, it leaves open the possibility that acquired eccentric viewing may be reflected in reported recovery rate. Studies that have assessed for changes in visual field following steroid treatment report dismally low rates of recovery, on the order of 4%–5% of improved central visual field, confirming the generally grim prognosis once vision is lost [13, 26]. Nonetheless, there remains an overall trend for better visual outcome if steroids are begun immediately after visual loss and anecdotal reports of remarkable recovery continue to give hope for some chance of visual recovery with aggressive treatment efforts. Steroids do appear to stabilize the amount of visual loss from GCA. In patients with visual loss at presentation and treated promptly with highdose steroids, two recent studies have reported widely different rates of deterioration (4% versus 27%) but both studies agree that if further deterioration of vision occurs, it happens in the first 5–6 days of steroid initiation [13, 26]. Once the visual loss is stabilized and disease activity controlled with steroids, recurrent visual loss is rare. One recent study found an exceptionally high rate of recurrent ischemic optic neuropathy (7 of 67, 10%), all of which occurred between 3 and 36 months after the initial visual loss [10]. The most important action of steroids lies in their ability to prevent visual loss before it happens.
13.7.3 Methotrexate Methotrexate has received attention as an adjuvant therapy for GCA based on its success in the treatment of other vasculitides. As the treatment of GCA is long in duration, often requiring 1–5 years of steroids, it is not surprising that steroidrelated complications pose another source of morbidity for this aged patient population. Common side-effects include diabetes, secondary infections, osteoporosis and bone fracture, myopa-
thy and psychosis and underscore the need for a steroid-sparing agent with equal or superior efficacy in controlling disease activity and relapse. The most recent randomized, placebo-controlled trial using adjuvant methotrexate failed to find any significant effect of methotrexate for controlling disease activity, decreasing the cumulative steroid dose or reducing the incidence of steroidrelated complications [31]. At present, there is no role for methotrexate in the standard treatment regimen of patients with GCA. In patients with severe adverse reactions to steroids or steroidrefractive disease, methotrexate is considered a viable second-line alternative [22].
13.7.4 Other Adjuvant Therapies Emerging adjuvant therapies for GCA include azathioprine, cyclophosphamide, ciclosporin, anti-tumor necrosis factor (TNF), soluble TNF receptors and antibodies targeted against adventitial dendritic cells. There is far less clinical experience with these therapies than with methotrexate and there is no standard recommendation at this time for their use. Future studies are anticipated to define their efficacy in managing inflammatory activity [22]. Aspirin is commonly used by many elderly persons for other reasons (ischemic heart disease, transient ischemic attack) and it may have a protective effect against ischemia due to GCA. In a retrospective review of 175 patients, Nesher et al. [41] noted that the patients who were already on aspirin at the time of their diagnosis of GCA were less likely to present with a cranial ischemic complication such as visual loss or stroke. Additionally, patients who took both prednisone and aspirin were less likely to suffer a cranial ischemic complication during the course of their treatment compared to patients on prednisone only (3% compared to 13%). These authors postulated that the protective mechanism of aspirin may be related to its antiplatelet effect and its anti interferon-γ action. However, any potential benefit of combination therapy is offset by an increased risk of gastrointestinal hemorrhage. In clinical practice, the use of aspirin as an adjuvant therapy in patients with GCA remains determined on an individual basis until further evidence-based studies can attest to its efficacy.
13.7.5 Treatment of LargeVessel Involvement It is unknown whether current steroid regimens are adequate for treating large-vessel vasculitis, i.e., alleviating symptomatic claudication, restoring flow through occluded arteries or aborting aortitis and preventing aneurysm formation. Although GCA-related aneurysms are generally associated with elevated acute-phase reactants (ESR, CRP), it is unclear if active aortic inflammation is reflected by these markers, which are used to guide steroid dosing. If symptoms of large-vessel stenosis persist while the patient is on steroid therapy, endovascular intervention has been proposed [7]. Anecdotal results using balloon angioplasty for the treatment of symptomatic arteritic occlusion of the subclavian, axillary and brachial arteries have been favorable. If asymptomatic aortic aneurysm is detected, the choice between surveillance and surgery is dependent on patient factors and size of aneurysm. Current data suggest no difference in long-term survival between patients without large artery involvement and patients with aortic aneurysm except for the subgroup with aortic dissection who have a markedly high mortality rate.
References 1. Alvarez-Lafuente R, Fernandez-Gutierrez B, Jover JA et al (2005) Human parvovirus B19, varicella zoster virus, and human herpes virus 6 in temporal artery biopsy specimens of patients with giant cell arteritis : analysis with quantitative real time polymerase chain reaction. Ann Rheum Dis 64:780–782 2. Amor-Dorado JC, Llorca J, Garcia-Porrua C et al (2003) Audiovestibular manifestations in giant cell arteritis: a prospective study. Medicine 82:13–26 3. Becourt-Verlomme, C, Barouky R, Alexandre C et al (2001) Symptômes inauguraux de la maladie de Horton sur une série de 260 patients. Rev Med Interne 22:631–637 4. Bley TA, Wieben O, Uhl M et al (2005) Integrated head-thoracic vascular MRI at 3T: assessment of cranial, cervical and thoracic involvement of giant cell arteritis. MAGMA 18: 193–200
References 5. Bley TA, Wieben O, Uhl M et al (2005) High-resolution MRI in giant cell arteritis: imaging of the wall of the superficial temporal artery. AJR Am J Roentgenol 184: 283–287 6. Blockmans D, de Ceuninck L, Vanderschueren S et al (2006) Repetitive 18F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients. Arthritis Rheum 55: 131–137 7. Bongartz T, Matteson EL (2006) Large-vessel involvement in giant cell arteritis. Curr Opin Rheumatol 18: 10–17 8. Campbell FA, Clark C, Holmes S (2003) Scalp necrosis in temporal arteritis. Clin Exp Dermatol 28: 488–490 9. Carroll SC, Gaskin BJ, Danesh-Meyer HV (2006) Giant cell arteritis. Clin Exp Ophthalmol 34: 159–173 10. Chan CC, Paine M, O’Day J (2005) Predictors of recurrent ischemic optic neuropathy in giant cell arteritis. J Neuroophthalmol 25: 14–17 11. Cid MC, Font C, Oristrell J et al (1997) Association between strong inflammatory response and risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis. Arthritis Rheum 41: 26–32 12. Costello F, Zimmerman MB, Podhajsky PA, Hayreh SS (2004) Role of thrombocytosis in diagnosis of giant cell arteritis and differentiation of arteritic from non-arteritic anterior ischemic optic neuropathy. Eur J Ophthalmol 14: 245–257 13. Danesh-Meyer H, Savino PJ, Gamble G (2005) Poor prognosis of visual outcome after visual loss from giant cell arteritis. Ophthalmology 112: 1098–1103 14. Evans JM, O’Fallon WM, Hunder GG (1995) Increased incidence of aortic aneurysm and dissection in giant cell (temporal) arteritis: a population based study. Ann Intern Med 122: 502–507 15. Fietta P, Manganelli P, Zanetti A et al (2002) Familial giant vell arteritis and polymyalgia rheumatica: aggregation in 2 families. J Rheumatol 29: 1551–1555 16. Foroozan R, Danesh-Meyer H, Savino PJ et al (2002) Thrombocytosis in patients with biopsyproven giant cell arteritis. Ophthalmology 109: 1267–1271 17. Glutz Von Blotzheim S, Borruat F-X (1997) Neuro-ophthalmic complications of biopsyproven giant cell arteritis. Eur J Ophthalmol 7: 375–382
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Giant Cell Arteritis 18. Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ et al (2005) Giant cell arteritis. Disease patterns of clinical presentation in a series of 240 patients. Medicine 84: 1–8 19. Gonzalez-Gay MA, Lopez-Diaz MJ, Barros S et al (2005) Giant cell arteritis. Laboratory tests at the tie of diagnosis in a series of 240 patients. Medicine 84: 277–290 20. Gonzalez-Gay MA, Garcia-Porrua C, Llora H et al (2005) Visual manifestations of giant cell arteritis: trends and clinical spectrum in 161 patients. Medicine 79: 283–292 21. Hall JK, Volpe NJ, Galetta Sl et al (2003) The role of unilateral temporal artery biopsy. Ophthalmology 110: 543–548 22. Hall JK, Balcer LJ (2004) Giant cell arteritis. Curr Treat Options Neurol 6: 45–53 23. Hayreh SS, Podhajsky PA, Raman R et al (1997) Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 123: 285–296 24. Hayreh SS, Podhajsky PA, Zimmerman B (1998) Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 125: 521–526 25. Hayreh SS, Podhajsky PA, Zimmerman B (1998) Ocular manifestations of giant cell arteritis. Am J Ophthalmol 125: 509–520 26. Hayreh SS, Zimmerman B (2003) Management of giant cell arteritis. Ophthalmologica 217: 239–259 27. Hernandez-Rodriguez J, Garcia-Martinez A, Casademont J et al (2002) A strong initial systemic inflammatory response is associated with higher corticosteroid requirements and longer duration of therapy in patients with giant-cell arteritis. Arthritis Rheum 47: 29–35 28. Hernandez-Rodriguez J, Segarra M, Vilardell C et al (2004) Tissue production of pro-inflammatory cytokines (IL-1β, TNFα and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology 43: 294–301 29. Hernandez-Rodriguez J, Garcia-Martinez A, Espigol-Frigole G et al ( 2006) Sustained spontaneous clinical remission in giant cell arteritis: report of 2 cases with long-term follow-up. Arthritis Rheum 55: 160–162
30. Herve F, Choussy V, Janvresse A et al (2006) Aortic involvement in giant cell arteritis. A prospective follow-up of 11 patients using computerized tomography. Rev Med Interne 27: 196–202 31. Hoffman GS, Cid MC, Hellman DB et al (2002) A multicenter, randomized, double-blind, placebocontrolled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 46: 1309–1318 32. Hunder GG, Bloch DA, Michel BA et al (1990) The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 33: 1122–1128 33. Hunder GG (2002) Epidemiology of giant-cell arteritis. Cleve Clin J Med 69 [Suppl. 2]: 79–82 34. Langford CA (2005) Vasculitis in the geriatric population. Clin Geriatr Med 21: 631–647 35. Lee AG, Tang RA, Feldon SE et al (2001) Orbital presentations of giant cell arteritis. Graefes Arch Clin Exp Ophthalmol 239: 509–513 36. Levine SM, Hellman DB (2002) Giant cell arteritis. Curr Opin Rheumatol 14: 3–10 37. Liozon E, Boutros-Toni F, Ly K et al (2003) Silent, or masked, giant cell arteritis is associated with a strong inflammatory response and a benign short term course. J Rheumatol 30: 1272–1276 38. Meller J, Strutz F, Siefker U et al (2003) Early diagnosis and follow-up of aortitis with [(18)F]FDG PET and MRI. Eur J Nucl Med Mol Imag 30: 730–736 39. Miller NR (2001) Visual manifestations of temporal arteritis. Rheum Clin North Am 27: 781–797 40. Narvaez JA, Narvaez JM, Nolla JM et al (2004) Giant cell arteritis and polymyalgia rheumatica: usefulness of vascular magnetic resonance imaging studies in the diagnosis of aortitis. Rheumatology 44: 479–483 41. Nesher G, Berkun Y, Mates M et al (2004) Lowdose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 50: 1332–1337 42. Nordborg E, Nordborg C, Bengtsson B-A (1992) Giant cell arteritis. Curr Opin Rheum 4: 23–30 43. Nuenninghoff DM, Hunder GG, Christianson TJH et al (2003) Incidence and predictors of largeartery complication (aortic aneurysm, aortic dissection, and/or large-artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years. Arthritis Rheum 48: 3522–3531
44. Ostberg G (1971) Temporal arteritis in a large necropsy series. Ann Rheum Dis 30: 224–235 45. Pless M, Rizzo JF III, Lamkin JC et al (2000) Concordance of bilateral temporal artery biopsy in giant cell arteritis. J Neuroophthalmol 20: 216–218 46. Powers JF, Bedri S, Hussein S et al (2005) High prevalence of herpes simplex virus DNA in temporal arteritis biopsy specimens. Am J Clin Pathol 123: 261–264 47. Rahman W, Rahman FZ (2005) Giant cell (temporal) arteritis: an overview and update. Surv Ophthalmol 50: 415–428 48. Reitblat T, Ben-Horin CL, Reitblat A (2003) Gallium-67 SPECT scintigraphy may be useful in diagnosis of temporal arteritis. Ann Rheum Dis 62: 257–260 49. Rockey JG, Anand R (2002) Tongue necrosis secondary to temporal arteritis: a case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94: 471–473 50. Salvarani C, Silingardi M, Ghirarduzzi A et al (2002) Is Duplex ultrasonography useful for the diagnosis of giant-cell arteritis? Ann Intern Med 137: 232–238 51. Schmidt WA, Kraft HE, Vorpahl K et al (1997) Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 337: 1336–1342
References 52. Schmidt WA, Gromnica-Ihle E (2005) What is the best approach to diagnosing large-vessel vasculitis? Best Pract Res Clin Rheumatol 19: 223–242 53. Schmidt WA (2006) Current diagnosis and treatment of temporal arteritis. Curr Treat Options Cardiovasc Med 8: 145–151 54. Smeeth L, Cook C , Hall AJ (2006) Incidence of diagnosed polymaylgia rheumatica and temporal arteritis in the United Kingdom, 1990 to 2001. Ann Rheum Dis 65(8): 1093–1098 55. Wagner AD, Gerard HC, Freseman T et al (2000) Detection of Chlamydia pneumoniae in giant cell vasculitis and correlation with the topographic arrangement of tissue-infiltrating dendritic cells. Arthritis Rheum 43: 1543–1551 56. Weyand CM, Fulbright JW, Hunder GG et al (2000) Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 43: 1041–1048 57. Weyand CM, Goronzy JJ (2003) Giant-cell arteritis and polymyalgia rheumatica. Ann Intern Med 139: 505–515 58. Weyand CM, Ma-Krupa W, Goronzy JJ (2004) Immunopathways in giant cell arteritis and polymyalgia rheumatica. Autoimmun Rev 3: 46–53 59. Weyand CM, Ma-Krupa W, Pryshchep O et al (2005) Vascular dendritic cells in giant cell arteritis. Ann N Y Acad Sci 1062: 195–08
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Part V
Oculomotility
Chapter 14
14
Cerebral Control of Eye Movements Charles Pierrot-Deseilligny
Core Messages
■ Eye movements are rapid (saccades) or
slow (smooth pursuit and vestibulo-ocular reflex, VOR), conjugate or disconjugate (convergence), and organized, at least at the brainstem level, in the horizontal and the vertical planes. At bedside examination, saccades and fixations in the four cardinal positions of the eyes should be tested first during rapid motion to detect any abnormality in the movement (reduced in amplitude or velocity) and secondly during fixation (if there is nystagmus). When this eye examination is normal, it is not useful to test other movements. If saccades are impaired, examination of the VOR (oculocephalic reflex) and convergence may determine whether impairment involves all types of eye movements, which implies nuclear or infranuclear (nerve or muscle) damage, or only one type of eye movement, which implies supranuclear damage.
■
■ The abducens nucleus (VI), at the pontine
level, controls all ipsilateral eye movements, with abduction mediated via the abducens rootlets and adduction via the medial longitudinal fasciculus (MLF). Damage to the latter results in internuclear ophthalmoplegia (with adduction paralysis and monocular nystagmus in the contralateral eye), which is the most frequent horizontal eye movement paralysis. In “one-and-a-half ” syndrome, both the MLF and the sixth nucleus are damaged on the same side of the pons. The oculomotor nucleus (III) and trochlear (IV) nucleus, at the midbrain level, control all vertical eye movements and convergence. Third nerve nucleus syndrome comprises an ipsilateral oculomotor paralysis and a contralateral superior rectus paralysis, because of decussation of the superior rectus motoneurons. Bilateral damage to the rostral interstitial nucleus of the MLF (controlling vertical saccades), at the upper midbrain level, results in downward and upward saccade paralysis. Unilateral damage to the posterior commissure, at the postero-superior extremity of the midbrain, results in upward saccade paralysis, which is the most frequent vertical eye movement paralysis.
■
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Core Messages
■ Nystagmus may be pendular (with equal
velocity of phases) and then often congenital, or jerk (with slow and quick phases) and then often acquired. Horizontal jerk nystagmus is usually due to peripheral or central vestibular damage. Upbeat nystagmus results from brainstem damage affecting the ventral tegmental tract coursing in the ventral pons and midbrain, or from damage to its medullary collateral branch or from intoxication. Downbeat nystagmus is due to floccular cerebellar damage (degenerative disease or cranio-cervical junction malformations) or from intoxication. Seesaw nystagmus may result from damage to the nucleus of Cajal (in the upper
14.1 Introduction
14
■
midbrain) or from progressive visual loss (mostly large parasellar masses), whereas convergence-retraction nystagmus is due to tectal lesions (upper midbrain). The other abnormal eye movements, saccadic in nature – such as ocular flutter, opsoclonus and square wave jerks – are due to damage to cerebello-brainstem pathways not yet well identified. Cerebellar damage results in saccade dysmetria and smooth pursuit impairment, whereas cerebral hemispheric lesions have to be bilateral to result in Balint’s syndrome or acquired ocular motor apraxia, comprising more or less severe saccade and smooth pursuit impairment.
Eyes can move rapidly or slowly. Rapid eye movements are saccades (voluntary saccades and quick phases of nystagmus) and slow eye movements comprise smooth pursuit, the vestibuloocular reflex (VOR) and convergence. Eye movement commands originate in various cerebral hemispheric areas (for saccades, smooth pursuit and convergence) or in labyrinths (for the VOR). They are carried out in the brainstem by the immediate premotor structures and the motor nuclei. Conjugate lateral eye movements are largely organized in the pons, and vertical eye movements and convergence in the midbrain. In the first part of this chapter, we will see the anatomophysiological organization of eye movements in the brainstem and the main types of eye-movement paralysis resulting from brainstem lesions. Such types of abnormalities are easily detected at the bedside by studying three main types of eye movements, allowing the examiner to determine whether damage is nuclear-infranuclear or supranuclear (Fig. 14.1): saccades, i.e., rapid eye movements made towards a visual target (such as the examiner’s finger); the vestibular ocular reflex (VOR), tested using the oculocephalic move-
ment by passively moving the subject’s head; and convergence, tested using a small object drawing near to the subject’s nose. Smooth pursuit is relatively difficult to interpret and may be omitted at bedside examination. In the second part of this chapter, eye-movement disturbances due to cerebellar and cerebral hemispheric lesions, resulting in relatively more subtle syndromes, will be reviewed briefly. The last part of the chapter deals with some abnormal eye movements.
Summary for the Clinician
■ Routine ■
bedside examination of eye movements comprises saccades (voluntary movements) and fixation in the four directions of gaze, and this is sufficient if no abnormality is detected. When saccades are abnormal, the VOR (oculocephalic reflex) and/or convergence should be tested to determine the location of damage: nuclear-infranuclear (nerves, extraocular muscles) or supranuclear.
14.2 Brainstem
Fig. 14.1. Eye movement examination at bedside
14.2 Brainstem 14.2.1 Horizontal Eye Movements 14.2.1.1 Final Common Pathway The final common pathway of conjugate lateral eye movements (saccades, smooth pursuit and VOR) begins in the abducens nucleus, which contains: (1) the motoneurons projecting onto the ipsilateral lateral rectus; and (2) the internuclear neurons, which decussate at the level of the abducens nucleus, run through the medial longitudinal fasciculus (MLF) and project to the medial rectus motoneurons in the contralateral oculomotor nucleus [7] (Figs. 14.2, 14.3). Lesions affecting the abducens nerve rootlets in the lower basis pontis result in complete paralysis of abduction in the ipsilateral eye, with marked esotropia. This paralysis is rarely isolated
and usually results from small lacunar or demyelinating lesions located in the brainstem between the abducens nucleus and the beginning of the sixth nerve. If the lesion is relatively large, a contralateral hemiparesis is associated, due to damage to the adjacent pyramidal tract. Lesions affecting the MLF, between the abducens nucleus and the oculomotor nucleus, result in internuclear ophthalmoplegia (INO), which includes: (1) paralysis of adduction in the ipsilateral eye for all conjugate eye movements, usually with preservation of convergence, since this eye movement is organized at the midbrain level (Fig. 14.2); and (2) nystagmus in the contralateral eye when this eye is in abduction. INO is often bilateral, as both MLFs are near to each other in the dorsal tegmentum. The pathophysiology of the nystagmus remains unclear. An adaptive mechanism involving quick phases could account for such nystagmus [7]. A
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14
Fig. 14.2 Brainstem, horizontal views. (C Premotor centre of convergence, d down, III third nerve nucleus, IR inferior rectus, LR lateral rectus, MLF medial longitudinal fasciculus, MR medial rectus, SR superior rectus, u up, V abducens nucleus)
gaze-evoked vertical nystagmus is also common in INO, resulting from damage to the vestibulooculomotor pathways passing through the MLF [21]. A skew deviation (vertical tropia relatively constant whatever the gaze direction) may also be observed in INO, due to damage to the central otolithic pathways [3]. INO is the most frequent central ocular motor paralysis. The main
causes are multiple sclerosis in young patients and small infarctions, usually in elderly patients. An abducens nucleus lesion results in paralysis of all ipsilateral eye movements [11]. Convergence is preserved. As the fibres of the facial nerve are in the immediate vicinity, usually there is also an ipsilateral peripheral facial paralysis.
14.2 Brainstem
This syndrome is relatively rare and is usually due to a demyelinating or vascular lesion. A lesion affecting both the abducens nucleus and the MLF on the same side will result in complete paralysis of lateral conjugate eye movements in one direction (abducens nucleus lesion) and INO in the other direction (MLF lesion), the so-called one-and-a-half syndrome [5, 14] (Fig. 14.2). Consequently, the eye ipsilateral to the lesion remains immobile during all lateral eye movements, whereas the other eye can only abduct. Abduction nystagmus also exists in the latter. Both eyes can converge and move vertically. This syndrome is not very rare and may be observed after demyelinating, vascular or tumoral lesions.
Summary for the Clinician
■ Internuclear ophthalmoplegia (INO), af-
fecting the medial longitudinal fasciculus in the brainstem, is the most frequent cause of central lateral gaze paralysis: this syndrome comprises a paralysis of adduction in one eye and a monocular abduction nystagmus in the other eye. Multiple sclerosis (in young adults) and small vascular lesions (usually in elderly patients) are the most frequent causes of INO.
■
14.2.1.2 Premotor Structures and Afferent Pathways The premotor structure of all lateral saccades – i.e., the final common pathway of these saccades (including quick phases of nystagmus), namely the generator of horizontal saccadic pulse – is the paramedian pontine reticular formation (PPRF) [7]. This structure is located on each side of the midline in the central paramedian part of the tegmentum, extending from the pontomedullary junction to the pontopeduncular junction (Fig. 14.3). Isolated unilateral lesions at this level are rare and result in paralysis of all ipsilateral saccades (including quick phases of nystagmus) with preservation of smooth pursuit, the VOR
and convergence. The premotor structure of lateral slow eye movements is the medial vestibular nucleus (MVN). This is well established for the VOR, but probably also true for smooth pursuit [7]. The MVN contains excitatory vestibular neurons, projecting to the contralateral abducens nucleus (Fig. 14.3). The afferents of the premotor structures are multiple. Two suprareticular structures appear to be crucial for saccade triggering (Fig. 14.3): the superior colliculus and the frontal eye field (FEF). The PPRF receives afferents from the contralateral superior colliculus, via the posterior tegmental tract (located in the paramedian dorsal tegmentum), and also from the contralateral FEF, via a tract following the pyramidal tract. The former decussates at the level of the superior colliculus (Meynert decussation), whereas the latter decussates in the upper pons. The superior colliculus, located dorsally in the upper part of the brainstem, is an important relay for saccades between the cortical areas and the premotor reticular formations. The MVN receives afferents from the ipsilateral labyrinth, via the vestibular nerve (Fig. 14.3), but also from the opposite vestibular nucleus, via the vestibular commissure. These pathways are involved during the VOR. The pathways involved in smooth pursuit come from the cerebellum, in particular the ipsilateral flocculus [7]. Before the cerebellar relay, smooth pursuit circuitry includes pontocerebellar and corticopontine neurons (Fig. 14.3). The latter probably originate in the medial superior temporal visual area, pass through the posterior limb of the internal capsule and the ventral part of the upper brainstem (in a region which is not yet well known) and project to the pontine nuclei (PN), located in the mid-pons. The PN neurons project to the contralateral flocculus. Lesions may involve the afferents to the premotor structures of saccades and smooth pursuit. A unilateral superior colliculus lesion results in impairment of contralateral saccades (increased latency and decreased accuracy) [19]. A lesion affecting the region of the PN results in ipsilateral smooth pursuit impairment and contralateral hemiparesis [23]. The ipsilateral impairment is explained by the existence of a
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Fig. 14.3. Brainstem, sagittal view. [C Premotor centre of convergence, FEF frontal eye field, III third nerve nucleus, MCP middle cerebellar peduncle, MLF medial longitudinal fasciculus, MST medial superior temporal area (smooth pursuit), MVN medial vestibular nucleus, OPC occipito-parietal cortex, PEF parietal eye field, PN pontine nuclei, PPRF paramedian pontine reticular formation, PTT posterior tegmental tract, riMLF rostral interstitial nucleus of the medial longitudinal fasciculus, SC superior colliculus, SVN superior vestibular nucleus, VOR vestibulo-ocular reflex, VTT ventral tegmental tract, VI abducens nucleus, VIII vestibular nerve, III f third nerve fibres, VI f sixth nerve fibres]
14.2 Brainstem
double decussation of smooth pursuit circuitry below the PN (ponto-floccular and vestibulonuclear).
Summary for the Clinician
■ A unilateral third nerve nucleus lesion
(in the midbrain) results in a complete ipsilateral oculomotor paralysis and in a contralateral superior rectus paralysis. A marked hypotropia in the contralateral eye (secondary to the isolated superior rectus paralysis) strongly suggests such a syndrome.
Summary for the Clinician
■
■ Lateral saccades may be specifically af-
fected in the brainstem at a supranuclear level (i.e., without associated impairment of the VOR). At the pontine level, this supranuclear saccade impairment is ipsilateral to the lesion, and, at the midbrain level, the saccade impairment is contralateral.
■
14.2.2 Vertical Eye Movements 14.2.2.1 Final Common Pathway The final common pathway of vertical eye movements is formed by the oculomotor and trochlear nuclei. The motoneurons of the trochlear nerve decussate in the brainstem. This is also the case for those innervating the superior rectus muscle, which pass through the contralateral oculomotor nucleus and rootlets (Fig. 14.2). Lesions affecting the oculomotor rootlets result in ipsilateral oculomotor paralysis. Such paralysis may be isolated [2] or, more often, combined with contralateral hemiparesis (Weber’s syndrome) or contralateral ataxia (Claude’s syndrome) when the lesion also affects either the pyramidal tract or, a little posteriorly, the red nucleus, respectively. When a lesion affects the oculomotor nucleus, there is complete oculomotor paralysis in the ipsilateral eye and isolated paralysis of the superior rectus muscle in the contralateral eye [13]. The latter, due to decussation of the motoneurons of the superior rectus muscle, is combined with a hypotropia of the contralateral eye, which results from a tonic imbalance due to the spared inferior rectus motoneurons and muscle, pulling the eye downwards. A dorsal lesion in the midbrain may also affect the trochlear nerve nucleus or rootlets [6]. Most of these different midbrain lesions are usually small and vascular in origin.
14.2.2.2 Premotor Structures and Brainstem Afferents The premotor structure of vertical saccades – i.e., the final common pathway of these saccades, namely the generator of the vertical saccade pulse – is the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), located at the level of the upper pole of the red nucleus [4] (Fig. 14.3). This nucleus contains the immediately premotor excitatory neurons involved in upward and downward saccades, both types of neurons being intermingled. The axons of these two types of neurons follow a similar route, through the rostral part of the MLF, before projecting ipsilaterally to the inferior rectus subdivision of the oculomotor nucleus (downward saccade neurons) or bilaterally to the superior rectus subdivision of this nucleus (upward saccade neurones [9, 10]. The riMLF receives afferents from the FEF and the nuclei of posterior commissure (NPC) located in this commissure. The NPC neurons, which also receive afferents from the FEF and the superior colliculus [4], decussate through the posterior commissure, project to the contralateral riMLF [8] and may be involved more in upward saccades than downward saccades. These various findings should be considered when interpreting the different types of vertical gaze paralysis observed in human pathology (see below). The vestibular nuclei (medial, lateral, superior nuclei and y-group) constitute the final common pathway of vertical slow eye movements. They contain excitatory and inhibitory neurons projecting (contralaterally and ipsilaterally, respectively) to the motor nuclei of the midbrain,
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mainly through the MLF but also through the ventral tegmental tract (VTT) for the upward VOR pathways (Fig. 14.3) (see below).
14.2.2.2.1 Supranuclear Vertical Gaze Paralysis Clinical syndromes with supranuclear vertical eye movement paralysis, which may be identified at the bedside, essentially result from different lesions affecting the riMLF region [1]. Bilateral lesions located medially to the red nucleus result in both downward and upward saccade paralysis (or in only downward saccade paralysis), with
preservation of the VOR and, at times, of smooth pursuit [15]. These lesions are usually due to a bilateral infarction in the territory of the posterior thalamo-subthalamic paramedian artery, but may also result from tumoral lesions. A single, unilateral lesion affecting the posterior commissure or the pretectal region immediately adjacent to this commissure results in upward saccade paralysis, i.e., upward gaze paralysis with preservation of the upward VOR [15,21]. This paralysis is probably due to damage to the fibres involved in upward saccades decussating through the PC. Upward gaze paralysis is the most frequent vertical gaze paralysis and may be observed after vascular, tumoral,
14
Fig. 14.4. Upbeat nystagmus due to a pontine lesion. (III Third nerve nucleus, IR inferior rectus, MLF medial longitudinal fasciculus, SR superior rectus, VTT ventral tegmental tract)
14.3 Suprareticular Structures
demyelinating, infectious lesions or in hydrocephalia. The dorsal midbrain syndrome – which includes damage to the posterior commissure and, therefore, upward gaze paralysis – may also involve other adjacent structures, resulting in various signs [7]: lid retraction (Collier’s sign), disturbances of vergence eye movements, convergence spasm (with pseudo-abducens palsy), convergence-retraction nystagmus (see below), skew deviation, and pupillary abnormalities (light-near dissociation).
Summary for the Clinician
■ The most frequent supranuclear paraly-
sis of vertical gaze involves upward saccades and is commonly called “upward gaze paralysis.” In this case, the lesion may be unilateral and affects the region of the posterior commissure at the upper brainstem level. Multiple causes are observed: hydrocephalia, multiple sclerosis, vascular lesions, tumours.
– may be more involved in an anti-gravitational role, depending on the instantaneous position of the head with regard to the vertical axis. Upbeat nystagmus may be observed after small medullar, pontine or midbrain lesions (either vascular or demyelinating), located along the course of the VTT (or its collateral medullar branch). Upbeat nystagmus may also be observed in degenerative diseases affecting the cerebellum or in some types of intoxication. Since there is no equivalent of the VTT for the downward vestibular eye movements, downward nystagmus cannot result from a focal brainstem lesion. As a matter of fact, this nystagmus is observed after cerebellar (floccular) degenerative lesions, malformations of the cranio-cervical junction (also affecting the flocculus) or some types of intoxication.
■
Summary for the Clinician
■ Upbeat nystagmus (existing in the pri-
mary position of gaze) may be due to either a brainstem lesion or to intoxication. Downbeat nystagmus (existing in the primary position of gaze) results from cerebellar atrophy, malformations of the cranio-cervical junction or from intoxication.
■
■
14.2.2.2.2 Vertical Nystagmus Pure lesions affecting the vestibular nuclei involved in the vertical VOR are not observed in clinical practice. However, lesions of the vestibulo-oculomotor pathways mediating this eye movement may result in specific syndromes. In particular, damage to the VTT (Figs. 14.3, 14.4), coursing in the anterior part of the tegmentum at the pontine level, results in upbeat nystagmus existing in all positions of gaze, since this tract is specifically involved in the upward VOR [12]. In INO, with damage to all other vestibulo-oculomotor tracts, i.e., involved both in the upward and downward VOR, vertical gaze is not visibly affected at bedside examination, except for the usual presence of a small upward and/or downward gazeevoked nystagmus. It should be noted that the VTT – which is the second tract involved in the upward VOR, besides that coursing in the MLF
14.3 Suprareticular Structures Outside the brainstem, a number of suprareticular structures located in the cerebellum and the cerebral hemispheres control eye movements. Damage to these structures results in disturbance to saccade and/or smooth pursuit movements that are usually much more subtle than those due to brainstem lesions. This section is brief since there are few implications in clinical practice.
14.3.1 Cerebellum The cerebellum (dorsal vermis) is involved in the control of saccade amplitude, with saccade dys-
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metria resulting from cerebellar lesions. Furthermore, the cerebellum is crucial for smooth pursuit since this eye movement ceases to exist after total cerebellectomy in the monkey [26]. The dorsal vermis and the floccular lobe are involved in the cerebellar control of smooth pursuit, which is affected by lesions of this structure [27].
Summary for the Clinician
■ Cerebellar lesions impair the amplitude of saccades (dysmetria) and reduce the velocity of smooth pursuit.
14.3.2 Cerebral Hemispheres
14
Saccades and pursuit eye movements are controlled by different cortical areas. Each hemisphere appears to control eye movements in both lateral directions. Consequently, ocular motor impairment resulting from unilateral hemispheral damage can be ascertained only by eye movement recordings. Two main cortical areas trigger saccades [18, 20] (Figs. 14.3, 14.5). The FEF, located at the intersection between the precentral sulcus and the superior frontal sulcus, controls voluntary saccades. The posterior parietal eye field (PEF), located in the posterior part of the intraparietal
sulcus, may be mainly involved in the triggering of reflexive saccades (made in response to visual targets that appear suddenly). These different parallel pathways explain how unilateral cerebral hemispheric lesions result in subtle saccade deficits, involving mainly intentional saccades after a FEF lesion and mainly reflexive saccades after a PEF lesion, with mostly an increase in saccade latency [20]. However, frontal or parietal acute unilateral damage to the cerebral hemisphere may result in ocular conjugate deviation, ipsilateral to the lesion, lasting several hours or days [25]. During this period, contralateral saccades, as well as smooth pursuit and even at times the VOR, may be performed with some difficulty (because of a tonic imbalance), but do in fact persist. Patients with unilateral cerebral lesions may not have ocular deviation when their eyes are open, but only on forced lid closure. Such deviation is contralateral much more often than ipsilateral to the lesion. The causes of these different forms of ocular deviation observed after unilateral cerebral damage are not yet well understood. Bilateral posterior parietal cortex lesions result in Balint’s syndrome, which includes optic ataxia, peripheral visual inattention and severe deficits of smooth pursuit, and reflexive visually guided saccades, whereas intentional saccades persist [16]. Bilateral lesions affecting both the PEF and the FEF result in acquired ocular motor apraxia, in which the triggering of all saccades
Fig. 14.5. Cortical areas triggering saccades. (FEF Frontal eye field, PEF parietal eye field)
14.4 Abnormal Eye Movements
(except vestibular quick phases) is severely impaired [17]. A typical patient with such a syndrome has great fixity of gaze, and saccades are rarely observed and performed only after head movements. Posterior-temporo-parietal lesions may specifically impair smooth pursuit, predominantly in the ipsilateral direction [8, 24]. Cells in the medial superior temporal areas (MST) respond to visual targets moving towards the ipsilateral side [7]. In humans, this area may lie at the parieto-temporo-occipital junction. Lastly, lesions affecting the FEF also result in an ipsilateral smooth pursuit impairment [8, 22].
Summary for the Clinician
■ An acute unilateral cerebral lesion may
induce an ipsilateral, tonic, conjugate eye deviation. This deviation is usually rapidly resolved, lasting a few hours or a few days. Only multiple, bilateral lesions of the cerebral hemispheres may severely affect saccades and smooth pursuit, at least at bedside examination.
■ ■
14.4 Abnormal Eye Movements Only the main abnormal eye movements will be described here. These movements are usually classified as nystagmic or non-nystagmic.
14.4.1 Nystagmus Nystagmus is an involuntary, to-and-fro, repetitive, rhythmic and generally conjugate eye movement. Examination should note the plane and direction of nystagmus (horizontal, vertical, torsional), its amplitude, frequency and rhythm, and the position of the eyes in which it occurs. Frenzel spectacles (preventing fixation and magnifying the eyes) or ophthalmoscopy may be useful. Nystagmus may be pendular, if the two oscillations are of identical velocity, or jerky if fast and slow oscillations alternate (Fig. 14.6).
Pendular nystagmus is usually congenital and may occur in diseases where central vision is lost early in life. Congenital nystagmus is often horizontal, does not induce oscillopsia, increases in amplitude during fixation and decreases during eyelid closure. The etiology remains unknown. Jerk nystagmus is more common and of great variety. The fast component gives the direction of nystagmus. The physiologic “endpoint” nystagmus may be distinguished from pathological gaze-evoked nystagmus by the following clinical features: low amplitude, low frequency, horizontal nystagmus on a lateral gaze or upbeating nystagmus on an upgaze, and unsustained nystagmus. Peripheral vestibular impairment typically induces horizonto-torsional nystagmus, beating away from the side of the lesion. It may be influenced by head position, and results in oscillopsia. Vertical nystagmus is specifically described above. Convergence-retraction and retractorius nystagmus (fast eyeball retractions into the orbit) strongly suggests a tectal lesion. Seesaw nystagmus (which may be pendular or jerk) comprises elevation and intorsion of one eye with synchronous depression and extorsion of the other eye. The lesion may be focal in the brainstem, affecting in particular the nucleus of Cajal, or more diffuse (progressive visual loss mostly associated with a large parasellar mass, brain irradiation or head trauma). Some other forms of nystagmus have little localizing value, such as periodic alternating nystagmus (the horizontal direction of nystagmus is alternately inverted) and circumduction nystagmus (rotatory movement around the eyeball axis, sweeping a circle or an ellipse). Monocular nystagmus is most often seen in internuclear ophthalmoplegia, in the abducting eye.
Summary for the Clinician
■ Pathological nystagmus may be pendu-
lar, with equal velocity of phases, or jerk, with slow phases and quick phases. Pendular nystagmus is often congenital, whereas pathological jerk nystagmus is usually due to lesions (peripheral or central) affecting the VOR pathways.
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14
Fig. 14.6. Main abnormal eye movements recorded electro-oculographically. The horizontal line indicates the midline. (D Down, L left, R right, U up)
14.4.2 Non-Nystagmic Abnormal Eye Movements Non-nystagmic eye movements are diverse, consisting of saccades or slow eye movements, and are of unknown physiopathology [7]. Ocular flutter consists of bursts (6–12 Hz) of horizontal saccadic oscillations (2°–5° amplitude), without intersaccadic intervals (Fig. 14.6). In opsoclonus, saccades are the same as in ocular flutter, except that they are omnidirectional and frequently as-
sociated with axial myoclonus. Flutter and opsoclonus may be congenital, or, in childhood, reveal a neuroblastoma. In adults, etiologies include several infectious diseases (salmonella, coxsackie), brainstem encephalitis, an underlying malignant pathology (paraneoplastic syndrome), medications (lithium, haloperidol) or fluid balance and electrolyte abnormalities. Square wave jerks (SWJ) consist of consecutive to-and-fro horizontal saccades of small amplitude (0.5°–3°), with a 200-ms intersaccadic interval (Fig. 14.6).
References
They usually increase during smooth pursuit and fixation. SWJ are found in cerebellar pathology, degenerative diseases, particularly in progressive supranuclear palsy, and, rarely, in hemispheric diseases. Ocular bobbing consists of an initial rapid downward eye movement, followed after a few milliseconds by a slow return to the initial position, with a frequency of 10–15 per minute (Fig. 14.6). It suggests a cerebellar or pontine lesion. Inverse ocular bobbing (or ocular dipping) consists of an initial slow downward movement, followed by a rapid return to the baseline. Reverse ocular bobbing consists of a rapid upward eye movement, followed by a slow return. These other forms of ocular bobbing have been described in widespread diseases (metabolic encephalopathy, bilateral hemispheric lesions). Ping-pong gaze consists of alternating (2–15/ min), large-amplitude (60°–80°) horizontal slow eye movements, and is observed in comatose patients suffering from bilateral mesodiencephalic lesions (Fig. 14.6). Superior oblique myokymia is a monocular vertico-rotatory fast eye movement, appearing spontaneously in midlife or rarely revealing a tumour, and may be reduced by carbamazepine (Fig. 14.6).
Summary for the Clinician
3.
4.
5.
6.
7. 8.
9.
10.
11.
■ Ocular
flutter (involuntary horizontal saccades) and opsoclonus (involuntary saccades in all directions of gaze) are the most frequent non-nystagmic abnormal eye movements. The most frequent causes are viral infections or paraneoplastic syndromes.
■
12. 13.
14.
References 1.
2.
Bhidayasiri R, Plant GT, Leigh RJ (2000) A hypothetical scheme for the brainstem control and vertical gaze. Neurology 54:1985–1993 Bogousslavsky J, Maeder P, Rogli F, Meuli R (1994) Pure midbrain infarction: clinical syndromes. MRI and etiologic patterns. Neurology 44:2032–2040
15.
Brandt T, Dieterich M (1993) Skew deviation with ocular torsion: a vestibular brainstem sign of topographic diagnostic value. Ann Neurol 33:528–534 Büttner-Ennever JA, Büttner U (1988) The reticular formation. In Büttner-Ennever JA (ed) Neuroanatomy of the oculomotor system. Elsevier, Amsterdam, pp 119–176 Fisher CM (1967) Some neuro-ophthalmological observations. J Neurol Neurosurg Psychiatry 30:383–392 Guy J, Day AL, Mickle JP et al (1989) Contralateral trochlear nerve paresis and ipsilateral Horner’s syndrome. Am J Ophthalmol 107:73–76 Leigh RJ, Zee DS (2006) The neurology of eye movements, 4th edn. Davis, Philadelphia Morrow MJ, Sharpe JA (1990) Cerebral hemispheric localization of smooth pursuit asymmetry. Neurology 40:284–292 Moschovakis AK, Scudder CA, Highstein SM (1991) Structure of the primate oculomotor burst generator. I Medium-lead burst neurons with upward on-directions. J Neurophysiol 65:203–217 Moschovakis AK, Scudder CA, Highstein SM, Warren JD (1991) Structure of the primate oculomotor burst generator. II. Medium lead-burst neurons with downward on-directions. J Neurophysiol 65:218–229 Pierrot-Deseilligny C, Goasguen J (1984) Isolated abducens nucleus damage due to histiocytosis X. Electro-oculographic analysis and physiological deductions. Brain 107:1019–1032 Pierrot-Deseilligny C, Milea D (2005) Vertical nystagmus. Brain 128:1237–1248 Pierrot-Deseilligny C, Schaison M, Bousser MG, Brunet P (1981) Syndrome nucléaire du nerf moteur oculaire commun: à propos de deux observations cliniques. Rev Neurol 137:217–222 Pierrot-Deseilligny C, Chain F, Serdaru M et al (1981) The “one-and-a-half ” syndrome: electrooculographic analyses of five cases with deduction about the physiologic mechanisms of lateral gaze. Brain 104:665–699 Pierrot-Deseilligny C, Chain F, Gray F et al (1982) Parinaud’s syndrome: electro-oculographic and anatomical analysis of six vascular cases with deductions about vertical gaze organization in the premotor structures. Brain 105:667–696
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Cerebral Control of Eye Movements 16. Pierrot-Deseilligny C, Gray F, Brunet P (1986) Infarcts of both inferior parietal lobules with impairment of visually guided eye movements, peripheral visual inattention and optic ataxia. Brain 109:81–97 17. Pierrot-Deseilligny C, Gautier JC, Loron P (1988) Acquired ocular motor apraxia due to bilateral frontoparietal infarcts. Ann Neurol 23:199–202 18. Pierrot-Deseilligny C, Rivaud S, Gaymard B et al (1991) Cortical control of memory-guided saccades in man. Exp Brain Res 83:607–617 19. Pierrot-Deseilligny C, Rosa A, Masmoudi K et al (1991) Saccade deficits after a unilateral lesion affecting the superior colliculus. J Neurol Neurosurg Psychiatry 54:1106–1109 20. Pierrot-Deseilligny C, Ploner CJ, Müri RM et al (2002) Effects of cortical lesions on saccadic eye movements in humans. Ann NY Acad Sci 956:216–229 21. Ranalli PJ, Sharpe JA (1988) Vertical vestibuloocular reflex, smooth pursuit and eye-head tracking dysfunction in internuclear ophthalmoplegia. Brain 111:1299–1317
14
22. Rivaud S, Müri RM, Gaymard B et al (1994) Eye movement disorders after frontal eye field lesions in humans. Exp Brain Res 102:110–120 23. Thiers P, Bachor A, Faiss J et al (1991) Selective impairment of smooth-pursuit eye movements due to an ischemic lesion of the basal pons. Ann Neurol 29:443–448 24. Thurston SE, Leigh RJ, Crawford T et al (1988) Two distinct deficits of visual tracking caused by unilateral lesions of cerebral cortex in humans. Ann Neurol 23:266–273 25. Tijssen CC (1990) Conjugate deviation of the eyes in cerebral lesions. In: Daroff RB, Neetens A (eds) Neurological organization of ocular movement. Kügler-Ghedini, Amsterdam, pp 245–258 26. Westheimer G, Blair SM (1974) Functional organization of primate oculomotor system revealed by cerebellectomy. Exp Brain Res 21:463–472 27. Zee DS, Yamazaki A, Butler PH et al (1981) Effects of ablation of flocculus and paraflocculus on eye movements in primate. J Neurophysiol 46:878–899
Chapter 15
Chronic Progressive External Ophthalmoplegia – A Common Ocular Manifestation of Mitochondrial Disorders
15
Marcus Deschauer, Stephan Zierz
Core Messages
■ Extraocular muscles are predominantly
affected in mitochondrial myopathies resulting in chronic progressive external ophthalmoplegia (CPEO). CPEO is one of the most common manifestations of mitochondrial disorders and can present as an isolated disorder or as part of syndromes with multisystemic involvement. Frequently patients suffer from exercise intolerance or proximal limb weakness. The underlying pathomechanisms are alterations of the respiratory chain due to mutations in mitochondrial or nuclear DNA. There are different modes of inheritance but sporadic occurrence is frequent. Diagnosis usually necessitates a limb muscle biopsy. There is limited causal therapy but there are several symptomatic treatments. Frontalis suspension is the method of first choice for ptosis surgery. Important differential diagnoses are ocu lopharyngeal muscular dystrophy and myasthenia.
■
■ ■ ■ ■ ■
15.1 Introduction Extraocular muscles are predominantly affected in mitochondrial myopathies resulting in chronic progressive external ophthalmoplegia (CPEO). The reason for this is not fully understood but several differences between extraocular muscles and skeletal muscles do exist. Extraocular muscles have smaller motor unit sizes, higher motor neuron discharge rates, higher blood flow, and higher mitochondrial content as compared to skeletal muscle (Yu Wai Man et al. 2005a). These differences may provide the extraocular muscles with a raised metabolic rate enabling them to achieve greater fatigue resistance than skeletal muscle. However, it is not understood why some but not other mitochondrial gene defects result in CPEO. The frequency of cytochrome c oxidase (COX) negative fibres normally increases with age, but COX-negative fibres are encountered six times more frequently in extraocular muscles than in skeletal muscles, indicating that mitochondrial function in extraocular muscles is more vulnerable (Yu Wai Man et al. 2005a). This is important since the presence of COX-negative fibres is also a typical finding in mitochondrial disorders. CPEO is caused by alterations of the respiratory chain localized at the inner mitochondrial membrane. The biochemical defects can be caused by primary defects of the mitochondrial DNA (mtDNA) or by defects within nuclear
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genes that encode for mitochondrial proteins that are imported into mitochondria. CPEO is one of the most common manifestations of mitochondrial disorders. The frequency of the most common mtDNA defect, single large-scale deletions, was estimated to be at least 1–2/100,000 in Finland and the UK (Chinnery et al. 2000; Remes et al. 2005). These deletions of mtDNA were found in approximately 50% of patients with CPEO. CPEO can present as an isolated disorder or as the leading manifestation of a syndrome characterized by multisystemic involvement. Although CPEO is a prominent feature of mitochondrial myopathies it is important to know that mitochondrial myopathies without CPEO and multisystemic involvement are now increasingly recognized (Müller et al. 2005; Swalwell et al. 2006).
15.2 Clinical Features 15.2.1 Ophthalmoplegia and Ptosis
15
Ptosis is frequently the first symptom, and old photographs are helpful for establishing the age of onset, which is variable: typically in the teenage years or early adulthood (Zierz et al. 1990) although childhood or late adulthood is also possible. Ophthalmoparesis develops over many years and may lead to complete ocular paralysis. Ptosis may occur unilaterally at first, but will subsequently become bilateral (Fig. 15.1). Additionally, many patients have some weakness of the orbicularis muscle. Patients with inadequate Bell’s phenomenon and lagophthalmos are at risk for corneal exposure especially after ptosis surgery. Severe weakness of the facial muscles can present as facies myopathica. Some patients come to medical attention only when ptosis is covering the optic axis. Patients use their frontalis muscles to lift their eyelids and show compensatory chin elevation. Ophthalmoplegia is often symmetrical and causes no complaints since patients simply turn their heads. A minority of patients suffer from diplopia. Sometimes there is no dipolpia because the unilateral ptosis results in the occlusion of one eye. Richardson et al. (2005) investigated 25 adult patients with CPEO: 13 patients showed a manifest deviation but only 7 had diplopia. The other 6 patients showed suppression (Richardson
et al. 2005). This is surprising since suppression usually only occurs in early childhood.
15.2.2 CPEO Plus: Multisystemic Involvement 15.2.2.1 Muscle Impairment Muscle weakness is often not restricted to the extraocular or facial muscles. Many patients suffer from exercise intolerance. In most but not all, neurological examination shows limb weakness, most prominent in the proximal muscles of the lower extremities. These patients typically have difficulties rising from a squatting position. However, many different multisystemic symptoms apart from muscle weakness are possible.
15.2.2.2 Visual Impairment Retinal degeneration in CPEO differs from typical retinitis pigmentosa and frequently assumes a salt-and-pepper like appearance (Fig. 15.2a), but there are also patients with areas of hypopigmentation and hyperpigmentation (Fig. 15.2b). Only a few patients have an optic atrophy or a juvenile cataract. Visual function is impaired in most patients with CPEO, but severe impairment of visual acuity is rare (Isashiki et al. 1998; Mullie et al. 1985).Yu Wai Man et al. (2005b) studied 40 patients using the Visual Function Index (VF-14), a questionnaire containing 14 questions to measure how sight problems affect health status. This study demonstrated visual impairment in 95% of the patients. Patients reported having most difficulties with reading small print and driving at night. However, there was no correlation between VF-14 scores and ocular motility parameters, ptosis, or retinopathy (Yu Wai Man et al. 2005b).
15.2.2.3 Specific CPEO Plus Syndromes Kearns-Sayre syndrome was defined as a very severe multisystemic phenotype characterized by CPEO with retinopathy, onset of the disease before
Fig. 15.1. Patient with chronic progressive external ophthalmoplegia (CPEO) showing ptosis (left > right) and divergent strabismus
Fig. 15.2a,b. a Retinopathy in a CPEO patient with a mtDNA deletion demonstrating a typical salt-andpepper like appearance. b Retinopathy in a patient with CPEO carrying the mtDNA point mutation 3243A>G with areas of extensive chorioretinal atrophy more pronounced in the left eye (right panel) including the macular area than in the right eye (left panel)
15.2 Clinical Features
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age 20, heart block, cerebellar ataxia, or elevated protein in cerebrospinal fluid. Two other multisystemic mitochondrial syndromes associated with CPEO are SANDO (sensory ataxia, neuropathy, dysarthria and ophthalmoplegia) and MNGIE (mitochondrial neurogastrointestinal encephalomyopathy). MNGIE is a rare disorder with prominent gastrointestinal symptoms leading to cachexia. However, there is significant overlap between these syndromes and there is doubt whether they all represent specific disease entities because most syndromes do not result from specific genetic defects. Thus the term CPEO plus was chosen to express multisystemic involvement in patients with CPEO. Typical multisystemic signs and symptoms of CPEO plus are shown in Fig. 15.3 and frequencies of the most import ones are listed in Table 15.1.
Summary for the Clinician
■ Chronic progressive external ophthal-
moplegia (CPEO) is one of the most common manifestation of mitochondrial disorders and can present as an isolated feature or as part of syndromes with multisystemic involvement (CPEO plus). Ptosis is frequently the presenting symptom of CPEO. Frequently patients suffer from exercise intolerance or proximal limb weakness. Some patients show retinopathy and many other organs can be involved.
■ ■ ■
15
15.3 Genetics 15.3.1 General Mitochondrial Genetics The protein subunits of the respiratory chain are encoded by nuclear and mitochondrial DNA (mtDNA). The nuclear genome encodes the large majority of the subunits of the respiratory chain complexes and most of the mtDNA replication and expression systems. These proteins have to be imported into the mitochondria. The small maternally inherited mitochon-
Table 15.1. Frequency of multisystemic signs and symptoms in patients with CPEO plus (n=31) (Zierz et al. 1990) Sign or symptom
Frequency (%)
Endocrine abnormalities
67
Retinopathy
65
Exercise intolerance and limb muscle weakness
61
Ataxia or tremor
39
Heart block
26
Neuropathy
23
Dementia
13
drial genome (16.6 kilobases, kb) encodes for only 13 subunits of the respiratory chain and some components of the mitochondrial translation system. Accordingly, disorders due to defects in the respiratory chain can follow both mendelian and maternal traits of inheritance. Mitochondrial genetics differ from mendelian genetics in several aspects. Due to the polyploid nature of the mitochondrial genome, with several thousand copies per cell, a mixture of mutant and normal mtDNA is frequently observed. This is called heteroplasmy and has implications for molecular diagnostics because the mutant mtDNA may be absent or present only in very low levels in certain tissues. Moreover, the level of heteroplasmy influences the phenotype: a threshold of mutant mtDNA has to be reached before biochemical effects and phenotypical abnormalities result.
15.3.2 Single Deletions of mtDNA In 1988 the first mutations of mtDNA were identified. Holt et al. (1988) detected single large-scale deletions of the mtDNA in patients with CPEO and Wallace et al. (1988) detected the first point mutation in Leber’s hereditary optic neuropathy. The deletions in CPEO are heteroplasmic with a length between 1 and 9 kb and are commonly located within the major arc of mtDNA between both origins of replication (origin of heavy-strand replication OH and light-strand replication OL)
15.3 Genetics
Fig. 15.3. Possible multisystemic involvement in patients with chronic progressive external ophthalmoplegia (CPEO)
(Fig. 15.4). There is one common deletion with a length of 5 kb. The deletion break points are typically characterized by direct repeats. In approximately 50% of patients with CPEO single deletions of mtDNA can be detected (Moraes et al. 1989). Most cases of CPEO with single deletions are sporadic. It is therefore postulated that deletions occur in the oocyte and mitotic segregation during embryogenesis results in high levels of deleted mtDNA in certain tissues such as muscle but low levels in other tissues including the germline cells. This can explain why mother-to-offspring transmission of single deletions is rarely observed, with a low risk of 4% for affected mothers of having an affected child (Chinnery et al. 2004).
15.3.3 Defects of Intergenomic Communication with Multiple Deletions of mtDNA In contrast to single deletions of mtDNA, multiple deletions of mtDNA were observed in patients with autosomal inheritance of CPEO (Zeviani et al. 1989), indicating that these mtDNA deletions are not the primary gene defect but secondary changes due to a nuclear gene muta-
tion. Consequently several nuclear gene defects have been identified in the last years. They are located in genes that are important for replication of mtDNA. Thus those forms of CPEO are classified as defects of intergenomic communication (Fig. 15.5). The most important nuclear genes are: polymerase gamma (POLG) 1, progressive external ophthalmoplegia (PEO) 1 (also called C10orf1 or Twinkle), and adenine nucleotide translocator (ANT) 1. POLG1 mutations are located in the catalytic subunit of the mitochondrial polymerase (Van Goethem et al. 2001). They are frequently associated with CPEO but also with other mitochondrial disorders. The PEO1 gene encodes for the mitochondrial helicase (Spelbrink et al. 2001). Mutations in the ANT1 gene were found in only some families with CPEO (Deschauer et al. 2005; Kaukonen et al. 2000). In patients with MNGIE, mutations in the thymidine phosphorylase (TP) gene were identified. There are single patients with TP mutations who show no gastrointestinal symptoms (Gamez et al. 2002) and have only CPEO. ANT1 and TP mutations result in an altered nucleotide pool in the mitochondria that can explain defective replication. Mutations in the ANT1 gene and in the PEO1 gene were identified in autosomal-dominant CPEO. Muta-
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Fig. 15.4. Schematic presentation of the mitochondrial genome (mtDNA) and two exemplary large-scale deletions of mtDNA. The genes that encode the subunits of complex I (ND1–ND6 and ND4L) are shown in light blue; cytochrome c oxidase (COX I–COX III) is shown in red; cytochrome b of complex III is shown in dark green; and the subunits 6 and 8 of the ATP synthase (complex V) are shown in light green. The two ribosomal RNAs (rRNAs; 12S and 16S) are shown in grey and the 22 tRNAs are shown in dark blue (not labeled). The displacement loop (D-loop), or non-coding control region, is shown in yellow. It contains sequences that are vital for the initiation of both mtDNA replication and transcription, including the origin of heavy-strand replication (shown as OH). The origin of light-strand replication is shown as OL
tions in the POLG1 gene were identified in autosomal-dominant as well as in recessive CPEO. Dominant POLG1 mutations are located in the catalytic domain and recessive mutations in the proof-reading domain. TP mutations are recessive mutations. In patients with sporadic CPEO and multiple mtDNA deletions, mutations in POLG1, PEO1 and ANT1 are rare, indicating that other probably autosomal recessive gene defects exist (Hudson et al. 2005). Recently a dominant mutation was identified in the POLG2 gene, the accessory
subunit of polymerase gamma, in a single patient among 100 patients with multiple mtDNA deletions but without mutations in POLG1, PEO1, and ANT1 genes, indicating that POLG2 defects are very rare (Longley et al. 2005).
15.3.4 Point Mutations of mtDNA Rarely, point mutations of mtDNA, which are inherited maternally, can be associated with CPEO. A common point mutation of mtDNA is the
15.3 Genetics
15.3.6 Genotype–Phenotype Correlation
Fig. 15.5. Defects of intergenomic communication. Mutations of different nuclear genes result in defect proteins that in turn cause (multiple) deletions of mtDNA
3243A>G mutation that is located in one of the two mitochondrial tRNA genes for leucine. This mutation is typically associated with MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes) syndrome, but CPEO was also observed in patients carrying this mutation (Deschauer et al. 2001). Moreover several very rare point mutations can be associated with CPEO (www. mitomap.org).
There are different defects of mtDNA and nuclear genes underlying CPEO. This also implies different modes of inheritance. Up to now no clear genotype–phenotype correlation has been established in patients with CPEO. However, there are hints that retinopathy can be observed in CPEO with single deletions or the 3243A>G mutation, but it seems to be uncommon in patients with multiple deletions of mtDNA (Kawai et al. 1995). A common symptom of patients with the 3243A>G mtDNA mutation is hearing loss (Deschauer et al. 2001). The SANDO syndrome is associated not only with POLG1 mutations but also with PEO1 mutations (Hudson et al. 2005). The MNGIE syndrome is typically associated with recessive mutations in the TP gene (Nishino et al. 1999), but sometimes also with POLG1 mutations. POLG1 mutations seem to be the most frequent nuclear gene defects within disorders of intergenomic communication. They can be associated with a broad spectrum of diseases including CPEO with parkinsonism but also classical mitochondrial syndromes such as MELAS without CPEO (Deschauer et al. 2007). The various genotypes, phenotypes, and modes of inheritance of these diseases are described in Table 15.2.
15.3.5 Coenzyme Q Deficiency Another rare autosomally inherited mitochondrial myopathy is caused by coenzyme Q deficiency. This is important since coenzyme Q deficiency is treatable by oral supplementation. Recently the first genetic defects in genes that are necessary for the biosynthesis of coenzyme Q were discovered, i.e., para-hydroxybenzoate-polyprenyl transferase, decaprenyl diphosphate synthase subunit 1 and 2 (DiMauro et al. 2007). However, mutations in these genes have not yet been identified in patients with CPEO, although coenzyme Q deficiency is documented in CPEO (Zierz et al. 1989). Probably there is a secondary coenzyme Q deficiency in CPEO. Frequent signs in patients with genetically proven primary coenzyme Q deficiency are myopathy and cerebellar ataxia (DiMauro et al. 2007).
Summary for the Clinician
■ More than half of patients show sporadic
CPEO and approximately one-third have an autosomal-dominant or -recessive inheritance pattern. Maternal inheritance, which is typical of other mitochondrial disorders, is rare in CPEO. Sporadic CPEO is associated with single deletions of mtDNA. Autosomal CPEO is caused by mutations in different nuclear genes that are important for mtDNA replication, secondarily leading to multiple deletions of mtDNA. Maternal inheritance is seen with point mutations of mtDNA.
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Chronic Progressive External Ophthalmoplegia Table 15.2. Possible gene defects in CPEO with associated modes of inheritance and phenotypical presentation Genotype
Phenotypes
Mode of inheritance
Single mtDNA deletions
CPEO, CPEO plus, KSS
Mainly sporadic
POLG1:
CPEO, CPEO plus, SANDO, MNGIE
Autosomal recessive or dominant
PEO1:
CPEO, CPEO plus, SANDO
Autosomal dominant
ANT1:
CPEO, CPEO plus
Autosomal dominant
POLG2:
CPEO plus
Autosomal dominant
TP:
MNGIE, CPEO
Autosomal recessive
CPEO, CPEO plus
Maternal
Multiple mtDNA deletions
Point mutations of mtDNA, e.g., 3243A>G
15.4 Diagnostics
15
Diagnosis of CPEO requires a close collaboration between the ophthalmologist, neurologist, and laboratory investigators. Analysis of the family history is extremely important. In this regard it is helpful to perform a clinical examination of the family members as some patients may be asymptomatic but have a mild form of CPEO. Moreover multisystemic involvement can be oligosymptomatic in family members, e.g., solely diabetes or hearing loss. In every patient with suspected CPEO, a full neurological examination should be performed in addition to the ophthalmological examination. Moreover additional laboratory or technical examinations can be helpful. Laboratory testing should include resting lactate, indicating impaired oxidative phosphorylation if elevated. A more sensitive test is to measure lactate after lowlevel cycling exercise (30 W for 15 min), showing a lactate increase (Fig. 15.6) with a sensitivity of 70%. Sometimes lactate elevation can be observed in patients with other myopathies, but specificity is 90% (Hanisch et al. 2006a). Elevated creatine kinase can indicate myopathy affecting the limbs. Measurement of glucose metabolism can disclose diabetes mellitus. An audiogram can detect subclinical hearing impairment; electrophysiological examination of the peripheral nerves, subclinical
neuropathy. Cardiac examination should include electrocardiography and echocardiography. To detect cerebral involvement, brain magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid (elevated protein or lactate) are helpful but not mandatory if no clinical signs of cerebral involvement are found. Apart from the
Fig. 15.6. Changes of serum lactate in 22 patients with CPEO after bicycle exercise shown in red compared to normal controls shown in blue. Error bars show one standard deviation, circles show mean values
diagnostic point of view, the search for diabetes and cardiac conduction defects are mandatory as these disorders are potentially treatable.
15.4.1 Myohistological Investigations Diagnosis can be confirmed by histological examination of a muscle biopsy sample. A biopsy of the extraocular muscles is not appropriate since CPEO patients show typical myohistological changes in biopsy samples from the limbs even without limb weakness. Mitochondrial proliferation is seen in modified Gomori Trichrome staining and in succinate dehydrogenase (SDH) staining showing ragged red fibres (Fig. 15.7a). Sequential histochemical staining for cytochrome c oxidase (COX) and SDH reveals a mosaic pattern of COX-positive and COX-negative fibres (Fig. 15.7b). However, mitochondrial abnormalities in muscle biopsy samples are also seen in ageing and other muscle diseases. On the other hand some patients with CPEO show only minor changes in histology (less than 5% abnormal fibres) (Deschauer et al. 2003). Thus, diagnosis of CPEO sometimes needs a multi-level approach and sometimes only molecular genetic testing can confirm the diagnosis. Electron microscopy typically shows enlarged and irregularly shaped mitochondria with paracrystalline
15.4 Diagnostics
inclusions. However, for diagnostic purposes electron microscopy is not necessary in general.
15.4.2 Biochemical Investigations Biochemistry of muscle biopsy samples also often shows mitochondrial proliferation, indicated by an increase of mitochondrial enzymes that are not encoded by mtDNA, such as citrate synthase or SDH. Additionally a decrease of respiratory chain complexes, characteristically a combined defect, can be observed (Gellerich et al. 2002). But generally, biochemistry is not as important as histology for the diagnosis of CPEO since measurement is complex and available only in specialized laboratories. However, if histology shows lipid accumulation in addition to mitochondrial proliferation, coenzyme Q levels in muscle should be measured, because coenzyme Q deficiency also impairs fatty acid metabolism. This is important in order to detect treatable coenzyme Q deficiency.
15.4.3 Molecular Genetic Investigations Genetic analysis is important not only for confirming the diagnosis but also for genetic counselling. The gold standard for detection of mtDNA
Fig. 15.7a,b. Histological investigation of a muscle biopsy sample of a patient with CPEO. a Modified Trichrome Gomori staining demonstrating a ragged red fibre with predominantly subsarcolemmal proliferation of mitochondria showing red staining. b Histochemical investigation demonstrating cytochrome-c-oxidase- (COX-) negative fibres shown in blue in sequential COX and succinate dehydrogenase (SDH) staining
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deletions has been Southern blot analysis from muscle DNA (Fig. 15.8). However, low levels of multiple deletions cannot be detected by Southern blot analysis. Thus, more sensitive techniques such as long-range polymerase chain reaction (PCR) are necessary in order not to overlook patients (Deschauer et al. 2003). However, due to the highly polymorphic nature of the mtDNA there is also a risk of false-positive results (Deschauer et al. 2004). Moreover it is important to know that low levels of mtDNA deletions are also observed in ageing. In general, deletions of mtDNA are detectable only in muscle and not in blood. However, with sensitive PCR techniques it is sometimes possible to detect single deletions in blood. In contrast to deletions, point mutation of the mtDNA, e.g., the 3243A>G mutation, can be detected in blood more easily. But levels of mutant DNA are generally higher in muscle than in blood (Deschauer et al. 2000). If multiple deletions of mtDNA are detected, a screening for the nuclear gene of intergenomic
communication defects should be performed. However, there are many different mutations in these genes and only few laboratories are performing diagnostic sequencing of the nuclear genes at the moment (e.g., Medizinisch Genetisches Zentrum Munich, Germany; Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK; HUSLAB, Laboratory of Molecular Genetics, Helsinki, Finland; Medical Genetics Laboratories, Huston, Texas, USA). If there is recessive inheritance of CPEO, there are two frequent POLG1 mutations that should be tested first (A467T and W748S) (Horvath et al. 2006).
Summary for the Clinician
■ Diagnosis
of CPEO requires a close collaboration between ophthalmologist, neurologist, and laboratory investigators. Laboratory testing should include measurement of lactate not only at rest but also during mild bicycle exercise. Usually a limb muscle biopsy is necessary for confirming the diagnosis of CPEO, showing histological and biochemical mitochondrial abnormalities. Molecular genetic analysis is not only important for genetic counseling; increasingly molecular genetic testing from blood can confirm a diagnosis thus avoiding muscle biopsy.
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15
15.5 Treatment 15.5.1 Pharmacological Therapy
Fig. 15.8. Detection of deletions of mtDNA by Southern blot analysis: Lane 1, normal control; lane 2, single deletion of mtDNA; lane 3, multiple deletions of mt DNA
In general supplementation with vitamins and cofactors has been shown not to be effective (Baker and Tarnopolsky 2003). However, in patients with proven coenzyme Q deficiency, supplementation with coenzyme Q can result in remarkable improvement as shown in a patient with Kearns-Sayre syndrome (KSS): cachexia, ataxia and tremor disappeared but ophthalmoplegia and retinopathy were unchanged after 2 years of treatment (Zierz et al. 1989). Coenzyme Q supple-
mentation might also be helpful in patients with normal coenzyme Q levels due to its anti-oxidative effect, since defects of the respiratory chain can result in an increased production of reactive oxygen species. In patients with KSS reduced levels of folinic acid were measured in cerebrospinal fluid and there is a report of a remarkable improvement after high-dose supplementation with folinic acid in a child with KSS (Pineda et al. 2006). Allogeneic stem cell transplantation was used in two patients with MNGIE syndrome to restore TP activity and to reduce the thymidine level. One patient improved and the other patient died of disease progression and sepsis 3 months after transplantation (Hirano et al. 2006).
15.5.2 Symptomatic Treatment Ptosis cannot only impair vision but it can also be a cosmetic problem and the subject of embarrassment for younger patients. However, surgery for ptosis should be recommended only if the visual axis is obscured since there is a risk of complications due to corneal exposure in cases of postoperative lagophthalmos. The preferred surgical technique is frontalis muscle suspension, avoiding levator palpebrae muscle resection, because this ensures better protection of the cornea. Lid height can be adjusted if necessary (Bau and Zierz 2005; Wong et al. 2002). Generally, corneal exposure symptoms are treated with lubricants. Some patients with ptosis get on well with “eyelid crutches” mounted on their glasses. Fresnel prisms can be helpful if there is diplopia, especially in patients with poor convergence. However, it is often difficult or impossible to suppress diplopia with prisms in the presence of incomitant strabismus. When spectacles are prescribed, the motility deficits should be taken into account (e.g., no bifocals in impaired downgaze) (Bau and Zierz 2005). Extraocular muscle surgery in cases of strabismus with diplopia is recommended only in carefully selected patients. Because of the progressive nature of the disease, the benefit might be only temporary. Deviation should be stable for several months before operation. Resection as well as recession can be used depending on results of forced ductions at the time of surgery (Wallace et al. 1997).
15.5 Treatment
Heart conduction blocks should be checked at frequent intervals because timely placement of a pacemaker can be lifesaving (Nitsch et al. 1990). Endurance training to reduce exercise intolerance is safe and efficient (Jeppensen et al. 2006; Taivassalo et al. 2006). In treatment of seizures valproic acid should be avoided since it can trigger hepatic failure in patients with POLG1 defects (Horvath et al. 2006). Amplification aids can help against hearing loss. If necessary, cochlear implants can be safely and successfully installed (Sinnathuray et al. 2003). In patients with dysphagia due to incomplete opening of the upper esophageal sphincter (cricopharyngeal achalasia) myotomy can help (Kornblum et al. 2001). Diabetes mellitus should be treated in the standard way. However, metformin should be avoided because this drug can cause lactic acidosis (Walker et al. 2005). During surgery and anesthesia patients with mitochondrial disorders need special care because certain drugs can inhibit the respiratory chain in vitro (e.g., propofol and midazolam) and malignant hyperthermia has been reported in single cases, thus trigger agents (e.g., succinylcholine and inhalation anesthetics) should be avoided if possible (Shipton and Prosser 2004).
15.5.3 Gene Therapy Due to the complex genetics of mitochondrial disorders different strategies toward gene therapy are under current development, albeit at an early stage. One promising strategy is to reduce the ratio of mutant to wild-type mitochondrial genomes (“gene shifting”) due to inhibition of the replication of mutant genomes. Based on the observation that satellite cells of the muscle contain lower levels of mutant mtDNA compared to mature muscle fibres, two studies have been performed. Bupivacaine was injected in the levator palpebrae muscles of patients with CPEO to induce muscle necrosis, which activates satellite cells. However, no improvement of ptosis was observed (Andrews et al. 1999). Also high-intensity exercise stimulates satellite cells and was shown to be effective in a single patient (Taivassalo et al. 1999). Maternal transmission of mtDNA point mutations can be prevented by nuclear transplantation. After in vitro fertilization of an oocyte carrying a mtDNA mutation the pronucleus is transferred
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into an enucleated normal donor oocyte. The resulting embryo has the nuclear genomes of the parents but mainly the mitochondrial genome of the donor women, thus showing only very low levels of heteroplasmy well below the threshold. This approach was successful in mice (Sato et al. 2005) and has been approved for human experiments in the UK (Brown et al. 2006).
Summary for the Clinician
■ In general, only symptomatic treatment
is presently available. Correction of the gene defects is not yet possible. Supplementation with vitamins and cofactors is rarely effective. However, patients with proven coenzyme Q deficiency may improve from supplementation with coenzyme Q and patients with Kearns-Sayre syndrome can improve with folinic acid supplementation. Lid surgery should preferably be frontalis suspension and not levator palpebrae resection because this ensures better protection of the cornea. Because of the progressive nature of the disease, strabismus surgery is recommended only in carefully selected patients with diplopia. Prisms can be also helpful. Timely placement of a pacemaker can be lifesaving. Endurance training can reduce exercise intolerance.
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15.6 Differential Diagnosis 15.6.1 Oculopharygeal Muscular Dystrophy Another inherited myopathy (with autosomaldominant trait) leading to external ophthalmoplegia is oculopharyngeal muscular dystrophy (OPMD). These patients also present with severe ptosis but ocular motility is usually less severely impaired than in CPEO. Moreover, in contrast to CPEO, age of onset is typically after the age
of 40 and nasal speech and dysphagia are more frequent than in CPEO. Similarly to CPEO, many patients with OPMD also show proximal limb weakness. Distal muscle weakness was also observed in a few families, defining a distinct disease called oculopharyngodistal myopathy (Satayoshi and Kinoshita 1977). Genetically, OPMD is due to an elongation in the PABPN1 gene within a repeat region showing additional GCG or GCA triplets. This elongation can be easily detected by PCR in patients with OPMD (Müller et al. 2006).
15.6.2 Myasthenic Syndromes Myasthenic syndromes are disorders due to defective neuromuscular transmission due to either autoimmune processes (myasthenia gravis and Lambert-Eaton syndrome) or hereditary defects of the synaptic system (congenital myasthenic syndromes). Myasthenic syndromes are frequent and are an important differential diagnosis that should not be overlooked because they are treatable. Ptosis and restricted eye movements may be the predominant feature or even the sole feature (ocular myasthenia). Typically, ptosis fluctuates and double vision is frequent in contrast to CPEO. Similarly to CPEO, patients suffer from exercise intolerance. Myasthenia gravis is frequently due to autoantibodies against the acetylcholine receptor. A few years ago it was shown that the so-called seronegative myasthenia without antibodies against acetylcholine receptors is caused by antibodies against the muscle specific tyrosine kinase (MuSK) in half of the cases (Hoch et al. 2001). Similar to acetylcholine-receptor-positive myasthenia gravis, MuSK-positive myasthenia gravis can occur as ocular myasthenia with weakness sparing muscles of the limbs (Hanisch et al. 2006b). MuSK antibody testing is now available in many laboratories. Lambert-Eaton syndrome is a paraneoplastic myasthenic syndrome due to antibodies against voltage-gated calcium channels. Congenital myasthenic syndromes, which can also become manifest in later life, are due to mutations in at least ten different genes that play a role in neuromuscular transmission (Müller et al. 2007).
References
15.6.3 Congenital Fibrosis of the Extraocular Muscles Another rare inherited disorder leading to weakness of the extraocular muscles is congenital fibrosis of the extra ocular muscles (CFEOM), which is not a myopathy, but results from a dysinnervation of the extraocular muscles leading to a secondary fibrosis. There are different forms of CFEOM associated with various gene defects that have autosomal dominant or autosomal recessive inheritance. In contrast to CPEO the disease is usually present at birth and is non-progressive in general. Progression was only rarely observed (Hanisch et al. 2005).
15.6.4 Ocular Myositis External ophthalmoplegia can also be caused by ocular myositis. Inflammation is due to an autoimmune disorder or results from infection, e.g., herpes zoster (Krasnianski et al. 2004). In contrast to CPEO typically the onset is acute and there is associated pain. Enlargement of the muscles can be seen with a high-resolution CT or more precisely with MRI.
15.6.7 Facioscapulohumeral Muscular Dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder with weakness predominantly of the facial and shoulder girdle muscles, rarely associated with external ophthalmoplegia (Krasnianski et al. 2003).
15.6.8 Congenital Myopathies This group of myopathies is defined by distinctive and characteristic structural abnormalities in skeletal muscle (e.g., central nuclei, nemaline rods, multicores, and tubular aggregates). Although onset is often at birth, there are also lateonset forms with no or only mild progression of limb weakness. Rarely, the limb girdle myopathy is associated with ophthalmoplegia (Beyenburg and Zierz 1993; Jones and North 1997). In contrast to mitochondrial CPEO the external ophthalmoplegia in these diseases is usually not the prominent manifestation.
Summary for the Clinician
■ The two most important differential di-
agnoses of CPEO are oculopharyngeal muscular dystrophy (OPMD) and myasthenia. OPMD can be easily identified by molecular genetic testing. Myasthenia should not be overlooked because it is treatable.
15.6.5 Endocrine Ophthalmopathy Endocrine ophthalmopathy can present with external ophthalmoplegia. However, typically there is no ptosis but proptosis and widening of the palpebral fissure. Muscle enlargement can be observed by CT or MRI, similar to ocular myositis.
15.6.6 Myotonic Dystrophy Myotonic dystrophy is an autosomal dominant repeat disorder with predominant weakness of the distal limb muscles in type 1 and proximal muscles in type 2. Both forms show myotonia that is characterized by slowing of relaxation of muscle contraction. Ptosis is typically observed in many patients with type 1, rarely also with ophthalmoplegia (Yamashita et al. 2004), but not in patients with type 2. Cataract is frequent in both types.
■ ■
References 1.
2.
Andrews RM, Griffiths PG, Chinnery PF, Turnbull DM (1999) Evaluation of bupivacaine-induced muscle regeneration in the treatment of ptosis in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. Eye 13:769–772 Baker SK, Tarnopolsky MA (2003) Targeting cellular energy production in neurological disorders. Expert Opin Investig Drugs 12:1655–1679
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Bau V, Zierz S (2005) Update on chronic progressive external ophthalmoplegia. Strabismus 13:133–142 4. Beyenburg S, Zierz S (1993) Chronic progressive external ophthalmoplegia and myalgia associated with tubular aggregates. Acta Neurol Scand 87:397–402 5. Brown DT, Herbert M, Lamb VK, Chinnery PF, Taylor RW, Lightowlers RN, Craven L, Cree L, Gardner JL, Turnbull DM (2006) Transmission of mitochondrial DNA disorders: possibilities for the future. Lancet 368:87–89 6. Chinnery PF, Johnson MA, Wardell TM, SinghKler R, Hayes C, Brown DT, Taylor RW, Bindoff LA, Turnbull DM (2000) The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48:188–193 7. Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C, Carrara F, Lombes A, Laforet P, Ogier H, Jaksch M, Lochmüller H, Horvath R, Deschauer M, Thorburn DR, Bindoff LA, Poulton J, Taylor RW, Matthews JNS, Turnbull DM (2004) The risk of developing a mitochondrial DNA deletion disorder. Lancet 364:592–596 8. Deschauer M, Neudecker S, Müller T, Gellerich FN, Zierz S (2000) Higher proportion of mitochondrial A3243G mutation in blood than in skeletal muscle in a patient with cardiomyopathy and hearing loss. Mol Genet Metab 70:235–237 9. Deschauer M, Müller T, Wieser T, Schulte-Mattler W, Kornhuber M, Zierz S (2001) Hearing impairment is common in various phenotypes of the mitochondrial DNA A3243G mutation. Arch Neurol 58:1885–1888 10. Deschauer M, Kiefer R, Blakely EL, He L, Zierz S, Turnbull DM, Taylor RW (2003) A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia. Neuromuscul Disord 13:568–572 11. Deschauer M, Krasnianski A, Zierz S, Taylor RW (2004) False-positive diagnosis of a single, largescale mitochondrial DNA deletion by Southern blot analysis: the role of neutral polymorphisms. Genet Test 8:395–399 12. Deschauer M, Hudson G, Müller T, Taylor RW, Chinnery PF, Zierz S (2005) A novel ANT1 gene mutation with probable germline mosaicism in autosomal dominant progressive external ophthalmoplegia. Neuromuscul Disord 15:311–315
13. Deschauer M, Tennant S, Rokicka A, He L, Kraya T, Turnbull DM, Zierz S, Taylor RW (2007) MELAS associated with mutations in the POLG1 gene. Neurology 68(20):1741–1742 14. DiMauro S, Quinzii CM, Hirano M (2007) Mutations in coenzyme Q10 biosynthetic genes. J Clin Invest 117:587–589 15. Gamez J, Ferreiro C, Accarino ML, Guarner L, Tadesse S, Marti RA, Andreu AL, Raguer N, Cervera C, Hirano M (2002) Phenotypic variability in a Spanish family with MNGIE. Neurology 59:455–457 16. Gellerich FN, Deschauer M, Müller T, Chen Y, Opalka JR, Zierz S (2002) Mitochondrial respiratory rates and activities of respiratory chain complexes correlate linearly with heteroplasmy of deleted mtDNA without threshold and independently of deletion size. Biochim Biophys Acta 1556(1):41–52 17. Hanisch F, Bau V, Zierz S (2005) Congenital fibrosis of extraocular muscles type 1 with progression of ophthalmoplegia. Eur J Med Res 10:366–368 18. Hanisch F, Müller T, Muser A, Deschauer M, Zierz S (2006a) Lactate increase and oxygen desaturation in mitochondrial disorders – evaluation of two diagnostic screening protocols. J Neurol 253:417–423 19. Hanisch F, Eger K, Zierz S (2006b) MuSK-antibody positive pure ocular myasthenia gravis. J Neurol 253:659–660 20. Hirano M, Marti R, Casali C, Tadesse S, Uldrick T, Fine B, Escolar DM, Valentino ML, Nishino I, Hesdorffer C, Schwartz J, Hawks RG, Martone DL, Cairo MS, DiMauro S, Stanzani M, Garvin JH Jr., Savage DG (2006) Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology 67:1458–1460 21. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A (2001) Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7:365–368 22. Holt IJ, Harding AE, Morgan-Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–719 23. Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S, Lamantea E, Prokisch H, Lochmuller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M,
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34. Longley MJ, Clark S, Yu Wai Man C, Hudson G, Durham SE, Taylor RW, Nightingale S, Turnbull DM, Copeland WC, Chinnery PF (2006) Mutant POLG2 disrupts DNA polymerase gamma subunits and cuases progressive external ophthalmoplegia. Am J Hum Genet 78:1026–1034 35. Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S et al (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320:1293–1299 36. Müller T, Deschauer M, Neudecker S, Zierz S (2005) Dystrophic myopathy of late onset associated with a G7497A mutation in the mitochondrial tRNASer(UCN) gene. Acta Neuropathol 110:426–430 37. Müller T, Deschauer M, Kolbe-Fehr F, Zierz S (2006) Genetic heterogeneity in 30 German patients with oculopharyngeal muscular dystrophy. J Neurol 253:892–895 38. Müller JS, Herczegfalvi A, Vilchez JJ, Colomer J, Bachinski LL, Mihaylova V, Santos M, Schara U, Deschauer M, Shevell M, Poulin C, Dias A, Soudo A, Hietala M, Äärimaa T, Krahe R, Karcagi V, Huebner A, Beeson D, Abicht A, Lochmüller H (2007) Phenotypical spectrum of DOK-7 mutations in congenital myasthenic syndromes. Brain 130:1497–1506 39. Mullie MA, Harding AE, Petty RK, Ikeda H, Morgan-Hughes JA, Sanders MD (1985) The retinal manifestations of mitochondrial myopathy. A study of 22 cases. Arch Ophthalmol 103:1825–1830 40. Nishino I, Spinazzola A, Hirano M (1999) Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283:689–692 41. Nitsch J, Zierz S, Janssen KP, Jung W, Manz M, Jerusalem F, Luderitz B (1990) Indications for pacemaker therapy in ophthalmoplegia plus and Kearns-Sayre syndrome. Z Kardiol 79:60–65 42. 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 leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol 59:394–398
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Chapter 16
Treatment of Specific Types of Nystagmus
16
Marianne Dieterich
Core Messages
■ The function of the ocular motor system
is to hold images stable on the fovea. The vestibular system and the vestibulo-ocular reflex (VOR) also play an important role in this function. The VOR connects the peripheral vestibular endorgans – the semicircular canals and otoliths – with their appropriate pair of eye muscles via a three-neuronal arc. A direct result of the inability to maintain stable foveal vision is acquired or congenital nystagmus, which causes decreased visual acuity, blurred vision, and the illusion that the observed surroundings are moving (i.e., oscillopsia). Vestibular neuritis is characterized by an acute rotatory vertigo with horizontalrotatory nystagmus and ipsilateral perceptual deficits and falls. It most likely has a viral etiology. Patients with vestibular neuritis should be given cortisone (e.g., methylprednisolone) as early as possible (within the first 3 days after disease onset), since it significantly improves the long-term outcome. Early physical therapy, at least two times a day, has been proven to normalize impaired body sway of patients with vestibular neuritis within 2–3 weeks. All these exercises are used to recalibrate the VOR in its three major planes of action for perfect eye–head coordination. Antivertiginous drugs are contraindicated for patients with chronic dizziness or positioning vertigo, since these drugs suppress central compensation.
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■
■
■ There is growing evidence that vascu-
lar compression of the trochlear nerve, as occurs in trigeminal neuralgia, must be assumed to be the underlying cause of superior oblique myokymia. Patients with longer-lasting symptoms should be administered anticonvulsants (carbamazepine, gabapentin). Central vestibular disorders frequently occur as a dysfunction in the sagittal (pitch) plane. Examples are downbeat (DBN) and upbeat (UBN) nystagmus, which are caused by paramedian lesions of the ponto-medullary brainstem or the cerebellar flocculus. The pathophysiology is still not completely understood. The individual components of DBN can differ, since there are obviously several pathogeneses: a vestibular one with imbalance in the graviceptive VOR (impairment in the projection of otolithic information), or imbalance due to dysfunction of the neuronal ocular motor integrator, the saccade-burst generator, or the vertical smooth pursuit system. The treatment of patients with persisting DBN and UBN should include GABAergic substances such as baclofen and clonazepam, gabapentin (probably a calcium channel blocker), and the potassium channel blocker 4-aminopyridine.
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Core Messages
■ The most common etiologies of acquired
pendular nystagmus (APN) are lesions due to multiple sclerosis or infarctions at different sites of the brainstem (inferior olive, medial vestibular nucleus, red nucleus in the rostral midbrain). It has been hypothesized that APN may arise from instability of the neural integrator for eye movements. Patients receiving APN treatment should start with memantine or gabapentin as an alternative. If side-effects occur at higher dosages, a combination of both drugs can be useful.
16.1 Introduction
16
The ocular motor system holds images stable on the fovea. A direct result of the inability to maintain stable foveal vision is acquired or congenital nystagmus. It causes decreased visual acuity, blurred vision, and the illusion that the observed world is moving (i.e., oscillopsia). Abnormal eye movements may also interfere with spatial localization and the ability to perform accurate limb movements. For these functions the vestibular system and the vestibulo-ocular reflex (VOR) play an important role. The VOR connects the peripheral vestibular end-organs, the semicircular canals, with their appropriate pair of eye muscles by a three-neuronal arc (Fig. 16.1) [9]. This three-neuronal reflex arc makes compensatory eye movements possible during rapid head and body movements. Some acquired nystagmus syndromes have a peripheral or central vestibular origin and are caused by lesions along the neuronal pathways that mediate the VOR. These pathways travel from the peripheral labyrinth over the vestibular nuclei in the medullary brainstem to the ocular motor nuclei (III, IV, VI) and the supranuclear integration centers in the pons and midbrain (interstitial nucleus of Cajal, INC; and rostral interstitial nuclei of the medial longitudinal fasciculus, riMLF). Another branch runs over the posterolateral thalamus up to the multisensory
vestibular areas in the temporoparietal cortex, such as the parietoinsular vestibular cortex ( ), retroinsular areas, areas in the superior temporal gyrus, the inferior parietal lobe, and the precuneus as well as the anterior cingulum. These cortical areas mediate the perception of head/ body position and motion in space. Descending pathways travel from the vestibular nuclei along the medial and lateral vestibulospinal tract into the spinal cord bilaterally to mediate postural control. In addition, there are also pathways to the vestibulo-cerebellum and the hippocampus. Thus, disorders of the VOR are characterized not only by ocular motor deficits, but also by disorders of perception due to impaired vestibulocortical projections of the VOR and by disorders of postural control due to impaired vestibulospinal projections of the VOR. For the clinician it is often useful for a topographical diagnosis to identify the specific abnormalities of eye movements, since lesion site and etiology may influence the therapy. Although a lot is known about the anatomy, physiology, and pharmacology of the ocular motor and vestibular systems, treatment options for certain specific ocular motor syndromes remain limited. Treatments based on pharmacologic mechanisms are in general preferred. However, since most drug treatments are based only on case reports and a few controlled treatment trials with a small number of patients, all treatment recommendations have to be classified as class C [52].
16.2 Peripheral Vestibular and Ocular Motor Disorders 16.2.1 Acute Peripheral Vestibulopathy, Vestibular Neuritis An acute episode of severe rotational vertigo is usually accompanied by horizontal-rotatory spontaneous nystagmus toward the affected side, a tendency to fall to the normal side, and severe nausea and vomiting. It gradually resolves over days to weeks. The cause is an acute peripheral vestibulopathy, the second most common cause of vertigo after benign paroxysmal positional vertigo [9]. Its etiology may be bacterial labyrin-
16.2 Peripheral Vestibular and Ocular Motor Disorders
Fig. 16.1. Schematic drawing of the vestibulo-ocular reflex with the three-neuron arc that connects the peripheral vestibular end-organs, the semicircular canals (A anterior, H horizontal, P posterior, UT utricle), via the vestibular nucleus (VIII) in the ponto-medullary brainstem and the ascending pathways with the ocular motor nuclei bilaterally (III oculomotor nucleus, IV trochlear nucleus) and the adequate pair of eye muscles (RI inferior rectus muscle, OS superior oblique muscle). In addition, further ascending pathways travel to the temporoparietal cortex mediating perception, and descending pathways to the spinal cord (lateral and medial vestibulospinal tract) mediating postural control
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thitis (otitis media), stroke, or trauma; however, in most cases there is viral involvement of the vestibular nerve (vestibular neuritis is its idiopathic form). Auditory dysfunction is absent in vestibular neuritis, which is characterized by a partial rather than a complete vestibular paresis. This condition mainly affects patients between the ages of 30 and 60. Caloric testing of the ears shows ipsilateral hypo-responsiveness (33%) or non-responsiveness (66%) of the horizontal semicircular canal function, which resolves in 70%–80% of the patients after a few months. Relief of the symptoms within 2–3 weeks (rarely up to 6 weeks) is due to the central compensation of the vestibular tonus imbalance. Later on, restoration of peripheral function takes place, which may lead to a mild spontaneous nystagmus beating in the opposite direction. In the few cases of no or only minor
peripheral restoration of labyrinthine function, oscillopsia may persist during rapid head movements. This is caused by a deficit of the VOR in the higher frequency range, which cannot be compensated for centrally.
16.2.1.1 Etiology Vestibular neuritis most likely has a viral etiology such as “idiopathic facial paresis,” but this has not yet been proven [4, 23, 47]. Arguments that support a viral etiology are the endemic occurrence at certain seasons, autopsy studies showing inflammatory degeneration of the vestibular nerve, and the presence of elevated protein levels in the cerebrospinal fluid. The detection of latent herpes simplex virus type 1 in human vestibular ganglia has been interpreted to be a sign of viral inflam-
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Fig. 16.2. Unilateral vestibular neuritis within 3 days after disease onset and after 12 months. Vestibular function was measured by caloric irrigation of both ears to determine the degree of paresis. The box plots for each treatment group give the mean (solid line), the 25th, 50th, and 75th percentiles (horizontal lines), the SDs (error bars above and below the boxes), and the 1st and 99th percentiles (crosses). Analysis of variance showed significantly more improvement with methylprednisolone. The combination of methylprednisolone and valacyclovir gave no further benefit (adapted from [55])
16.2 Peripheral Vestibular and Ocular Motor Disorders
mation of the vestibular nerve or of its superior part in vestibular neuritis [1, 22, 56]. This is further supported by recent magnetic resonance imaging (MRI) findings using a 3-tesla magnet and high-dose contrast enhancement, which showed an isolated enhancement of the vestibular nerve only on the affected side [32].
16.2.1.2 Therapeutic Recommendations For symptomatic relief, vestibular sedatives (e.g., dimenhydrinate) should be administered parenterally on days 1–3, when nausea and vomiting are severe. The patient should rest in bed and avoid head movements. These drugs should be given only as long as nausea lasts, because antivertiginous drugs suppress and prolong the mechanisms of central compensation. Treatment with steroids (methylprednisolone) should be considered in cases of viral vestibular neuritis, since a prospective, placebo-controlled study found evidence that early treatment with cortisone improves the long-term outcome (Fig. 16.2) [55]. In a total of 141 patients who were randomized within 3 days of symptom onset to one of four treatment options – placebo, methylprednisolone (starting with 100 mg daily), valacyclovir, or a combination of valacyclovir and methylprednisolone – the group receiving methylprednisolone had a better final outcome with about 60% recovery of peripheral vestibular function after 12 months compared to 36%–39% for the placebo/valacyclovir groups. The combination of methylprednisolone and valacyclovir gave no additional benefit. Further management includes early physical therapy, i.e., starting with exercises in bed (days 3–5). To suppress nystagmus by visual fixation, the patient should perform voluntary saccades and eccentric gaze-holding, as well as practice sitting freely. During days 5–7, when the spontaneous nystagmus is suppressed by fixation but there is continued gaze nystagmus in the direction of the fast phase, upright stance and then head oscillations during free stance should be trained. Afterwards during weeks 2–3 and later on, balance exer-
cises should become more complex, gradually increasing in difficulty (e.g., during active head oscillations with increasing frequencies) to reach a level above the demands for postural control under everyday life conditions. Early physical therapy at least two times per day has been proven to normalize impaired body sway of patients with vestibular neuritis within 2–3 weeks [53]. All these exercises are used to recalibrate the VOR in its three major planes of action (yaw, pitch, and roll) for perfect eye–head coordination.
Summary for the Clinician
■ Patients with vestibular neuritis should
be given cortisone (e.g., methylprednisolone for about 14 days, starting with 100 mg daily, reducing the dosage by 20 mg every 3 days) as early as possible (within the first 3 days after disease onset), since it significantly improves the long-term outcome. This is especially mandatory in patients with severe vestibular deficits (e.g., caloric unresponsiveness) to prevent deficits in the high-frequency range of the VOR, which will persist despite central compensation. Physical therapy should also start as early as possible to improve the recalibration of the VOR in its three major planes of action. To ensure adequate therapy is administered for vertigo, it is necessary to consider that antivertiginous drugs will suppress compensatory mechanisms, because most of these drugs are vestibular sedatives. Therefore, vestibular suppressants should only be administered for the first few days when vertigo is accompanied by distressing nausea and vomiting, i.e., in acute peripheral vestibulopathy or acute brainstem and cerebellar lesions. These antivertiginous drugs are contraindicated for patients with chronic dizziness or positioning vertigo.
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16.2.2 Superior Oblique Myokymia Superior oblique myokymia (SOM) is a peripheral ocular motor disorder of the trochlear nerve. Patients with SOM complain of recurrent attacks of oscillopsia and double vision with oblique images due to monocular oscillations [29]. Phasic episodes with oscillations caused by high-frequency torsional nystagmic eye movements as well as tonic episodes with diplopia secondary to an intorsion and elevation of the affected eye may occur sequentially or simultaneously. Spontaneous remissions for days or weeks, even up to years, are known to occur [34, 37].
facial spasm has to be assumed as the underlying cause [28, 61].
16.2.2.2 Therapeutic Recommendations Anticonvulsants such as carbamazepine [10, 52] and gabapentin have been reported to be effective [57] as has propranolol [59]. Microvascular decompression of the fourth nerve was found to be a beneficial surgical treatment [46]; however, the danger of a transient or persistent fourth nerve palsy as a side-effect of this surgical decompression is great.
16.2.2.1 Etiology To date the mechanism of this condition has not been completely clarified. In recent years evidence has accumulated showing that a vascular compression of the trochlear nerve (Fig. 16.3) similar to that in trigeminal neuralgia and hemi-
Summary for the Clinician
■ Patients with longer-lasting symptoms
of superior oblique myokymia should be administered anticonvulsants (carbamazepine, gabapentin).
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Fig. 16.3a,b. a Axial magnetic resonance imaging of a patient with superior oblique myokymia on the right side using a three-dimensional Fourier transformation constructive interference in steady-state (3D CISS) sequence. A right medial superior cerebellar artery branch lies in direct contact with the trochlear nerve 1 mm distal to the point of exit from the brainstem (arrow). b The corresponding non-contrast 3D time-of-flight magnetic resonance sequence (3D TOF MRA) confirms the presence of arterial compression of the trochlear nerve (arrow) (adopted from [61])
16.3 Supranuclear Ocular Motor Disorders 16.3.1 Central Vestibular Disorders For a simple clinical overview, the central vestibular brainstem syndromes can be classified according to the three major planes of action of the VOR [8, 9, 17]: Horizontal plane (yaw) pseudoneuritis,” spontane- “Vestibular ous horizontal nystagmus - Horizontal past-pointing to the right/left (subjective straight-ahead) - Postural instability, tendency to fall to one side, turning in the Unterberger-step test Sagittal plane (pitch) - Downbeat nystagmus, upbeat nystagmus - Deviation of the subjective horizontal upwards or downwards - Postural instability with a tendency to fall forward or backward
16.3 Supranuclear Ocular Motor Disorders
Frontal plane (roll) - Torsional nystagmus, ocular tilt reaction, skew deviation, ocular torsion, head tilt - Deviation of the subjective visual vertical (SVV) clockwise or counterclockwise - Postural instability with a tendency to fall to one side Central vestibular disorders frequently occur as a dysfunction in the sagittal (pitch) plane with downbeat and upbeat nystagmus.
16.3.1.1 Vestibular Syndromes in the Sagittal (Pitch) Plane These syndromes have so far been attributed to lesions in the following three locations: paramedian bilaterally in the medullary and pontomedullary brainstem, the pontomesencephalic brainstem with the adjacent cerebellar peduncle, or the cerebellar flocculus bilaterally (Fig. 16.4) [9].
Fig. 16.4. Schematic drawing of the brainstem with the sites where a lesion can cause upbeat (light blue) and downbeat (dark blue) nystagmus syndromes in the pitch plane of the vestibulo-ocular reflex. Note that the lesions are located at or around the midline of the ponto-mesencephalic and in particular the medullary brainstem as well as the cerebellar flocculus bilaterally. (III, IV, VI, VIII: nuclei of the cranial nerves; adopted from [8])
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Despite many clinical reports on downbeat nystagmus (DBN) and upbeat nystagmus (UBN) as well as multiple hypotheses about their possible mechanisms, their pathophysiology is still not completely understood [33, 40]. Several clinical findings and experimental data now suggest that asymmetries in the cerebello-brainstem network, which normally stabilizes vertical gaze, could cause an imbalance in the following structures: (1) the vertical cerebello-vestibular “neural integrator,” (2) the central connections of the vertical VOR including both the semicircular canal and the otolith responses, or (3) the vertical smooth pursuit system. In a recent review by Pierrot-Deseilligny and Milea [42], DBN is attributed to a floccular lesion that results in disinhibition of the pathway from the superior vestibular nucleus via the central ventral tegmental tract and thereby in relative hyperactivity of the elevator muscles, which induce an upward slow phase. Indeed, the crucial role of the flocculus in DBN was confirmed only recently in a 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) study, which detected glucose hypometabolism in the cerebellar flocculus and tonsil. The DBN was improved by effective medical therapy with 4-aminopyridine (Fig. 16.5) [6].
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16.3.1.1.1 Downbeat Nystagmus Syndrome The DBN syndrome is characterized by a fixational nystagmus, frequently acquired, which beats downward in primary gaze position, is exacerbated on lateral gaze and in head-hanging position, may have a rotatory component, and is accompanied by a combination of visual and vestibulocerebellar ataxia with a tendency to fall backward and past-pointing upward as well as by vertical smooth pursuit deficits [3, 9, 26]. Some authors found that DBN was more prominent in prone than in supine body positions [39], but this could not be confirmed by others. Convergence can suppress or enhance it in some patients; visual fixation has little effect. The syndrome is frequently persistent. The individual components can differ, since there are obviously other pathogeneses besides the vestibular one with imbalance in the gravi-
ceptive VOR (impairment in the projection of otolithic information), e.g., imbalance by dysfunction of the neuronal ocular motor integrator, the saccade-burst generator, or the vertical smooth pursuit system [24, 40].
16.3.1.1.1.1 Etiology DBN is often the result of a bilateral lesion of the flocculus or the paraflocculus (e.g., intoxication due to anticonvulsant drugs) or is caused by a lesion at the bottom of the fourth ventricle [3, 34]. Accordingly, it is mostly a drug-induced dysfunction or congenital: about 25% of patients have craniocervical junction anomalies (Chiari malformation), approximately 20% have cerebellar degeneration, and about 50% of the cases are of unknown etiology. It can also be caused by a paramedian lesion of the medulla oblongata [13] and more rarely by multiple sclerosis, hemorrhage, infarction, or tumor. DBN occurs in channelopathy episodic ataxia type 2, for which a new treatment option was recently developed [54]. DBN due to a lesion in the upper medulla at the level of the rostral nucleus prepositus hypoglossi has so far only been found in monkeys, not in humans [62].
16.3.1.1.2 Upbeat Nystagmus Upbeat nystagmus (UBN) is rarer than downbeat nystagmus. It is also a fixation-induced nystagmus that beats upward in primary gaze position, and is combined with a disorder of the vertical smooth pursuit eye movements, a visual and vestibulospinal ataxia with a tendency to fall backward, and past-pointing downward [9, 30]. UBN usually increases on upgaze. In some patients it changes to DBN during convergence.
16.3.1.1.2.1 Etiology The anatomic location of most acute lesions is near the median plane in the medulla oblongata in neurons of the paramedian tract (PMT), close to the caudal part of the perihypoglossal nucleus [30, 49], which are responsible for ver-
16.3 Supranuclear Ocular Motor Disorders
Fig. 16.5a,b. 18F-Fluorodeoxyglucose-positron emission tomography (PET) of a patient with downbeat nystagmus syndrome without treatment and on medication with 4-aminopyridine. Both show a reduced cerebellar glucose metabolism only in the region of the tonsil and the flocculus/paraflocculus bilaterally. a Right and left mesial view on three-dimensional standard surface-projected images of the patient. Dark colours represent a reduced local glucose metabolism relative to the control mean. b Cerebellar areas with statistical differences in the contrast normal database versus patient projected onto a standard template brain (SPM99; p≤0.001)
tical gaze-holding (Fig. 16.6) [11]. These lesions probably affect the ascending pathways from the anterior semicircular canals (and/or otoliths) at the pontomedullary or pontomesencephalic junction [20]. However, lesions have been reported near the median plane in the tegmentum of the pontomesencephalic junction, the bra-
chium conjunctivum, and probably in the anterior vermis [41]. Only recently a lesion of the paramedian pontine brainstem was described which affected the central ventral tegmental tract [43]. The symptoms of UBN persist as a rule for several weeks but are usually not permanent. Be-
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Fig. 16.6 MRI of a patient with upbeat nystagmus syndrome due to an acute paramedian infarction of the medullary brainstem (arrow) at the level of the vestibular nerves and nuclei. The infarction affects neurons of the paramedian tract close to the caudal part of the perihypoglossal nucleus
16
cause the eye movements generally have larger amplitudes, oscillopsia in UBN is very distressing and significantly impairs vision. Upbeat nystagmus due to damage to the pontomesencephalic brainstem is frequently combined with a unilateral or bilateral internuclear ophthalmoplegia (INO), indicating that the medial longitudinal fasciculus (MLF) is affected. The main etiologies are bilateral lesions in multiple sclerosis (MS), brainstem ischemia or tumor, Wernicke’s encephalopathy, cerebellar degeneration, and dysfunction of the cerebellum due to intoxication (e.g., nicotine).
Recently, the potassium channel blockers 3,4-diaminopyridine and 4-aminopyridine were shown to effectively reduce DBN in some but not all patients with DBN and UBN [31, 54]. Potassium channels are abundant in cerebellar Purkinje cells, the output neurons from cerebellar cortex. The related agent, 4-aminopyridine, is reported to increase the discharge of these neurons by affecting the slow depolarizing potential [19]. Such enhancement of Purkinje cell activity could restore the inhibitory influence of the cerebellar cortex on vertical vestibular eye movements to normal [33]. This appeared to hold true in a patient with DBN who showed an improvement of both DBN and pursuit deficits after 4-aminopyridine as well as improvement of the hypometabolism of the cerebellar flocculus/tonsil in FDG-PET (Fig. 16.5) [6]. From these studies it was concluded that: (1) 4-aminopyridine reduces the downward drift in UBN by augmenting smooth pursuit commands, and (2) 3,4-diaminopyridine minimizes the gravityindependent velocity bias and improves deficient inhibitory cerebellar control on overacting otolith-ocular reflexes. A surgical decompression, in which parts of the occipital bone were removed in the region of the foramen magnum, proved beneficial to isolated patients with a craniocervical anomaly [48]. Sometimes base-down prisms may help to reduce DBN during reading, because DBN is generally less pronounced during upward gaze.
Summary for the Clinician
■ The treatment options for patients with
16.3.1.1.3 Therapeutic Recommendations The course and prognosis of UBN and DBN depend on the underlying illness. Positive effects have been seen in non-placebo-controlled studies with a limited number of patients. It is therapeutically expedient to attempt to treat the symptoms of persisting DBN by administering gabapentin, probably a calcium channel blocker (3× 200 mg/ day p.o.) [2], the GABA-B agonist baclofen (3× 5–15 mg/day p.o.) [18], or the GABA-A agonist clonazepam (3× 0.5 mg/day p.o.) [15]. Treatment of UBN with baclofen led to an improvement in several patients (3× 5–10 mg/day p.o.) [18].
persisting symptoms of DBN and UBN should include GABAergic substances such as baclofen and clonazepam, gabapentin (probably a calcium channel blocker), and the potassium channel blocker 4-aminopyridine.
16.3.1.1.4 Seesaw Nystagmus Seesaw and hemi-seesaw nystagmus are rare pendular or jerk oscillations. One half-cycle consists of elevation and intorsion of one eye with
concurrent depression and extorsion of the other eye. During the next half-cycle there is a reversal of the vertical and torsional movements. The frequency in the pendular form (2–4 Hz) is lower than in the jerk form.
16.3.1.1.4.1 Etiology Jerk hemi-seesaw nystagmus was found in patients with unilateral meso-diencephalic lesions [27], which affected the interstitial nucleus of Cajal (INC) and its vestibular afferents from the vertical
16.3 Supranuclear Ocular Motor Disorders
semicircular canals [44]. It was also seen in patients with Chiari malformation (Fig. 16.7a) [7]. The pendular form was observed in patients with lesions that affected the optic chiasm. The loss of crossed visual input seems to be crucial for its pathophysiology [49].
16.3.1.1.4.2 Therapeutic Recommendations An improvement of the seesaw component of the pendular nystagmus was observed in a small group of only three patients who received gabapentin [2]. Older case reports described beneficial effects with clonazepam [12] and ethanol (1.2 g alcohol/kg body weight), more recent ones with the GABA-B agonist baclofen (Fig. 16.7b) [7].
16.3.1.1.5 Periodic Alternating Nystagmus Patients with acquired periodic alternating nystagmus (PAN) often complain of increasing or decreasing oscillopsia for specific time intervals. This is due to a horizontally beating spontaneous nystagmus that periodically changes its direction. The nystagmus amplitude of PAN gradually
Fig. 16.7a,b. T2-weighted MRI scan (a) and three-dimensional videooculography (b) of a patient with hemi-seesaw nystagmus who responded well to baclofen (3× 5 mg daily). Brain imaging disclosed a Chiari malformation (arrow) (adopted from [7])
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decreases, then the nystagmus reverses its direction, and the amplitude increases again. The periods of oscillation typically last 1–2 min (range: 1 s to 4 min). Patients with PAN experience no spontaneous improvement.
16.3.1.1.5.1 Etiology Periodic alternating nystagmus is caused by instability of the velocity storage mechanism for vestibular eye movements; an adaptive mechanism produces the oscillations that have a period of about 4 min [36]. Animal experiments showed causative lesions of the inferior cerebellar vermis (e.g., nodulus and uvula), which lead to disinhibition of the GABA-ergic velocity storage mechanism mediated in the vestibular nuclei [21, 60]. Vestibulocerebellar lesions are commonly found in humans with MS, cerebellar degenerations, craniocervical anomalies, tumors, brainstem infarctions, or rarely intoxication (e.g., lithium). Periodic alternating nystagmus can also be caused by bilateral visual loss. It resolves when vision improves [14].
16.3.1.1.5.2 Therapeutic Recommendations
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Case reports described beneficial effects of the GABA-B agonist baclofen (3× 5–10 mg p.o. per day) as well as of barbiturates and phenothiazine [12].
16.3.2 Central Ocular Motor Disorders 16.3.2.1 Acquired Pendular Nystagmus Acquired pendular nystagmus (APN) is characterized by monocular or binocular sinusoidal oscillations with a predominant horizontal, vertical, or oblique trajectory and a frequency of 2–7 Hz [25, 35]. The nystagmus is often associated with visual impairment; head, trunk, and limb ataxia; and head titubation that is not synchronized with the nystagmus [52].
16.3.2.1.1 Etiology The most common etiologies of APN are lesions due to MS or brainstem infarctions [38, 52]. Other etiologies include toluene abuse, Whipple’s and Pelizaeus-Merzbacher diseases, and brainstem cavernoma or hemorrhage. It can also occur as a component of oculopalatal tremor syndrome (myoclonus). Observations in patients with brainstem lesions at different sites (inferior olive, medial vestibular nucleus, central tegmental tract, red nucleus in the midbrain; Fig. 16.8) led to the hypothesis that APN may arise from instability in the neural integrator for eye movements [49].
16.3.2.1.2 Therapeutic Recommendations Most of the older case reports or case series described the beneficial effect of anticholinergic treatment with trihexiphenidyl (20–40 mg p.o. daily). However, in a double-blind study only one of six patients experienced any improvement [52]. More recently significant improvements of the nystagmus and visual acuity were reported in 10 of 15 patients who received gabapentin [2] and in all 9 tested patients on memantine, a glutamate antagonist and N-methyl-d-aspartate (NMDA) modulator (15–60 mg p.o. daily; Fig. 16.9) [50]. This was confirmed in a recent examiner-blind, cross-over study on 11 patients with MS, in which gabapentin (up to 1200 mg p.o. daily) and memantine (40 mg or 60 mg daily) were compared [51]. Both drugs significantly reduced APN and increased near visual acuity from 0.35 to 0.46 (40 mg memantine) and to 0.43 (1200 mg gabapentin) or 0.60 (60 mg memantine). Reduction of nystagmus amplitude and frequency was consistent for the horizontal and vertical planes with memantine, but significantly stronger for the vertical than the horizontal plane with gabapentin. Memantine appeared to be even more effective for the horizontal component of APN and the visual acuity, especially at the higher dosage of 60 mg/day. Both medications were well tolerated [51]. Gabapentin was superior to vigabatrin in a small series of patients [5]. Cannabis, which
16.3 Supranuclear Ocular Motor Disorders
Fig. 16.8a,b. T2-weighted MRI scan of a patient with acquired pendular nystagmus due to multiple sclerosis (MS). a One MS plaque affected the vestibular nucleus in the medullary brainstem; b another affected the red nucleus in the midbrain
Fig. 16.9a,b. Three-dimensional videooculography of both eyes (H horizontal, V vertical, T torsional eye movements) of a patient with acquired nystagmus predominantly in the horizontal plane without medication (a) and with memantine (30 mg per day) (b)
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acts as a presynaptic inhibitory transmitter, also seems to have a similar effect [16].
Summary for the Clinician
■ Treatment for patients with APN should
start with memantine (15–60 mg p.o. daily) or as an alternative with gabapentin (3× 300–400 mg p.o. daily). If side-effects occur at higher dosages, a combination of both drugs can be useful. If there is no sufficient effect or major side-effects occur with memantine and/ or gabapentin, then try clonazepam (3× 0.5–1.0 mg p.o. daily).
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adults: carcinoma of lung, breast, uterus, or ovary).
16.3.2.2.2 Therapeutic Recommendations Therapy has to first focus on the underlying process, for example encephalitis or tumor. In such cases treatment with cortisone and immunoglobulins can be effective. Valproic acid (2× 500–1000 mg p.o. daily) [58], propranolol (3× 40–80 mg p.o. daily), nitrazepam (15–30 mg p.o. daily), and clonazepam (3× 0.5–2.0 mg p.o. daily) improve the oscillations (overview: [12]).
References 16.3.2.2 Opsoclonus and Ocular Flutter
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Opsoclonus is characterized by repetitive bursts of fast, high-frequency conjugate saccadic oscillations without intersaccadic intervals [34]. The oscillations may have horizontal, vertical, and torsional components and are often triggered by saccades, pursuit, eye closure, and convergence. Amplitudes range from 2º to 15º. The same pattern but limited to the horizontal plane is seen in ocular flutter. Ocular symptoms may be associated with gait and limb myoclonus (“dancing feet, dancing eye syndrome”).
16.3.2.2.1 Etiology A functional disturbance of the active saccadic suppression by the pontine omnipause neurons is assumed to be the most probable pathophysiological mechanism. A functional lesion of the glutaminergic cerebellar projections from the fastigial nuclei of the cerebellum to the omnipause cells is a likely cause for this disinhibition [52]. However, histological abnormalities of these neurons have not yet been shown [45]. Opsoclonus was described in cerebellar diseases such as cerebellar encephalitis (post-viral, e.g., coxsackie B37; post-vaccinal) or paraneoplastic cerebellar syndrome (infants: neuroblastoma;
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References Brandt T, Dieterich M (1995) Central vestibular syndromes in role, pitch, and yaw planes. Topographic diagnosis of brainstem disorders. Neuroophthalmology 15:291–303 Brandt T, Dieterich M, Strupp M (2005) Vertigo and dizziness. Common complaints. Springer, Berlin Heidelberg New York Brazis PW, Miller NR, Henderer JD, Lee AG (1994) The natural history and results of treatment of superior oblique myokymia. Arch Ophthalmol 112:1063–1067 Büttner-Ennever JA, Horn AKE, Schmidtke K (1989) Cell groups of the medial longitudinal fasciculus and paramedian tracts. Rev Neurol 145:533–539 Carlow TJ (1986) Medical treatment of nystagmus and ocular motor disorders. Int Ophthalmol Clin 26:251–264 Cox TA, Corbett JJ, Thompson S et al (1981) Upbeat nystagmus changing to downbeat nystagmus with convergence. Neurology 31:891–892 Cross SA, Smith JL, Norton EW (1982) Periodic alternating nystagmus clearing after vitrectomy. J Clin Neuroophthalmol 2:5–11 Currie J, Matsuo V (1986) The use of clonazepam in the treatment of nystagmus induced oscillopsia. Ophthalmology 93:924–932 Dell’Osso LF (2000) Suppression of pendular nystagmus by smoking cannabis in a patient with multiple sclerosis. Neurology 13:2190–2191 Dieterich M, Brandt T (1993) Ocular torsion and tills of subject visual vertical or sensitive brainstem signs. Ann Neurol 33:292–299 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 Etzion Y, Grossman Y (2001) Highly 4-aminopyridine sensitive delayed rectifier current modulates the excitability of guinea pig cerebellar Purkinje cells. Exp Brain Res 139:419–425 Fisher A, Gresty M, Chambers B, Rudge P (1983) Primary position upbeating nystagmus: a variety of central positional nystagmus. Brain 106:949–964 Furman JMR, Wall C, Pang D (1990) Vestibular function in periodic alternating nystagmus. Brain 113:1425–1439 Furuta Y, Takasu T, Fukoda S et al (1993) Latent herpes simplex virus type I in human vestibular ganglia. Acta Laryngol 503:85–89
23. Gacek RR, Gacek MR (2002) The three phases of vestibular ganglionitis. Ann Otol Rhinol Laryngol 111:103–114 24. Glasauer S, Hoshi M, Kempermann U, Eggert T, Büttner U (2003) Three-dimensional eye position and slow phase velocity in humans with downbeat nystagmus. J Neurophysiol 89:338–354 25. Gresty M, Ell JJ, Findley LJ (1982) Acquired pendular nystagmus: its characteristics, localising value and pathophysiology. J Neurol Neurosurg Psychiatry 45:431–439 26. Halmagyi MG, Rudge P, Gresty MA, Sanders MD (1983) Downbeating nystagmus. A review of 62 cases. Arch Neurol 40:777–784 27. Halmagyi MG, Aw ST, Dehaene I, Curthoys IS, Todd MJ (1994) Jerk-waveform see-saw nystagmus due to unilateral meso-diencephalic lesion. Brain 117:775–788 28. Hashimoto M, Ohtsuka K, Hoyt WF (2001) Vascular compression as a course of superior oblique myokymia disclosed by thin-slice magnetic resonance imaging. Am J Ophthalmol 31:676–677 29. Hoyt WF, Keane JR (1962) Superior oblique myokymia: report and discussion of five cases of benign intermittent uniocular microtremor. Arch Ophthalmol 84:461–467 30. Janssen JC, Larner AJ, Morris H, Bronstein AM, Farmer SF (1998) Upbeat nystagmus: clinicoanatomical correlation. J Neurol Neurosurg Psychiatry 65:380–381 31. Kalla R, Glasauer S, Schautzer F, Lehnen N, Büttner U, Strupp M, Brandt T (2004) 4-Aminopyridine improves downbeat nystagmus, smooth pursuit, and VOR gain. Neurology 62:1228–1229 32. Karlberg M, Annertz M, Magnusson M (2004) Acute vestibular neuritis visualised by 3-T magnetic resonance imaging with high-dose gadolinium. Arch Otolaryngol Head Neck Surg 130:229–232 33. Leigh RJ (2003) Potassium channels, cerebellum and treatment for down-beat nystagmus. Neurology 61:158–159 34. Leigh RJ, Zee DS (1999) The neurology of eye movements, 3rd edn. Oxford University Press, New York 35. Leigh RJ, Tomsak RL (2003) Drug treatments for eye movement disorders. J Neurol Neurosurg Psychiatry 74:1–4 36. Leigh RJ, Khanna S (2006) What can acquired nystagmus tell us about congenital forms of nystagmus? Semin Ophthalmol 21:83–86
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Treatment of Specific Types of Nystagmus 37. Leigh RJ, Tomsak RL, Seidman SH, Dell’Osso LF (1991) Superior oblique myokymia. Quantitative characteristics of the eye movements in three patients. Arch Ophthalmol 109:1710–1713 38. Lopez LI, Bronstein AM, Gresty MA, Du Boulay EP, Rudge P (1996) Clinical and MRI correlates in 27 patients with acquired pendular nystagmus. Brain 119:465–472 39. Marti S, Palla A, Straumann D (2002) Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus. Ann Neurol 52:712–721 40. Marti S, Straumann D, Glasauer S (2005) The origin of downbeat nystagmus: an asymmetry in the distribution of on-directions of vertical gaze-velocity Purkinje cells. Ann N Y Acad Sci 1039:548–553 41. Nakada T, Remler MP (1981) Primary position upbeat nystagmus. J Clin Neuroophthalmol 1:185–189 42. Pierrot-Deseilligny C, Milea D (2005) Vertical nystagmus: clinical facts and hypotheses. Brain 128:1237–1246 43. Pierrot-Deseilligny C, Milea D, Sirmai Jm Papeix C, Rivaud-Pechoux S (2005) Upbeat nystagmus due to a small pontine lesion: evidence for the existence of a crossing ventral tegmental tract. Eur Neurol 54:186–190 44. Rambold H, Helmchen C, Büttner U (1999) Unilateral muscimol inactivations of the interstitial nucleus of Cajal in the alert rhesus monkey do not elicit seesaw nystagmus. Neurosci Lett 272:75–78 45. Ridley A, Kennard C, Scholtz CL, BüttnerEnnever JA, Summers B, Turnbull A (1987) Omnipause neurons in two cases of opsoclonus associated with oat cell carcinoma of the lung. Brain 110:1699–1709 46. Samii M, Rosahl SK, Carvalho GA, Krzizok T (1998) Microvascular decompression for superior oblique myokymia: first experience. J Neurosurg 89:1020–1024 47. Schuknecht HF, Kitamura K (1981) Vestibular neuritis. Ann Otol Rhinol Otolaryngol 90 [Suppl. 78]:1–19 48. Spooner JW, Baloh RW (1981) Arnold-Chiari malformation. Improvement in eye movements after surgical treatment. Brain 104:51–60 49. Stahl JS, Averbuch-Heller L, Leigh RJ (2000) Acquired nystagmus. Arch Ophthalmol 118:544–549
50. Starck M, Albrecht H, Pöllmann W, Straube A, Dieterich M (1997) Drug therapy of acquired nystagmus in multiple sclerosis. J Neurol 244:9–16 51. Starck M, Albrecht H, Pöllmann W, Straube A, Dieterich M (1999) Memantine vs gabapentin in acquired pendular nystagmus: an observer-blind cross-over study. J Neurol 246 (Suppl. 1): 41 52. 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 53. Strupp M, Arbusow V, Maag KP et al (1998) Vestibular exercise improves central vestibulo-spinal compensation after vestibular neuritis. Neurology 51:838–844 54. Strupp M, Schüler O, Krafczyk S et al (2003) Treatment of downbeat nystagmus with 3,4-diaminopyridine – a prospective, placebo-controlled, double-blind study. Neurology 61:165–170 55. Strupp M, Zingler V, Arbusow V et al (2004) Methylprednisolone, valacyclovir, all the combination for vestibular neuritis. New Engl J Med 341:354–361 56. Theil D, Derfuss T, Stupp M, Gildon DH, Arbusow V, Brandt T (2002) Cranial nerve palsies: herpes simplex virus type I and varicella-zoster virus latency. Ann Neurol 51:273–274 57. Tomsak RL, Kosmorsky GA, Leigh RJ (2002) Gabapentin attenuates superior oblique myokymia. Am J Ophthalmol 133:721–723 58. Traccis S, Marras MA, Puliga MV et al (1997) Square-wave jerks and square-wave oscillations: treatment with valproic acid. Neuroophthalmology 18:51–58 59. Tyler RD, Ruiz RS (1990) Propranolol in the treatment of superior oblique myokymia. Arch Ophthalmol 108:175–176 60. Waespe W, Cohen B, Raphan T (1985) Dynamic modification of the vestibuloocular reflex by the nodulus and uvula. Science 228:199–202 61. Yousry I, Dieterich M, Naidich TP, Schmid UD, Yousry TA (2002) Superior oblique myokymia: magnetic resonance imaging support for the neurovascular compression hypothesis. Ann Neurol 51:361–368 62. DeJong JMBV, Cohen B, Matsuo V, Uemura T (1980) Midsagittal pontomedullary brainstem section: effects on ocular adduction and nystagmus. Exp Neurol 68: 420–442
Part VI
Rehabilitation
Chapter 17
Rehabilitation in Neuroophthalmology
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Susanne Trauzettel-Klosinski
Core Messages
■ The purpose of rehabilitation is to opti-
mize the use of residual vision by compensating strategies aimed at regaining and maintaining the patient’s independence and quality of life. Visual field defects involving the visual field center cause reading problems. Fluent reading requires sufficient resolution and a sufficiently large retinal area used for reading, i.e., the reading visual field. It is important to know whether fixation is central or eccentric. Diminished resolution, as in central scotoma, can be compensated for by using a healthy visual field area at the edge of the scotoma (eccentric fixation) as well as text magnification.
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■ In cases with a reduced size of the read-
ing visual field and central fixation, it is crucial for the patient to learn to use an eccentric fixation locus despite intact foveal function. In ring scotomas only then reading is regained by magnification. In hemianopia, eccentric fixation of 1º–2º creates a small perceptual area along the vertical midline, while magnification is contraindicated. Here saccadic search strategies are also helpful. In concentric fields, contrast enhancement of small print sometimes helps to get enough letters into the central seeing island. Peripheral visual field defects cause difficulties with spatial orientation, which can be improved by visual and tactile aids as well as mobility training. Any attempt to rehabilitate a patient is worthwhile, because the success rate of technical aids in combination with training is high. Training needs to be specifically tailored to the patient’s deficits and needs, and it should be relevant to everyday life.
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17.1 Introduction Neuroophthalmologic diseases are often associated with persisting visual deficits, which cannot be treated with surgery or pharmacological therapies. The nature of these deficits and accordingly
their significance for activities of daily living can be quite different. The aim of rehabilitation is to enable patients to cope with everyday life and to improve their quality of life. There is an increasing demand for neuroophthalmologic rehabilitation. The increased inci-
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dence of vascular disorders involving the circulation of the visual pathways, especially the occipital lobe, requires an enhanced effort to manage the problems caused by homonymous visual field defects – especially impairment of reading and spatial orientation. Visual impairment occurs in 20%–30% of patients suffering from brain damage caused by disease or accident. Optic neuropathies of various origin cause visual field defects, such as central scotoma or arcuate scotoma, with resulting difficulties in reading and orientation. Cortical visual impairment (CVI) is a symptom complex that can be associated with visual field defects and/or higher cortical dysfunctions caused by difficulties in information processing. Cortical visual impairment is the most common cause for severe visual impairment in children in the Western world (Baker-Nobles and Rutherford 1995; Good et al. 2001; Hoyt 2003). Methods for quantitative assessment of this disorder are still insufficient and hindered by the fact that many of these children have multiple disabilities. Therefore, developing and providing specific rehabilitation programs are of high priority. Visual acuity, widely used as the only visual parameter, does not consider the nature of the visual deficit and its impact on disabilities in everyday life. Some rather unspecific complaints of patients with neuroophthalmologic diseases can be associated with reduced contrast sensitivity, crowding, glare, oculomotor disorders, asthenopia due to diplopia, and accommodation deficit. The exact assessment of the disorder is crucial for optimal rehabilitation.
17.2 Psychophysics of Normal Reading Reading difficulties are the main complaint of patients with visual field defects involving the field center. Knowledge about physiology of reading is essential for understanding reading disorders. With increasing eccentricity, visual acuity decreases rapidly. For reading newspaper print at a distance of 25 cm, a visual acuity of about 0.4 is necessary (20/50). However, testing of visual
acuity assesses recognizing just one optotype at a time. However, reading requires an area right and left of the fixation point of about 2º as a minimum reading visual field. Only within this area is the text perceived clearly. This minimum reading visual field (Aulhorn 1953) corresponds approximately to the “word recognition span” and the “visual span” (Legge et al 1997; Rayner 1975). The total “perceptual span” during one fixation can be extended up to 5º (or 15 letters) in the reading direction (McConkie and Rayner 1975). The perceptual span is asymmetric in favor of the reading direction (McConkie and Rayner 1976), thus providing a pre-view benefit based on parafoveal information processing (Fig. 17.1). Even though not all letters are seen clearly within the total perceptual span, this area provides information about word length, word shape, capitalization, etc., and is therefore useful for guiding the next saccade to the appropriate landing position. Information processing occurs during the holding positions of a mean duration of 250 ms (O’Regan 1980). The typical sequence of holding positions and saccades can be seen as a staircase pattern in the eye movement recording (see Fig. 17.7, right side, left recording). The retinal area used for reading comprises only a few square millimeters but is highly magnified in the visual cortex (Rovamo and Virsu 1979). The central 10º of the visual field, accounting for approximately 2% of the total visual field, utilize more than 50% of the primary visual cortex (Horton and Hoyt 1991; McFadzean et al. 1994). After visual analysis of a word in the occipital lobe, information is transferred to the angular gyrus and the temporal superior lobe (Wernicke region), mainly in the left hemisphere, where visual information is transformed into sounds, e.g., phonological decoding, grapheme-phoneme transformation. Then the activity spreads into the inferior frontal lobe (Broca region) for motor processing, preparing the articulation program for the motor cortex. This classical model of Geschwind (1978) has been supplemented by brain imaging studies, which showed complex additional activation in various brain regions, but the principle concept of Geschwind (1978) is still valid (see also Trauzettel-Klosinski et al. 2006).
17.3 Diseases of the Visual Pathways and their Functional Deficits
Fig. 17.1. Visual acuity dependent on eccentricity (yellow), minimal reading visual field (2° right and left of fixation, 1° above and below, red) and total perceptual span (up to 5° in reading direction, blue) related to a text. Due to the visual acuity function, only the letters within the minimum reading visual field can be seen clearly. Parafoveal information processing from the extended perceptual span provides a pre-view benefit for guiding the next saccade to the following word or group of letters
Summary for the Clinician
■ Field defects involving the visual field center cause reading disability. ■ Reading requires not only sufficient
resolution, but also a minimum size of a reading visual field. Therefore, measuring visual acuity is not sufficient to test reading ability as this assesses only one letter at a time. Reading is composed of a sequence of oculomotor holding phases for information processing and saccades leading the eye to the next group of letters.
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17.3 Diseases of the Visual Pathways and their Functional Deficits 17.3.1 Optic Neuropathies 17.3.1.1 Central Scotomas Optic neuropathies (ON) often cause central or cecocentral scotomas (Fig. 17.2; 1 and 2). The causes can be inflammatory (optic neuritis), toxic (cecocentral, especially tobacco-alcohol ON), metabolic (especially diabetic), hereditary (Leber’s optic atrophy, juvenile dominant ON), and ischemic (anterior and mainly posterior ON). A central scotoma can also be caused by a bilateral occipital pole lesion (typically marked
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Fig. 17.2. Visual field defects in optic neuropathies: 1: central scotoma; 2: cecocentral scotoma; 3: nerve fiber bundle defects (arcuate scotoma) according to the path of the retinal nerve fibers (4); 5: ring scotoma with preserved central seeing island; 6: constricted field; only a central seeing island remains
17.3 Diseases of the Visual Pathways and their Functional Deficits
Fig. 17.3a,b. The reading visual field related to the 30° visual field (a) and a text (b). Left: normal subject (compare Fig. 17.1). Middle: absolute central scotoma with central fixation; the reading visual field is covered by the scotoma and does not function. Hence, reading is impossible. Right: in many patients with an absolute central scotoma, a valuable adaptation process occurs. They use a healthy area of the visual field near the edge of the scotoma for fixation. This new reading visual field becomes the new center of the visual field. Thus, the scotoma is shifted (here upwards) together with the blind spot (a). The new retinal area used for reading does not have sufficient resolution for newspaper print because of its eccentricity (b, upper part). This can be compensated by text magnification (b, lower part)
by a step along the vertical midline of the visual field). The most common reasons for central scotoma are maculopathies, especially age-related maculopathy, but this is not subject of this chapter.
17.3.1.2 Arcuate Scotomas: Nerve Fiber Bundle Defects Arcuate scotomas typically arise in ON of ischaemic origin (anterior ischemic optic neuropathy or AION, glaucoma), and less frequently in inflammatory disease (optic neuritis) (Fig. 17.2; 3 and 4).
17.3.1.3 Ring Scotomas Ring scotomas consist of upper and lower arcuate scotomas. They can also occur in an intermediate
stage of maculopathies with a persisting central seeing island in a central scotoma (Fig. 17.2; 5).
17.3.1.4 Constricted Fields Constriction of the visual fields is found in advanced glaucoma, in bilateral cortical lesions with sparing of the occipital pole (in this case with a step along the vertical midline), and in degenerative retinal diseases (Fig. 17.2; 6).
17.3.1.5 The Impact of Visual Field Defects on Reading Performance In central scotoma and central fixation the reading visual field is covered and functionless. These patients have to learn a valuable adaptive strategy: eccentric fixation. They use a healthy area of the visual field at the margin of the scotoma. “Eccen-
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Fig. 17.4a–c. a Ring scotoma: the central island is too small for reading. b Eccentric fixation with upwards shift of the scotoma combined with text magnification enables reading. c Constricted field: the central island is too small, but there is no peripheral area available for eccentric reading
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tric fixation” is the situation when the patient has adopted the new viewing direction as “straight forward,” whereas “eccentric viewing” corresponds to the condition in which the viewing direction is still connected to the fovea and the patient has purposely to look to one side. In the following, eccentric fixation will be used as the generic term for any extrafoveal fixation, also independently from the stimulus (fixation target or words). Fixation below the scotoma corresponds to fixation above the fovea. The eccentric fixation locus is also called the preferred retinal locus (PRL), even though a patient might use more than one eccentric locus. The new fixation locus becomes the new center of the visual field (Aulhorn 1975). Therefore, it can be seen that in the perimetry the scotoma is permanently shifted together with the blind spot. The blind spot can serve as a reference scotoma and shows the extent of the shift. The new retinal area used for reading is healthy, but does not allow sufficient resolution to read newspaper print. If the text is magnified, reading ability is regained (Fig. 17.3). This process, eccentric fixation plus magnification of the text, is the basis of the effectiveness of magnifying visual aids for patients with a central scotoma. A patient with a ring scotoma has a problem in that there is a small central island within a central scotoma which is not large enough to include a sufficient number of letters for fluent reading (Fig. 17.4a). If this patient learns to use an eccentric retinal area instead of the fovea, reading can be re-learned but only if the text is magnified (Fig. 17.4b). However, it is very difficult for the patients to use an eccentric retinal locus in the presence of an intact fovea. An even worse situation exists when there is advanced constriction of the field. Here the central
island is too small for reading, but there is no peripheral vision to allow compensation by eccentric fixation (Fig. 17.4c). In some of these cases contrast enhancement in combination with very small print size can help to get enough letters into the central island.
17.3.1.5.1 Direction of Scotoma Shift The shift of gaze, and with it the central scotoma, towards the upper visual field is the most favorable for reading: the line of text is free for reading and the lower visual field is free for spatial orientation. However, 20%–50% (Guez et al. 1993; Fletcher and Schuchard 1997; Sunness et al. 1996; Trauzettel-Klosinski and Tornow 1996; Messias et al. 2007) of patients shift the central scotoma to the right or left, which is specially unfavorable for reading. It is puzzling why such an unfavorable fixation locus is chosen by some patients. Additionally, the PRL is not solely dependent on the eccentricity and therefore the highest resolution around the scotoma. One possible explanation of these findings is that patients with a central scotoma benefit from permanently shifting their sustained attention to an eccentric location in the visual field. Sustained focal attention facilitates stimulus discrimination (Pilz et al. 2006). As the ease with which such attention shifts can be performed can depend on the direction of the shift, a new area for fixation and reading below the scotoma may be very difficult to achieve for some subjects (MacKeben 1999). In a subsequent study, we have shown that this can indeed explain seemingly awkward choices of an eccentric retinal fixation locus in some pa-
17.3 Diseases of the Visual Pathways and their Functional Deficits
tients with maculopathies (Altpeter et al. 2000). Patients who had good attentional capabilities in the lower visual field showed a fixation locus below the scotoma. If attentional capabilities were reduced in the lower visual field, these patients preferred a fixation locus left or right of the scotoma, since attentional capability was generally better on the horizontal meridian. There are some indications that these attentional mechanisms can be improved by training. Therefore, it should be possible to detect locations with reduced attentional capabilities before eccentric fixation develops and to provide goal-directed training for those patients who are at risk of developing an unfavorable PRL.
Summary for the Clinician
■ Optic neuropathies can cause various field defects. ■ It is crucial that patients with a central
scotoma use an eccentric fixation locus, the reduced resolution of which can be compensated for by text magnification. Stable eccentric fixation can be determined by the position of the blind spot in the perimetry, as it is shifted together with the scotoma. Ring scotomas and arcuate scotomas can lead to an insufficient size of the reading visual field. In these cases, one may have to wait for the central fields of both eyes to develop absolute scotomas, so that eccentric fixation can develop. In constricted concentric fields, the central seeing island can be too small for reading. Contrast enhancement with very small letter size can be helpful.
■
blind temporal hemifields, resulting in a completely blind triangular area posterior to fixation (Kirkham 1972). In patients with bitemporal hemianopia there is no normal overlap of the nasal visual fields, which prevents fusion. Therefore, pre-existing phorias easily decompensate to tropias, thus causing the “hemifield slide phenomenon” (Fig. 17.5). In cases of pre-existing esophoria or intermittent esotropia, patients will experience a separation of the nasal hemifields, causing a blind area in the center of the field. Patients with pre-existing exophoria or intermittent exotropia will have an overlap of the two hemifields, and patients with pre-existing hyperdeviations will experience a vertical separation of the images crossing the vertical meridian (Kirkham 1972). This hemifield slide phenomenon has a severe impact on everyday life by causing difficulties with reading or separation of a sequence of optotypes, which can be specially disabling in the case of long numbers, for example a banker does not know if an account has 500 000 Euro or 5 000 or maybe even 5 millions (see Fig. 17.5). It is important that patients be made aware of this phenomenon to guard against misinterpretations of reading material. Monocular reading can be helpful in these cases.
■
Summary for the Clinician
■ Bitemporal hemianopia causes problems
with spatial orientation due to the constricted temporal fields (“blinkers visual fields”). The lack of overlap of the nasal fields can cause the hemifield slide phenomenon with severe confusion during reading. Patients have to be made aware of this phenomenon to protect themselves from misinterpretations.
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17.3.2 Optic Chiasmal Syndromes Other disturbances have to be considered in addition to the well-known orientation impairment caused by limited temporal fields: one type affects depth perception, which leads to difficulties with near-distance tasks such as sewing, threading needles or using precision instruments. In these cases, convergence causes crossing of the two
17.3.3 Suprachiasmatic Lesions of the Visual Pathways Visual field defects are typified by the location of their causative lesion. In suprachiasmatic lesions the visual field defect is homonymous, mostly an upper or lower quadrant, or a complete hemiano-
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Fig. 17.5. Hemifield slide phenomenon in bitemporal hemianopia: absence of the normal overlap of the nasal visual fields prevents fusion and causes overlap of the two hemifields in exodeviation, separation of the two hemifields in esodeviation and vertical separation in hyperdeviation (after Kerkham 1972). This hemifield slide phenomenon causes severe problems with reading words and especially long numbers (see text)
17
pia with macular splitting. In cases with sparing of the occipital pole there is a sparing of 2°–5° in the blind hemifield along the horizontal meridian, called macular sparing (Trauzettel-Klosinski and Reinhard 1998; Reinhard and TrauzettelKlosinski 2003). Alternatively, in cases showing an isolated lesion of the occipital pole, a small paracentral homonymous defect can result. The pathogenesis of homonymous field defects is mostly ischemia (59%–89%), less often tumors or hemorrhage (3%–23%), surgery and trauma (2%–14%), and others (4%–7%) (summarized results of several studies in Kölmel 1988; Trobe et al. 1973; Zihl and von Cramon 1986; Zhang et al. 2006). In the majority of cases the lesion is located in the occipital lobe (45%) and in the optic radiation (32%) (Zhang et al. 2006).
17.3.3.1 Hemianopic Reading Disorder Homonymous hemianopia causes severe reading problems, since in complete hemiano-
pia half of the reading visual field is obscured (Fig. 17.6a; 1). If there is a macular sparing, the reading visual field can be preserved and reading can be normal, despite the fact that there is a large field defect in the remaining hemianopic side (Fig. 17.6a; 2). Then again, a small paracentral homonymous scotoma, which occurs in cases with an isolated lesion of the occipital pole, causes severe problems with reading, because it covers half of the reading visual field (Fig. 17.6a; 3). These small paracentral scotomas are easily overlooked in automated perimetry if the grid of the test program is not dense enough. Hence, an especially dense grid should be chosen, while manual perimetry allows for a specific search for small scotomas. The severity of the reading problems in hemianopia not only depends on the distance of the visual field defect from the center, i.e., the size of the reading visual field, but is also influenced by the side of the defect. In left to right readers a hemianopic field defect to the right side is extremely impairing, because the visual field defect is in the reading direction. Figure 17.7 shows on the left the eye movements for a normal subject; in the middle, for a patient with right hemianopia. This patient needs many more saccades per line and makes a lot of regressions to get through the line. A patient with left hemianopia (right) gets through the line quite easily, but has difficulties in finding the beginning of the next line, which is shown by the additional steps during the return sweep. Patients with hemianopia can learn compensating strategies: they perform frequent eye movements towards the blind hemifield, i.e., explorative saccades to increase the field of gaze. In early stages they often show a staircase pattern, and later an overshoot or predictive strategy (Meienberg et al. 1981). Another compensating strategy can be eccentric fixation in cases with macular splitting (Fig. 17.6b). The patient in Fig. 17.6b uses a slightly eccentric retinal locus for fixation, which causes little sacrifice of visual acuity, and creates an extended perceptual span along the vertical midline that is crucial for fluent reading. Eccentric fixation causes a shift of the field defect towards the hemianopic side in conventional perimetry, which can be misinterpreted as improvement of the visual field. This process indicates a
17.3 Diseases of the Visual Pathways and their Functional Deficits
high cortical plasticity, because the new eccentric fixation locus is not only used as the new center of the visual field, but also as the new center of the coordinates of the reading eye movements, which means a shift of the sensory and motor reference. It should be emphasized that these pa-
tients have intact foveal vision and are still able to use an eccentric fixation locus if it is required by the task. When visual acuity is tested, they use their foveola for highest resolution (TrauzettelKlosinski 1997).
Fig. 17.6a,b. The impact of a homonymous field defect on reading performance. a 1: In macular splitting half of the reading visual field is covered by the field defect, which leaves no ability to read. 2: If there is a macular sparing, reading ability is preserved, even though there is a large field defect, which causes spatial orientation problems. 3: A small paracentral homonymous defect causes severe reading problems. b 1: Eccentric fixation of 1°–2° by a shift of the retinal fixation locus towards the healthy retina (SLO image). This creates a new functional midline and a shift of the visual field border towards the hemianopic side in conventional perimetry (2). 3: Eccentric fixation creates a small perceptual area along the midline, which widens the reading visual field
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Fig. 17.7. Left: text on an SLO fundus image (the subject sees the text upright, the examiner sees it upside-down). Right: eye movements during reading of one line of text (schematic). The normal subject needs four saccades to get through the line and performs an accurate return sweep. A patient with right hemianopia makes many more saccades and several regressions per line, has a markedly prolonged reading time, but has no problems with the return sweep. On the other hand, a patient with left hemianopia has no major problems getting through the line, but he/she has difficulties finding the beginning of the next line, as indicated by several additional steps during the return sweep
17.3.3.2 Hemianopic Orientation Disorder
17
Summary for the Clinician
■ Patients with right-sided hemianopia are
Patients with hemianopia are severely impaired in spatial orientation. They often bump into obstacles on the hemianopic side and have to learn to perform explorative saccades towards the hemianopic side, which many patients start doing spontaneously. In conventional perimetry, this behavior shifts the field defect to the blind side and this is often misinterpreted as an improvement of the visual field.
more impaired than those with a leftsided hemianopia, because the field defect is in the reading direction. They have to make many saccades to get through a line of text. Patients with left-sided hemianopia have difficulties finding the beginning of the next line. Small paracentral homonymous defects can easily be overlooked in routine perimetry. Apply manual perimetry or a dense grid in automated procedures! Eccentric fixation can be helpful to create a small perceptual span along the vertical midline. Spatial orientation problems caused by homonymous hemianopia can be improved by frequent saccades towards the blind hemifield.
■ ■
Summary for the Clinician
■
■ Hemianopic reading disorder is charac-
terized by a reduced size of the reading visual field. If there is a macular sparing of 2º–5°, reading is normal, otherwise it is severely disturbed.
■
■
17.4 Diagnostic Procedures to Examine Reading Ability
17.3.4 Cortical Visual Impairment Cortical visual impairment (CVI) is an underestimated diagnosis. Many causes exist, but the most common one is hypoxic-ischemic brain injury in preterm and term infants (Dutton and Jacobson 2001; Good et al. 2001; Hoyt 2003). Equally important and often ignored is the fact that quite different patterns of brain damage can result from hypoxic-ischaemic insults depending on the child’s age, as well as the location, severity and duration of hypoxia. A certain degree of recovery occurs in cases of striate cortex injury, but not in those of periventricular leucomalacia (Hoyt 2003). The main problem is the quantitative assessment of residual visual function, which is hindered by reduced compliance and the fact that many of these children have multiple disabilities. Measuring visual acuity is not sufficient, and there is a need for more specific tests to improve functional diagnostics in regard to specific rehabilitation programs. Many children do not only have reduced visual acuity, but also visual field defects, strabismus, nystagmus, decreased contrast sensitivity, and oculomotor disorders. Often they have difficulties in information processing and integration, sometimes specific agnosias; for example, central achromatopsia (color desaturation), prosopagnosia ( problems in recognizing faces), cerebral akinetopsia (inability to perceive moving targets), simultanagnosia ( inability to focus on more than one visual object at a time), astereocognosis (difficulties with depth perception), and topographic agnosia (problems with orientation) (Good et al. 2001). Early assessment is critical. Visual and cognitive development are closely related (Good et al. 2001). For children with CVI, a simplified visual environment is more beneficial than diverse stimulation, because it forces them to focus attention on a particular visual stimulus (BakerNobles and Rutherford 1995; Good et al. 2001). Color, high contrast, and use of motion may facilitate recognition of an object (Baker-Nobles and Rutherford 1995).
17.4 Diagnostic Procedures to Examine Reading Ability • Specific diagnostics in regard to the existing and the potential reading ability is the basis for rehabilitation programs. • Exact determination of the refractive error is necessary because insufficient corrections would be enhanced while using magnifying visual aids. • Visual acuity for distance: if visual acuity ≤0.1, the measurement should be performed by ETDRS charts, because they allow more steps in the low vision range by reducing the distance. • Near visual acuity and range of accommodation. • The most important examination is determination of the magnification requirement. This tells immediately whether magnification is effective at all and, if so, how much magnification is necessary. Different charts are available in different languages: MN-Read charts and Reading Navigator in many languages, Zeiss charts, Radner charts in German, and, for children, Lea Symbols. The smallest print size that can be read fluently corresponds to the magnification need. Even though mathematically there is a reciprocal relationship between visual acuity and magnification need, in reality there is often a discrepancy (for example, in a ring scotoma with good visual acuity versus high magnification need, see above). Therefore, measurement of magnification need is crucial for the future visual aid. • Examination of parafoveal contrast sensitivity: for determination of potential reading ability, also for assessment of eccentric retinal areas that are suitable for reading, the Macular Mapping Test (MacKeben et al. 1999; Trauzettel-Klosinski et al. 2003) is a valuable method. • Reading speed should be determined by reading a text passage aloud. A whole text passage is preferable to a single sentence for more accurate speed measurement and judgment of fluency and mistakes. For this test, a newly developed set of equivalent texts in different languages is available, which can also be used for repeated testing. The texts are com-
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parable not only within one language, but also between different languages. Therefore, they are optimally suited to be used in international studies (the texts are available at the moment in English, French, Finnish, German, soon also in Brazilian-Portuguese, Arabic and other languages – see www.amd-read.net). • Determination of fixation behavior is necessary if discrepancies between good visual acuity and impaired reading performance arise. Perimetry, specially the manual kinetic procedure, is a very suitable method for localizing the blind spot. The fixation locus can also be determined by direct ophthalmoscopy with the fixation star or with a newly developed modified slit lamp. Fixation photography, corneal reflexes, and fixation at the Scanning Laser Ophthalmoscope (SLO) are further methods. • Recording of eye movements during reading is a valuable method for scientific studies, showing the oculomotor reading strategy in detail. • A standardized test set for the required diagnostic steps is provided as a Low Vision Test Battery (see www.amd-read.net).
Summary for the Clinician
■ Visual acuity, refraction and accommodation are basics. ■ Magnification need guides to the future visual aid requirement and indicates whether magnification is effective. Reading speed with standardized texts provides crucial information regarding how well the patient is coping with reading demands in everyday life. A Low Vision Test Battery can be used as a standardized test set for clinical and research examinations.
17
■ ■
17.5 Rehabilitation Programs The aim of rehabilitation is to optimize the use of residual vision, with the particular goal of improving reading and spatial orientation, so that the patient’s independence and quality of life can be regained or maintained.
Table 17.1 lists the different approaches for rehabilitation.
17.5.1 Visual Aids in Reading Disorders Magnifying visual aids are a main tool (Tables 17.2, 17.3) in the rehabilitation of patients with a central scotoma, because in these cases they are particularly effective. In some patients, additional contrast enhancement can be helpful. It is important to provide sufficient illumination and, thus, optimal contrast. Figure 17.8 shows some examples of the wide spectrum of magnifying visual aids; for example, handheld magnifiers, stand magnifiers, simple high plus spectacles, and telescopic spectacles. Handheld and stand magnifiers have the advantage of a comfortable working distance. When using magnifying spectacles the text has to be moved markedly closer, especially when using simple high plus spectacles. Telescopic magnifying spectacles allow a longer viewing distance, but they are cosmetically unfavorable. In patients with a magnification requirement of more than 8 times, who have no experience with optical magnification, mostly an electronic reading device (CCTV monitor) should be chosen. Illumination should be without glare and free of UV and IR light (should contain a cold light source). It is helpful if the brightness can be varied, which can be achieved by a simple dimmer switch. The success rate of magnifying visual aids regarding reading ability is high: in a cohort of 763 patients of our low vision service, only 13% were able to read newspaper print before consultation, but 90% were able after consultation. The cohort of all patients with a central scotoma (n=293) showed a success rate of 94% and the subgroup of patients with age-related macular degeneration (AMD) (n=191) also showed a success rate of 94%. This shows that age alone is no obstacle (Trauzettel-Klosinski et al. 2000). Selection of the appropriate visual aid depends on: ▶ the kind of visual field defect ▶ magnification need ▶ the kind of task ▶ dexterity ▶ motivation ▶ prognosis
17.5 Rehabilitation Programs
Table 17.1. Rehabilitation approaches to reading disorders Visual aids
Magnifying Contrast enhancing Illuminating
Training
Handling of the visual aids Learning compensation strategies Utilization of the best retinal fixation locus Special reading training
Counseling in regard to public support
Considering the effect of the visual impairment on education, profession and leisure time
Table 17.2. Visual aid approaches Magnification
Visual aids, optical and electronic
Contrast enhancement
Tinted glasses Cut-off filters Polarizing cut-off filters Illumination CCTV monitor
Glare reduction
Tinted glasses
Table 17.3. Magnifying visual aids Optic
Electronic
Handheld magnifiers
Handheld magnifiers
Simple magnifying spectacles (high plus lenses)
Video magnifiers
Telescopic spectacles
PC work stations
Handheld telescopes
Video spectacles
17.5.2 Visual and Other Aids in Spatial Orientation Problems Visual aids for distance are telescopes, so-called monoculars, which are available in different magnification steps (Fig. 17.8; 13). They enable
patients to read numbers on a bus, and the names of streets, for example. Often it is necessary to provide orientation and mobility training and training for daily living skills. In some patients, an ultrasonic device for detecting obstacles can be an additional help.
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Fig. 17.8a,b. Visual aids. a 1–13: Optical magnifying visual aids [1 Stand magnifier, 2 chest-supported magnifier, 3–7 handheld magnifiers: hand-held magnifier with illumination (3), dome magnifiers (4, 5), pocket magnifier (6), bar magnifier with underlining (7), 8 clip-on magnifier, 9 magnifying spectacles (high plus lenses, hyperoculars), 10–12 telescopic spectacles: Galilei system (10, 11), 12 Kepler system. 13 cut-off filters for contrast enhancement.] b Electronic magnifying aids: video magnifiers with different options (left: contrast inversion; middle: with real colors; right: portable systems)
17.5.3 Training 17.5.3.1 Training for Patients with Circumscribed Scotomas in the Central Field Training in operating the visual aids is crucial. Patients need to learn that they can use only a limited distance to the reading material when they use a magnifying spectacle, and that they can benefit from moving the text in front of their
eyes when a very short reading distance is used. A book rest is helpful in maintaining an ergonomically good posture for longer periods of reading. Learning compensating strategies will become increasingly important: on the one hand, this could be training to use the best retinal locus for reading; on the other hand it could be specific reading training, which can widen the perceptual span and improve the saccadic strategy. Regarding eccentric fixation training, several studies have reported positive results (Frennesson et al. 1995; Nilsson.et al. 2003; Watson 2002).
17.5.3.2 Training for Patients with Homonymous Field Defects 17.5.3.2.1 The Controversy about Training in Hemianopia The following issues with training studies should be considered (see also Trobe et al. 2005): • Specificity: spontaneous recovery can occur, especially in the first few months. Further, a control group is crucial to verify any improvement. • Reliability: the way in which the training effect is assessed is important, i.e., whether appropriate methods are used to detect any changes. • Aim: another important point is how improvement is defined. From what degree of change is an improvement clinically relevant? Spontaneous recovery can occur at a range of 7%–53 %, depending on the definition of improvement and the cohort of observed patients (Kölmel 1988; Trobe et al. 1973; Zihl and von Cramon 1986). Studies in which only behavioral parameters were judged showed an improvement of 60% to over 80% (Hier et al. 1983). The problems of conventional perimetry are: (1) limited spatial resolution, (2) scattering light of the stimulus, and (3) insufficient fixation control. In contrast, the scanning laser ophthalmoscope (SLO) presents an inverse stimulus without light scattering. Additionally, the SLO allows simultaneous fixation control during stimulus presentation. The vertical visual field border depends essentially on the quality of fixation: if fixation is stable and central, there is good agreement between conventional perimetry and SLO perimetry. If fixation is unstable or eccentric, the visual field border is shifted towards the hemianopic side in conventional perimetry, which can mimic an improvement of the visual field defect (Trauzettel-Klosinski and Reinhard 1998). Therefore, for judging the visual field border, it is necessary also in conventional perimetry to control fixation and to be aware of shifts by eye movements. There are two different approaches and goals for training: restitution and compensation. In
17.5 Rehabilitation Programs
former studies with restitution training the stimulation was performed at the border of the hemianopic field defect. Here the risk is stray light and eye movements towards the stimulus (Kasten et al. 1998; Zihl and von Cramon 1979). The goal of restitution training is to re-activate incompletely damaged neurons in the blind field and to enlarge the visual fields by stimulation at the border of the field defect. Perimetric targets were presented at threshold along the visual field border (Zihl and von Cramon 1979). The authors reported an improvement of the visual field up to 40º. In a later study (Balliet et al. 1985) these results could not be confirmed. In the study by Kasten et al. (1998) visual restitution training (VRT) was performed by presenting perimetric targets above threshold along the visual field border. The authors described an extension of the seeing hemifield by approximately 5º. Then againhand, Reinhard et al. (2005) performed an SLO study before and after VRT using fundus perimetry with simultaneous fixation control and a grid of 0.5° spatial resolution horizontally and 1° vertically in the 10° visual field. In this case, no improvement of the visual field could be found. Also in a study with conventional perimetry no relevant effect after VRT was described (Schreiber et al. 2006). The restitution training studies present the stimulus along the vertical field border, which should be differentiated from another kind of stimulation performed in the periphery of the visual field and where residual vision was described in a few, well-trained patients. This “blindsight” is an unconscious perception of visual stimuli via the superior colliculus to extrastriate regions without activation of V1 (Pöppel et al. 1975; Vanni et al. 2001; Weiskrantz 2004). It is an open question whether training can improve this kind of residual vision to a level that is relevant for everyday life. Compensating training assumes a stable border between the seeing and non-seeing hemifields. The goal here is to enlarge the field of gaze by frequent eye movements into the blind hemifield by shifting attention to the blind side. This kind of training can be effective at improving the utilization of the blind hemifield (Kerkhoff et al. 1992; Pambakian et al. 2004). Optical aids are controversial; mirrors and prisms were described as beneficial in single
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cases but were not really adopted by large patient groups, because most patients are confused by the double images and the resulting interference with spatial orientation.
Summary for the Clinician
■ Training is important for optimizing the use of residual vision. ■ Training has to be specific to the visual deficit. ■ The value of training should be related to
17.5.3.2.2 Recommended Methods • Training to shift visual attention towards the blind hemifield • Compensatory search strategies - Frequent saccades towards the hemianopic side for enlargement of the saccadic search field - Specific visual search to systematize search strategies • Utilization of information from the blind hemifield to the seeing one (parts of objects, stray light, reflections) • Training in the real-life environment of the patient • Training with an orientation and mobility trainer • Specific explorative training at a monitor or on a sheet of paper (Kerkhoff et al.1992; Pambakian et al. 2004; Zihl 1995), which was reported to be beneficial, but none of these studies included a control group
17
Approaches to improve the hemianopic reading disorder include: • Training predictive saccades, especially in left-sided hemianopia to improve the ability to find the beginning of the next line • Training to improve orientation on the page, visual and tactile tools (bar magnifier with underlining, ruler or forefinger are helpful) • Special reading training with scrolling text (Kerkhoff et al. 1992; Zihl et al. 1984) • Moving the text into a vertical or diagonal position may be beneficial, but has not been tested in a larger patient group • Another approach can be eccentric fixation to enlarge the perceptual span A general recommendation is to explain to the patient and relatives the special nature of the visual impairment in detail and to inform them that he/ she is not allowed to drive. (This law is valid in Europe and some of the states in the USA, where exceptions exist for getting a restricted license.)
its relevance for everyday life.
17.5.4 Counseling Regarding Public Support When the procedure of selection, adaptation, and coordination of visual aids and of training is completed, consideration should be given to how the visual impairment will affect the patient’s education, profession, leisure time and, in elderly patients, the ability to maintain an independent life style. Self-help organizations, and help from neighbors and other social services can be very valuable and can help to maintain a patient’s independence. Sometimes it is necessary to include a psycho-social consultation, especially if the eye disease additionally causes depression in elderly patients. In addition, it is important to find out whether, and to what degree, the patient can expect receiving support from government agencies and institutions, which may vary between different countries.
17.6 Summary and Conclusions The ability to read can be regained if foveal function is lost and fixation is eccentric. The reduced spatial resolution of retinal areas outside the fovea can be compensated by magnification of the text. If the fovea is intact (for example, in patients with a ring scotoma or hemianopia) and fixation is central, the problem is the limited size of the reading visual field. Here, eccentric fixation has to be waited for or trained, or the print size has to be kept very small in conjunction with contrast enhancement. For hemianopic patients, diagonal or vertical text orientation might be helpful, and help via tactile or visual orientation on the page can be recommended. The precondition for reading is therefore sufficient spatial resolution of the retinal area used for reading as well as sufficient
References
size of the reading visual field. Eccentric fixation means shifting the zero point of not only the sensory coordinates but also the oculomotor system. This indicates a high cortical plasticity. Attempts to rehabilitate are always worthwhile, because the success rate is high. Future developments of new electronic visual aids and specific training procedures will be of increasing importance. The demand for ophthalmological and neuroophthalmologic rehabilitation will increase because of the growing number of patients with age-related maculopathy, of children with CVI, and of vascular disorders of the brain that are associated with hemianopic field defects. More services for visual rehabilitation are required. Furthermore, rehabilitation procedures should become more specific by being tailored to the individual’s impairment. The main aim of rehabilitation is to improve patients’ quality of life. A further important point is also to avoid secondary costs by keeping the patients independent. Research in neuroophthalmologic rehabilitation is not only important for the patients, it also bridges a gap between the fields of neuroophthalmology and low vision and can stimulate future scientific projects. Research in the field of neuroophthalmologic rehabilitation is of great scientific interest due to the involvement of cortical plasticity and sensorimotor adaptation. Especially important questions in the future will be: which visual deficits cause which disabilities in everyday life and which treatments, aids and training methods are most relevant for everyday life? Measuring performance in activities of daily living tasks will be of ever growing importance.
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Subject Index
13-cis-retinoic acid 191 3243A>G mutation 273 3D scene 119
A abcr–/– knockout mouse model 190 abducens nerve paresis 211 abnormal axonal metabolism 39 ACR. see American College of Rheumatology acute idiopathic blind spot enlargement 173, 178 – fluorescein angiography 173 acute idiopathic optic neuritis 12 – intravenous methylprednisolone 12 – oral prednisone 12 acute macular neuroretinopathy 178 acute peripheral vestibulopathy 284 acute retinal necrosis 222 acute zonal occult outer retinopathy 178, 179 – EOG 179 – ERG 179 acute zonal occult outer retinopathy complex 179 acyclovir 179, 222 adenine nucleotide translocator 271
ADOA. see autosomaldominant optic atrophy adventitial layer 228 afferent pupillary defect 173 age-related macular degeneration 185, 186 age-related maculopathy, 317 agnosias 311 AIBSE. see acute idiopathic blind spot enlargement AIDS 209, 221 AIF. see apoptosis-inducing factor AION. see anterior ischemic optic neuropathy albendazole 210 albinism 154 – mfVEP 154 – visual pathway 154 allogeneic subretinal transplantation 193 altitudinal loss 26 altitudinal visual field defect 20 Alzheimer disease 113, 187 amacrine 196 amaurosis fugax 233 AMD. see age-related macular degeneration (AMD); see age-related macular degeneration American College of Rheumatology 241 amiodarone 29 anemia 32, 240 aneurysm 237 angioid streaks 40
ANT. see adenine nucleotide translocator anterior ischemic optic neuropathy 19, 20, 46, 234, 242, 305 – arteritic 20, 234 anterior vermis 291 anti-angiogenic protein 198 anti-retinal antibody 171 antigen 163, 166 – 23-kDa 166 antioxidant 189, 191 aorta 237 aortitis 237 APD. see afferent pupillary defect apoptosis 167 – inducing factor 187 apoptosome 188 arachnoid hyperplasia 74 arenaviridae family 220 argon laser 105 – photocoagulation 46 Argyll Robertson 215 ARN. see acute retinal necrosis ARRON. see autoimmunerelated retinopathy and optic neuropathy arteritis 222 arthralgias 231 aspartate-specific endopeptidase 187 aspirin 25, 31, 246 astereocognosis 311 astrocyte 83, 195 ataxia 290, 294 atovaquone 207
322
Subject Index
autofluorescence 41 autoimmune – disease 179 – retinopathy 163 autoimmune-related retinopathy and optic neuropathy 171 automated perimetry 308 automated static perimetry 152 autosomal-dominant optic atrophy 52 – prevalence 52 axonal – damage 13 – regeneration 92 – transport 89 – interruption 89 azithromycin 207 AZOOR. see acute zonal occult outer retinopathy
B B. burgdorferi senso lato 211 baclofen 292, 293 Balint’s syndrome 262 balloon angioplasty 247 barbiturate 294 Bartonella 214 – henselae 214 Bcl-2 family 188 BCNU 29 BDNF. see brain-derived neurotrophic factor BDUMP. see bilateral diffuse uveal melanocytic proliferation Behr’s syndrome 64 Bell’s phenomenon 268 BENEFIT 13 beta-galactosidase 193 bilateral diffuse uveal melanocytic proliferation 164, 169, 170, 171 – fluorescein angiography 170 – melanocytic proliferation 171
– radiation 171 – systemic steroid 171 bilateral homonymous hemianopia 221 binocular disparity 129 binocular receptive field 120 bipolar cell 196 birefringence 107 blastocyst 195 blind – field 315 – hemifield 308, 315 blindness 185 blindsight 315 blind spot 306 – enlargement 172, 178 blind spot enlargement. see also enlargement blind spot blinkers visual field 307 blockade of axoplasmic flow 39 blood-oxygen-level dependent 120, 121, 129 – response 121 – signal 129 BOLD. see blood-oxygen-level dependent bone-marrow-derived mesenchymal stem cell 195 Borrelia burgdorferi 210 brachium conjunctivum 291 Bradyzoite 206 brain-derived neurotrophic factor 198 – transgene 192 brain MRI 11 brainstem cavernoma 294 breast carcinoma 76 – metastasis 76 Broca region 302 Bruch’s membrane 38, 73 bupivacaine 277 buried drusen 37
C C-reactive protein 24, 230, 239 C10orf1 271 calcarine sulcus 147 calcium
– antagonist 189 – channel blocker 167, 168 – homeostasis 89 calpain 188 cancer-associated retinopathy 164 capillary 83 CAR 166. see cancerassociated retinopathy – antigen 166 carbamazepine 265, 288 carcinomatous meningitis 164 carotidynia, 236 caspase 187 – inhibitor 167, 168 cataract 100, 279 cathepsin 188 – B 188 – D 188 – L 188 cat scratch disease 214 – fluorescein angiography 214 CB. see ciliary body cecocentral scotoma 303 cell transplantation 193 central – achromatopsia 311 – retinal artery occlusion 235 – vein occlusion 46 – vestibular disorder 289 – visual acuity 186 centro-caecal defect 52 cerebellar – ataxia 273 – encephalitis 296 – purkinje cell 292 cerebellum 261 cerebral toxoplasmosis 209 cerebrospinal fluid 86 CFEOM. see congenital fibrosis of the extra ocular muscles chalk-white pallor 22 CHAMPIONS 13 CHAMPS 8, 13 channelopathy episodic ataxia type 2 290 checkerboard pattern 143 Chiari malformation 290 chiasmal disease 173 chlamydia pneumoniae 228
choriocapillaris 177 chorioretinitis 210, 220 choroidal – effusion 215 – filling 27 – infarction 235 – ischemia 22, 234 – reflectivity 177 choroiditis 215 chromatic stimulus information 126 chromosome 55, 58, 59, 64, 72 – 18q12.2-q12 58 – 19q13.2-q13.3 58 – 22 72 – 3q28-qter 55 – 4p16.1 64 – 4q22-q24 64 – 8q21-q22 59 chronic papilledema 111 chronic progressive external ophthalmoplegia 267, 271, 272 – autosomal-dominant 271 – recessive 272 chronic progressive external ophthalmoplegia plus 268 – multisystemic involvement 268 ciliary – artery occlusion 234 – body 196 – marginal zone 196 – neurotrophic factor 192, 198 – transgene 192 cilioretinal artery occlusion 22, 235 cisplatin 29 citrate synthase 275 CJD. see Creutzfeldt-Jakob disease Claude’s syndrome) 259 clinoidal meningiomas 79 clonazepam 293 Cloquet’s canal 112 CMV infection 222 CNTF. see ciliary neurotrophic factor CNV. see choroidal neovascularization (CNV)
Subject Index
cochlear implant 277 coenzyme Q 276 – supplementation 276 coenzyme Q deficiency 273 Collier’s sign 261 colour vision deficit 71 compartment syndrome 26, 84 compensating – strategy 308 – training 315 compensatory search strategies 316 computational algorithms 121 confocal scanning laser – ophthalmoscopy 152 – tomography 100 congenital – fibrosis of the extra ocular muscles 279 – myasthenic syndrome 278 – myopathy 279 – toxoplasmosis 205, 206 congenitally crowded optic disc 112 contralateral – hemisphere 154 – visual loss 25 contrast enhancement 307 convergence 254, 261 – spasm 261 correlation coefficient 149 cortical – blindness 211 – magnification 143 – neuron 120 – representation 143 – visual impairment 302, 311 cortico-thalamic projection 121 corticosteroid 5, 10, 24, 86, 168, 169, 179, 244 Costeff ’s syndrome 64 cotton-wool spot 217, 233 cotton wool patches 22 COX-negative fibres 275 CPEO. see chronic progressive external ophthalmoplegia cranial – arteritis 236 – nerve 211 – neuropathy 212, 232
Creutzfeldt-Jakob disease 220 – Heidenhain variant 221 – iatrogenic 221 cricopharyngeal achalasia 277 cross-correlation 149 crowded optic disc 39 CRP. see C-reactive protein crumble cheese and ketchup 218 Ctenocephalides felis 214 cup-to-disc ratio 100, 106, 108 CVI. see cortical visual impairment CWS. see cotton-wool spot cytochrome c 57 – oxidase (COX) negative fibres 267 cytokine 189, 239 cytomegalovirus 218 – infection 218 – retinitis 112, 218
D dancing eye syndrome 296 dancing feet 296 dartboard-like pattern 143 DBN. see downbeat nystagmus deafness 64 decaprenyl diphosphate synthase subunit 1 and 2 273 dendritic cell 228 deoxyhemoglobin 119 diabetes 28 – mellitus 274 dichoptic masking 132 diffuse unilateral subacute neuroretinitis 210 dilated episcleral vessel 170 dimenhydrinate 287 diplopia 235, 277 disc – at risk 26 – edema 14 disinfection 221 DMTU 191 DNA cleavage 187 DNases 89 donor tissue 193
323
324
Subject Index
dorsal – midbrain syndrome 261 – stream 129 – vermis 261 downbeat nystagmus 261, 290 doxycycline 213 Drp1 57 drusen 186 DUSN. see diffuse unilateral subacute neuroretinitis dyschromatopsia 45, 52, 168, 177
E eccentric retinal fixation locus 306 eccentric viewing 306 edema 84 edematous retina 112 EGF 197 electronegative ERG 168 electronic reading device (CCTV monitor) 312 electron transport chain 61 – complexes I–IV 61 electroretinogram 139, 166 – retinopathy 166 ELISA test 212 embryonic stem 197 – cell 195 encephalitis 209, 212, 215 endocrine ophthalmopathy 279 EndoG. see endonuclease G endogenous stem cell 193 endonuclease 189 – G 187 endopeptidase 187 endoscopic optic nerve decompression 86 endurance training 278 enlarged blind spot 173, 176 EOND. see endoscopic optic nerve decompression ERG. see electroretinogram erythema migrans 211 erythrocyte sedimentation rate 23, 238
ES. see embryonic stem esotropia 255 ESR. see erythrocyte sedimentation rate ETDRS charts 311 ethanol 293 ETOMS 8, 13 exophoria 307 exotropia 307 exposed drusen 37 external ophthalmoplegia 279 extracellular matrix 83 extraretinal signal 120 extrastriate cortex 129 extrinsic pathway 188 ex vivo gene – therapy 193 – transfer 198 eye–head coordination 287 eyecup 196 eye movement 253, 302 – recording 302
F facial injury 84 facial nerve paresis 211 facies myopathica 268 facioscapulohumeral muscular dystrophy 279 FADD 188 Fas/CD95 188 fast Fourier transform 121 fatty acid metabolism 275 FCC. see fixed corneal compensator FEF. see frontal eye field fetal eyes 193 fetal retinal neuroblastic progenitor cell 194 fetal tissue 193 fever 211, 236 – of unknown origin 236 FFA. see flourescein angyography FFT. see fast Fourier transform FGF 197 fibrinogen 230 fibrosis 279
first-order kernel 142 fixation behavior 312 fixed corneal compensator 107 fixity of gaze 263 FLAIR 11 flame hemorrhages 20 flash electroretinogram 60 Flavivirus 210 floater 168 flocculus 290 flu-like symptom 206 fluorescein angiography 22, 27, 30, 44, 59 fMRI. see functional magnetic resonance imaging focal ERG 173 foscavir 222 fourth nerve palsy 288 foveal granularity 176 free radicals 89 frontal eye field 129, 257, 262 frozen sectioning 241 FSHD. see Facioscapulohumeral muscular dystrophy FTA-ABS test 216 functional magnetic resonance imaging 119 funduscopy 84 fundus photography 101
G G11778A 62 G3460A 62 GABA-ergic velocity storage mechanism 294 Gabapentin 294 ganglion cell 87, 89, 90, 149, 153 – apoptosis 87, 89 – arteritis 244, 245, 247 – balloon angioplasty 247 – atrophy 87, 90 – axon 84 – damage 153 – localize 153 – responses 149 gangrene 238
Gaussian-enveloped sinusoidal (Gabor) pattern 129 GCA. see giant cell arteritis GDx. see Scanning Laser Polarimeter gene – shifting 277 – therapy 198 generalized constriction 45 genetically engineered mouse model 189 genetic counselling 275 genotype–phenotype correlation 273 GFAP. see glial fibrillary acidic protein GFP. see green fluorescent protein giant cell arteritis 19, 20, 21, 32, 227, 231, 232, 233, 240, 241, 243 – audiovestibular manifestation 232 – color Doppler imaging 243 – diagnosis 240 – duplex ultrasonography 243 – endovascular intervention 247 – incidence 227 – MRI 243 – negative biopsy 241 – occult 21 – occult manifestation 232 – SPECT scintigraphy 243 – spontaneous remission 231, 244 – transient visual loss 233 – ultrasound 243 – visual loss 245 – visual manifestation 233 glatiramer acetate 13 glaucoma 100, 107, 108, 111, 152, 186 Glaucoma-Scope 103 glial fibrillary acidic protein 196 glioma 69, 74, 76 – radiotherapy 76 gliosis 88
Subject Index
gliotic proliferation 88 glucose metabolism 274 Gomori Trichrome staining 275 Goodpasture’s syndrome 163 granulom 210 granulomatous uveitis 211 granzyme 188, 189 Graves’ disease 163 green fluorescent protein 193 – mouse 193
H HAART. see highly active antiretroviral therapy halk-white pallor 22 halo sign 243 headache 20, 231, 236 head titubation 294 hearing loss 232, 273 heart conduction blocks 277 heat shock cognate protein 70 167 Heidelberg Laser Tomographic Scanner 105 Heidelberg Retinal Tomograph II 106 HeLa cells 56 helium-neon laser 105 hematopoietic cell 195 hemi-seesaw nystagmus 292 hemianopia 308 hemianopic reading disorder 308 hemifield slide phenomenon 307 hemiretina 154 hemorrhage 46, 84, 217, 294 herpes simplex 222 – virus 228 herpes simplex virus type 1 286 herpes zoster 32, 222, 279 herpetic encephalopathy 222 herpetic retinopathy 222 heteroplasmy 62, 270 highly active antiretroviral therapy 209, 219
hippocampus 284 histogenesis 187 HIV. see human immunodeficiency virus HLA-DR4 228 HLA-DRB1*04 228 HLA DRB1*04 allele 233 homeostasis 191 homocysteine 28 homonymous – defect 148 – hemianopia 308 horizontal-rotatory spontaneous nystagmus 284 horizontal cell 196 horizontal eye movement 255 – abducens 255 HSC70. see heat shock cognate protein 70 human immunodeficiency virus 112, 216, 217 – retinopathy 217 human visual area 121 human visual cortex 120 – retinotopic map 120 Humphrey® OCT3-Optical Coherence Tomography Scanner 109 Humphrey Retinal Analyzer 102 hyperbaric oxygen 31 hypercholesterolemia 28 hyperdeviation 307 hypoxic-ischemic brain injury 311
I ICGA. see indocyanine green angiography idebenone 63 idiopathic facial paresis 286 idiopathic optic neuritis 4, 5 – low-dose oral prednisone 5 – MRI 4 – natural history of acute 4 – recurrence 5
325
326
Subject Index
– spontaneous visual recovery 4, 5 IL-1β 240 IL-6 236 immune privilege 193 immunoglobulins 296 immunohistochemistry 193 impaired oxidative phosphorylation 274 INC. see interstitial nucleus of Cajal indirect optic neuropathy 84 indocyanine green angiography 44 infarct 26 – retrolaminar region 26 information processing 120 inherited optic neuropathy 51 inhibitory binocular interaction 125 innate immune response 230 INO 292. see internuclear ophthalmoplegia intentional saccade 262 interferon – alpha 29 – γ 229 intergenomic communication 271 – defect 271 interleukin (IL) – IL-6 230 interleukin-2 230, 239 internal elastic lamina 230 International Optic Nerve Trauma Study 86 internuclear – ophthalmoplegia 255, 292 interocular – latency difference 149 interstitial nucleus of Cajal 293 intorsion 288 intracellular calcium 167 intrachiasmatic craniopharyngioma 74 intraocular pressure 186 intravenous – immunoglobulin 13 – methylprednisolone 12
intrinsic pathway 188 IONDT. see Ischemic Optic Neuropathy Decompression Trial IONTS. see International Optic Nerve Trauma Study ipsilateral hemisphere 154 ipsilateral peripheral facial paralysis 256 ischemia 91 ischemic optic neuropathy 19, 234 – recurrent episode 234 Ischemic Optic Neuropathy Decompression Trial 23, 31 IVIG. see intravenous immunoglobulin Ixodes ricinus 210, 211
J Jarisch–Herxheimer reaction 215 jaw claudication 20, 231, 232, 236 JC virus 221 jerk – nystagmus 263 – oscillation 292 juvenile cataract 268 juxtapapillary retinochoroiditis 208
K Kaplan Meier curve 77 Kearns-Sayre syndrome 268, 276 KSS. see Kearns-Sayre syndrome
L l-carnitine 63 lactic acidosis 277 lagophthalmos 268 Lambert-Eaton syndrome 278
lamina cribosa 39, 114 large-vessel vasculitis 237 – magnetic resonance imaging 237 – Positron emission tomography (PET) 237 lateral geniculate nucleus 121 layer 4cα of primary visual cortex 125 LCMV. see lymphocytic choriomeningitis virus Leber’s hereditary optic neuropathy 59, 60, 111, 270 – MRI 60 Leber’s optic atrophy 303 Leber’s stellate neuroretinitis 112 LEDGF. see lens epithelium derived growth factor lens epithelium derived growth factor 191 Lentivirus 216 LESC. see limbal epithelial stem cell leucocoria 210 levator palpebrae muscle 277 levodopa/carbidopa 31 LGN. see lateral geniculate nucleus LHON 114. see Leber’s hereditary optic neuropathy light-induced neurodegenerative animal model 191 light-near dissociation 261 light damage 191 – animal model 190 limbal epithelial stem cells 197 limb claudication 238 linear regression analysis 108 lipofuscin 191 lipohyalinosis 26 lithium 294 local object motion 128 low-coherence reflectometry 109 LTS. see Heidelberg Laser Tomographic Scanner lumbar puncture 12 lupus erythematosus 32
lyme disease 211, 212 lymphocytic choriomeningitis virus 220 lymphocytic meningitis 212 lymphoma 76
M m-sequence 124, 140 macrophage 229 macula 186 macular – mapping test 311 – scar 207 – splitting 308 – star 214 maculopathy 305 magnetic resonance imaging (MRI) 114 – extremely highresolution 114 – µMRI 114 magnifying visual aid 312 mammalian eye 195 mapping 120 MAR. see melanomaassociated retinopathy masquerade 74, 76 maternal transmission 277 medial longitudinal fasciculus 255, 292 medial superior temporal areas 263 medial vestibular nucleus 257 medication toxicity 29 megadose steroid 86 melanocytic proliferation 171 melanoma-associated retinopathy 164, 168 MELAS syndrome 273 meningeal thickening 88 meningioma 69, 71, 75, 76, 79 – radiotherapy 79 meningitis 86, 211, 215, 217, 220 meningoencephalitis 209, 211, 217, 220 metformin 277 methotrexate 246
Subject Index
methylprednisolone 24, 91, 245, 287 MEWDS. see multiple evanescent white dot syndrome mfERG. see multifocal ERG mfVEP 149, 154 – abnormality 154 – latency 149 mfVEPs. see multifocal visual evoked potentials micro-saccade 129 microglial cell 83 microvascular decompression 288 midazolam 277 middle superior temporal area 127 middle temporal area 127 minimum reading visual field 302 mirror sign 121 mitochondrial calcification 39 mitochondrial DNA 61, 267, 272, 273 – human 61 – multiple deletions 272 – point mutation 61, 272 – replication 273 – single deletions 271 mitochondrial endopeptidase 56 mitochondrial function 191 – in extraocular muscle 267 mitochondrial genetics 270 mitochondrial inheritance 51 mitochondrial membrane integrity 191 mitochondrial mutation 62 – LHON-Associated 62 mitochondrial proliferation 275 mitotic segregation 271 MLF. see medial longitudinal fasciculus MNGIE 270 MNGIE syndrome 273 mobility training 313 molecular mimicry 164 monocular 313
– oscillation 288 – reading 307 monoptic visual masking 132 mother-to-offspring transmission 271 motile chorioretinal nematode 210 motion perception 5 motion stimuli 127 – contrast-modulate 127 – luminance modulate 127 MRI. see magnetic resonance imaging (MRI) MS. see multiple sclerosis MST. see middle superior temporal area; see medial superior temporal areas mtDNA. see mitochondrial DNA Müller glia 196, 199 multifocal choroiditis 178 multifocal ERG 139 multifocal visual evoked potentials 139 multinucleated giant cell 241 multiple evanescent white dot syndrome 112, 176, 177, 178 – fluorescein angiography 176 – foveal granularity 177 – indocyanine green angiography 177 – ocular coherence tomography 177 multiple sclerosis 4, 5, 9, 112, 154 – brain MRI 5 – like symptom 61 – McDonald criteria 9 – predictor 5 – risk of developing 5 multisystemic symptom 268 muscle biopsy 275 – biochemistry 275 muscle specific tyrosine kinase 278 MuSK. see muscle specific tyrosine kinase Mutton fat precipitates 207
327
328
Subject Index
MVN. see medial vestibular nucleus myasthenia gravis 163, 278 myasthenic syndrome 278 myelin-associated glycoprotein 89 myelin sheath 88 myelitis 215 myoclonus 294 myofibroblast 230 myotonic dystrophy 279
N N-methyl-d-aspartate (NMDA) 294 NAION. see nonarteritic anterior ischemic optic neuropathy nanophthalmos 40 nasal – atrophy 108 – retina 154 NASCIS. see National Acute Spinal Cord Injury Study National Acute Spinal Cord Injury Study 91 near visual acuity 311 necrotizing retinitis 222 neovascularization 190 nerve axon 84 nerve fiber bundle defect 45 nerve fiber layer thickness 108 – inter-eye symmetry 108 nerve growth factor 198 neural integrator, 290 neurite inhibitor 89 neuroblastoma 264 neurofibromatosis – type 1 69, 71 – type 2 72 neuron 195 neuroophthalmologic – disease 301 – rehabilitation 317 neuropathy 232 neuroprotection 91 neuroretinitis 210, 211, 214, 215 neurosarcoidosis 74
neurosyphilis 215 neurotrophin 198 NF1. see neurofibromatosis type 1 NGF. see nerve growth factor night-blindness 166, 168, 185 nitrazepam 296 nocturnal systemic hypotension 27 Nogos (NogoR) 89 Non-caspase protease 188 nonarteritic anterior ischemic optic neuropathy 25, 26, 29, 30 – fellow eye involvement 30 – fluorescein angiography 30 – incidence 25 – medication 29 – MR imaging 30 – prevalence 25 – progressive 26 – static 26 – ultrasonography 30 normal tension glaucoma 27 NPC. see nuclei of posterior commissure NTG. see normal tension glaucoma nuclear gene mutation 271 nuclear marker 193 nuclear transplantation 277 nuclei of posterior commissure 259 nystagmus 52, 58, 64, 146, 220, 263, 283, 284, 289 – acquired syndrome 284
O objective visual field testing 151 obliterative vasculitis 214 occipital lobe 146 – infarction 235 OCT. see optical coherence tomography ocular bobbing 265 – inverse 265 – reverse 265 ocular conjugate deviation 262
ocular dipping 265 ocular dominance column 125 ocular flutter 264, 296 ocular ischemic syndrome 236 ocular motor – apraxia 262 – system 284 ocular myositis 279 ocular paralysis 268 ocular toxoplasmosis 205 oculomotility 84 oculomotor – center 121 – nuclei 259 – nucleus 255 – paralysis 259 oculopalatal tremor syndrome 294 oculopharyngeal muscular dystrophy 278 oculopharyngodistal myopathy 278 ODC. see ocular dominance column ODD. see optic disc drusen oligoclonal IgG bands 12 oligodendrocyte 83, 88, 195 omputational algorithm 121 ON. see optic neuritis one-and-a-half syndrome 257 ONSF. see optic nerve sheath fenestration ONSM. see optic nerve sheath meningioma ONTT. see Optic Neuritis Treatment Trial oocyte 271 OPA1 55, 56, 64 – gene 55, 64 – protein 56 OPA2 59 OPA3 58, 64 – gene 58, 64 – protein 58 OPA4 58 OPA5 59 open-angle glaucoma 152 OPG. see optic pathway gliomas ophthalmoparesis 268 ophthalmoplegia 64, 268
ophthalmoscopy 100 OPMD. see oculopharyngeal muscular dystrophy opportunistic infection 217 opsin 198 opsoclonus 264, 296 optic – ataxia 262 – atrophy 73, 220 – canal 39 – flow 130 – flow stimuli 128 – neuritis 112, 153, 211, 215, 222, 303 – pit 112 – radiation 221, 308 optical – aid 315 – signal 125 optical coherence tomography 39, 43, 100, 109, 111, 218 – reproducibility 109 – sensitivity 111 – specificity 111 optic canal – decompression 86 – fracture 87 optic chiasm 78 – radiotherapy 78 – surgical debulking 78 optic chiasmal syndrome 307 optic disc 152 – cupping 23 – drusen 37, 38, 41, 45 – B-scan ultrasound 41 – buried drusen 37 – exposed drusen 37 – prevalence 38 – visual field defect 45 – edema 11, 211 – traction syndrome 112 optic nerve 39, 52, 69, 74, 77, 83, 84, 86, 87, 90, 100, 112, 114, 154, 186, 198 – anatomy 83 – atrophy 84, 100, 112 – axons – transection 84 – concentric enlargement 74 – degeneration 186, 198
Subject Index
delay compression 86 fusiform enlargement 74 glioma 69 head 99, 101, 102 magnetic resonance imaging (MRI) 52, 114 – misrouting 154 – myelin 90 – prelaminar portion 39 – sheath fenestration 48 – surgical decompression 86 – transection 87 optic nerve head – analyzer 102 – imaging 99 – stereoscopic photograph 101 optic nerve sheath meningioma 30, 72, 75 – female preponderance 71 – MRI scanning 75 – tubular arrangement 75 optic nerve tumour 69 – imaging 74 – magnetic resonance imaging (MRI) 74 – radiotherapy 78 – spontaneous tumour regression 77 – surgery 78 Optic Neuritis Treatment Trial 5, 8 optic neuropathy 112, 215, 302 – ethambutol-associated 112 optic pathway gliomas 70, 71 – anteriorly situated 71 – in adults 78 – in children 77 – radiotherapy 78 optociliary shunt vessel 72 optotype 302 orbit-penetrating foreign body 84 orbital – apex syndrome 86 – fissure 86 – infarction syndrome 236 – inflammation 76 – ischemia 236 orientation – column 125 – – – – –
– impairment 307 – specificity 125 osteoporosis 246 otolith-ocular reflexe 292 outer retinopathy 172 oxidative phosphorylation 63
P P23H transgenic rat 191 PABPN1 gene 278 pain 4 pallid disc edema 234 pallor of the optic nerve head 89 PAN. see periodic alternating nystagmus panarteritis 241 papilledema 112 papillitis 208, 210, 214, 215 papillomacular bundle 51, 63, 106 – small axon 63 para-hydroxybenzoatepolyprenyl transferase 273 paracentral homonymous scotoma 308 paracrystalline inclusion 275 paraflocculus 290 parafoveal – contrast sensitivity 311 – information processing 302 paralysis of abduction 255 paramedian – pontine reticular formation 257 – tract 290 paraneoplastic – cerebellar syndrome 296 – myasthenic syndrome 278 – retinopathy 164 parietoinsular vestibular cortex 284 parinaud’s oculoglandular syndrome 214 Parkinson’s disease 187 PARL. see presenilin-associated rhomboid-like protease pattern-reversal – stimulation 142
329
330
Subject Index
– visual-evoked response 60 pattern electroretinogram (ERG) 44, 153 pattern VEP 153 pattern visually evoked cortical potential 44, 55 PBN 191 PCN. see peripapillary choroidal neovascularization PCR. see polymerase chain reaction PDT. see photodynamic therapy (PDT) peak-to-trough measure 148 PEDF. see pigment epitheliumderived factor pediatric optic neuritis 14 – bilateral involvement 14 PEF. see posterior parietal eye field pegaptanib 192 Pelizaeus-Merzbacher disease 294 pendular nystagmus 263 penicillin G 216 perceptual span 314 pERG. see pattern electroretinogram periodic alternating nystagmus 263, 293 periorbital facial bone fracture 86 peripapillary choroidal neovascularization 46 – surgical removal 46 periventricular leucomalacia 311 phagocytosis 197 phase-encoded – flatmap 122 phase-encoding – method 124 phenothiazine 294 phlebitis 222 phorias 307 photodynamic therapy 46 photophobia 207, 220 photopsias 166, 168, 172, 173, 176, 178, 179, 180 photoreceptor 169, 190, 194
– death 185 – degeneration 194 – destruction 179 – layer 186 photorefractive keratectomy 108 pigmented paravenous retinochoroidal atrophy 40 pigment epithelium – derived factor 192 – layer 196 pilocytic astrocytomas 70 pinwheel organization 125 PION. see posterior ischemic optic neuropathy PIVC. see parietoinsular vestibular cortex PMR. see polymyalgia rheumatica PMT. see paramedian tract pneumosinus dilatan 75 POAG. see primary open angle glaucoma POEMS syndrome 41 POLG. see polymerase gamma polyarteritis nodosa 32 polymerase – chain reaction 240 – gamma 271 polymyalgia rheumatica 21, 243 polyneuropathy 232 polyomavirus 221 pontomedullary 291 pontomesencephalic junction 291 PORN syndrome 222 posterior commissure 259, 260 posterior ischemic optic neuropathy 19, 32, 235 – classification 33 posterior parietal – cortex 133 – eye field 262 posterior uveitis 207 postnatal tissue 193 PPRF. see paramedian pontine reticular formation precocious puberty 70 precuneus 132
prednisolone 86 prednisone 25, 169, 207, 244, 245 preferred retinal locus 306 presenilin-associated rhomboid-like protease 57 presynaptic inhibitory transmitter 296 primary open angle glaucoma 27 primate visual cortex 121 prion protein (PrpSc) 220 PRL. see preferred retinal locus pro-apoptotic stimuli 192 progenitor cell 194 programmed cell death 187 progressive external ophthalmoplegia 271 progressive multifocal leukoencephalopathy 221 projection abnormality 154 propofol 277 propranolol 296 proptosis 70 prosopagnosia 311 proteasomal protease 188 pseudo-Foster Kennedy syndrome 30 pseudo-presumed ocular histoplasmosis syndrome 178 pseudoxanthoma elasticum 40 psycho-social consultation 316 ptosis 268, 277 – younger patient 277 punctuate inner choroidopathy 178 pupil abnormality 236 pupillary reflex 84 pyrimethamine 207
R radial optic neurotomy 31, 47 radiculitis 215 RAIDD 188 ranibizumab 192 Raynaud phenomenon 238 RCC. see retino-choroidal collateral
rd1-mouse 191 reactive – nitrogen species 189 – oxygen species 189 reading – ability 306 – speed 311 recessive optic atrophy 58 recording. see eye movement – electrode 147 recoverin 166, 167 – antibody 167 reflexive saccade 262 refractive error 143, 311 response 149 – latency 149 – magnitude 148 restitution training 315 retinal artery occlusion 46 retinal bipolar cell 169 retinal detachment 170 retinal eccentricity 122 retinal ganglion cell 39, 52, 55, 63, 185 – loss 55 retinal image 143 retinal ischemic lesion 234 retinal lamination 194 retinal nerve fiber layer 99, 100 – photography 100 retinal pigment epithelial lesion 170 retinal progenitor 195 retinal regeneration 92 – in vitro model 92 retinal sheet 193 retinal transplantation 193 retinal vascular complication 46 retinal vasculitis 215 retinitis 211 – pigmentosa 40, 185 retino-choroidal collateral 72, 73 retinoblastoma 210 retinotopic – cortex 130 – representation 146, 147 retractorius nystagmus 263 RGC. see retinal ganglion cell
Subject Index
rhodopsin 166 riMLF. see rostral interstitial nucleus of the medial longitudinal fasciculus RMS. see root-mean-square RNFL. see retinal nerve fiber layer RNS. see reactive nitrogen species Rochalimaea henselae 214 rod 185 Rodenstock Optic Nerve Head Analyzer 102 Rodenstock System 105 root-mean-square 148 – measure 148 ROS. see reactive oxygen species rosette 193, 194 rostral interstitial nucleus of the medial longitudinal fasciculus 259 RP. see retinitis pigmentosa RPE 194. see pigment epithelium layer – allograft 194
S saccade 121, 129, 253, 254 – control 129 – visually guide 129 saccadic – eye movement 120 – strategy 314 salt-and-pepper like appearance 268 SANDO 270 – syndrome 273 sarcoidosis 76 SAS. see sleep apnea syndrome scalp necrosis 236 scalp tenderness 20, 231, 232, 236 scanning laser ophthalmoscope 41, 103, 315 Scanning Laser Polarimeter 107, 108 – False-negative results 108
– sensitivity 108 – specificity 108 scanning laser polarimetry 44, 90, 100 schisis-like cavity 112 scleral canal 39 scotoma 149, 166, 305 SDH. see succinate dehydrogenase second-order kernel 140, 142 seesaw nystagmus 263, 292 sensorimotor adaptation 317 sensory retina 196 serine protease 188 seronegative myasthenia 278 serous retinal detachment 112 shift of gaze 306 short posterior ciliary – arteries 234 – vessel 22 signal-to-noise ratio 148 sildenafil 29 simultanagnosia 311 sine wave grating 127 single cell transplantation 197 single gene mutation 185 siRNA. see small interfering RNAs; see small interfering RNA skew deviation 256 skip lesion 241 sleep apnea syndrome 28 slit-lamp microscopy 90 SLO. see scanning laser ophthalmoscope SLP. see scanning laser polarimetry small-diameter laser beam 104 small interfering RNA 57, 198 smoking 28 smooth pursuit 254 SNR. see signal-to-noise ratio SOM. see superior oblique myokymia southern blot analysis 276 spatial orientation 310 specific explorative training 316 spiramycin 207 spontaneous nystagmus 286 square wave
331
332
Subject Index
– jerks 264 – response function 124 SR. see sensory retina Stargardt’s disease 190 stellate maculopathy 214 stem-cell-based therapy 194 stereopsis 120 steroid 86, 91, 233, 287 – tapering 245 strabismus 277, 311 – extraocular muscle surgery 277 subclinical neuropathy 274 submacular fluid 111 succinate 63 – dehydrogenase 275 succinylcholine 277 superior colliculus 257 – lesion 257 superior oblique myokymia 265, 288 suprachiasmatic lesion 307 supranuclear – integration centers 284 – ocular motor disorders 289 – vertical gaze paralysis 260 sustained focal attention 306 SWJ. see square wave jerks syphilis 12, 215 – indocyanine green angiography 215 systemic – hypertension 28 – hypotension 29, 32 – inflammation 231 – inflammatory – syndrome 236
T T-cell 229 – CD4+ subtype 229 – leukemia 216 – mediated disease 228 T14484C 62 tamoxifen 107 telangiectatic microangiopathy 59 temporal artery biopsy 24, 241
– false-negative error rate 24 temporal retina 154 TGF-beta 200 thrombocytosis 24, 25, 239 thymidine phosphorylase 271 – mutation 271 tick 210 – borne encephalitis 210 tissue homeostasis 187 TON. see traumatic optic neuropathy tongue necrosis 236 Topcon IMAGEnet 102 topographic agnosia 311 total blindness 87 total macular volume score 113 toxocara canis 205, 210 toxocariasis 210 toxoplasma gondii 206 toxoplasmosis 206, 207, 209 – AIDS patient 209 – neuroimaging 209 – neurologic manifestation 207 – therapy 207 – transmission 207 TP. see thymidine phosphorylase TPHA 216 training predictive saccade 316 tram tracking 75 transduction 166 transient visual loss 22 transplanted photoreceptor 194 transsphenoid decompression 87 transvitreal neurotomy 31 traumatic optic neuropathy 83, 87, 90, 91 – computed tomography (CT) 90 – histopathology 87 – indirect 87 – magnetic resonance imaging (MRI) 90 – neuroprotection 91 – surgical decompression 91
– therapeutic concept 91 – ultrasonography 90 Treponema pallidum 215 trihexiphenidyl 294 trisomy 15q 41 tritanopia 52 trochlear – nerve 288 – nuclei 259 tropias 307 tumor necrosis factor alpha (TNFα) 188, 240 Twinkle 271
U UBN. see upbeat nystagmus Uhthoff phenomenon 4, 5, 59 ultrahigh-resolution OCT 112 unilateral meso-diencephalic lesion 293 upbeat nystagmus 261, 290 upward gaze paralysis 261 Usher syndrome 40 uveitis 170
V V3A 126 V3B 126 V4d topology 127 valacyclovir 179, 222, 287 valganciclovir 219 valproic 296 – acid 277 variable corneal compensator 107 vasa vasorum 228 vascular – compression 288 – disorder 302 – disorders of the brain 317 – endothelial growth factor 190, 192 – antagonist 192 – occlusion 210 – shunt 46 vasculitis 228
– large-sized arteries 228 – medium-sized arteries 228 VCC. see variable corneal compensator VDRL. see Venereal Disease Laboratory Test VEGF. see vascular endothelial growth factor Venereal Disease Laboratory Test 216 ventral – occipital cortex 126 – tegmental tract 260, 261 VEP. see visual evoked cortical potential – conventional 153 verteporfin 46, 186 vertical – eye movement 259 – nystagmus 256, 261 vertical smooth pursuit – deficit 290 – system 290 vestibular – eye movement 294 – nerve 286, 287 – neuritis 284, 286 – nuclei 259 – pseudoneuritis 289 – sedative 287 – syndrome 289 – tonus imbalance 286 vestibulo-cerebellum 284 vestibulo-ocular reflex 254 vigabatrin 294 visceral larva migran 210 visual – consciousness 120
Subject Index
– cortex 143 – cycle 190 – deficit 301, 317 – illusion 120 – imagery 130 – inattention 262 – loss 25, 71, 294 – neuron 121 – prognosis 5 – recovery 25, 62, 246 – representation 120 – restitution training 315 – span 302 – working memory 120, 130 visual evoked – cortical potential 90, 139, 153 – potential 11 – response 60 visual field defect 44, 148, 178, 222, 311 – incidence 44 visual field loss 100, 106 visual field perimetry 152 visual field response 146 visual field testing 108, 146 visual field topography 152, 154 Visual Function Index (VF14) 268 visuotopic mapping 130 vitritis 166, 168, 176, 178, 211, 215, 222 voltage-sensitive dye 125 VOR. see vestibulo-ocular reflex VRT. see visual restitution training
VTT. see ventral tegmental tract
W WBC. see white blood cells Weber’s syndrome 259 Wegener’s granulomatosis 243 Wernicke region 302 Western blot test 213 Whipple’s disease 294 white blood cells 239 white dot syndrome 179 white lesion 176 Wolff-Parkinson-White syndrome 60 Wolfram Syndrome 64 word recognition span 302
X X-chromosomal haplotype 63 X-linked optic atrophy 59 Xp11.4-p11.2 59
Z Zeiss Confocal Scanning Laser Ophthalmoscope 106 zoonosis 206
333
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Essentials in Ophthalmology Series Editors: G.K. Krieglstein; R.N. Weinreb Glaucoma
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