Otolith Function and Disorders (Advances in Oto-Rhino-Laryngology, Vol. 58)

............................ Otolith Function and Disorders

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Advances in Oto-Rhino-Laryngology Vol. 58

Series Editor

W. Arnold, Munich

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Otolith Function and Disorders

Volume Editors

P. Tran Ba Huy, Paris M. Toupet, Paris

36 figures, 1 in color and 3 tables, 2001

............................ Prof. P. Tran Ba Huy, Prof. M. Toupet Hoˆpital Lariboisie`re 2, rue Ambroise Pare´ F–74574 Paris (France)

Library of Congress Cataloging-in-Publication Data Otolith function and disorders / volume editors, P. Tran Ba Huy, M. Toupet. p.; cm. – (Advances in oto-rhino-laryngology, ISSN 0065-3071; vol. 58) Papers from a conference held in Paris in Jan. 22, 2000. Includes bibliographical references and indexes. ISBN 3805571305 (hard cover : alk. paper) 1. Otolith organs – Pathophysiology – Congresses. 2. Otolith organs – Abnormalities – Congresses. 3. Vertigo – Congresses. I. Tran, Patrice Ba Huy. II. Toupet, M. (Michel) III. Series. [DNLM: 1. Otolithic Membrane – physiopathology – Congresses. 2. Otolithic Membrane – abnormalities – Congresses. 3. Vertigo – Congresses. 4. Vestibular Diseases – Congresses. WV 255 O88 2001] RF268 .O86 2001 617.8€82–dc21 00-049737

Bibliographic Indices. This publication is listed in bibliographic services, including Current ContentsÔ and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Ó Copyright 2001 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0065–3071 ISBN 3–8055–7130–5

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Contents

VII Preface 1 The Mammalian Otolithic Receptors: A Complex Morphological and

Biochemical Organization Sans, A.; Dechesne, C.J.; Demeˆmes, D. (Montpellier)

15 Pathophysiology and Clinical Testing of Otolith Dysfunction Gresty, M.A. (London); Lempert, T. (Berlin) 34 Otolithic Vertigo Brandt, T. (Munich) 48 Physiopathology of Otolith-Dependent Vertigo. Contribution of the Cerebral

Cortex and Consequences of Cranio-Facial Asymmetries Berthoz, A. (Paris); Rousie´, D. (Lille)

68 Clinical and Instrumental Investigational Otolith Function ¨ dkvist, L. (Linko¨ping) O 77 The Subjective Visual Vertical Van Nechel, Ch. (Paris/Bruxelles); Toupet, M. (Paris); Bodson, I. (Paris/Lie`ge) 88 Clinical Application of the Off Vertical Axis Rotation Test (OVAR) Wiener-Vacher, S. (Paris) 98 VEMP Induced by High Level Clicks. A New Test of Saccular Otolith Function de Waele, C. (Paris) 110 Peripheral Disorders in the Otolith System. A Pathophysiological and

Clinical Overview Tran Ba Huy, P.; Toupet, M. (Paris)

129 Subject Index

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Preface

For decades, peripheral vestibular function and its related pathologies have been attributed to the canal system. In this view, vertigo could only give rotatory sensations. Otherwise, the disorder was automatically considered as central in nature. For almost a century, functional explorations were limited to caloric and/or rotatory testing. From the responses arising from a single pair of canals, the lateral ones, generations of otologists have founded the science of Vestibulology. Yet, clinicians facing dizzy patients on a daily basis were aware that this clinical and instrumental approach was oversimplified and reductionistic. Indeed, they knew of two small and mysterious sensory structures hidden within the bony vestibule, but largely ignored their exact role in pathophysiology and lacked the techniques to investigate them. During recent years, a considerable body of experimental and clinical work has demonstrated the direct involvement of the otolith organs in stabilizing body and gaze and led to the development of specific functional tests. Thanks to these advances, an otolith semiology has emerged. We now know that drunken-like sensations and movements, lateropulsion, gait disturbance, visual symptoms, disorientation or erroneous sensations of upright posture, to quote but a few ill-defined or bizarre symptoms, must direct the clinician toward an otolith problem. New investigative tools are now available which can demonstrate the direct involvement of the utricle and saccule in the pathology. On the 22th of January, 2000, an international meeting devoted to ‘Otolith Function and Disorders’ was held in Paris with the participation of some of the pioneers in the field. All aspects of otolith function were covered. Alain Sans, of the INSERM at Montpellier, presented the ultrastructural features

VII

of the two maculae with special emphasis on the neuromediators involved in vestibular signal processing. Michael Gresty, from London, reviewed the physiology of the otolith organs and underlined some fascinating and unexpected roles of these structures in current clinical symptoms. Thomas Brandt discussed the principal otolith-related syndromes drawing upon his exceptional clinical experience. Alain Berthoz developed his thoughts on the role of otoliths ¨ dvkist opened the session on clinical in the perception of movement. Lars O and instrumental investigation of otolith function, and presented a critical appraisal of the tests used in vestibulometric practice, with emphasis on his experience in eccentric rotatory testing. Following this, Christian Van Nechel, Sylvette Wiener-Vacher and Catherine de Waele reported their use of the subjective visual vertical test, off-vertical axis rotation and click-evoked myogenic potentials as tools for functional investigations of the otolith organs. This volume gathers together the contributions of these authors in an attempt to provide an exhaustive view of a new field in vestibulology. We hope that it will prove to be a valuable clinical tool concerning a system which has remained the wild card of sensory pathology for too long. Patrice Tran Ba Huy Michel Toupet

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Tran Ba Huy P, Toupet M (eds): Otolith Functions and Disorders. Adv Otorhinolaryngol. Basel, Karger, 2001, vol 58, pp 1–14

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The Mammalian Otolithic Receptors: A Complex Morphological and Biochemical Organization Alain Sans, Claude J. Dechesne, Danielle Demeˆmes INSERM U 432, Montpellier, France

The vestibular sensory organs of vertebrates detect angular accelerations, by means of the ampullar receptors, and linear accelerations, by means of the otolithic receptors. The otolithic receptors consist of the utricle and the saccule, each being formed by a sensory epithelium, covered by the otoconial membrane, which supports calcium carbonate crystals, the otoliths or otoconia, in the form of aragonite or calcite. The utricle and saccule specifically perceive linear accelerations induced by movements of the head in the gravity field. This sensory information is used by the central nervous system to control eye movement and body position. This chapter does not aim to describe the morphology of the mammalian otolithic receptors, which is already well documented, for the vestibular sensory epithelia by Hunter-Duvar and Hinojosa [1], and for the otoconial membrane by Lim [2]. Instead, it deals with correlations between anatomy and function by taking into account the distribution of specific proteins in the various sensory cells and their afferent and efferent nerve fibers: (1) calcium-binding proteins in the type I and type II sensory cells and their afferent nerve fibers, and (2) the neurotransmitters involved in afferent and efferent regulation. Work carried out in our laboratory has shown regional biochemical differences in the organization of the otolithic organs, suggesting that there may be functional differences between the central and peripheral parts of the macular receptors.

Fig. 1. Surface views of the rat utricle. Both utricles are similarly oriented with the medial part, with respect to the axis of the body, on the right-hand side. a Immunocytochemical labeling for calretinin, observed by confocal microscopy. In the striolar area (S), indicated by a dotted line, the calyces surrounding the type I sensory cells are labeled (see fig. 5b). In the extra-striolar zones, calretinin immunostaining is detected in type II sensory cells. b Scanning electron microscopy identifies the hair bundles. Note that the borders of the utricle are slightly raised.

The Otolithic Receptors: An Overview of Their Morphological Characteristics (schematic diagram fig. 7a) Scanning Electron Microscopy The Utricle. The utricular macula is kidney-shaped, with the concave part in the medial position and the convex part in the lateral position (fig. 1). In some mammals, such as rodents, the anterior part is tilted at an angle of 30º from the horizontal. In humans, the utricle is in the horizontal plane when the head is held in the vertical position. The sensory surface is covered by the sensory hair bundles. This sensory epithelium is covered by a gelatinous membrane, the otoconial membrane, upon which rest the otoconia. The lower surface of this membrane is attached to the supporting cells of the sensory epithelium by a filamentous network known as the subcupular meshwork [2]. The otoconial membrane and the subcupular meshwork delimit the alveoli, into which the hair bundles are inserted (fig. 2a). In birds and mammals, the otoconia consist of calcite crystals of various sizes, depending on their location. Those in the lateral parts of the utricle are large whereas

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a

b Fig. 2. Otoconial membrane and otoconia overlying the utricle observed by scanning electron microscopy. a After partial removal of the otoconia (o), the otoconial membrane shows a honeycomb structure. The hair bundle stereocilia (st) are inserted into the cells of the honeycomb. b Regional differences in the size of the otoconia on the otoconial membrane. The otoconia in the striolar area (S) are smaller and the surface they form is lower than that of the otoconia in the extra-striolar zones.

those in the striolar area, a crescent-shaped depression located off-center to the lateral side, are small (fig. 1b, 2b). The striolar area is a specific zone of the sensory epithelium with the following characteristics: (1) inverse polarization of the hair bundles (the kinocilia face each other); (2) the stereocilia are smaller than those of the cells in the medial and peripheral extra-striolar zones; (3) there is almost no subcupular meshwork. This lack of the subcupular meshwork in the striolar area results in the formation of a space, delimited by the otoconial membrane, in the form of a curved tunnel. Due to the small size of the stereocilia and the presence of a unique cavity in the striolar area, the hair bundles in this area are free and are not joined to the otoconial membrane, unlike those of the extra-striolar zones. This anatomical feature undoubtedly affects the processes of the mechanic transmission in this area, which accounts for about 10% of the total sensory surface area. The Saccule. The saccular macula is hook-shaped and the anterior end differs in length and curvature between species. In humans, the saccule is in the vertical plane when the head is held erect. The general architecture of the saccule is similar to that of the utricle. However, there are several important differences: the otoconia of the striolar region protrude slightly above the surface of the otoconial membrane. The hair bundles in the striolar region are polarized inversely to those in the utricle (the stereocilia face each other).

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Fig. 3. Transmission electron micrograph of a transverse section of a guinea pig utricular epithelium. The type I hair cells (1) are surrounded by afferent nerve calyces containing numerous mitochondria. The type II hair cells (2) are contacted at their bases by afferent endings and by efferent boutons (dark arrows). The nuclei of the supporting cells (sc) line the lower part of the epithelium and these cells have numerous intracytoplasmic secretory granules at their apices. ST>Stereocilia.

Transmission Electron Microscopy The sensory epithelium of the otolithic receptors has been extensively described. It consists of two types of sensory hair cell: type I cells, which are pear-shaped and surrounded by an afferent nerve calyx, and type II cells, which are rectangular parallelepipeds and contacted by afferent and efferent boutons (fig. 3). These cells are separated by the supporting cells, the lower part of which rests on the basal membrane. There are, however, regional differences in the shape of these sensory cells and their afferentation by nerve fibers. The striolar area is a zone with a specific organization with regard to which the extra-striolar zones are defined. Type I cells are more globular in the striolar area than in the lateral areas and are contacted exclusively by complex afferent calyx endings from large-diameter nerve fibers. In contrast, the type II hair cells of the peripheral zones are mainly contacted by afferent boutons originating from thin nerve fibers. The type I and II hair cells in the peristriolar zones are connected by dimorphic nerve fibers that provide mixed innervation to both hair cell types [3, 4]. To this general scheme should be added two types of result

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Fig. 4. Microvesicles located at the apex of the afferent nerve calyx surrounding a type I hair cell (transmission electron microscopy). a Transverse section of a type I hair cell showing the bundle of microtubules in the neck of the cell. The upper part of the nerve calyx contains clear microvesicles (small dark arrows). b Transverse section in the plane indicated by the dotted line in (a). The microtubules present in the neck of the nerve calyx appear as small circles. The microvesicles present in the nerve calyx (c) correspond to clear vesicles (small dark arrows) and dense-cored vesicles (white arrows).

demonstrating the complex regional regulation of the vestibular sensory information. Our group has shown that, at the apex of afferent nerve calyces, there are clear microvesicles and dense-cored microvesicles [5]; (fig. 4a, b). In this part of the calyces proteins are also found which are usually associated with synaptic

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vesicles in presynaptic compartments: synapsin I and synaptophysin [6], which are associated with the membrane of the synaptic vesicle [7, 8], and rab 3A [9], a protein essential for vesicle docking and the last steps of exocytosis [8]. We have also shown that there are glutamate receptors on the membrane of the sensory cells [10]. Although the synaptic release of neuromediators by the apex of the calyces has not yet been demonstrated experimentally, the results obtained consistently provide evidence for the existence of a short control loop regulating the type I hair cell activity by their afferent calyces. Ross [11] has demonstrated the presence of extensions of fibers or afferent calyces, forming synaptic contacts with the adjacent type II cells, which face subsynaptic membrane cisternae. Asymmetric synaptic contacts are also found at the base of the calyces and of intramacular nerve fibers. These extensions, rich in small (40–60 nm in diameter) clear vesicles, form a network at the base of the macular epithelium. Extensions from the neck of the afferent nerve calyces are also found (fig. 4b). These extensions contact their neighboring sensory cells and also contain clear microvesicles as well as large (80 nm diameter) dense-cored vesicles. This double network, basal and apical, probably regulates the early mechanosensory messages before their transmission to the central nervous system.

Differential Expression of Parvalbumin, Calretinin and Calbindin in the Utricle (schematic diagram fig. 7a) Calcium plays a key role in the physiology of sensory cells and neurons. A large number of calcium-binding proteins have been detected by immunocytochemistry in the sensory hair cells and afferent nerve fibers of the vestibular sensory epithelium. The distributions of the three main calcium-binding proteins, parvalbumin, calretinin and calbindin, differ not only with respect to each other, but also in the different regions of the utricle. Parvalbumin [12] is present mostly in the type I cells of the striolar region (fig. 5a), whereas calretinin [13] is present in the type II cells of the periphery of the macula and in the afferent nerve calyces of the striolar region (fig. 1a, 5b). Finally, calbindin [14] is detected in very large amounts only in the nerve calyces of the striolar area (fig. 5c). These regional differences in the distribution of calcium-binding proteins almost certainly reflect differences in cellular calcium metabolism between the sensory cells located in the striolar area and those of the peristriolar zones, particularly those of the peripheral zones. In addition, in the striolar zone, only the fibers ending in calyces and multicalyces contain calretinin whereas

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Fig. 5. Differences in the distribution of calcium-binding proteins in the rat utricle. Immunolabeling of parvalbumin (a), calretinin (b) and calbindin (c) observed by laser confocal microscopy. a Most of the parvalbumin-immunoreactive hair cells are type I hair cells in the striolar area (S, limits are indicated by two white arrowheads). A few immunoreactive cells are located outside the striolar area. The insert shows the cytosolic labeling of a type I hair cell. b Calretinin is detected in nerve calyces in the striolar area (see also insert) and in a few type II hair cells outside the striolar area. c Calbindin is found only in the nerve calyces of the striolar area.

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the calyces of the dimorphic fibers do not contain calretinin [15]. This is reflected in the vestibular ganglion in which only the large-diameter neurons ending in calyces contain calretinin [16] and present low voltage-activated currents [17]. These biochemical results thus demonstrate that it is essential to consider the electrophysiological properties of the vestibular sensory cells not only in relation with their cell type (I or II), but also in relation with their type of afferentation and their location in the utricular macula.

Efferent and Afferent Systems: Differential Expression of CGRP and Substance P in the Utricle (schematic diagram fig. 7b) Efferent System The cell bodies of the efferent nerve fibers are located in the brainstem below the 4th ventricle. These fibers contact type II cells directly, or afferent fibers and calyces, controlling and regulating the transmission of sensory information. The neuromediators of the vestibular efferent system are acetylcholine and the calcitonin gene-related peptide (CGRP) [18–21]. Both are colocalized in the efferent boutons. Acetylcholine is thought to have an inhibitory role and CGRP is thought to be excitatory. Thus, the presence of these two neuromodulators of antagonist effects at the same location suggests that there is a complex peripheral regulation of the afferent activity by the efferent system. In addition, it is known that the distribution of efferent fibers differs between utricular regions. It has been shown by autoradiography that there are more efferent endings in the medial and peripheral zones of the utricle than in the striolar area [22]. This result has been confirmed by immunocytochemical labeling of the efferent fibers and boutons with an anti-CGRP antibody (fig. 6a). It therefore seems that the control exerted by the efferent system over the transmission of sensory information in the maculae differs between the striolar and extra-striolar zones. Afferent System The afferent nerve fibers that contact the sensory cells transmit sensory information to the central nervous system via the vestibular nuclei. The afferent system is essentially glutamatergic. Glutamate is present in all the sensory cells and ionotropic [23] and metabotropic glutamatergic receptors are found in the vestibular afferent neurons. Immunocytochemical detection of the ionotropic glutamate receptors AMPA and NMDA in the sensory epithelia showed no regional differences in their distribution.

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Fig. 6. Differences in the distribution of neuropeptides in the efferent and afferent fibers of the rat utricle. a Surface view of the utricle immunostained with an antibody directed against the calcitonin-gene related peptide (CGRP). CGRP is present in the efferent fibers and endings. Immunolabeled fibers and endings are more dense in the medial (M) and lateral (L) regions than in the striolar area (indicated by a dotted line). A remnant of the otoconial membrane shows nonspecific staining (white arrow). b Transverse section of a utricle immunostained with an antibody directed against substance P. Substance P is detected in the afferent boutons and calyces, mostly outside the striolar area (S, limits are indicated by two white arrowheads).

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Fig. 7. a Schematic diagram of a transverse section of a mammalian utricle showing the different distributions of two calcium-binding proteins. The utricle is divided by a virtual line, the striola (S), with opposite polarization of the hair bundles on either side of that line. In the striolar region, all the hair bundles are located in a common cavity and are not connected to the otoconial membrane. In the extra-striolar zones, the hair bundles are located in individual cavities of the otoconial membrane and the kinocilia are connected to this membrane (red dotted line). The striolar and extra-striolar zones also differ in the distribution of calcium-binding proteins. In the striolar area, parvalbumin (blue) is present in type I sensory cells (I) and calretinin (red) is present in the calyces and multicalyces surrounding the parvalbumin-positive type I sensory cells. In the peripheral extra-striolar zones, calretinin is present in some type II sensory cells (II). The otoconia (O) are smaller in the striolar area than elsewhere. The synaptic bodies (sb in dark blue) are indicated in the sensory cells. The apical part of the nerve calyces contains microvesicles (yellow). The efferent fibers are shown in solid black. sc>Supporting cell. b Schematic diagram of a transverse section of a utricle

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In contrast, the neuropeptides substance P and neurokinin A are present in specific afferent nerve endings and fibers [24]. These neuropeptides are detected exclusively in the extra-striolar areas and are absent from afferent fibers ending in calyces [24] and containing calretinin (fig. 6b). The presence of substance P in the postsynaptic afferent endings may appear surprising, but we have already shown that there are clear microvesicles in the afferent fibers, which probably contain glutamate, and vesicles with electron-dense cores, characteristic of the presence of neuropeptides.

Discussion Lim [2] demonstrated that the hair bundles in the striolar zone are short and not attached to the otoconial membrane, unlike those of the peristriolar and peripheral zones in which the stereocilia are longer and which partly penetrate the otoconial membrane [25]. This led him to suggest that hair cells in the striolar region would be more strongly stimulated than those elsewhere by fluid drag, and would be sensitive to velocity rather than displacement. The ampullar cristae of the mouse have be shown to be organized in a similar manner, with the hair bundles in the apical and central areas having short stereocilia and those in the basal and peripheral areas having long stereocilia included in the cupula [26]. Recent morphological and immunocytochemical studies have confirmed these observations suggesting that each vestibular receptor should be considered to consist of two different parts, the central and peripheral areas. In the central part of the macula, the striolar area, type I cells are immunostained for parvalbumin. These cells are enclosed in calyces or multicalyces arising from fibers with a very large diameter and containing calretinin (fig. 7a). These high-threshold fibers are controlled by rare efferent endings (fig. 7b). In this case, peripheral regulation may essentially involve feedback control (short control loop) involving the release of neurotransmitters by the microvesicles located at the apex of the calyces [5, 6, 27]. This local control is probably supplemented by control via the neighboring vesiculated ‘efferent’ fibers from

showing the differences in distribution of neuromediators in the nerve fibers. In the striolar area (S), afferent fibers and calyces do not contain substance P; efferent fibers and endings immunostained for CGRP (green) are more sparse than in the other zones. In the extrastriolar areas, afferent fiber endings in boutons and calyces contain substance P (orange) and the CGRP-positive efferent fibers and endings are more numerous. Microvesicles (yellow) containing glutamate are present in the apical part of the afferent nerve calyces. Modified from Lim [2].

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afferent origin, as shown by Ross [11]. This latter control may be exerted at the apex and base of the epithelia by two parallel networks. The vestibular information produced by the striolar zone would thus be extensively pretreated before its transmission to the vestibular nuclei and there would be minimal efferent control of central origin. The more peripheral areas contain type II cells contacted by small size fibers forming bouton-type units, and type I and II cells contacted by mixed units forming calyces and boutons at the ends of medium-size fibers. With the exception of a few peristriolar type I cells, these cells do not contain parvalbumin. Some type II cells in the most peripheral zones contain calretinin. These cells are contacted by afferent fibers that are strongly immunostained for substance P. In addition, in these extrastriolar zones, the efferent endings originating from the central nervous system are very dense and probably exert considerable control over the transmission of sensory information. In conclusion, the results obtained indicate that the messages produced by the utricular and saccular maculae differ greatly according to the regions activated. The hair cells of the striolar zones would be directly sensitive to the displacement of endolymph, that would result in the sensory cells rapidly sending a phased message to the central nervous system, via large-caliber fibers. This message would be extensively refined and regulated by feedback controls originating from the short loops involving both the type I sensory cells and their calyces, and the intraepithelial afferent networks carrying messages between the neighboring units. The extrastriolar zones would be sensitive to the relative displacement of the otoconial membrane with regard to the hair bundles. The sensory cells contacted by fibers of medium or small diameter would send an essentially tonic message to the central nervous system, mostly regulated by a long loop involving the central efferent neurons. This morphological and functional organization presents some similarity to that of another, even more complex organ, the retina. However, in the vestibule, the respective roles of the central and peripheral zones in the organization of the sensory message with regard to the type of stimulus are unknown.

Acknowledgments We thank D. Orcel for the diagram drawings. Partly supported by CNES grants 793/98 and 793/99.

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References 1 2 3 4

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10 11 12 13

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Hunter-Duvar I, Hinojosa R: Vestibule: Sensory epithelia; in Friedmann I, Ballantyne J (eds): Ultrastructural Atlas of the Inner Ear. London, Butterworths, 1984, pp 211–244. Lim D: The development and structure of the otoconia; in Friedmann I, Ballantyne J (eds): Ultrastructural Atlas of the Inner Ear. London, Butterworths, 1984, pp 245–269. Fernandez C, Goldberg J, Baird R: The vestibular nerve of the chinchilla. III. Peripheral innervation patterns in utricular macula. J Neurophysiol 1990;63:767–780. Goldberg J, Desmadryl G, Baird R, Fernandez C: The vestibular nerve of the chinchilla. V. Relation between afferent discharge properties and peripheral innervation patterns in the utricular macula. J Neurophysiol 1990;63:791–804. Sans A, Scarfone E: Afferent calyces and type I hair cells during development: A new morphofunctional hypothesis. Ann NY Acad Sci 1996;781:1–12. Scarfone E, Demeˆmes D, Jahn R, De Camilli P, Sans A: Secretory function of the vestibular nerve calyx suggested by presence of vesicles, synapsin I, and synaptophysin. J Neurosc 1988;8:4640–4645. De Camilli P: Keeping synapses up to speed. Nature 1995;375:450–451. Ludger J, Galli T: Exocytosis: SNAREs drum up! Eur J Neurosci 1998;10:415–422. Dechesne CJ, Kauff C, Stettler O, Tavitian B: Rab 3A immunolocalization in the mammalian vestibular end-organs during development and comparison with synaptophysin expression. Dev Brain Res 1997;99:103–111. Devau G, Lehouelleur J, Sans A: Glutamate receptors on type I vestibular hair cells of guinea-pig. Eur J Neurosc 1993;5:1210–1217. Ross M: Morphological evidence for local microcircuits in rat vestibular maculae. J Comp Neurol 1997;379:333–346. Demeˆmes D, Eybalin M, Renard N: Cellular distribution of parvalbumin immunoreactivity in the peripheral vestibular system. Cell Tissue Res 1993;274:487–492. Dechesne CJ, Winsky L, Kim HN, Goping G, Vu TD, Wenthold RJ, Jacobowitz DM: Identification and structural localization of a calretinin-like calcium binding protein (protein 10) in the guinea pig and rat inner ear. Brain Res 1991;560:139–148. Dechesne CJ, Thomasset M: Calbindin (CaBP 28 kDa) appearance and distribution during development of the mouse inner ear. Dev Brain Res 1988;40:233–242. Desmadryl G, Dechesne CJ: Calretinin immunoreactivity in chinchilla and guinea pig vestibular end organs characterizes the calyx unit subpopulation. Exp Brain Res 1992;89:105–108. Demeˆmes D, Raymond J, Atger P, Grill C, Winsky L, Dechesne CJ: Identification of neuron subpopulations in the rat vestibular ganglion by calbindin-D 28K, calretinin and neurofilament protein-immunoreactivity. Brain Res 1992;582:168–172. Desmadryl G, Chambard JM, Valmier J, Sans A: Multiple voltage-dependent calcium currents in acutely isolated mouse vestibular neurons. Neuroscience 1997;78:511–522. Tanaka M, Takeda N, Senba E, Tokyama M, Kubo T, Matsunaga T: Localization of calcitonin gene-related peptides in the vestibular end-organs in the rat: An immunohistochemical study. Brain Res 1988;447:175–177. Wackym P: Ultrastructural organization of calcitonin gene-related peptide immunoreactive efferent axons and terminals in the vestibular periphery. Am J Otol 1993;14:41–50. Demeˆmes D, Broca C: Calcitonin gene-related peptide immunoreactivity in the rat efferent vestibular system during development. Dev Brain Res 1998;108:59–67. Scarfone E, Ulfendahl M, Landberg T: The cellular localization of the neuropeptides substance P, neurokinin A, calcitonin gene-related peptide and neuropeptide Y in guinea-pig vestibular sensory organs: A high-resolution confocal microscopy study. Neuroscience 1996;75:587–600. Raymond J, Demeˆmes D: Efferent innervation of vestibular receptors in the cat: Radioautographic visualization. Acta Otolaryngol 1983;96:413–419. Demeˆmes D, Lleixa A, Dechesne CJ: Cellular and subcellular localization of AMPA selective glutamate receptors in the mammalian peripheral vestibular system. Brain Res 1995;671:83–94. Demeˆmes D, Ryzhova I: Ontogenesis of substance P in the rat peripheral vestibular system. Hearing Res 1966;114:252–258.

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Alain Sans, INSERM U 432, UM 2, CC 89, Place Bataillon, F–34095 Montpellier cedex 5 (France) Tel. +33 467 14 48 10, Fax +33 467 14 36 96, E-Mail [email protected]

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Tran Ba Huy P, Toupet M (eds): Otolith Functions and Disorders. Adv Otorhinolaryngol. Basel, Karger, 2001, vol 58, pp 15–33

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Pathophysiology and Clinical Testing of Otolith Dysfunction Michael A. Gresty a, Thomas Lempert b a

b

MRC Human Movement and Balance Unit, National Hospital for Neurology and Neurosurgery, London, UK; Neurologische Klinik, Charite´, Campus Virchow-Klinikum, Berlin, Germany

This paper is based on a talk on the pathophysiology of the otolith organs which was given in Paris in the early days of this third millennium. The purpose was to attempt a didactic statement about our understanding of the otolith which could be of value to physicians and surgeons dealing with patients who present with vestibular disease. As such it would be a cultural affront and an expression of historical ignorance not to commence with a reference to the views of FH Quix who gave his lectures ‘Les Me´thodes d’Examen de L’Organe Vestibulaire’ in that same city more than 70 years ago [1]. Figure 1 is reproduced from lecture notes and shows Professor Quix demonstrating the orientations of the utricles and saccules using his hands to indicate the planes of the maculae. Figure 2 reproduces Quix’s illustration of the changes of posture, including eye movements, which follow asymmetrical tonus between the right and left vestibular organs. Quix’s experimental method for producing tonus in normal man was by galvanic stimulation across the mastoids. The figures show that in the case of canal asymmetry there is principally a turn of all parts of the body in the frontal and horizontal planes. In the case of otolithic asymmetry the major effect is the tilt of the body towards the hypotonic side; notably involving also a tonic tilt in cyclotorsion of the eyes to this side. Within these general schemata Quix also made a distinction between the functional responses of the utricles and succules which, I believe, even today could provoke thought for experimentation. What we have learnt since Quix? Certainly we have learnt much about the detailed physiology of these organs and their central connections, but

Fig. 1. Portraits of FH Quix illustrating the orientations of the utricules and saccules [1].

Fig. 2. Quix’s illustrations of schematic postural responses to canalicular and otolithic asymmetrical tonus taken from Quix [1].

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mainly in animals. We have also ascertained the dynamics of some of their functions in man but the writers remain convinced that many clinical problems remain little understood and without adequate investigative techniques. Before commencing a detailed account of otolith pathophysiology, it is appropriate to place the problem in a pointed context by asking the reader the following question: ‘Conceive the possibility of a surgical intervention which could repair in some way the whole or part of the otolith organ. The procedure would be a craniotomy with the usual risks of deafness of paralysis of the facial nerve or worse. Which symptoms would you accept as definite indications of an otolithic disorder and which tests, of which the results are indications of abnormal and lateralised otolithic disorder, you would accept?’

Relevant Basic Anatomy and Electrophysiology of the Otolith Apparatus It is appropriate to start with a brief discussion of the anatomy and electrophysiology of the otolith organs because their basic structure and transduction properties suggest the ways in which their signals may be used by the nervous system. The basic hair cell of the maculae is an initial force transducer and as such responds to linear acceleration of the head and (its Einsteinian equivalent) changes in the strength and orientation of the gravitational vector. The multitudinous orientations of the hair cells ensure transduction of these initial forces in all orientational directions in three-dimensional space. The dynamics of otolithic unit responses show that they are sensitive to static initial forces, such as would be effected by a tilt of the head with respect to gravity or prolonged acceleration down a runway in an aeroplane, up to the high frequency movements of the head experienced during sparring in boxing or running. A subclass of the otolith units also renders a signal which approximates the rate of acceleration, suggesting that they can give a very fast triggering response [2]. According to the nature of otolithic signals one would presume they may contribute to a variety of important behavioral functions [3]: viz, the sense or perception of linear acceleration and gravitational tilt; compensatory and balancing movements of the eye head and body as well as autonomic responses, particularly the regulation of blood pressure and volume distribution which are so critically dependent on changes in spatial orientation. Each of these possible functions will now be discussed in turn.

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Perception of Spatial Orientation One would presume that the otolith plays a role in the perception of subjective verticality, detection of thresholds and directions of linear motion and estimating trajectory. There are apparently only two systematic studies which have tried to establish the thresholds of perception of linear acceleration in normal subjects in comparison with patients with bilateral absence of vestibular function [4–6]. In Gianna’s experiment, the subject sat on a train running on linear rails and was exposed to linear accelerations with several configurations including sinusoidal oscillations, ramp and parabolic onset accelerations. The threshold for perception for normal subjects was found to be about 5 cm/s/s whereas patient thresholds were only slightly raised at a mean of 7 cm/s/s which was not statistically significantly different. One might conclude from this study that otolithic signals only reduce the noise around the threshold for detection of linear motion; no more. Incidentally, the thresholds found in Gianna’s study were similar to those established by numerous laboratories for exposure to linear motion on the part of normal subjects. There is a certain similarity between sensitivity to tilt from gravitational upright and thresholds for linear motion, since tilt detection requires the ability to detect a slight change in the magnitude and direction of an imposed static linear acceleration. One would think that the otolith apparatus, with its sensitive hair cells optimally orientated in the utricles for detection of tilt from upright, would give very precise and sensitive estimates of tilt of the body from upright. However, when other somatosensory cues are masked by immersion in water, as with undersea divers, the ability to sense the subjective vertical is seriously degraded to the extent that divers readily become spatially disorientated when deprived of visual cues; a very dangerous situation which has been extensively studied [7, 8]. Thus, it would seem that the signals from the otolith organs, when used in isolation from contextual somatosensory cues, are neither sensitive nor accurate cues for estimating the subjective postural vertical. This conclusion has been borne out by parallel studies which have compared the performance of normal subjects with patients with labyrinthine lesions [9–11]. When exposed to low-frequency passive tilting in a flight simulator the ability of patients with bilateral unilateral labyrinthine disorders to indicate the true direction of earth vertical is similar to that of normal subjects which leads to the conclusion that somatosensory signals predominate in determining the subjective vertical. In an attempt to mask somatosensory signals, a recent experiment used vibration of the simulator to degrade the value of the somatosensory input to estimates of the subjective vertical [12]. Subjects sat on the simulator and with the aid of a joystick were tasked with returning themselves to upright then the simulator tilted gently away from the

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normal upright attitude. Without vibration both normal subjects and patients with unilateral vestibular loss could maintain an upright flight attitude with ease. However, when the whole simulator vibrated, in the subjects with unilateral vestibular loss the simulator tilted by up to 10º to the side of their lesion. Patients’ tilts were found to be a robust effect observed in both the acute and chronic (up to 10 years) stages after vestibular loss. The authors argued that the otolith signal to indicate uprightness had a more significant influence during simulator oscillation and the asymmetry of orientation was due to the differences in densities of hair cells of the utricular macula oriented, respectively, in the rightwards and leftwards direction so that the total output gave a slightly biased tonus which could be corrected by tilting to the lesion side. The effect of vibration was thought to be either by masking somatosensory input alternatively by putting time pressure on the nervous system so that appropriate cross checks between somatosensory and vestibular signals could not be made adequately, thereby revealing the slightly erroneous estimate from the otolith apparatus.

Vertigo in Otolithic Disease One might think that canal activity, e.g. pro-rotatory stimulation, lends a sensational perception of turning whereas otolithic activity lends a perception of linear movement or of tilt or perhaps of a sudden fall. Certainly, the first of these suppositions is false. For example, when an aviator pulls out of a prolonged roll maneuver he may experience the illusion of a tilted and torting visual horizon with accompanying sensations of bodily tilting due to the nystagmic and perceptual consequences of post-rotatory activity in the vertical canals [13–15]. This scenario may provoke accidents since it is the temptation on the part of the aviator to make a sudden and inappropriate attitude correction of his aircraft if he believes that the craft is actually continuing to roll. The illusion does not have an otolithic component since there is no otolith stimulation of tilt or turn in the level attitude achieved immediately after the roll. Thus, a perception of tilt can be imparted by canal activity. Similarly, if a false otolithic signal causes a perception of tilt in the body there may also be an associated component of tilting as the false signal develops. A tilting is also a rotation in the vertical plane ‘the one implies the other’ and it is not clear whether one can separate these perceptions. The question becomes philosophical. In conclusion, it is not so apparent that symptoms of tilting or turning of the body are strong indications for lesions for particular part of the labyrinth, vis-a`-vis canal verses otolithic disorder. In case of a pure linear movement as, for example, the illusion of surging forwards in a vehicle

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or moving purely linearly up and down one might think that they could have a purely otholithic origin but would presumably imply fairly symmetrical bilateral changes in otholithic functional status. This would be rare to say the least and the authors have almost never encountered patients who have complained of a purely linear movement. By far the most common symptoms, the illusory motions we tend to ascribe to a possible otolithic disorder are those of tilting as if on the deck of a ship. Turning and rotation in some way are implicit in this illusion so it is doubtful that one can definitely ascribe them to a purely otolithic disorder.

Compensatory Eye Movement Reflexes Linear Movement in Horizontal and Vertical Planes and Results of Lesions As with the canals, the otoliths provide eye movement reflexes which compensate for movement of the head [16–20] (fig. 3). These reflexes maintain the directional view on visual targets through the linear components of movement, for example through vertical linear head movements encountered when sparring. From geometrical considerations (that parallel lines meet at infinity), it is apparent that one needs linear compensatory eye movements only when targets are fairly close to the subject since when one looks into the distance the effect of a small movement of the head on the direction on vision gaze is negligible. Of significance which will appear below it is noteworthy that linear compensatory eye movements are fast, commencing with a latency of about 20 ms after head motion in man. Certainly bilateral vestibular loss abolishes all compensatory eye movement that would normally be evoked by linear head acceleration [17, 21]. It would not be immediately clear, however, what happens to compensatory eye movements after one unilateral loss of vestibular function. Since hair cells of the surviving utriclar maculae have directional orientations in both the rightwards and leftwards direction, it is possible that signals derived from these two orientations could be used to drive both rightwards and leftwards eye movements and thus compensate for contralateral loss of function. By recording the compensatory eye movements evoked by lateral acceleration from subjects seated on a motorised train, it has been shown that, in the acute stage of unilateral vestibular loss, there is a specific reduction in amplitude of compensatory eye movement generated by linear acceleration to the side of the lesion (fig. 3). In a period of several months this may compensation so that bi-directional responses are regained. In the surviving utricle it is the medially situated hair cells which are stimulated by acceleration to the lesion side and laterally cited hair cells which are excited by acceleration stimuli to

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Fig. 3. Normal repertoire of compensatory eye movements attributable to the otolithic components of vestibular-ocular reflexes.

the intact side. Thus for acceleration towards the intact side the lateral hair cells of the intact organ generate a normal compensatory eye movement. However, for linear acceleration to the lesion side it would seem that excitatory stimulation of the medial hair cells of the intact utricle cannot generate a robust compensatory eye movement, at least in the acute phase of unilateral

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vestibular loss [22–26]. Since static ocular counter-rolling is weak when the head tilts to the side of the of the lesion (fig. 4), which depresses activity of the medial hair cells of the surviving utricle, and is robust when the head tilts to the intact side which excited these medial located hair cells one would also conclude that the medial located hair cells of the utricle preferentially control compensatory ocular counter-rolling. This division of the utricle maculae into laterally located cells responsible for horizontal compensatory eye movements and medially located cells response for static ocular counter-rolling as determined by behavioral observations in man is in accordance with the much earlier observations of Fluur [27] employing microstimulation of different regions of the otolith organ in the cat. Otolithic Control of Cyclo-Version (Ocular Counter-Rolling) In contrast with the robust eye movements evoked by lateral and vertical linear acceleration of the head, tilt of the head with respect to gravitational vector evokes cyclotorsional compensatory eye movements which, in man, are weak in comparison with those to be observed in lateral-eyed animals [28]. It is possible to provoke static cyclo-version, which is attributed largely to otolith function, not only by tilt but also by linear acceleration. When provoked by lateral linear acceleration cyclo-torsion appears in a more ‘pure otolithic’ form uncontaminated by the more robust dynamic counter-rolling nystagmus which is largely driven by the vertical semi circular canals. The amplitude of cyclo-torsional compensatory eye movement evoked by lateral linear acceleration is small and the latency is long, typically around 300 ms in a normal subject. Such a long latency implies a low pass characteristic which is a consequence of brain mechanisms filtering the high-frequency components of the otolithic signal [20, 28]. It is been proposed that this filtering mechanism for cyclo-versional eye movement which has a perceptual counterpart in the perceptual response of tilting when it is exposed to a laterally acting acceleration (as in the centrifuge or on certain fair ground rides) is a mechanism used by the brain to distinguish between tilts with respect to the gravitational vector and actual acceleratory motion across the earth’s surface. It is perhaps worth emphasising this latter point in greater detail. If, for example, a subject is suddenly accelerated laterally with a constant level of acceleration then the first eye movement response would be a horizontal plane compensatory movement at short latency. If the motion was sustained it would then follow the development of the slow ocular cyclotorsion as if the subject was actually tilting and eventually the perception of subjective tilt would develop. In the case of a subject remaining seated upright, the new ‘inertial force vertical’ is determined by the vector sum of gravitational acceleration and the linear acceleration of the vehicle. This is

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Fig. 4. Abnormal eye deviations and nystagmus following acute unilateral loss of otolith function. The schema are partly hypothetical and continue to be the subject of debate. One rarely sees the full repertoire of abnormality in any one patient. In this paper we attribute the spontaneous cyclo-version observed with the head in the normal upright position to unopposed tonus of the medial portion of the surviving utricle. Previous authors have proposed that it arises from a net tonic imbalance which results from summing hair cell activity over the whole utricle [30–32].

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tilted in the direction of vehicle motion, in which case the subject would experience being tilted away from upright. Ocular Cyclo-Torsion and the Visual Vertical in Unilateral Otolithic Lesions It is been known for a very long time, certainly since Quix [1] (fig. 2), that an asymmetry of the vestibula can lead to a tonic tilt of the eyes attributable to asymmetrical otolithic function. In recent times this was exploited first by Friedman [29] in the form of the visual vertical as a ‘test’ for unilateral otolithic disorder. In simple terms, the visual vertical is determined largely by the retinal coordinates of the eye. If the eye tilts for any reason a subject will set a visual vertical target line tilted by approximately the same amount as the eye rotation and in the direction of the eye rotation. Accordingly, if a unilateral vestibular lesion deviates the eyes in cyclo-torsional tilt to the lesion side the visual vertical is set according to the ocular tilt and thus in turns becomes an indicator of the laterality of vestibular loss by virtue of its tilt towards the side of lesion. This effect is relatively acute and the visual vertical may become apparently normal or near normal within 6 months to a year [30–34]. Apparently simple, this scheme can be difficult to apply to clinical investigation. In the first place, any cyclo-torsional nystagmus will also influence the visual vertical and this type of nystagmus is frequently present in patients with acute vestibular lesions [35–42]. Secondly, a pre-existing ophthalmologic disorder may effect the visual vertical as possibly would other sensory inputs, particularly from the neck which is so interrelated to vestibular function. Finally, the assumption that a static cyclo-torsion following vestibular injury reflects the otolithic component to disordered function seems to stem from an implicit assumption that static eye deviations are generally otolithic in origin whereas nystagmus events are canalicular in origin. It is not at all clear that this is necessarily the case [41, 42]. Here one could use a similar argument for the one detailed above for canal versus otolith vertigo. Since we know that otolith stimulation can produce both static eye deviations and nystagmus (in the form of L nystagmus) why is it not also possible that canal stimulation can produce small static bias effects on eye position as well as the more frank nystagmus? If the latter case is true then it is possible that tilt of the visual vertical could have a canalicular origin; particularly in vertical canal asymmetry. Symptoms of Disorder Linear Compensatory Eye Movement: Oscillopsia From the point of view of symptoms one would wonder whether patients who have bilateral otolithic lesions suffer from oscillopsia when undergoing linear motion with respect to nearby targets in parallel with the oscillopsia they would experience from head rotations. Perhaps this is so but the oscillopsia

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provoked by canal lesions is much worse and would certainly dominate symptomatically. However, there is experimental evidence that patients with bilateral otolithic lesions do suffer from oscillopsia when trying to reach targets during linear head oscillation [22]. The experience was undertaken with subjects sitting immobilised on a train running on a straight tract. It was found that during oscillatory motion of the train in the lateral direction normal subjects were able to read an earth-fixed target whereas patients with bilateral loss of vestibular function reported oscillopsia and suffered a marked loss of visual acuity. Thus, the consequences to visual acuity of bilateral otolithic loss are quantifiable but the technical requirements mean that it is expensive to do.

Otolith-Spinal Function It is very difficult to ascribe any subdivision of vestibulo-spinal reflexes to a specific otolith function because the sort of body movements which stimulate the otoliths would also stimulate well nigh every other sensory system in the body. Accordingly, the following discussion is concerned with vestibulo-spinal responses and effects which we believe to be largely otolithic in origin. A rapid fall or tilt of the body which involves abrupt movement of the head provokes a generalised response in most skeletal muscles which is thought to be in part a startle response [43–49]. However, the earliest part of this startle response is purely vestibular in origin. It is very likely that this response is triggered by stimulation of the otolith apparatus as one could tentatively suggest by the irregular units specifically. These early responses are abolished in patients with bilateral loss of vestibular function. A tilt of the floor which affects the body provokes a coordinated balancing response in which the various parts of the body return towards upright: this response is a compensation for the tilt illustrated in figure 2 by Quix. A very similar coordinated postural adjustment may be seen with low levels of galvanic stimulation of the labyrinth, suggesting that small currents tend to preferentially stimulate the otoliths [50–52]. A further feature of galvanic stimulation is that the body tends to lean slightly in the direction of stimulation and this leaning can be vectored by turning the head so for example one ear faces to the front. This lean has been ascribed to a subtle shift in the frame of reference of standing posture caused by otolithic stimulation [52] roughly similar to the tilted attitude adopted by unilateral labyrinthine defectives when flying in a flight simulator as described above [12]. Presently there is perhaps only one clinical test which is specific for vestibulo-spinal function. This depends on the effect of loud noise on the

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sacculus. A brief loud click (0.1 ms, greater than 95 dB HL) to the ear evokes an inhibitory response in the ipsilateral sternocleidomastoid muscle with a latency of 8 ms [53–58]. The whole muscle response has a positive signal peak at 13 ms with a negative peak at 23 ms and is abolished by vestibular neurectomy, although preserved in the case of profound hearing loss. Experiments in animals and in patients with diverse lesions of the vestibular apparatus suggest that the origin of this response is in stimulation of the sacculus [57–64]. In the case of certain disorders of the labyrinth, such as the phenomenon of Tullio [65], it is possible to observe an accentuation of this response suggesting hyperexcitability of the labyrinth. In such cases we do not know if the response remains a function of the saccule or whether other parts of the labyrinth have become similarly sensitive to noise. In conclusion, although responses of the neck to auditory clicks demonstrate the integrity of saccular function their application in investigating disorders of the labyrinth remains experimental.

Otolithic Control of Autonomic Function Spatial reorientations demand adjustments of blood pressure and blood volume distribution. The vestibular apparatus is the only sensory organ specialised for signalling spatial reorientations and therefore its signal should be important for guiding the patterning of neuro-vegetative responses to reorientation. In addition, as they can be so fast, vestibular signals are ideally suited to trigger patterns of autonomic response. It is perhaps Yates and his associates’ work in particular that has shown in the cat that there are important fairly direct pathways by which the otolith organ regulates the mechanism of blood pressure and respiratory muscle [66–68]. It is interesting that animal work has also failed to show any cannalicular pathways for controlling neurovegetative functions of comparable significance. In general terms there are two sorts of mechanisms proposed to explain symptoms of malaise in patients with disorders of the vestibular apparatus. The first involves the fairly direct pathways recently described in animal experiments. If the otoliths provide important signals for controlling heart rate, blood pressure, and respiration during rapid spatial reorientation, then one could easily imagine how abnormal otolithic functions either spontaneously or as a consequence of inadequate response to spatial reorientation lead to the vaso-vagal symptoms (and occasional syncope) frequently encountered in patients with vestibular disease. The second route by which vaso-vagal symptoms could be provoked in vestibular patients is through the route of motion sickness mechanisms [69]. It is well established that motion sickness

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Fig. 5. Respective alignment and misalignment of an active, anticipating driver and passive, unprepared passenger with respect to the inertial ‘vertical’ during acceleration in a vehicle. If the driver maintains his alignment he experiences little otolithic stimulation.

is provoked when vestibular signals are in conflict or ‘mismatched’ (fig. 5) with somaesthetic or visual information. In addition the most provocative circumstances for motion sickness involve movements which change orientation of the body with respect to vertical and thereby stimulate the otoliths. Clearly, a unilateral vestibular lesion could be the source of conflict because of the mismatch between signals from the diseased part of the labyrinth and signals from healthy labyrinthine receptors and other sensory inputs. In this view, the malaise experienced by patients with vestibular disease is a form of motion sickness.

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Several recent experiments have addressed the problem of understanding the causes of malaise in vestibular disease in man with emphasis on the involvement of otolith function. Brief linear acceleration of the body has been shown to provoke a pressor response with elevation of blood pressure and heart rate (up to 10 mm Hg systolic) which lasts approximately 10 s after a period of linear acceleration of 1–2 s duration [68]. This pressor response is probably largely a function of the otolith stimulation during linear acceleration because it is much diminished in patients with bilateral loss of vestibular function. Our own unpublished observations have shown that it matters little exactly what spatial reorientation is undertaken. If the movement is fast a pressor response is provoked with the obvious function of preparing the body for any counteraction that may be necessary. This is the reason perhaps that one encounters patients with bilateral vestibular loss who feel faint when they move quickly or suffer vertigo, the reason being that they have lost the vestibularly triggered pressor response required for dealing with spatial reorientation whether illusory or real.

Applications of Otolith Physiology Finally, we would like to discuss an important possible application of otolithic physiology which is the problem of inappropriate autonomic changes provoked during passive motion in a vehicle. In addition to motion sickness experienced by normal subjects there is some evidence suggesting that ambulance transport can compromise even further the state of an already sick patient. The reason for this is not clear and could be a combination of motion sickness [70, 71], inability to make rapid autonomic changes in response to accelerations of the vehicles, and inability to deal with passive shifting of the body fluids, particularly the blood, also due to vehicle acceleration. The question is can one protect the passenger from inappropriate stimulation by acceleration? Consider the motorbike driver who leans into the direction of acceleration when opening the throttle to accelerate his bike and thereby maintains his head and torso in alignment with the inertial force vector which tilts forwards as the bike accelerates forwards (fig. 5). In contrast, his unwary passenger may be thrown backwards when the bike takes off thus tilting markedly with respect to the inertial upright (fig. 5). The driver receives very little change in otolithic stimulation whereas the passenger receives a strong otolithic signal of tilt with respect to the upright (fig. 6). Since, in animals at least, it is the otoliths that primarily drive vaso-vagal responses one would presume that the driver is relatively protected against autonomic

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Fig. 6. Sensory systems stimulated by various tactics of alignment with the inertial ‘vertical’ during vehicle acceleration. Although alignment with the inertial vector will tend to minimise otolith stimulation it provokes sensory mismatch. It is an unresolved question as to which would be more detrimental to cardiovascular control.

changes which are inappropriate for a person sitting and being passively transported in a vehicle. To determine what happens during acceleration with the body aligned with the inertial upright and misaligned, we exposed subjects to brief linear accelerations with a visual display which guided them to make head movements which aligned and compensated for the linear acceleration or alternatively misaligned: similar to the body movements of the motorbike driver and passenger, respectively [72]. In the aligned condition heart rate and blood pressure changes measured tonometrically on the radial artery were minimal during accelerations whereas in the misaligned conditions a marked pressor response was evoked with a mean peak systolic blood pressure change of 7 mm Hg. A similar experiment has also been conducted in Japan [73] on subjects who were carried within a vehicle on an actively suspended stretcher which would similarly align or misalign their body with the inertial force vector generated by accelerating and breaking of the vehicle. The authors similarly found that the subjects were protected against blood pressure changes when the stretcher aligned with the tilting of the inertial force vector. With the recent advent of active suspension systems, for example, as available in Citroen motorcars, it should be possible to tune the ‘ride’ of a vehicle to protect passengers against inappropriate autonomic changes. It

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remains to be seen whether this would help protect patients during transport in ambulances or normal subjects who are particularly susceptible to motion sickness.

Conclusions It is difficult to ascribe any set of clinical signs or symptoms and results of related investigations as specific to otolithic disorder. Appropriate testing can be expensive and yield equivocal results. In future, attention should be paid to validation and assessment of sensitivity and specificity of tests purporting to evaluate otolith dysfunction.

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Tribukait A: Semicircular canal and saccular influence on the subjective visual horizon during gondola centrifugation. J Vest Res 1999;9:347–357. Greenwood R, Hopkins A: Muscle responses during sudden falls in man. J Physiol 1976;254: 507–518. Greenwood R, Hopkins A: Landing from an unexpected fall and a voluntary step. Brain 1976;99: 375–386. Halmagyi GM, Gresty MA: Blink reflexes to sudden free falls: A test of otolith function. J Neurol Neurosurg Psychiatry 1983;46:844–847. Ito Y, Corna S, von Brevern M: Neck muscle responses to abrupt free fall of the head: Comparison of normal with labyrinthine-defective human subjects. J Physiol 1995;489:911–916. Ito Y, Corna S, von Brevern M: The functional effectiveness of neck muscle reflexes for headrighting in response to sudden fall. Exp Brain Res 1997;117:266–272. Bisdorff AR, Bronstein AM, Gresty MA: Responses in neck and facial muscles to sudden free fall and a startling auditory stimulus. EEG Clin Neurophysiol 1994;93:409–416. Bisdorff AR, Bronstein AM, Wolsley C: EMG responses to free fall in elderly subjects and akinetic rigid patients. J Neurol Neurosurg Psychiatry 1999;66:447–455. Britton TC, Day BL, Brown P: Postural electromyographic responses in the arm and leg following galvanic vestibular stimulation in man. Exp Brain Res 1993;94:143–151. Day BL, Severac-Cauquil A, Bartolomei L: Human body-segment tilts induced by galvanic stimulation: A vestibularly driven balance protection mechanism. J Physiol 1997;500:661–672. Inglis JT, Shupert CL, Hlavacka F: Effect of galvanic vestibular stimulation on human postural responses during support surface translations. J Neurophysiol 1995;73:896–901. Colebatch JG, Halmagyi GM, Skuse NF: Myogenic potentials generated by a click-evoked vestibulocollic reflex. J Neurol Neurosurg Psychiatry 1994;57:190–197. Halmagyi, GM, Curthoys IS, Colebatch JG: New tests of vestibular function. Ballie`re’s Neurol 1994;3:485–500. Murofushi T, Halmagyi GM, Yavor RA: Vestibular evoked myogenic potentials in vestibular neuritis: An indicator of inferior vestibular nerve involvement. Arch Otolaryngol Head Neck Surg 1996; 122:845–848. Murofushi T, Matsuzaki M, Mizuno M: Vestibular evoked myogenic potentials in patients with acoustic neuromas. Arch Otolaryngol Head Neck Surg 1998;124:509–512. Halmagyi GM, Curthoys IS: Clinical testing of otolith function. Ann NY Acad Sci 1999;871: 195–204. Didier A, Cazals Y: Acoustic responses recorded from the saccular bundle on the eighth nerve of the guinea pig. Hearing Res 1989;37:123–128. Murofushi T, Curthoys IS: Physiological and anatomical study of click-sensitive primary vestibular afferents in the guinea-pig. Acta Otolaryngol (Stockh) 1997;117:66–72. McCue MP, Guinan JJ: Sound-evoked activity in primary afferent neurons of the mammalian vestibular system. Am J Otol 1997;18:355–360. Murofushi T, Curthoys IS, Topple AN: Responses of guinea pig primary vestibular neurons to clicks. Exp Brain Res 1995;103:174–178. Murofushi T, Curthoys IS, Gilchrist DP: Response of guinea pig vestibular nucleus neurons to clicks. Exp Brain Res 1996;111:149–152. Uchino Y, Sato H, Sasaki M: The sacculocollic reflex arc in cats. J Neurophysiol 1997;77:3003– 3012. Young ED, Fernandez C, Goldberg JM: Responses of squirrel monkey vestibular neurons to audiofrequency sound and head vibration. Acta Otolaryngol (Stockh) 1977;84:352–360. Colebatch JG, Day BL, Bronstein AM: Vestibular hypersensitivity to clicks is characteristic of the Tullio phenomenon. J Neurol Neurosurg Psychiatry 1998;65:670–678. Yates BJ: Vestibular influences on the sympathetic nervous system. Brain Res Rev 1992;17: 51–59. Yates BJ: Autonomic reaction to vestibular damage. Otolaryngol Head Neck Surg 1998;119:106–112. Yates BJ, Aoki M,Burchill P: Cardiovascular responses elicited by linear acceleration in humans. Exp Brain Res 1999;125:476–484.

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69 70 71 72 73

Benson AJ: Motion sickness; in Ernsting J, Nicholson AN, Rainford DJ (eds): Aviation Medicine. Oxford, Butterworth Heinemann, 1999, pp 455–471. Bles W, Bos JE, de Graaf B, Groen E, Wertheim AH: Motion sickness: Only one provocative conflict? Brain Res Bull 1998;47:481–488. Bos JE, Bles W: Modelling motion sickness and subjective vertical mismatch detailed for vertical motions. Brain Res Bull 1998;47:537–542. Aoki M, Burchill P, Yates B: Graviceptive control of blood pressure in man. Arch Ital Biol 2000; 138:93–97. Sagawa K, Inooka H, Ino-oka E, Takahashi T: On an ambulance stretcher suspension concerned with the reduction of patient’s blood pressure variation. Proc Inst Mech Eng 1997;211:199–208.

Dr. Michael A. Gresty, Senior Scientist, MRC Human Movement and Balance Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG (UK) Tel. +44 171 8373 611, E-Mail [email protected]

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Tran Ba Huy P, Toupet M (eds): Otolith Functions and Disorders. Adv Otorhinolaryngol. Basel, Karger, 2001, vol 58, pp 34–47

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Otolithic Vertigo Thomas Brandt Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Munich, Germany

There are several reasons why most vestibular syndromes involve both semicircular canal function and otolithic function: (1) The different receptors for perception of angular and linear accelerations are housed in a common labyrinth. (2) Their peripheral (eighth nerve) and central (e.g. medial longitudinal fascicle) pathways take the same course. (3) Otolith and semicircular canal input converge at all central vestibular levels, from the vestibular nuclei to the vestibular cortex. Thus, most vestibular syndromes are mixed as regards otolithic and canal function. A peripheral prototype of such a mixed syndrome is vestibular neuritis. It is caused by inflammation of the superior division of the vestibular nerve that subserves the horizontal and the anterior semicircular canals and the maculae of the utricle and the anterosuperior part of the saccule. A central prototype is Wallenberg’s syndrome. In this disorder the medial and superior vestibular nuclei are involved where otolith and canal input converge. Wallenberg’s syndrome typically causes ocular and body lateropulsion and torsional spontaneous nystagmus. Nevertheless, with caloric irrigation of the external acoustic meatus it is possible to selectively stimulate single canals. The prototype of a semicircular canal disease is benign paroxysmal positioning vertigo of the posterior or horizontal canal. Typical signs and symptoms of semicircular canal vertigo are: (a) Rotational vertigo and deviation of perceived straight-ahead. (b) Spontaneous vestibular nystagmus with oscillopsia. (c) Postural imbalance with Romberg fall and pastpointing. (d) Nausea and vomiting if severe.

The 3-D spatial direction of nystagmus and vertigo depends on the spatial plane of the affected semicircular canal and on whether the dysfunction is caused by ampullofugal or ampullopetal stimulation or by a unilateral loss of afferent information. Malfunction of a single or more than one semicircular canal can be detected by 3-D analysis of spontaneous nystagmus [1–3] or perception of rotation [4]. Central vestibular syndromes may hide the semicircular canal or otolithic types. They are best classified according to the three major planes of action of the vestibular ocular reflex: yaw, roll, and pitch. To put it simply, ‘dynamic’, rotatory vertigo and nystagmus indicate that (angular) canal function is affected, whereas ‘static’ ocular tilt reaction, body lateropulsion, or tilts of perceived vertical point to (linear) otolith function. The following is largely adopted from a more detailed presentation in the monograph Vertigo – Its Multisensory Syndromes [5]. This review focuses on peripheral rather than central otolithic syndromes.

Otolithic Syndromes Although the pathophysiology of otolithic dysfunction is poorly understood, a disorder of otolithic function at a peripheral or central level should be suspected if a patient describes symptoms of falls, sensations of linear motion, or tilt, or else shows signs of specific derangements of ocular motor and postural orienting and balancing responses [6]. A significant number of patients presenting to neurologists have signs and symptoms that suggest disorders of otolithic function. Nevertheless, diseases of the otoliths are poorly represented in our diagnostic repertoire (table 1). Of these diseases, posttraumatic otolith vertigo [7] may be the most significant. The rare otolith Tullio phenomenon may be the most thoroughly studied [8, 9]. Other examples are vestibular drop attacks (Tumarkin’s otolithic crisis) and a number of central vestibular syndromes that indicate tone imbalance of graviceptive circuits (skew deviation, ocular tilt reaction, lateropulsion, room-tilt illusion), some of which manifest without the sensation of dizziness or vertigo.

Vestibular Drop Attacks (Tumarkin’s Otolithic Crisis) Vestibular drop attacks can occur not only in the later stages of endolymphatic hydrops [10, 11] but at any time during the course of Menie`re’s disease [12]. In exceptional cases it may even be the initial manifestation [13]. Over a 10-year period Baloh and coworkers identified only 12 of 175 patients with Menie`re’s disease to have drop attacks. and colleagues [14] reported a

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Table 1. Peripheral and central vestibular syndromes affecting otolith function [5] Disorder

Signs/symptoms

Mechanism

head motion intolerance, gait ataxia, to-and-fro vertigo, tilt of perceived vertical, skew deviation, lateropulsion

dislodged otoconia cause unequal heavy loads with ‘graviceptive’ tone imbalance

Vestibular drop attacks (Tumarkin’s otolithic crisis in Menie`re’s disease)

sudden falls, sensation of being pushed to the ground, Menie`re’s triad

sudden changes in endolymphatic fluid pressure with inappropriate otolith stimulation causing reflex-like vestibulospinal loss of postural tone

Endolymphatic hydrops

episodic to-and-fro vertigo, unsteadiness, Menie`re’s disease

‘floating labyrinth’, deformation or pressure changes in the membranous labyrinth

Perilymph fistula (otolith type)

to-and-fro vertigo, gait ataxia with sneezing, coughing, or physical exercise, positive fistula signs (e.g. Valsalva’s maneuver)

perilymph leakage, abnormal elasticity of the bony labyrinth with irritative otolith stimulation during head motion, intracranial pressure changes

Peripheral vestibular Labyrinth Posttraumatic Otolith vertigo

Vestibular atelectasis

episodic to-and-fro vertigo, gait ataxia

Otolith Tullio phenomenon

Eighth nerve/or labyrinth Ocular tilt reaction Eighth nerve Vestibular (otolithic) Paroxysmia Central vestibular Cortical Vestibular epilepsy

sound or pressure-induced paroxysms of perceived tilt, oscillopsia, skew deviation, and lateropulsion

collapse of the walls of the ampulla and utricle inadequate mechanical stimulation of otolith by hypermobile stapes footplate (stapedius reflex) caused by loud sounds

triad of head tilt, skew deviation, and ocular ‘graviceptive’ tone imbalance due to unilateral ocular torsion associated with perceived tilt loss or irritation of (utricular) otolithic function paroxysms of vertical and torsional diplopia, neurovascular crosscompression of the perceived tilt, head and body lateropulsion (utricular?) nerve with ephaptic spreading

paroxysmal perceived tilts and body falls with or without ocular motor abnormalities

epileptic discharges in vestibular cortex

Cortical lateropulsion

body tilt and tilts of perceived vertical

cortical ‘graviceptive’ tone imbalance with acute lesions of the parieto-insular vestibular cortex

Room-tilt illusion

transient illusions of upside-down vision or apparent 90º tilts of the visual scene

cortical mismatch of visual and otolithic 3-D maps of spatial orientation

lateropulsion and tilt of perceived vertical

‘graviceptive’ tone imbalance with acute lesions of vestibular subnuclei

Thalamus Thalamic astasia

Brainstem Ocular tilt reaction see above Lateropulsion see above Room-tilt illusion see above Upbeat/downbeat nystagmus provoked or modulated by changes in head position

Brandt

see above see above see above

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similar incidence (11 of 200 patients). The drop attacks occur from a standing or sitting position without typical triggers or prodromi. The patients describe the typical features [11, 13] in the following ways: (a) they felt they were being pushed or shoved to the ground, or (b) the surroundings suddenly moved or tilted, causing their fall. As distinct from patients with syncopies or epileptic seizures, these patients have no associated loss of consciousness and are able to stand up immediately. Contrary to patients with transient upside-down vision or room-tilt illusions, patients with drop attacks fall without appropriate postural reflexes. According to the pathophysiological viewpoint, sudden changes in endolymphatic fluid pressure cause inappropriate end-organ stimulation that results in a reflex-like vestibulospinal loss of postural tone or an inappropriate vestibulospinal reflex that leads to a fall. In the series of Baloh et al. [13], the first drop attack occurred from less than 1 year to 29 years after onset of Menie`re’s disease, and the total number of attacks varied from 2 to 18, with only 2 of 12 patients having more than six attacks. Drop attacks tend to occur in a flurry during a period of 1 year or less and are followed by spontaneous remission [12, 13]. Therefore, conservative management is recommended, not surgical intervention as Black et al. [14] proposed. Drop attacks disappeared completely after gentamicin treatment (applied intratympanally) [15]. Transtympanic aminoglycoside treatment is increasingly being preferred to surgery. All reported experience with this kind of treatment indicates that one injection per week (1–2 ml of concentrations less than 30 mg/ml) on an outpatient basis is recommended in order to better monitor the delayed ototoxic effects.

Traumatic Otolithic Vertigo Patients often describe their posttraumatic vertigo as a nonrotatory toand-fro vertigo that is particularly associated with head acceleration and an unsteadiness of gait similar to walking on pillows. Since these posttraumatic symptoms resemble otolith dysfunction in many patients, one can speculate that the otolith, a vulnerable accelerometer, is affected by trauma [7]. The calcareous material embedded in its gelatinous matrix may loosen, resulting in unequal loads on the macula beds and a tonus imbalance between the two. This has been shown in centrifuge experiments with animals [16, 17]. Engineering accelerometers are just as vulnerable. Such a mechanism also fits the finding of DeWit and Bles [18] that postural sway is increased after headshaking in dizzy patients who have suffered a concussion. For these

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patients visual stabilization plays a greater role than in normal subjects. The authors erroneously believed their findings could be ascribed to the brainstem concussion. A considerable proportion of traumatic vertigo can be assumed to be due to dislodged otoconia, with or without concurrent benign paroxysmal positional vertigo, which depends on the position of the debris within the membraneous labyrinth. No clinical test is yet available to establish a diagnosis of traumatic otolithic vertigo, but our own unpublished measurements of transient deviation of the subjective visual vertical in these patients provide evidence of the condition. Central compensation (rearrangement) would account for the gradual recovery within days or weeks, thus supporting the view that exercise is the best therapy.

Benign Paroxysmal Positioning Vertigo (Otolithic Canalolithiasis) Benign paroxysmal positioning vertigo (BPPV; also known as positional vertigo) was initially defined by Ba´ra´ny [19] in 1921. The term itself was coined by Dix and Hallpike [20]. BPPV is only labeled an otolithic vertigo in the context of this review, since otolithic debris in the semicircular canals are causative. Lanska and Remler [21] describe in detail the history of BPPV, its original description, the proper eponymic designation for the provocative positioning test, and the steps leading to our current understanding of its pathophysiology. BPPV is the most common cause of vertigo, particularly in the elderly. By age 70, about 30% of all elderly subjects have experienced BPPV at least once. This condition is characterized by brief attacks of rotatory vertigo and concomitant positioning rotatory-linear nystagmus. These attacks are elicited by rapid changes in head position relative to gravity. BPPV is a mechanical disorder of the inner ear in which the precipitating positioning of the head causes an abnormal stimulation, usually of the posterior semicircular canal (p-BPPV) of the undermost ear, less frequently of the horizontal semicircular canal (h-BPPV). Schuknecht [22] and Schuknecht and Ruby [23] hypothesized that heavy debris settle on the cupula (cupulolithiasis) of the canal, transforming it from a transducer of angular acceleration into a transducer of linear acceleration. It is now generally accepted that the debris float freely within the endolymph of the canal (‘canalolithiasis’) [24–26]. The debris – particles detached from the otoliths – congeal to form a free-floating clot (plug). Since the clot is heavier than the endolymph, it will always gravitate to the most dependent part of the canal during changes in head position which alter the angle of the

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cupular plane relative to gravity. Analogous to a plunger, the clot induces bidirectional (push or pull) forces on the cupula, thereby triggering the BPPV attack. Canalolithiasis explains all the features of BPPV: latency, short duration, fatigability (diminution with repeated positioning), changes in direction of nystagmus with changes in head position, and the efficacy of physical therapy [26–28] (fig. 1). In 1980, Brandt and Daroff [29] proposed the first effective physical therapy (positioning exercises) for BPPV. Based on the assumption that cupulolithiasis was the underlying mechanism, the exercises were a sequence of rapid lateral head/trunk tilts, repeated serially to promote loosening and, ultimately, dispersion of the debris toward the utricular cavity. In 1988, Semont et al. [30] introduced a single liberatory maneuver, and Epley promoted a variation in 1992, which Herdman et al. [31] later modified. If performed properly, all three forms of therapy (Brandt-Daroff exercises and Semont and Epley’s liberatory maneuvers) are effective in BPPV patients [31, 32]. The efficacy of physical therapy makes selective surgical destruction such as transsection of the posterior nerve [33] or nonampullary plugging of the posterior semicircular canal [34] largely unnecessary. About 5–10% of BPPV patients suffer from horizontal canalolithiasis (h-BPPV) [35]. h-BPPV is elicited when the head of the supine patient is turned from side to side, around the longitudinal z-axis. Combinations are possible, and transitions from p-BPPV to h-BPPV occur, if the clot moves from one to the other semicircular canal. Transitions from canalolithiasis to cupulolithiasis in h-BPPV patients have been described [36]. Most of the cases appear to be idiopathic (degenerative?), their incidence increasing with advancing age. Prolonged bedrest also facilitates their occurrence. Other cases arise due to trauma, vestibular neuritis, or inner ear infections. For the time being, the recommended treatment is prolonged bedrest with the head turned toward the unaffected ear [37]. This should be maintained for up to 12 h. If no effect is observed after 2 days, we advise the patients to perform the exercises described by Brandt and Daroff [29]. Both physical therapies can be performed at home and do not require the presence of a physical therapist. The diagnosis of typical BPPV is simple and safe: the patient must have the usual history and exhibit positioning nystagmus toward the causative, undermost ear. Diagnosis is less easy in rare cases, for example, in patients with horizontal semicircular canal cupulolithiasis who exhibit positional nystagmus beating toward the uppermost ear for several minutes. Differential diagnosis includes different forms of central vestibular vertigo or nystagmus, vestibular paroxysmia, perilymph fistula, drug or alcohol intoxication, vertebrobasilar ischemia, Menie`re’s disease and psychogenic vertigo.

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Fig. 1. Schematic drawing of the Semont liberatory maneuver in a patient with typical BPPV of the left ear. Boxes from left to right: position of body and head, position of labyrinth in space, position and movement of the clot in the posterior canal and resulting cupula deflection, and direction of the rotatory nystagmus. The clot is depicted as an open circle within the canal; a black circle represents the final resting position of the clot. (1) In the sitting position, the head is turned horizontally 45º to the unaffected ear. The clot, which is heavier than endolymph, settles at the base of the left posterior semicircular canal. (2) The patient is tilted approximately 105º toward the left (affected) ear. The change in head position, relative to gravity, causes the clot to gravitate to the lowermost part of the canal and the cupula to deflect downward, inducing BPPV with rotatory nystagmus beating toward the undermost ear. The patient maintains this position for 1 min. (3) The patient is turned approximately 195º with the nose down, causing the clot to move toward the exit of the canal. The endolymphatic flow again deflects the cupula such that the nystagmus beats toward the left ear, now uppermost. The patient remains in this position for 1 min. (4) The patient is slowly moved to the sitting position; this causes the clot to enter the utricular cavity. A, P and H>Anterior, posterior, horizontal semicircular canals; Cup>cupula; UT> utricular cavity; RE>right eye; LE>left eye. From Brandt et al. [28].

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Perilymph Fistulas The perilymph space surrounds the endolymph-filled membranous labyrinth, and both are encapsuled by the bony labyrinth. Perilymph fistulas (PLF) – abnormal communications between the perilymph space and the middle ear – are caused by traumatic pressure changes in either the cerebrospinal fluid (explosive force) and/or the middle ear (implosive force). PLF may lead to episodic vertigo and sensorineural hearing loss, owing to pathological elasticity of the otic capsule or leakage of perilymph, usually at the oval and round windows. The fistula and a partial collapse of the membranous labyrinth (‘floating’ labyrinth) permit abnormal transfer of ambient pressure changes to maculae and cupulae receptors. The typical history is that of an ‘otolithic ataxia’, or a semicircular canal type of vertigo, and/or a sudden hearing loss resulting from barotrauma (flying, diving), trauma to the head, to the ear (e.g. postsurgery), or from strenuous activity, such as lifting of heavy weights (excessive Valsalva maneuver). As trauma is a frequent etiology of the first manifestations of PLF, the subsequently vulnerable patients often report on typical triggers (lifting weights, nose blowing, traveling through mountains) that set off the clinical signs of episodic vertigo and/or sensorineural hearing loss. In some patients PLF appear as sound-induced vestibular symptoms, which are called the Tullio phenomenon, either of the semicircular canal or otolith type. The clinical picture of PLF is characterized by a wide range of symptoms: pure vestibular symptoms; pure hearing loss; combinations of both, including tinnitus and fullness of the ear; or the absence of symptoms. Patient history is very important, especially if the first manifestation is associated with head trauma. With respect to vertigo and vestibular function two types of PLF can be distinguished: (1) The semicircular canal type by rotational vertigo and nystagmus. (2) The otolith type by unsteadiness, gait ataxia, and oscillopsia. Both types manifest in episodes lasting from hours to days. Frequent triggers are ambient pressure changes transferred to the inner ear, certain head positions in space, head movements, or locomotion.

Otolith Type of PLF Healy et al. [38, 39] were the first to stress that this condition should be suspected in patients with severe gait disturbance and ataxia without

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evidence of central nervous system disease, even in the absence of gross hearing defects. In our experience, these patients represent a well-defined subgroup of fistula patients. It is justified to call this syndrome ‘otolith type of PLF’, since the vertigo symptoms can be explained by inappropriate otolithic stimulation secondary to oval window fistulas. Most of these patients are free from vertigo with the head stationary, but they experience a distressing to-and-fro movement of both body and surroundings with head accelerations, for example, when rising from a sitting position and particularly when walking. The sensation, described as ‘walking on pillows’, is similar to that described by patients in the initial phase of BPPV or in phobic postural vertigo. The gait is broad-based and ataxic, but clinical examination does not reveal cerebellar or spinal ataxia. It is striking that head movements, which preferentially stimulate the canals (horizontal oscillation in yaw), are much better tolerated than linear accelerations. Sometimes a linear vertigo, described as a tilt or slow falling, is precipitated in the supine position (especially with the affected ear undermost). Nausea and vomiting are rare, unlike in canal disease. Symptoms most often associated with this otolithic vertigo are fluctuating fullness of the ear, tinnitus, and sensorineural hearing loss. The disease is more often episodic than chronic. Episodes are sometimes induced by strenuous activities such as lifting heavy objects, jogging, or all kinds of Valsalva pressure increases (sneezing, coughing). The severity of the episodes varies. Some patients, who are able to detect the beginning of an episode by an audible ‘pop’ or increasing fullness of the ear, can prevent the development of more severe symptoms merely by stopping the precipitating activity.

Tullio Phenomenon Sound-induced vestibular symptoms such as vertigo, nystagmus, oscillopsia, and postural imbalance in patients with PLF are commonly known as the Tullio phenomenon [40]. The occurrence of a distressing ‘Tullio symptomatology’ presupposes PLF pathology; however, only rare patients with PLF suffer from the Tullio phenomenon. It seems, nevertheless, justified to give a detailed and separate description of the Tullio phenomenon in conjunction with PLF, since this pathological condition has revealed new details about human vestibular function in connection with ocular motor and postural control. Oculographic, posturographic, and EMG studies allow a unique analysis of vestibulo-ocular and vestibulospinal otolith reflexes in humans using sound stimulation.

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Clinical Types of Tullio Phenomena Two mechanisms are generally acknowledged to be involved in a Tullio phenomenon in humans: more than one mobile window or a fistula opens into the vestibular labyrinth [41, 42] and there is a pathological contiguity of the tympano-ossicular chain and the membranous labyrinth, for example, if the stapes is in contact with the saccule because of endolymphatic hydrops [42–44]. Within the heterogeneous group of Tullio phenomena, an otolith type and a semicircular canal (nystagmus) type, e.g., due to window rupture, can and must be differentiated. In the latter, the pathological elasticity of the bony labyrinth makes it possible for high-intensity sound to move the periendolymph system of the canals rather than to push the otoliths. Click-evoked vestibulocollic reflexes were studied in a patient with a unilateral Tullio phenomenon who showed an abnormally low threshold and larger reaction when elicited from the symptomatic side [45, 46]. This is compatible with a pathological increase in the normal vestibular sensation to sound. Most of the older case descriptions in the literature suffer from imprecise descriptions or the failure to register induced eye/head movements, so that it is impossible retrospectively to classify them as an otolith or a semicircular canal type.

Otolith Tullio Phenomenon There is evidence based on an otoneurological examination of a typical patient as well as the reevaluation of cases described in the literature that an otolith Tullio phenomenon due to a hypermobile stapes footplate typically manifests with the pattern of sound-induced paroxysms of ocular tilt reaction (OTR) [8, 44, 47]. The patients complain of distressing attacks of vertical oblique and rotatory oscillopsia (apparent tilt of the visual scene) as well as postural imbalance (fall toward the unaffected ear and backward). These attacks are elicited by loud sounds, particularly when the sounds are applied to the affected ear at a maximum frequency (e.g. 500 Hz). Uttering vowels or blowing the nose causes similar symptoms of varying severity. The clinical picture of simultaneous paroxysms of eye-head synkinesis (OTR) includes the triad of skew deviation (ipsilateral over contralateral hypertropia), ocular torsion, and head tilt toward the undermost eye. Electronystagmographic recordings as well as special video analysis (time resolution: 1,000 images/s) revealed a latency for the eye movements of 22 ms with an initial rapid and phasic rotatory-upward deviation [8], which was

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followed by a smaller tonic effect as long as sound stimulation lasted. This short latency agrees with the short-latency compensatory eye movements (16.4– 18.5 ms) found during brief periods of free fall in the monkey [48]. Skew deviation in the patient is caused by a disconjugate larger deviation of the ipsilateral eye. Repetitive sound stimulation leads to habituation of the phasic component of eye movements. Rottach et al. [49] reported a latency of 16 ms for sound stimuli-induced horizontal-torsional nystagmus in a patient with Tullio phenomenon. Cohen et al. [50] described oscillopsia and vertical eye movements with a longer latency of 2.2 s in another patient. Our patient exhibited a surprisingly short latency vestibulospinal reflex on electromyographic recording [47]; there was an EMG response after 47 ms in the tibialis anterior muscle and after 52 ms in the gastrocnemius muscle during upright stance. Using a posturography platform we measured a considerable postural perturbation: the shortest latency was 80 ms and there was a direction-specific diagonal body sway. Increasing intracranial pressure by Valsalva’s maneuver may evoke slow tonic eye movements and oscillopsia opposite in direction to those of the Tullio phenomenon. The hypothesis that the Tullio phenomenon arises from non-physiological mechanical otolith stimulation is based on (1) the location of the otoliths directly adjacent to the stapes footplate, and (2) the typical response pattern of OTR. Surgical exploration of the middle ear of our patient revealed a subluxated stapes footplate; the hypertrophic stapedius muscle caused pathologically large amplitude movements during the stapedius reflex. OTR is an eye-head synkinesis initiated by stimulation [51] or lesion [52] of the otoliths or graviceptive pathways. Inadvertent utricular damage following stapedectomy causes an ipsilateral transient OTR [53]. This specific role of the utricle in the generation of OTR has been supported by findings in animal experiments in cats [54] and in guinea pigs [55] using electrical stimulation of single utricular nerves or localized electrical stimulation of spots on the utricular macula, respectively. Synaptic organization of utricular input provides a pattern of activation for both spinal motor neurons (head tilt, body sway) and conjugate cyclodeviation with disconjugate vertical divergence [56–59]. A 3-D mathematical model based on the known peripheral and central utricular-ocular circuitry can adequately simulate skew deviation and ocular torsion in patients with unilateral utricular loss, lesions of the vestibular nuclei, and central ‘graviceptive’ pathways lesions [60]. Otolith Tullio phenomena may not be as rare as originally thought. The two most obviously detailed case descriptions of a Tullio phenomenon by Deecke et al. [61] and by Vogel et al. [62] include typical features of OTR, although they described the syndrome in different terms. The patient described by Deecke et al. [61] exhibited head tilt to the left with disconjugate ocular

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torsion to the left, both of which lasted throughout an utterance. The patient of Vogel et al. [62] showed mainly vertical eye movements, consisting of an initial component followed by a slower resetting movement, which was often divided into two parts with different velocities. These authors discussed the possibility of an otolithic mechanism without, however, providing surgical proof of the site of the fistula. Another patient, described by Spitzer and Ritter [63] in retrospect, suffered from an otolith Tullio phenomenon, which in his case was due to fracture of the medial wall of the tympanon and involved the stapes footplate, causing sound-induced contraversive head and body tilt without nystagmus.

Conclusion A disorder of otolithic function at a peripheral or central level should be suspected if a patient describes symptoms of falls, sensations of linear motion, or tilt, or else shows signs of specific derangements of ocular motor and postural orienting and balancing responses. A significant number of patients presenting to neurologists have signs and symptoms that suggest disorders of otolithic function. Of these, posttraumatic otolith vertigo may be the most significant; the rare otolith Tullio phenomenon may be the most thoroughly studied. Other examples are otolithic types of perilymph fistulas, vestibular drop attacks (Tumarkin’s otolithic crisis) and a number of central vestibular syndromes that indicate tone imbalance of graviceptive circuits (skew deviation, ocular tilt reaction, lateropulsion, room-tilt illusion), some of which manifest without the sensation of dizziness or vertigo.

References 1 2 3 4 5 6 7 8

Straumann D, Zee DS: Three-dimensional aspects of eye movements. Curr Opin Neurol 1995;8: 69–71. Bo¨hmer A, Straumann D, Fetter M: Three-dimensional analysis of spontaneous nystagmus in peripheral vestibular lesions. Ann Otol Rhinol Laryngol 1997;106:61–68. Fetter M, Haslwanter T, Misslich H, Tweed D: Three-Dimensional Kinematics of Eye, Head and Limb Movements. Amsterdam, Harwood Academic Publishers, 1997. von Brevern M, Faldon ME, Brookes GB, Gresty MA: Evaluating 3D semicircular canal function by perception of rotation. Am J Otol 1997;18:484–493. Brandt Th: Vertigo – Its Multisensory Syndromes, ed 2. London, Springer, 1999. Gresty MA, Bronstein AM, Brandt T, Dieterich M: Neurology of otolith function: Peripheral and central disorders. Brain 1992;115:647–673. Brandt Th, Daroff RB: The multisensory physiological and pathological vertigo syndromes. Ann Neurol 1980;7:195–203. Dieterich M, Brandt Th, Fries W: Otolith function in man: Results from a case of otolith Tullio phenomenon. Brain 1989;112:1377–1392.

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Fries W, Dieterich M, Brandt T: Otolith contributions to postural control in man: Short latency motor responses following sound stimulation in a case of otolith Tullio phenomena. Gait Posture 1993;1:145–153. Tumarkin A: The otolithic catastrophe: A new syndrome. Br Med J 1936;i:l75–177. Kuhl W: Vestibular-cerebral syncopes. Dtsch Med Wochenschr 1980;105:41–42. Jansen VD, Russel RD: Conservative management of Tumarkin’s otolithic crisis. J Otolaryngol 1988;17:359–361. Baloh RW, Jacobson K, Winder T: Drop attacks in Meniere’s syndrome. Ann Neurol 1990;28: 384–387. Black FO, Effron MZ, Burns DS: Diagnosis in management of drop attacks of vestibular origin: Tumarkin’s otolithic crisis. Otolaryngol Head Neck Surg 1982;90:256–262. ¨ dkvist LM, Bergenius O: Drop attacks in Menie`re’s disease. Acta Otolaryngol (Stockh) 1988; O (suppl 455):82–85. Hasegawa T Die Vera¨nderungen der labyrintha¨ren Reflexe bei zentrifugierten Meerschweinchen. Pflu¨gers Arch Ges Physiol 1933;232:454–465. Igarashi M, Nagaba M: Vestibular end-organ damage in squirrel monkeys after exposure to intensive linear acceleration. Third Symposium on the Role of the Vestibular Organs in Space Exploration, NASA SP-152, 1968, pp 63–67. DeWit G, Bles W: A stabilographic study of the role of optic stimuli in maintaining the postural position in patients suffering from postconcussional dizziness. Agressologie 1975;16:9–14. Ba´ra´ny R: Diagnose von Krankheitserscheinungen im Bereiche des Otolithenapparates. Acta Otolaryngol (Stockh) 1921;2:334–437. Dix R, Hallpike CS: The pathology, symptomatology and diagnosis of certain common disorders of the vestibular system. Ann Otol Rhinol Laryngol 1952;6:987–1016. Lanska DJ, Remler B: Benign paroxysmal positioning vertigo: Classic descriptions, origins of the provocative positioning technique, and conceptual developements. Neurology 1997;48:1167–1177. Schuknecht HF: Cupulolithiasis. Arch Otolaryngol 1969;90:765–778. Schuknecht HF, Ruby RRF: Cupulolithiasis. Adv Oto-Rhino-Laryngol 1973;22:434–443. Parnes LS, McClure JA: Posterior semicircular canal occlusion in the normal hearing ear. Otolaryngol Head Neck Surg 1991;104:52–57. Epley JM: The canalith repositioning procedure for treatment of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 1992;107:399–404. Brandt Th, Steddin S: Current view of the mechanism of benign paroxysmal positioning vertigo: Cupulolithiasis or canalolithiasis? J Vestib Res 1993;3:373–382. Baloh RW, Jacobson K, Honrubia V: Horizontal semicircular canal variant of benign positional vertigo. Neurology 1993;43:2542–2549. Brandt Th, Steddin S, Daroff RB: Therapy for benign paroxysmal positioning vertigo, revisited. Neurology 1994;44:796–800. Brandt Th, Daroff RB: Physical therapy for benign paroxysmal positional vertigo. Arch Otolaryngol 1980;106:484–485. Semont A, Freyss G, Vitte E: Curing the BPPV with a liberatory maneuver. Adv Oto-RhinoLaryngol 1988;42:290–293. Herdman SJ, Tusa RJ, Zee DS, Proctor LR, Mattox DE: Single treatment approaches to benign paroxysmal positional vertigo. Arch Otolaryngol Head Neck Surg 1993;119:450–454. Herdman SJ: Treatment of benign paroxysmal positional vertigo. Phys Ther 1990;70:381–387. Gacek RR: Further observations on posterior ampullary nerve transection for positional vertigo. Ann Otol Rhinol Laryngol 1978;87:300–306. Pace-Balzan A, Rutka JA: Non-ampullary plugging of the posterior semicircular canal for benign paroxysmal positional vertigo. J Laryngol Otol 1991;105:901–906. McClure JA: Horizontal canal BPPV. J Otolaryngol 1985;14:30–35. Steddin S, Brandt T: Horizontal canal benign paroxysmal positioning vertigo (h-BPPV): Transition of canalolithiasis to cupulolithiasis. Ann Neurol 1996;40:918–922. Vannucchi P, Giaconnoni B, Pagnini P: Treatment of horizontal semicircular canal benign paroxysmal positional vertigo. J Vestib Res 1997;7:1–6.

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Healy GB, Strong MS, Feldman RG: Ataxia secondary to labyrinthine fistula. Laryngoscope 1973; 83:502–507. Healy GB, Strong MS, Sampogna D: Ataxia, vertigo, and hearing loss: A result of rupture of inner ear window. Arch Otolaryngol 1974;100:130–135. Tullio P: Das Ohr und die Entstehung der Sprache und Schrift. Mu¨nchen, Urban & Schwarzenberg, 1929. Cawthorne T: Chronic adhesive otitis. J Laryngol Otol 1956;70:559–564. Kacker SK, Hinchcliffe R: Unusual Tullio phenomena. J Laryngol Otol 1970;84:155–166. Cody DTR, Simonton KM, Hallberg OE: Automatic repetitive decompression of the saccule in endolymphatic hydrops (Tack operation). Laryngoscope 1967;77:1480–1501. Brandt Th, Dieterich M, Fries W: Otolithic Tullio phenomenon typically presents as paroxysmal ocular tilt reaction. Adv Oto-Rhino-Laryngol 1988;42:153–156. Colebatch JG, Rothwell JC; Bronstein A, Ludmann H: Click-evoked vestibular activation in the Tullio phenomenon. J Neurol Neurosurg Psychiatry 1994;57:1538–1540. Bronstein AM, Faldon M, Rothwell J, Gresty MA, Colebatch J, Ludman H: Clinical and electrophysiological findings in the Tullio phenomenon. Acta Otolaryngol (Stockh) 1995;(suppl 520):209–211. Fries W, Dieterich M, Brandt Th: Otolithic control of posture: Vestibulo-spinal reflexes in a patient with a Tullio phenomenon. Adv Oto-Rhino-Laryngol 1988;41:162–165. Bush GA, Miles FA: Short-latency compensatory eye movements associated with a brief period of free fall. Exp Brain Res 1996;108:337–340. Rottach KG, von Maydell RD, DiScenna AO,Zivotofsky AZ, Averbuch-Heller L, Leigh RJ: Quantitative measurements of eye movements in a patient with Tullio phenomenon. J Vestib Res 1996;6:255–259. Cohen H, Allen JR, Congdon SL, Jenkins HA: Oscillopsia and vertical eye movements in Tullio’s phenomenon. Arch Otolaryngol Head Neck Surg 1995;12:459–462. Westheimer G, Blair SM: The ocular tilt reaction: A brainstem oculomotor routine. Invest Ophthalmol 1975;14:833–839. Brandt Th, Dieterich M: Pathological eye-head coordination in roll: Tonic ocular tilt reaction in mesencephalic and medullary lesions. Brain 1987;110:649–666. Halmagyi GM, Gresty MA, Gibson WPR: Ocular tilt reaction with peripheral vestibular lesion. Ann Neurol 1979;6:80–83. Suzuki JI, Tokumasu K, Goto K: Eye movements from single utricular nerve stimulation in the cat. Acta Oto Laryngol 1969;68:350–362. Curthoys PD: Eye movements produced by utricular and saccular stimulation. Aviat Environ Med 1987;58(suppl 9)A:192–197. Gacek RR: Anatomical demonstration of the vestibulo-ocular projections in the cat. Laryngoscope 1971;81:1559–1595. Reisine H, Highstein SM: The ascending tract of Deiters’ conveys a head velocity signal to medial rectus motoneurons. Brain Res 1979;170:172–176. Lang W, Bu¨ttner-Ennever JA, Bu¨ttner U: Vestibular projections to the monkey thalamus: An autoradiographic study. Brain Res 1979;177:3–17. Carpenter MB, Cowie RJ: Connections and oculomotor projections of the superior vestibular nucleus and cell group ‘y’. Brain Res (Amsterdam) 1985;336:256–287. Glasauer S, Dieterich M, Brandt Th: Simulation of pathological ocular counter-roll and skewtorsion by a 3-D mathematical model. NeuroReport 1999;10:1843–1848. Deecke L, Mergner T, Plester D: Tullio phenomenon with torsion of the eyes and subjective tilt of the visual surround. Ann NY Acad Sci 1981;374:650–655. Vogel P, Tackmann W, Schmidt FJ: Observations on the Tullio phenomenon. J Neurol 1986;233: 136–139. Spitzer H, Ritter K: Ein Beitrag zum Tullio-Pha¨nomen. Laryngol Rhinol 1979; 58:934–936.

Thomas Brandt, MD, FRCP, Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistrasse 15, D–81377 Munich (Germany) Tel. +49 89 7095 2570, Fax +49 89 7095 8883, E-Mail [email protected]

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Physiopathology of Otolith-Dependent Vertigo Contribution of the Cerebral Cortex and Consequences of Cranio-Facial Asymmetries A. Berthoz a, D. Rousie´ b a b

College de France, Paris, et Universite´ de Lille, France

Vertigo is a conscious perception of the disorientation between the body and space and of illusory movements of the body and/or the environment. Vertigo is not only due to sensory conflicts but can also be due to a conflict between defective or biased sensory inputs and internal representations of the body. In particular, some forms of spatial disorientation are not due to peripheral deficits but to high level mechanisms involving the cerebral cortex and the hippocampus which contribute to the construction of the coherence of perception and the solution of perceptual ambiguities [1, 2]. It has been proposed that a number of spatial orientation disorders involve hippocampus and the parieto-hippocampal-prefontal networks for spatial memory during navigation [2], ‘spatial neglect’ and the general problem of the perception of the subjective mid-sagittal plane of the body [3] and visuo-spatial anxiety [4].

Cognitive Contribution of Otoliths to Spatial Orientation and to the Perception of Movement The Ambiguity of Perception The otoliths organs of the vestibular system are linear acceleration sensors. They detect the changes of head velocity in the planes of the maculae with a sensitivity of a fraction of one centimeter per second squared. In addition they detect the static tilts of the head with respect to gravity because gravity

is a kind of linear acceleration whose component on the maculae are indistinguishable from a linear acceleration. It has also been suggested that the otoliths do contribute to the estimation of the angular acceleration of the head in cooperation with the semicircular canals. The ambiguity of the otolith information (which therefore codes for linear acceleration and static tilt) requires a cooperation with the information given by vision or proprioception in order to estimate properly the movement and orientation of the body. But visual signals themselves are ambiguous because they cannot distinguish between movement of the body in space. For example Lackner [5] has shown that the same otolithic stimulation can be interpreted in several ways: For instance if one takes a subject in a prone position and rotates him in total darkness around a horizontal axis (the so-called ‘barbecue experiment’), the subject first feels that he is rotating horizontally around the main axis of his body. If then one just applies a pressure on the subject’s feet he suddenly shifts to a percept indicating that he is still rotating around the main axis of his body but this time he is upright. We have ourselves shown [6] that the rotation around an axis inclined with respect to the vertical, that we have been the first to introduce in France, induces a perception of a conic rotation whose characteristics can be calculated from an appropriate model of otolith dynamics and geometry. But this percept itself can vary according to the context of the turn. It is therefore not surprising that many types of spatial disorientation and vertigo can occur depending upon the various reasons for which the coherence or sensory input is destroyed. Perception of the Subjective Vertical Can Be Modified by Imagination The interpretation of otolithic information is therefore under the control of central mechanisms of perception which vary according to the reference frame in which movements are coded. I have insisted upon the flexibility of these reference frames [7] which vary depending upon the action in which a subject is involved. We now know that the brain codes movements of limbs, eyes, body, environment in several action-dependant reference frames. Among all these frames the subjective vertical is a fundamental one: it corresponds to the perception of the angle of the main axis of the body with respect to the gravitational vertical. The subjective vertical is an essential element of the maintenance of our equilibrium and of the orientation of our body in space. As demonstrated by the experiment using the off vertical axis rotation chair the otoliths play a fundamental role in the perception of the vertical together with proprioceptive inputs. An abundant literature deals with this

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Fig. 1. Perception of forward linear translation. Diagram of the experimental procedure. The subject viewed either the target I or the target II, located, respectively, at 0.8 or 2.4 m away from S (start). Target was straight ahead if the displacement of the sled was programmed along the X-axis, and on the left side of the subject if the programmed displacement was along the Y-axis. Then the subject was blindfolded and was required to push a button when crossing the previously seen target. The sled moved from S to E (outward) and then back to S (return). Expected (theoretical) responses are situated at target locations on the travelled path from T1 to T4. From Israe¨l et al. [21].

aspect and I will not come back to these well-known properties. Recently we have shown, for the first time experimentally, that ‘top-down’ cognitive influences may modify the percept of subjective vertical [8]. Perception and Memory of Pure Angular or Linear Motion When we move around in the world we remember our movements. This ‘topokinetic’ or ‘topokinesthetic’ memory is, in part, subserved by a memory of our head movement measured by the vestibular system. We have studied this ‘vestibular memory’ in our laboratory. We have first shown that the brain can use angular acceleration detected by the semicircular canals for the memory of rotations [9–11]. However, the capacity of the brain to use otolithic information during navigation for the memory of travelled paths is still under discussion. Our group has demonstrated the fact that otolithic information interferes and cooperates with visual optic flow for the perception of translations [12–14]. We were the first to demonstrate that during vestibular stimulation along a linear path the vestibular system can inhibit visual motion perception. We

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Fig. 2. Simulation of subjective position. Bottom part: Sled acceleration (×1 m/s2; thick line) and otolith response (estimate of translational acceleration; thin line). Top part: Sled position (thick line), target position (horizontal dotted lines), and estimate of subjective position through double integration of the otolith response (thin line). Open squares show the observed average responses, and filled squares are the simulated expected responses, i.e. the projection of the simulated subjective position onto sled position when the former is equal to target position. From Israe¨l et al. [21].

have observed and measured a striking suppression of visual motion perception during vestibular linear stimulation which suggested this cross-modal inhibitory interaction recently also found in brain imaging experiments. In addition, we have shown that otolithic stimulation improves the tracking of acoustic targets [15–17]. We also know that otolith information can contribute to the control of gaze during passive displacements when the subject has to follow a target with both the eyes and the head [18]. Finally, we have demonstrated that otolith information can be used for estimation and memory of displacement during passive linear translations (fig. 1) and, most importantly, that the perception of subjects can be predicted with mathematical models of the otolith organs and the perceptual processes [19–23]. All these results, however, suggest that the precision at which a subject can evaluate his or her translations from otoliths is not as good as the estimation of rotations from the semicircular canals. The reason for this difference is still unknown.

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Fig. 3. Mobile robot for the study of the perception of 2D motion. A Experimental setup: The subject sits on the robot with seat belt fastened, wearing black goggles and earphones. To replicate passive transport he or she uses a joystick. Connection with the microcomputer is provided by wireless modems. B Procedure: A sample trial measured by odometry. B The subject can indicate, eye closed, the orientation of his body with respect to space with the use of a pointer on a tablet held on his knees (see A ). During the rotation of the robot the subject has indicated with a great accuracy the rotation. C Schematic view of applied trajectories.

Interaction between Canals and Otoliths for the Perception of 2D Displacement Trajectories It is very rare that during our natural displacements we only perform pure rotations or translations. Most of the time we experience combinations of rotations and translations. The perception of these displacements implies therefore both canals and otoliths. Using a mobile robot (fig. 2), we have studied the interaction between canals and otoliths in the perception of 2D trajectories [24]. In these experiments, the subjects were seated on the mobile robot in darkness. They were submitted to pure rotations (180º), or pure

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Fig. 4. Semicircular motion (combination of canal and otolith stimulation). A Schematic view of the applied trajectory. The evolution of the linear acceleration vector is shown with the arrows. B Rotation and change in magnitude of the linear acceleration vector relative to the head (the numbers denote the time from the beginning of motion in seconds). C Mean of pointer position responses for all subjects (×1 SEM, thin lines) and actual seat orientation in space. D Superimposed drawings by the subjects of the perceived trajectory. From Ivanenko et al. [24].

translations (4.5 m) or semicircular trajectories (radius 1.5 m, angular acceleration: 0.2 radians per second per second) (fig. 3, 4 and 5). The capacity of subjects to orient themselves eyes closed during their passive transport was measured by asking them to orient a hand-held pointer towards a target fixed in the environment. In addition, after the experiment they were asked to draw their trajectory on a paper. Several manipulations of the movement of the body on the robot during the displacement allowed the identification of the respective role of canals and otoliths in the perception of 2D motion.

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In general, the subjects perceived correctly their rotations during the semicircular trajectory. This suggests a great independence of the perception of rotations with respect to the perception of translation. Our hypothesis is therefore that the brain separates these two kinds of perceptions. It could, however, be that this is dependent upon the intensity of the accelerations. If confirmed this would have very important implications in the study of the pathology of vertigo. The second interesting result of this work is that the perceived trajectory, as reproduced by drawing, reveals illusions of false trajectories in certain conditions: the trajectory perceived by the subjects is mainly explicable by the stimulation of the semicircular canals in all cases? In fact, the subjects had a correct perception of their trajectory only when the orientation of the body was coherent with the general direction of their movement. The subject perceived linear motion when only translations were imposed, but circular trajectories were perceived when a 360º rotation was combined with a translation.

Neural Basis of Otolithic Contribution to Spatial Orientation and Perception of Displacement We now know of at least two pathways for carrying vestibular information to the cerebral cortex. One of these pathways is through an area called the ‘vestibular cortex’. Vestibular Fields in the Cortex Experimental proof of the existence of the PIVC in the monkey was reported by Gru¨sser and colleagues [25, 26]. Recording the Macaca fascicularis, these authors showed that about two-thirds of the neurons in this area respond to angular vestibular stimulation. The others respond mostly to somatosensory stimulation of the neck and shoulders. Nearly all the vestibular responding neurons are also activated by movements of the visual environment and by somatosensory stimulation. The main property of the vestibular neurons in the PIVC is their sensitivity to angular rotations in various planes, to visual motion in the directions corresponding to the opposite of the direction of head motion in which they are sensitive, and to neck movements in the same direction as the vestibular response. These properties suggest that the PIVC neurons are coding head movement in space from a combination of vestibular, visual, and somatosensory cues. It is speculated that one of the operations accomplished in the PIVC is the extension of the coding of head motion in planes that are more numerous than in the vestibular nuclei. It is well known that the vestibular and the

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Fig. 5. Examples of three experimental conditions for the study of canal otolith interaction. The subjects are seated on the robot eye closed and are passively transported according to the indicated paradigm. A Semicircular motion. B Drawing of the perceived trajectory after the motion. C Semicircular motion with the head stabilized in one direction, the resultant acceleration vectors are shown. D Drawing by the subject of his perceived trajectory, note that the circular trajectory has not been perceived. E Translation with a rotation of the subject on the robot. F Perceived trajectory. Note that the subject has not perceived the translational component of the trajectory. From Ivaneko et al. [24].

optokinetic coding of head motion (through the accessory optic pathways) is done in the planes of the semicircular canals. This geometric selection is probably useful for matching these two signals at the level of the brainstem. At the level of the cortex, however, the representation of head movements is probably matched with visual inputs from the medio-temporal (MT) and other areas, and with various intentions of movement. Therefore, the coding may be more complex. It is important in the future to study the deficits in patients with lesions in this area (see Israe¨l et al. 1995). It was also proposed that the PIVC area 3aV, and area 7ant form an ‘inner vestibular circuit’.

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Fig. 6. Cortical activation induced by a galvanic vestibular stimulation (Lobel et al., J. Neurophysiol. 1998).

A second line of evidence [27] comes from the discovery of an influence of head tilt (i.e. otolithic signals on the receptive field of visual neurons in areas V2 and V3). These authors demonstrated that nearly 40% of the neurons in area V2 show modifications of their processing of contours during a static head tilt. They concluded that otolithic signals contribute to the mechanisms of contour processing at the early stages of visual pathways. Cortical Areas Involved in Vestibular Processing during Galvanic Stimulation Anatomic and electrophysiological studies in the monkey revealed the existence of multiple interconnected areas in which vestibular signals converge with visual and/or somatosensory inputs. Although recent functional imaging studies using caloric vestibular stimulation (CVS) [28, 29] suggest that vestibular signals in the human cerebral cortex may be similarly distributed, the present knowledge of the human cortical vestibular system is imprecise. Galvanic vestibular stimulation (GVS) has been used for almost 200 years for the exploration of the vestibular system. By contrast with CVS, which mediates its effects mainly via the semicircular canals (SCC), GVS has been shown to act equally on SCC and otolith afferents. Since galvanic stimuli can be precisely controlled, GVS is ideally suited for the investigation of the vestibular cortex by means of functional imaging techniques. We studied [30] the brain areas activated by sinusoidal GVS using functional magnetic resonance imaging (fMRI) (fig. 6). An adapted set-up including LC filters tuned for resonance at the Larmor frequency protected the volunteers

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against burns through radiofrequency pickup by the stimulation electrodes. Control experiments ensured that potentially harmful effects or degradation of the functional images did not occur. Six male, right-handed volunteers participated in the study. In all of them GVS induced clear perceptions of body movement and moderate cutaneous sensations at the electrode sites. Comparison with anatomic data on the primate cortical vestibular system and with imaging studies using somatosensory stimulation indicated that most activation foci could be related to the vestibular component of the stimulus. Activation appeared in the region of the temporo-parietal junction, the central sulcus and the intraparietal sulcus. These areas may be analogous to areas PIVC, 3aV and 2v, respectively, in the monkey brain, which form the ‘inner vestibular circle’, as named by Gru¨sser, of the cortical vestibular system. Activation also occurred in premotor regions of the frontal lobe. Although undetected in previous imaging-studies using CVS, involvement of these areas could be predicted from anatomic data showing projections from areas 6pa and 8a of the frontal lobe to the ‘inner vestibular circle’ and the vestibular nuclei. Using a simple paradigm we showed that GVS can be safely implemented in the fMRI environment. Manipulating stimulus waveforms and thus the GVS-induced subjective vestibular sensations in future imaging studies may yield further insights into the cortical processing of vestibular signals. Other investigations of the cortical areas involved in the processing of vestibular information have been recently performed [28, 31, 32]. It is also interesting to compare the areas involved in the processing of vestibular signals with those involved in the perception of the mid-sagittal plane of the body which also involve parieto-frontal areas [3]. The Head Direction Cell System Vestibular signals may also reach the cerebral cortex and the hippocampus through a second route. A ‘head direction’ cell system has been discovered [33, 34]. These neurones, first discovered in the post-subiculum of the rat, fire whenever the head of the animal is directed towards a particular direction in space independently of where the animal is located in the room. These neurones are influenced by visual cues and their direction is closely related to the organisation of the ‘place cells’ in the hippocampus which code location of the animal in space. Further studies [35, 36] have revealed that this head direction information from the vestibular nuclei, through the anterior thalamus, the mamillary bodies and the subiculum, could reach the hippocampus after receiving visual environmental information from the parietal cortex, and contribute to the reconstruction at this level of spatial localisation and

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Fig. 7. Patient suffering from a craniofacial asymmetry (torsion of the basio-cranium). Observe the asymmetrical positions of the eyes and ears, the deviation of the nose and the head tilt (with permission).

orientation. At present, only horizontal directions (in the plane of the horizontal semicircular canals) have been found in these cells. The brain has therefore at least two main pathways which seem to carry vestibular information: the PIVC route which codes angular head rotation in many planes, and the head direction system which codes static head direction in all horizontal directions. The important result here is that neither of these systems seems specific to carry translational information from the otoliths. The neural system underlying otolithic information about translations is therefore still a mystery. Cranio-Facial Asymmetry: A New Pathology of the Vestibular System We would like to report here a new set of symptoms [37] which are probably due to a fundamental asymmetry of the anatomical disposition of the vestibular organs following cranio-facial asymmetry (CFA) which concern, at different levels, all the units of the cephalic pole: the vault, the basicranium, the maxillary and the jaw. These CFA are largely spread in the European population but they have never been studied as malformative syndrome because they are located between the ‘normal’ and the ‘pathological’. These patients have a number of symptoms (fig. 7): laterocolis (head tilt in roll), most of the time, to the right side, eye skew deviations, ocular torsion, cephalic and back pains, scoliosis, spatial disorientation and some-

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Fig. 8. Asymmetry of the otoliths organs of the labyrinth. MRI measurement of the asymmetrical position of the labyrinths: The auditory meatus or the horizontal canals are used as markers to estimate the asymmetry (in position and in orientation) between the right and left labyrinths. Observe the concomitant asymmetry of the inferior temporal lobe. 1>Auditory meatus; 2>horizontal canal. From Rousie´ [39].

times agoraphobia, etc., which have been studied (Rousie´ D. 1999) on more than 2,500 patients with the collaboration of several departments of the University of Lille (Pr. Hache, Pr. Gieu, Dr. Van Tichelen, Dr. Deroubaix and Dr. Pertuzon). We shall only report here a summary of these deficits and the results of some functional tests. Most of the tests which we have performed so far are static and the contribution of otolithic asymmetry cannot be separated from the consequence of semicircular canal asymmetries. In addition, we cannot exclude that, given that these patients present a head tilt, and a pronounced spatial asymmetry of the anatomy of the orbits, proprioceptive biases do contribute to some of the postural or even oculomotor asymmetries observed. We believe that a fundamental component of the functional perturbations of posture and of the oculo-vestibular system as well as some cognitive dysfunctions are due to a distortion in the body schema induced, to distortion in the vestibular anatomy and to an uncompensated asymmetrical anatomy of the otoliths, and the orbital asymmetry.

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Methods These cranio-facial asymmetries are induced by asymmetries of the basicranium which have been measured using MRI scanning (fig. 8) and a new reference frame. The use of this reference allows comparisons between differents subjects [37, 38]. The principle of MRI exploration consists of determining an intracranial reference system formed by two planes: a vertical (median sagittal) and a horizontal plane, perpendicular to each other. These two planes are constructed by using points as close as possible to the embryonic epicenter of the cerebral growth [38, 39]. We have used neural tube points: middle of the hypophysis, the steepest point of the third ventricle, one or more points of the stalk of the pituitary. This reference makes it possible to obtain reproducible measurements independent of the position of the patient’s head in the machine. Therefore, it is necessary to re-orient the subject’s head in the three axes of possible movement: along the craniocaudal axis (roll) and the transverse axis (pitch). The pitch position was determined by the deviation from the perpendicular given in the two other planes mentioned above. This determination is facilitated by placing the head in the Frankfort orientation before the examination. We used a high-field Philips gyroscan (1.5 Tesla) which allows double correction of angulation. Its reliability was evaluated at 1º and 1 mm. The topographic asymmetry of the two posterior hemibases, expressed by the respective positions of the external semicircular canals, the cochleae or the auditory meatus taken as reference points, is easily obtained by multiplying the number of sections separating these structures by the distance between sections. Anatomical Findings The asymmetries in otolith anatomy had to be derived from the observation of the geometrical disposition of the semicircular canals. The analysis of 62 cases of CFA allowed the classification of several types of CFA according to the spatial position of the external semicircular canals taken as points of reference. Anteroposterior Asymmetry. The horizontal semicircular canals appear on the same horizontal section but on different coronal sections. This indicates that one of the canals is anterior to the other in the median sagittal plane. This induces an A-P positional asymmetry of the two posterior hemibases constituting the petrous bones. We have observed variations between 0 and 6.6 mm. In 14 cases of such A-P asymmetry, we have observed 11 cases in which the left canals were anterior to the right canals (78.5%). In this type of asymmetry, most subjects had canals strictly parallel to each other. In this study, asymmetry of orientation was only encountered once.

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Examination of the position of the orbital cones revealed an identical asymmetry: the face demonstrates exactly the anomalies of the underlying basis. Thus, for a left canal placed more anteriorly in the coronal plane, a more anterior left orbital cone will be found. Keeping in mind the law of correspondence of the visual axes activated during fixation (Law of Correspondence of Hering), we looked for an expression of this asymmetry at the level of the eyeballs and we observed a significant proportion of esophorias or of convergent strabisms located in the more posterior eye, as though the eyes were attempting to compensate the deeper position in the orbit. This deviation of the eyeball was accompanied by an abnormal position of the head – in rotation (yaw) as though the patients were compensating for the retreat into the orbit with their head and seeking a ‘mean’ position of comfort, perhaps with a desire to regulate depth perception to the best extent possible? In any case, the stereotypic test used (Wirt) did not reveal any extreme anomaly, no doubt because it is not precise enough. Asymmetry in Torsion. The canals appear on different sections, both in the horizontal and in the coronal plane. This indicates a true torsion of the base of the skull. This is by far the most frequent type of asymmetry (62.9% out of 62 patients). In this population, analysis of the variations included between 2.2 and 6.6 mm revealed a much larger proportion of elevated left labyrinths in the vertical plane (71.7%) associated, in the horizontal plane, with left labyrinths in a more anterior position (48.7%). This deformation is in agreement with the counter-clockwise cerebral deformation (petalia) described before [40–42]. This is an expression of the predominance of the left hemisphere. As in A-P asymmetries, the face follows the direction of the twisting of the base. This is expressed by frequent deviations of the nasal septum and of the spatial asymmetry of the orbital cones. Vertical Asymmetry. In these cases, asymmetry is only found in the vertical direction. Frequency is 15.3% out of 62 patients. This is a variant of torsional symmetry described above. Lateral Asymmetry. In these cases, it is the distance of a canal, taken as a reference point in relation to the midline, which presents a right/left asymmetry. The frequency is rare, at only 3 of 62. This type of CFA seems to have no effect on the oculo-labyrinthine system and rather seems related to a ‘fluctuating asymmetry’ as described by Lacy and Horner [43]. Asymmetries of Orientation. We have found 12 cases of asymmetries of orientation out of 62. It should be pointed out that within the framework of this study, no precise measurement was made of the difference in orientation between right and left canals.

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Fig. 9. Measurement of ocular torsion; the image of the scanner ophthalmoscope is used to calculate a static torsion. O is the center of the macula. OAB gives the angular value of the torsion. In this case torsion is 9º on the right eye and 0º on the left eye. From Rousie´ [39].

Visual Acuity We shall only, in the frame of this review, describe a few examples of the results obtained in the various functional tests which have been used to characterise the anomalies in these patients; detailed accounts have been published elsewhere [39]. Examinations of visual acuity undertaken to eliminate subjects with major ophthalmic anomalies which might bias the results have shown an increased frequency of astigmatism of curvature and/or of hypermetropia (70% of 50 patients), probably an expression of the asymmetry of orbital cones both in their shape and their spatial position. Standard oculomotor evaluations have shown an increased frequency of convergence insufficiency, especially in distant vision. SLO Examination In a group of 50 subjects carrying CFA, the comparison of foveal position right eye/left eye performed with a scanner ophthalmoscope (fig. 9) revealed a more elevated frequency of exocyclotorsion in the left eye, namely 30 cases out of 50 or 60%, whereas in the right eye it was in 16 cases out of 50 or 32%, for a difference of 28%. The mean value of cumulated torsions is –5.72º for the right eye and –8.04º for the left eye. In order to clearly separate the CFA pathological effect from nonpathological cases, we investigated eye position on two control groups. In a first group of 50 nonselected control subjects, we found a more elevated frequency of cyclotorsion in the left eye (21 cases out of 50 or 42%) than in the right eye (7 cases out of 50 or 14%). This gives a difference of 28%. The mean value of the cumulated torsions of the left eye is –5.70º and

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Fig. 10. Test of the index. This test is performed eye closed and the patient is asked to indicate the subjective horizontal. The photograph is taken when small body oscillations appear indicating that the subject has lost the memory of the visual vertical. The angle made with respect to the true horizontal (or the true vertical) which can be measured by reference to a line drawn on the wall (behind the subject) gives the measure of the deviation of the subjective nonvisual horizontal.

for the right eye, –3.08º. Thus, on the average, the foveal positions are located closer to the horizontal central pupillary axis of reference than in CFA subjects. This group is interesting because it calls attention to the frequency of the foveal position in a control population: we found a 44% frequency of foveal symmetry in which the difference between right and left was less than 2º. It should be kept in mind that because of the frequency of occurrence of CFA in the population, this group presented an epidemiological bias which justified studying the second group. A second group of subjects composed of selected control subjects presenting no scoliosis, no use of eye glasses, no instability, no multiple musculoarticular pain or CFA visible to the naked eye. In this group, only one case of cyclotorsion was found, in the right eye, representing a frequency of 2%. The mean value of the cumulated foveal positions of the right eye was –2.66º and of the left eye was –3º. The SLO made it possible to look for a possible exocyclotorsion associated with identified vestibular deficit as judged by the studies of Deroubaix. In a group of 45 CFA patients presenting some clinical signs of vestibular disorders, we found 100% high-level exocyclotorsions, in a range from 5º to 13º (with the average cumulative value for left and right of foveal positions being 8.4º, and with 23 torsions in the left eye and 22 in the right). Comparison between the eye with torsion and the defective labyrinth showed that in 39 cases, the torsion was on the same side as the vestibular deficit; in only 6 cases was there an inverse localization. In a control group of 17 patients having vestibular signs but no CFA, we also found 100% exocyclotorsion with a mean value identical to that of the

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Fig. 11. Scoliotic deformation in a patient with cranio-facial asymmetry. X-ray reveals a deformation of the spine with a left lumbar curvature associated with a right head tilt in the roll plane.

previous group. The torsion was always ipsilateral with the labyrinthine deficit. In these two groups, the comparison of the two ipsilateral signs (torsion and vestibular deficit) with the direction of the laterocolis showed an identical lateralization, in agreement with the ocular tilt reaction described by Brandt and Dieterich [44, 45]. Spinal Column and Posture The test of Fukuda (walking in place with eye closed and measuring the deviation of the orientation of the feet in the horizontal plane) was considered negative for a left or right rotation less than 30º. 34% of patients presented a right deviation and 66% presented a left deviation. It should be pointed out that these deviations are in a direction opposite to the head tilt and ipsilateral with the lumbar convexity. The mean value of the deviation is 50º, both to the right and to the left. The test of the nonvisual subjective horizontal (test of the index) showed (fig. 10), out of 50 patients, that 9 did not present inclination of the index fingers. 25 presented a right deviation (50%) and 16 presented a left deviation. The deviation of the slope of the index fingers was always ipsilateral with the head tilt. Scoliotic deformations (fig. 11) were also found with often a left lumbar curvature associated with right head tilt in the roll plane. This finding shows

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that probably the whole body scheme in these patients is distorted and further work is needed to understand the hierarchy of mechanisms between vestibular asymmetry, ocular deviation and postural asymmetries. Blind walking test: Patients were asked to walk straight, eyes closed, for a distance of about 5 m. Horizontal path deviation was always ipsilateral with the head tilt. Test of Videonystagmography A search for spontaneous nystagmus was carried out with open eyes, with and without focusing (on the center), with eyes open in darkness, always carried out at the beginning of the examination so that results can dictate the choice of another test: In a group of 45 patients with CFA, 3 presented a vertical nystagmus of cervical origin, 17 of 45 presented nystagmus with open eyes without fixation, that is, 37% of the cases. The patients were also submitted to a number of vestibular tests for horizontal canal function. The impulsional rotation test [46] revealed the largest number of anomalies in the two groups. Labyrinthine performance was measured on the Courtat graph: this test showed 100% interlabyrinthine asymmetry, with 15 cases of left-sided deficit and 30 cases of right-sided deficit. For 16 subjects, this asymmetry disappeared under the effect of intense stimulation (head-shaking test) whereas for 29 subjects, the asymmetry persisted. For these 29 subjects, other tests described here were able to refine the diagnosis. For 15 subjects, the failure of the asymmetry to disappear had a central origin, for 23 subjects, it had a central cervical origin, and for 7 subjects, a traumatic origin was found. More work is obviously needed to elucidate the contribution of the otoliths in this pathology but we would like to propose that vestibular asymmetry may be a common cause to symptoms which are treated separately and that these patients suffer from a more general distorsion of their body schema. This may explain some of the cognitive spatial disorders which are associated with cranio-facial asymmetry. It may also explain why wearing adequate prisms often improves a number of the symptoms.

Acknowledgements We thank F. Maloumian for the preparation of the figures. We also thank Dr. Deroubaix, Service ORL de Be´thune, Dr. Pertuzon, Service de Neuroradiologie, CHRU Lille, and Dr. Van Tichelen, rheumatologist, for their active collaboration, Prof. Hache, Service d’Exploration fonctionnelle de la vision, CHRU Lille, for his support and the use of the SLO, and Prof. Pellegrin for his support throughout this research. This work was supported by the Centre National d’Etudes Spatiales.

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Berthoz A: Le sens du mouvement. Paris, 1997, pp 1–347. Berthoz A: Hippocampal and parietal contribution to topokinetic and topographic memory; in Burgess N, Jeffery KJ, O’Keefe J (eds): The Hippocampal and Parietal Foundations of Spatial Cognition. Oxford, Oxford University Press, 1999, pp 381–399. Vallar G, Lobel E, Galati G, Berthoz A, Pizzamiglio L, Le Bihan D: A fronto-parietal system for computing the egocentric spatial frame of reference in humans. Exp Brain Res 1999;124:281–286. Viaud-Delmon I, Ivanenko Y, Berthoz A, Jouvent R: Anxiety and integration of visual vestibular information studied with virtual reality. Biol Psychiatry 1999. Lackner JR: Some proprioceptive influences on the perceptual representation of body shape and orientation. Brain 1988;111:281–297. Darlot C, Denise P, Droulez J: Modulation by horizontal eye position of the vestibulo-collic reflex induced by tilting in the frontal plane in the alert cat. Exp Brain Res 1985;58:510–519. Berthoz A: Reference frames for the perception and control of movement; in Paillard J (ed): Brain and Space. Oxford, Oxford University Press, 1991, pp 82–111. Mast F, Kosslyn S, Berthoz A: Visual mental imagery interferes with allocentric orientation judgments. Neuroreport 1999;10:3549–3553. Israe¨l I, Fetter M, Koenig E: Vestibular perception of passive whole body rotation about the horizontal and vertical axes in humans: Goal-directed vestibulo-ocular reflex and vestibular memory contingent saccades. Exp Brain Res 1993;96:335–346. Israe¨l I, Rivaud S, Gaymard B, Berthoz A, Pierrot-Deseilligny C: Cortical control of vestibularguided saccades in man. Brain 1995;118:1169–1183. Israe¨l I, Rivaud S, Pierrot-Deseilligny P, Berthoz A: ‘Delayed VOR’: An assessment of vestibular memory for self motion; in Requin J, Stelmach J (eds): Tutorials in motor neuroscience. Netherlands: Kluwer Academic Pub., 1991, pp 599–607. Berthoz A, Pavard B, Young L: Perception of linear horizontal self motion induced by peripheral vision (linear-vection). Exp Brain Res 1975;23:471–489. Pavard B, Berthoz A: Linear acceleration modifies the perceived velocity of a moving scene. Percept Psychophys 1977;6:529–540. Buizza A, Leger A, Droulez J, Berthoz A, Schmid R: Influence of otolithic stimulation by horizontal linear acceleration on optokinetic nystagmus and visual motion perception. Exp Brain Res 1980; 39:165–176. Buizza A, Leger A, Berthoz A, Schmid R: Otolithic acoustic interactions in the control of eye movement. Exp Brain Res 1979;36:509–522. Buizza A, Schmid R, Zambarbieri D, Berthoz A: Eye fixation of stationary acoustic targets during angular and linear acceleration. Proceeding XII Int Conf Med Biol Engineering 1979; pp 10–11. Leger A, Buizza A, Berthoz A, Schmid R: Otolithic contribution of ocular pursuit of accoustic target. Exp Brain Res 1978;32:3. Borel L, Le Goff B, Charade O, Berthoz A: Gaze stategies during linear motion in head-free humans. J Neurophysiol 1994;5:2451–2466. Glasauer S, Israe¨l I: The influence of otolithic thresholds on perception of passive linear displacement. Eur J Neurosci 1993(suppl 6):268. Israe¨l I, Berthoz A: Contribution of the otoliths to the calculation of linear deplacement. J Neurophysiol 1989;62:247–263. Israe¨l I, Chapuis N, Glasauer S, Charade O, Berthoz A: Estimation of passive linear whole body displacement in humans. J Neurophysiol 1993;70:1270–1273. Berthoz A, Israe¨l I, Georges-Franc¸ois P, Grasso R, Tsuzuku T: Spatial memory of body linear displacement: What is being stored? Science 1995;269:95–98. Israe¨l I, Berthoz A: Contribution of the otoliths to the calculation of linear deplacement. J Neurophysiol 1989;62:247–263. Ivanenko YP, Grasso R, Israe¨l I, Berthoz A: The contribution of otoliths and semicircular canals to the perception of two-dimensional passive whole-body motion in humans. J Physiol (Lond) 1997; 502:223–233.

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Gru¨sser OJ, Pause M, Schreiter U: Vestibular neurons in the parieto-insular cortex of monkeys (Macaca fascicularis): Visual and neck receptor responses. J Physiol 1990;430:559–583. Gru¨sser OJ: Cortical representation of head movement in space and some psychophysical considerations; in Berthoz A, Vidal PP, Graf W (eds): The Head Neck Sensory-Motor System. New York, Oxford University Press, 1991, pp 497–509. Sauvan XM, Henn V, Peterhans E: Mechanisms of contour processing in monkey prestriate cortex include information on direction of gravity (Abstract). Soc Neurosci 1994;20:710–714. Bottini G, Sterzi R, Paulelscu E, Vallar G, Cappa S, Erminio F, Passingham RE, Frith CD, Frackowiack RSJ: Identification of the central vestibular projections in man: A positron emission tomography activation study. Exp Brain Res 1994;99:164–169. Vallar G, Sterzi R, Bottini G, Cappa S, Rusconi ML: Temporary remission of left hemianesthesia after vestibular stimulation: A sensory neglect phenomenon. Cortex 1990;26:123–131. Lobel E, Kleine JF, Le Bihan D, Leroy-Willig A, Berthoz A: Functional MRI of galvanic vestibular stimulation. J Neurophysiol 1998;80:2699–2709. Brandt T, Dieterich M, Danek A: Vestibular cortex lesions affect the perception of verticality. Ann Neurol 1994;35:403–412. Bucher SF, Dieterich M, Wiesmann M, Weiss A, Zink R, Yousry TA, Brandt T: Cerebral functional magnetic resonance imaging of vestibular, auditory, and nociceptive areas during galvanic stimulation. Ann Neurol 1998;44:120–125. Ranck JB: Head direction cells in the deep layers of the dorsal presubiculum in freely moving rats. Soc Neurosci Abstr 1984, p 599. Taube JS, Muller RU, Ranck JB Jr: Head-direction cells recorded from the postsubiculum in freely moving rats. I. Description and quantitative analysis. J Neurosci 1990;10:420–435. Sharp PE, Blair HT, Etkin D, Tzanetos DB: Influences of vestibular and visual motion information on the spatial firing patterns of hippocampal place cells. J Neurosci 1995;15:173–189. Taube JS, Muller RU: Comparisons of head direction cell activity in the postsubiculum and anterior thalamus of freely moving rats. Hippocampus 1998;8:87–108. Rousie´ D, Hache JC, Pellegrin P, Deroubaix JP, Berthoz A: in Cohen B (ed): Oculomotor, postural and perceptual asymmetries associated with a common cause: Craniofacial asymmetries and asymmetries in vestibular organs anatomy, in Cohen B ed 8. New York, Annals New York Academy of Sciences, 1999. Rousie´ D, Baudrillard JC: Apport du plan neurosagittal me´dian dans l’e´tude des asyme´tries craniofaciales. Biol Hum Anthrop 1997;1–2:55–64. Rousie´ D: Asyme´tries cranio-faciales et syste`me oculo-labyrinthique. Universite´ de Lille; The`se de Sciences de la vie et de la Sante´, 1999. Connoly CJ: External Morphology: The Primate Brain. Springfield, Thomas, 1950. Wada JAR: Cerebral hemispheric asymmetry in humans. Arch Neurol 1975;32:239–246. Le May M: Morphological cerebral asymmetries of modern man, fossil man, and nonhuman primate. Ann NY Acad Sci 1976;280:349–364. Lacy RC, Horner BE: Effects of inbreeding of skeletal development of Rattus. J Hered 1996;87: 277–287. Dieterich M, Brandt T: Ocular torsion and tilt of subjective visual vertical are sensitive brainstem signs. Ann Neurol 1993;33:292–299. Brandt T, Dieterich M: Skew deviation with ocular torsion: A vestibular brainstem sign of topographic diagnostic value. Ann Neurol 1993;33:528–534. Vitte E, Se´mont A, Freyss G, Soudant J: Videonystagmoscopy: Its use in the clinical vestibular laboratory. Acta Otolaryngol (Stockh) 1995;115(suppl 520):423–426.

Dr. A. Berthoz, Colle`ge de France, UMR CNRS 9950, 11, Place Marcelin Berthelot, F–75005, Paris (France) E-Mail alain.berthoz@colle`ge-de-france.fr

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Tran Ba Huy P, Toupet M (eds): Otolith Functions and Disorders. Adv Otorhinolaryngol. Basel, Karger, 2001, vol 58, pp 68–76

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Clinical and Instrumental Investigational Otolith Function ¨ dkvist Lars O Department of Otolaryngology, University Hospital, Linko¨ping, Sweden

For balancing and oculomotor function the inner ears are of great importance. Proprioception and vision converge and cooperate with the inner ear afferents in the vestibular nuclei, the thalamus, the cerebellum and the cerebral cortex. The semicircular canals are transducers of the angular acceleration of the head and the otoliths, sacculus and utriculus, are the sensors for linear accelerations. These linear accelerations are the gravity and the forces developed when we perform motions. In health the afferents from vision, proprioception and inner ears result in harmonic and efficient movements, appropriate ocular movements and also perception of movement and position. In disease, malfunction of the otolithic organs may cause vertigo, illusion of tilt, balance disorders and oscillopsia.

Otolith Functions Utriculus and sacculus are endolymph filled and in near proximity to the semicircular canals. The neuroepiphelium is concentrated to a plate in each utriculus and sacculus. This plate consists of gelatinous substance with calciumcarbonate crystals, otoconia, embedded on the free surface and with cilia of hair cells projecting into the membrane. The specific weight of endolymph is around 1, and the density of the crystals is 2.7. When there are linear forces along the plane of the macula, the gelatinous material supported by the otoconia tend to slide somewhat according to inertia or force of gravity. Although the displacement of the otolithic membrane only is about 1 lm, it is enough to cause polarization or depolarization in the hair cells. This causes an increase or decrease of the firing rate in the utricular and saccular nerves.

The plane of the macula sacculi is vertical and thus the sacculus responds to vertical movements. The plane of the utricular maculi is in the plane of the lateral semicircular canals. Thus, they respond mostly to horizontal movements. In the utriculus the polarisation of the hair cells is such that 75–80% of the cells respond mostly to a force directed in the lateral direction. This means that the main response of a tilt towards right is coming from the right inner ear utricle. When tilting towards left the utricle in the left inner ear contributes with approximately 75% of the response, 25% coming from the right utricle. This background has importance for understanding of the utricle testing. Some otolithic afferents show a regular firing but others have an irregular pattern. The neurones with regular firings show little adaptation to maintained forces, but the irregular neurones have an intense reaction to the change of stimulus but adapt rapidly [1]. Otolithic stimulation causes eye movements [2]. Electrical stimulation causes a torsion of the eyes away from the stimulated side. Unilateral vestibular nerve sectioning causes a torsion of the eyes towards the contralateral side [3].

Ocular Counter Torsion In clinical investigations it is easy to see that tilting the head causes a torsion of the eyes around the visual axis to compensate for the head tilt. The amount of the torsion (counter-rolling) is approximately 10% of the head tilt. Subjects without otolith function do not have counter-rolling. Static countertorsion depends on otolithic influence and is not a semicircular canal response. The response is mainly a function of the utricles. The size of the counterrolling response is corresponding the shear force acting on the macula utriculi [4, 5]. Different studies are not in unison concerning the direction of countertorsion in unilateral loss which makes it somewhat uncertain whether measurements of ocular counter-rolling can localize unilateral lesions with certainty [6, 7]. For recording counter-rolling, a computer-based pattern recognition system is necessary.

Eccentric Rotatory Testing When a subject is seated in a rotatory chair and angular acceleration is performed, the semicircular canals are stimulated. In order to have the full response from the lateral semicircular canals, the head should be tilted 30º forwards during the test. As the canals react to acceleration, there is no response from the semicircular canals during constant velocity rotation. However, in

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Fig. 1. Eccentric rotatory testing in the clockwise direction. The patient is ready to adjust the LED bar in darkness.

this position and during constant velocity rotation there is a centripetal force acting upon the utricular maculae. In this test the patient should be seated some distance from the rotation center facing the direction of rotation which will provide a constant lateral acceleration stimulus (fig. 1). The effect of the initial angular acceleration will cease some time after the rotation has reached a constant speed. To exclude visual cues to the true orientation of the subject, the rotation takes place in complete darkness. Despite the pressure from the chair on the body and shoulder it is obvious the subject will experience a strong sensation of lateral tilt. He may then give a subjective estimate of how an imagined horizontal surface would be oriented in front of him. This angle, relative to true horizontal, is an estimate of subjective tilt. The sensation of tilt depends on information from both otolithic organs. The side which is directed outwards in the rotation gives the biggest contribution to the response and the opposite side contributes only to a minor extent. This is due to the orientation of the hair cells in the macula utriculi. Thus, the response can be considered mainly an estimate of the function of the otolith organ in the laterally directed ear. The equipment consists of a low torque rotatory chair with the subject 100 cm from the vertical rotation of axis facing the direction of the constant rotation. The chair may be turned around 180º on the bar in order to change the rotation direction. Rotation may be started with an angular acceleration of 10º/s2 until angular velocity 120º/s is reached. Using this param-

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Fig. 2. Top: The bias bar with LEDs. Bottom: In darkness, only the dimly lit row of LEDs are visible.

eter the theoretical tilt angle is 24º (fig. 3). The room is in total darkness. Approximately 60 cm in front of the subject’s eyes a dimly lit light emitting diode (LED) bar is turned on for the subject to adjust (fig. 2). This is performed via a three-button keyboard in the patient’s hands. The patient is asked to position the bar in the position horizontal water surface would have. By definition, a perceived tilt outwards results in a positive angle due to the tilt illusion the patient has during the constant velocity rotation. A software in the computer administrates the test via an operator and reads the set angles of the LED bar. The subject is strongly strapped to the chair to minimize body movements and the head is held in an adjustable frame. Eight or six measurements of perceived horizontal are performed before rotation is started. The mean and standard deviation is computed. The chair is started in one

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Fig. 3. Accelerations acting on a person in eccentric rotation. ah>Horizontal acceleration; g>gravity; R>resulting linear acceleration; />angle of vertical illusion.

direction and after 1 min of constant rotation, another eight measurements are done. The chair is decelerated and after 1 min of complete stop another eight measurements are conducted. After some minutes the chair is turned in order to conduct an identical series of measurements using the other rotation direction, again with the patient facing the directional rotation. Before rotation the subjects do not perceive any significant tilt from true vertical. During constant rotation a tilt outwards of about 20º is perceived. After rotation an inwards tilt of only roughly 0.5º is experienced. For practical purposes obviously this very small illusion of postrotatory tilt is neglected. A standard deviation of about 6º in each direction is found in healthy subjects. In the same healthy subjects there was no difference between the responses with the right ear outwards compared to the left ear outwards. As the test is performed in darkness, vision has no horizontal structures to relate to. We have also shown that the results are the same even if the test is performed only with one eye open and the other closed. The fact that the reported tilt as a mean is 20º and not 24º may be due to the influence of proprioceptive cues from the position of the body and head in the rotatory chair. The instruction to

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the patient is important so that the patient does not try to adjust the LED bar in perpendicular line to the body axis. In clinical practice, the eccentric rotatory test is useful to monitor unilateral or bilateral loss of utricular function. It is also possible to record recovery after certain types of nonpermanent vestibular lesions and also the improvement caused by central compensatory mechanisms [8–10].

Subjective Visual Horizontal Test without Rotation If a person is sitting in a chair, in a totally dark room and ask to align an LED bar horizontally, most persons come with an error smaller than 2º [8]. If the test is performed before and after vestibular nerve sectioning, after having been normal, after surgery they set the bar tilted towards the lesion’s side between 5 and 15º. The reason is that they see the gravitationally horizontal bar tilted towards the intact side. Many months and even years after the lesion they often have a subjective horizontal error of approximately 4º [9]. The test using the LED bar in darkness for subject horizontal testing is very useful in clinical practice.

The Tilting Chair The subjective visual horizontal may be measured in different tilt positions. The chair with an adjustable tilt in the lateral direction is used. The patient should be secured in the chair with support for body and head. The head should be tilted approximately 10º nose down compared to natural head position. In front of the eyes at a comfortable distance there is a LED bar which is adjustable concerning tilt with a remote control. The patient is tested in 10º, 20º and 30º tilt. The tilt makes the test more sensitive than test in zero tilt [11, 12].

Vestibular-Evoked Myogenic Potentials Loud monaural clicks evoke myogenic potentials in the ipsilateral sternocleido muscle. It is obvious that these potentials are evoked by the vestibular organ in the inner ear. They appear even if the ear is deaf. Thus, the vestibularevoked myogenic potentials can be used as a clinical test of the vestibulocolic reflex. The origin of the reflex is the sacculus situated close to the cochlea and being stimulated by endolymph movement caused by the clicks. The click

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should be 0.1 ms with 95 dB loudness. The electrode placed over the sternocleido muscles picks up a short latency response usually sized 60–300 mV. During the test, the patient in the prone position should be contracting the sternocleido muscles by lifting the head somewhat. The positive/negative potential has peaks at 13 and 23 ms. If there is no vestibular function due to, e.g. neurectomy the responses are absent. Sensorineural hearing loss does not inhibit the reflex. The reflex is generated by synchronous discharges of muscle cells. If there is a conductive hearing loss, the click does not reach the inner ear fluids and there is a very low intensity of the response. In those cases a bilateral myogenic potential can be stimulated by using small rubber hammer tap the forehead [13].

Discussion In some instances it is of value to know if a patient has utricular and saccular function in the inner ear. The patient may have symptoms that lead to the suspicion that there is faulty function of the otolithic organs. Also in the diagnostics of a possible acoustic neuroma the rotatory test investigates both lateral semicircular canals and the caloric test mainly is able to diagnose the function of the lateral semicircular canal. This canal is represented in the upper part of the vestibular nerve but a test for the inferior vestibular nerve seems necessary. For testing of the sacculus, vestibular evoked myogenic potentials seems to be a method of choice using monaural clicks. The ipsilateral reaction in the sternocleido muscle can be detected and thus loss of function in the inferior vestibular nerve can be diagnosed [14]. Loss of hearing in the ear does not abolish the myogenic potential. In Me´nie`re’s disease a loss of sacculus function proven with vestibular evoked myogenic potentials is often found [15]. We have also found that in some Me´nie`re’s patients the utriculus function is diminished or absent according to the eccentric rotatory test. After gentamicin treatment usually the utricular function is lost or diminished but can be present even if the caloric response is gone. After gentamicin treatment the vertigo attacks are usually gone but sometimes the patient complains about some attacks of vertigo but without a sensation of rotation [13]. This might be due to a lack of vestibular rehabilitation and nonperfect central compensation but could also be due to otolithic reactions to variations of the endolymphatic pressure. If there is a remaining otolithic function, additional installments of gentamicin in the inner ear may solve the problem [16]. Not infrequently do patients after vestibular neuritis develop benign paroxysmal positioning vertigo. If there is no caloric response it may be intriguing

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for the physician that a nonfunctioning ear can cause the rotatory attacks. Caloric testing with the head positioned in such a way that the posterior semicircular canal is in the vertical plane may, however, show that there is some caloric response and furthermore a sacculus test can prove that the inferior vestibular nerve still has function. Thus, a benign paroxysmal positioning vertigo can appear from a functioning posterior semicircular canal [17]. Even in cases with hypermobile stapes and dehiscent superior semicircular canal the click-evoked myogenic potential test can be of help [18]. The myogenic potential test may even prove that in some patients there has been an acute loss of function in the inferior vestibular nerve proven by the evoked myogenic potential test in an ear with a normal caloric response thus proving the inferior nerve vestibular neuronitis [19]. For practical purposes the LED bias bar test seems to be simple to introduce and useful for utriculus testing [20]. This test using the subjective horizontal may be improved using the tilting chair. An even stronger stimulus is introduced with the eccentric rotatory chair. Introducing the click-evoked vestibular-evoked myogenic potential test seems possible in most laboratories as the statement for auditory testing usually can be applied for this procedure. The otolithic organs are often forgotten, but the new simple test methods offer the clinician tools for the relatively easy diagnostics.

References 1 2 3 4 5 6 7 8 9

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Goldberg, JM, Fernandez C: The vestibular system; in: Handbook of Physiology. The Nervous System III. Washington, American Physiologic Society, 1982, pp 977–1022. Suzuki J-I, Tokomasu K, Goto K: Eye movements from single utricular nerve stimulation in the cat. Acta Otolaryngol 1969;68:350. Dai MJ, Curthoys IS, Halmagyi GM: Linear acceleration perception in the roll plane before and after unilateral vestibular neurectomy. Exp Brain Res 1989;77:315–328. Woellner RC, Graybiel A: Counterrolling of the eyes and its dependence on the magnitude of gravitational or inertial force acting laterally on the body. J Appl Physiol 1959;14:632–634. Colenbrander A: Eye and otoliths. Aeromed Acta 1964;9:45–91. Krejcova H, Highstein S, Cohen B: Labyrinthine and extra-labyrinthine effects on ocular counterrolling. Acta Otolaryngol 1971;72:165–171. Diamond SG, Markham CH, Furya N: Binocular counterrolling during sustained body tilt in mormal humans and in a patient with unilateral vestibular nerve section. Ann Otol 1982;91:225–229. Curthoys IS, Dai MJ, Halmagyi GM: Human otolithic function before and after unilateral vestibular neurectomy. J Vestib Res 1991;1:199–209. Halmagyi GM, Curthoys IS, Dai MJ: The effects of unilateral vestibular deafferentation on human otolith function; in Sharpe JA, Barber HO (eds): The Vestibulo-Ocular Reflex and Vertigo. New York, Raven Press, 1993, pp 89–104. ¨ dkvist LM, Larsby B, Ledin T: Perceived subjective horizontal during eccentric Gripmark M, O rotatory testing; in Claussen CF, Sakata E, Itoh A (eds): Vertigo, Nausea, Tinnitus and Hearing Loss in Central and Peripheral Vestibular Diseases. Elsevier, Amsterdam, 1995, pp 355–359.

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Tribukait A, Bergenius J, Brantberg K: The subjective visual horizontal for different body tilts in the roll plane: Characterization of normal subjects. Brain Res Bull 1996;40:375–383. Bergenius J, Tribukait A, Brantberg K: The subjective horizontalat different angles of roll tilt in patients with unilateral vestibular impairment. Brain Res Bull 1996;40:385–391. Colebatch JG, Rothwell JC: Vestibular-evoked EMG responses in human neck muscles. J Physiol 1993;473:18P. Murofushi T, Matsuzaki M, Mizuno M: Vestibular evoked myogenic potentials in patients with acoustic neuromas. Arch Otolaryngol Head Neck Surg 1998;124:509–512. de Waele C, Tran Ba Huy, Dirad J-P, Freyys G, Vidal P-P: Saccular dysfunction in Me´nie`re’s disease. Am J Otol 1999;20:223. ¨ dkvist LM, Bergenius J, Mo¨ller C: When and how to use gentamicin in the treatment of Meniere’s O disease. Acta Otolaryngol (Stockh) 1997;(suppl 526):54–57. Colebatch JG, Rothwell JC, Bronstein A, Ludman H: Click-evoked vestibular activation in the Tullio phenomenon. J Neurol Neurosurg Psychiatry 1994;57:1538–1540. Minor LB, Solomon D, Zinreich JS, See DS: Tullio’s phenomenon due to bone dehiscence of the superior semicircular canal. Arch Otolaryngol Head Neck Surg 1998;124:249. Fetter M, Dichgans J: Vestibular neuritis spares the inferior division of the vestibular nerve. Brain 1996;119:755. ¨ dkvist LM, Ledin T, Larsby B, Gripmark M, Noaksson L, Olsson S: Otolithic tests in Menie`re’s O disease; in So¨ren V, Morten K, Pernille M (eds): Me´nie`re’s Disease. 16th Danavox Symposium, September 19–22, 1995, pp 247–254. Koldning, Scanticon, 1995.

¨ dkvist, Department of Otolaryngology, University Hospital, Lars O SE–581 85 Linko¨ping, (Sweden) Tel. +46 13 22 20 00, Fax +46 13 22 25 04, E-Mail [email protected]

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The Subjective Visual Vertical Ch. Van Nechel a, b, M. Toupet a, c, I. Bodson a, d a

IRON (Institut de Recherche en Oto-Neurologie), Paris, France; Unite´ de Neuro-Ophtalmologie, Cliniques Universitaires de Bruxelles Erasme et CHU Brugmann, Service de Revalidation Neurologique, Bruxelles, Belgium; c Centre d’explorations fonctionnelles otoneurologiques, Paris, France; d CHU La Citadelle, Service ORL, Lie`ge, Belgium b

The subjective visual vertical (SVV) is the angle between the physical vertical line (gravitational axis) and the position of a visual linear marker adjusted vertically by a subject. This SVV is probably computed from the same sensory information as the postural vertical (position of the body axis when the subject estimates he is vertical), but the respective contribution of each of these informations to the estimation of these two verticals is highly different. The SVV is probably not an intermediate stage in the elaboration of the postural verticals. This explains the discrepancies between tiltings of postural and visual vertical. As far as the SVV is considered here as an approach to the evaluation of the otolithic function and not as a tool trying to explain an impaired posture, this discrepancy will not be further considered in this paper. The sensibility of otolithic organs to the gravity force suggests that they play the main role in the estimation of the physical vertical orientation. Visual information can, however, modify this perception [3]. Moreover, the efficient use of these otolithic and visual informations for the postural control implies an adjustment according to the position of the head with regard to the trunk. Cervical somatosensory but also cutaneous, muscular and articular information are able to contribute to the estimation of the physical vertical orientation. The SVV is frequently impaired in labyrinthic disorders [4], in lesions of the vestibular nerve [9], of the vestibular pathways within the brainstem [10] or in the vestibular cortical areas [6]. Is it allowed then to consider the measure of the SVV as a tool for the evaluation of the otolithic function?

To validate this measure, it is necessary first to prove its sensitivity to the otolithic dysfunctions and then to demonstrate that the methodology used reduces the risks of interference of the other sources of error, and is not affected by any substitutions for otolithic deficit.

The SVV in the Otolithic Disorders An isolated otolithic dysfunction is rare, it is chiefly based on complaints and, so far, the specific stimulation of this function requires a heavy instrumentation. The deficit of the otolithic function, in association with the other, more dynamic, labyrinthic components, is however warranted in surgical lesions such as labyrinthectomies or neurectomies. The SVV being a static measure, it is reasonable to think that the deficit of the dynamic components interferes little with it. So, ipsilateral tilt of the SVV in acute one-sided vestibular deficits resulting from labyrinthectomy and neurectomy [9, 13, 20] suggests the implication of otolithic organs in the estimation of the visual vertical. It is also frequently disturbed in less complete lesions. The rate of abnormalities of the SVV amounts to 89% in a group of vestibular neuritis [4] and to 47% in acute labyrinthitis [20]. The lesions of the central pathways originating from vertical canals and otolithic organs also lead to an ipsi- or contralateral tilt of the SVV according to their location [5, 6]. If the most striking clinical signs of benign paroxysmal positioning vertigo (BPPV) are very likely of canalar origin, the pathological starting point is well otolithic. One can thus wonder about the possible effect of otoconia loss on the SVV. A first study concerning 19 cases suggested the absence of abnormality of the SVV [4]. We studied the SVV in 1,000 consecutive cases of BPPV, of which 933 were one-side according to the clinical examination. The comparison of the distributions of the values for SVV measured binocularly, with straight head, in these patients with an estimation of the SVV in a normal population, computed on base of a group of 81 control subjects, shows a spreading of the distribution (fig. 1). Values of more than 2.8º, were present in less than 5% of control subjects, but were observed for 16.4% of the right BPPV and in 14.2% of the left BPPV. The deviation of the SVV is more often ipsilateral to the side considered as affected by the clinical examination (v2 test: p>0.002). The presence of contralateral tilts nevertheless calls for some comments. The area of the utricule macular disrupted by the loss of otoconia could be in cellular fields sensitive to ipsi- or contralateral head tilt. Another explanation could be a bilateral otolithic disorder expressing only by a one-sided BPPV. Finally, the structures of the visuo-vestibular integration could have developed a correction by moving contralaterally the

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Fig. 1. SVV distribution in 993 patients suffering from unilateral BPPV compared with a VVS estimation in a normal population (N), computed from a sample of 81 control subjects.

‘otolithic’ vertical (calibration of the zero point) to maintain a good agreement between vestibular and visual information. If the deviation of the SVV is frequent in acute lesions of the vestibular system, it becomes rare in chronic deficits, including bilateral vestibular areflexia [8]. So if the SVV seems rather sensitive to acute lesions disturbing the otolithic system, it is now necessary to consider its specificity. This leads us to look at the other factors likely to modify the SVV.

The Stages of the SVV Measure A model (fig. 2) resuming the various stages of the measure allows to identify the potential, not vestibular, sources of SVV impairments, or the substitution strategies capable of masking a vestibular disorder. The estimation of the subjective vertical can be performed by adjusting a marker using visual, somatosensory or postural information. We shall only consider measures in visual modality and in a frontal plane. The Visual Input The first stage of the SVV measure is the visual perception of a linear marker projected on the retina after a passage through the transparent struc-

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Fig. 2. Theoretical model of the VVS measure.

tures of the eye. This first stage can already introduce a deviation of the SVV. So, an uncorrected oblique astigmatism, or an ocular torsion (rotation around the optical axis of the eye) can, independently of any notion of verticality, lead to an error in the orientation perception of a visual object. These torsions are present in oculomotor palsies but also, physiologically, when the position of the eyes is a combination of horizontal and vertical rotations in the orbits (tertiary position). The direction of these physiological torsions can be predicted by the Listing law. This defines all the positions of the eyes by their rotation on the axis situated in an equatorial plane. The tilt of this axis is constant for every position of the eyes, whatever way this position is reached. As a consequence, the meridian of the eye, vertical in primary position bows for all the tertiary positions of the gaze. Precise measures of these eye torsions by magnetic coils confirmed the direction predicted by the Listing law [12]. This led us to study, by means of a Wilcoxon’s nonparametric test for paired observations, the direction of the deviation of the SVV according to the position of the eyes in the orbit [19]. Three of the four tertiary positions of the gaze showed highly significant modifications (p00.01) in the orientation of the SVV with regard to the measures in primary position. The direction of these deviations is in accordance with the predictions based on the Listing law. The discrepancy of the fourth position can result either from a bad estimation of the gaze primary position with a not strictly frontal Listing plane, or from unpredictable fluctuations in the eye torsions.

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The adjustment of the orientation of a linear visual marker with regard to a subjective notion of vertical implies first the elaboration of a subjective vertical reference and later a process of comparison (fig. 2). Subjective Vertical Reference This is built from one of several sources of information liable to give us indications on physical vertical or horizontal orientations. Visual Contribution. One of these sources is the visual system. During the maturation of the visual system, the innate orthogonal axes, related to the organization of the primary visual cerebral cortex [16], were reinforced by the repetitive experience of stimuli with strong horizontal and vertical dominants. There is thus a purely visual skill allowing to estimate the orientation of a linear stimulus in the space with regard to the physical vertical or horizontal. However, these orthogonal axes ‘engraved’ in the cerebral cortex and fixedly connected to the retinal receptors, were built according to the most frequent position of eyes in orbits and head with regard to the physical vertical. When the head and eyes are not in this most common position, the visual system, if besides it is deprived of any element usually taken as vertical or horizontal (door, building, horizon), cannot by itself estimate correctly horizontality or verticality of a neutral linear perception (having no usual orientation). Experimental data show the effect of attraction of a tilted structured background on the measure of the SVV [3]. With the increase of the tilt, the contribution of this visual information becomes more and more variable among subjects. Vestibular Contribution. This is probably dominant in the healthy subject. Otolithic organs are specific receptors of the gravitational force, but other sensors, especially close to the kidneys, and the vestibular dynamic information, reflecting the required movements around the equilibrium position, could also contribute to this perception. It is thus difficult to isolate the otolithic contribution to the SVV but the best approach is probably obtained by measures made in submersion, which neutralize somatosensory and visual contributions to the SVV. In these conditions the SVV is similar to that obtained on earth provided the body remains directed in the range of physiological functioning of the utricules [15]. Measures made in centrifuging room are less selective because they associate disturbances of the otolithic and somatosensory systems. Somatosensory Inputs. Many somatosensory data contribute to the elaboration of a vertical reference. Besides the cutaneous receptors (especially plantar), to the pressure, the muscular and tendon tension receptors provide data about the static and dynamic moments of inertia of the work of antigravific muscles. They are sources of information useful for the construction of a

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referential system [18]. This information is probably more determining in the adjustment of the postural vertical than for the SVV. The absence of somatosensory information does not however disturb the SVV in a patient who had lost all deep sensibility of the trunk and the members, when he sat with the head in straight position [21]. We wanted to estimate the influence of very asymmetrical proprioceptive cervical information of the SVV by measuring it in 4 healthy subjects lying on the left or the right side but with their head maintained vertical [19]. It seems that under normal functioning of the vestibular system and when the head remains straight, the cervical proprioception does not influence significantly the SVV. Nevertheless, the role of the somatosensory inputs become probably of prime necessity when otolithic information is no longer available as suggested by the measures of SVV made in immersion with important tilts of the body [8]. These inputs very likely explain the progressive normalization of the SVV in bilateral vestibular areflexia. Thus, these multimodal references contribute with a variable weight, according to the circumstances and possible disorders, to build an image of a vertical reference in our visual space representation. The site of this synthesis within the central nervous system is not known but a candidate of choice would be the human homologue of the parieto-insular vestibular cortex of the monkey, a site of confluence of vestibular, visual and somatosensory information. This mental representation of the vertical will then be compared with the orientation of the linear stimulus serving as marker of the SVV. The Comparison Process Visuo-spatial disorders, without known relation with the vestibular system, can impair this comparison process and so the SVV measures. The elementary comparison of the orientation of two linear stimuli presented simultaneously can be significantly impaired in cases of lesions of the associative visual vortex. Benton [2] asked his subjects to identify on a protractor the correct orientation of two lines. Results shows already a non-negligible rate of error in control subjects, a great increase of these errors in subjects presenting a right brain damage, and in a lesser degree in left hemispherical lesions. If the right hemisphere seems specifically qualified to estimate the orientation of the stimulus, the left hemisphere appears to play a role in the decision-taking process and specially in the decision of the marker adjustment [22]. We use a test made up of two oblique lines, one red and one green, presented on a computer screen of which only a circular window is left visible by a mask. The subject has to line up a line in the same direction as the other

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one. The model line and the mobile line are presented, either simultaneously, or with an interval of 10 s. This test confirms that the patients presenting a left lateropulsion resulting from a right hemispheric lesion, and very often a left tilt of the SVV, also have difficulties to reach the parallelism of the two lines. Thus, the mechanism of the impairment of the subjective visual vertical line in parieto-temporal cortical lesions is probably mixed, by failure of the integration and by impairment of specifical visual tasks related to the methodology. Considering this multisensory character of the SVV, how can the methodology be optimized?

Methodological Implications The Stimulus The main methodological point in the absence, during the test, of any visual element susceptible to supply a horizontal or vertical reference (computer screen, daylight under a door …). It is also necessary to take into account an effect of the visual memory of orientation. After transition to the darkness or after limitation of the visual field, the subject keeps in memory the vertical orientation of the surrounding objects. We tested this memory effect on oblique positions in 4 subjects [19]. Results obtained in our control subjects (n>80) shows that 98% have an SVV less then 3.4º. The average error during our visual memory task exceeds this value only 22 s after the disappearance of the model. It is so necessary to wait for this delay before performing the first measure and between successive measures. The initial position of the mark must be clearly oblique to prevent any indication of vertical reference. According to the size of the marker and the point stared at by the subject, it will fall completely or partially in one or the other visual hemi-field. Given the different hemispherical skill in visuo-spatial tasks, it seemed interesting to check if, in the same subject, the direction of the initial tilt of the marker was capable to modify the results significantly. One could also fear of a hysteresis phenomenon according to this initial tilt, similar to that described during the tilting of the subject [17]. No significant difference (n>72; paired t test: p>0.07) was observed between measures performed with an initial left or right tilt of the marker [19]. This probably results from the bi-hemispherical representation of the central part of the visual field and from the integrity of the inter-hemispherical transfer in the tested subjects. It is possible that the same measures performed in subjects

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Table 1. Means, SD and values at the cumulative frequencies (Fc) of 2.5 and 97.5% of the SVV distribution of the control group (n>81)

Binocular v Right eye v Left eye v Right eye r Left eye r Right eye l Left eye l

Mean

SD

Fc>2.5%

Fc>97.5%

–0.08 0.06 –0.64 –1.05 –0.15 –0.03 –0.51

1.43 1.83 1.98 3.9 3.8 3.65 4.11

–2.8 –3.5 –4.5 –8.7 –7.6 –7.2 –8.6

2.73 3.6 3.2 6.6 7.3 7.1 7.5

SVV were performed binocularly with a vertical head axis (v), monocularly with a vertical head axis (v), with the head axis tilted to the right (r) or to the left (l).

suffering from a parieto-occipital or callosal lesion would show a significant difference. The Subject The measures must be performed with the usual optical correction of the subject. For instance, measures performed with and without the correction in a patient suffering from an oblique astigmatism of +3 dpt differed by 3.8º. Is it necessary to record the SVV in monocular or binocular condition? The distribution of the normal values of our control group was sharper in binocular than in monocular vision (table 1) and this was also observed by other authors [11]. Binocular vision involves the mechanisms of torsional sensory fusion able to correct cyclodeviations between the two eyes. These are frequent in the normal population and usually completely asymptomatic due to this fusion mechanism. A monocular measure is thus susceptible to be corrupted by a cyclodeviation which is not of otolithic origin but results from an asymptomatic oculomotor imbalance. It is relevant in connection with this that congenital palsies of the superior oblique muscle are seldom associated with a tilt of the visual field despite the presence of an eye torsion. Unlike monocular measures, no abnormality of SVV was observed with binocular vision in acquired oculomotor palsies [11]. However, the otolithic system controls the torsional movements of the eye, especially by counter-torsion reflexes. Its disturbance can induce cyclotorsions which are not necessarily symmetrical in the two eyes. This appears clearly in the ocular tilt reaction. It is significant from this point of view, that the 3 patients presenting an

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impaired monocular SVV (patients 7, 28 and 35) among the 13 patients suffering from a Wallenberg’s syndrome of the Brandt’s study [7] had a major cyclotorsion of this eye (respectively, of 13, 14 and 16º) in the same direction as the deviation of the SVV. This was also confirmed in their 23 patients suffering from an infarct of the middle cerebral artery [6]. Three among these presented a deviation of the SVV only monocularly (patients 2, 12 and 15). These 3 patients were among the 4 subjects which presented during one of their examinations a monocular torsion of the same direction. In our study of 933 one-sided BPPV, monocular assessment of the SVV enabled us to identify only one supplementary defective case as compared with the binocular evaluation, when specific standards were used for every situation. Thus, it seems that the exclusively monocular deviations of the SVV, result most frequently from a cyclotorsion of the eye. This can be a sign of otolithic disorder or of a pure oculomotor imbalance. The binocular measures of the SVV reflect probably more specifically the otolithic action but with a lesser sensibility than monocular measures. The aim of our measure being to approach most selectively the otolithic component of the SVV, monocular measures of the SVV will probably be distorted by more false positives. The attempts of eye torsion quantification by measure of the orientation of the papillo-macular axis on fundus photos allows to reveal only important torsion. Actually, the normal range of this papillo-macular angle is about 12º and this is rarely known in a patient before his first complaints. The use of a physical constraint to keep the head in a vertical position is an essential condition when the angle of the SVV is measured with regard to a cephalic reference, as with the use of Maddox glasses (frame with rotating streaked glasses). Except for this situation, this constraint seems not to be justified. The proprioception is not relevant for the SVV when an otolithic information is available, as suggested by many results: our control group (table 1), the measures in immersion [15], the SVV of the patients suffering from spasmodic torticollis [1], our group of patients suffering from a BPPV (table 2) and our measures in subjects side-lying with straight head. On the other hand, if this otolithic information is not available, the constraining head position could supply an indication of an orthogonal reference able to mask an SVV deviation. The sitting position of the patient during the SVV measures in the complete darkness is especially justified for safety reasons. It is possible that the somatosensory input differences between the standing and sitting position can modify the SVV measures in the patients lacking of vestibular information and very dependent of their proprioception. But these patients are presenting the greatest risk of fall in darkness.

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Table 2. Frequencies of the SVV outside the confidence interval of 95%, performed with a vertical head axis (v), tilted to the right (r) or to the left (l) in patients who suffered from BPPV

Binocular v Right eye v Left eye v Right or left eye v Right eye r Left eye r Right eye 1 Left eye l

Right BPPV

Left BPPV

(n>551)

(n>382)

n

%

n

%

87 63 38 87 29 42 31 24

16 11 7 16 5 8 6 4

52 40 27 53 27 4 29 25

14 10 7 14 7 1 8 7

The Instrument The measuring can be very simple but has to be of a sufficient precision. Metrological error is usually considered to have an amplitude equivalent to half the tool graduation. The narrow range of normal measures (average: –0.08º, SD: 1.4º) imposes a precision at least equivalent to one degree. This precision is rarely reached with the Maddox glasses usually used in ophthalmology.

References 1 2 3 4 5 6 7 8

Anastasopoulos D, Bhatia K, Bronstein AM, Gresty MA, Marsden CD: Perception of spatial orientation in spasmodic torticollis. 2. The visual vertical. Mov Disord 1997;12:709–714. Benton AL, Varney NR, Hamsher K: Visuo-spatial judgment: A clinical test. Arch Neurol 1978; 52:364–367. Bischof N: Optic-vestibular orientation to the vertical. Handb Sensoriphysiol Vestib Sys 1974;VI: 155–190. Bo¨hmer A, Rickenmann J: The subjective visual verticals as a clinical parameter of vestibular function in peripheral vestibular disease. J Vestib Res 1995;5:35–45. Brandt T, Dieterich M: Skew deviation with ocular torsion: A vestibular brainstem sign of topographic diagnostic value. Ann Neurol 1993;33:528–534. Brandt T, Dieterich M, Danek A: Vestibular cortex lesions affect the perception of verticality. Ann Neurol 1994;35:403–412. Brandt T, Dieterich M: Cyclorotation of the eyes and subjective visual vertical in vestibular brain stem lesions. Ann NY Acad Sci 1992;22:537–549. Clark B, Graybiel A: Influence of contact cues on the perception of the oculogravic illusion. Acta Otolaryngol 1968;65:373–380.

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10 11 12 13 14 15

16 17

18 19 20 21 22

Curthoys IS, Halmagyi GM, Dai MJ: The acute effects of unilateral vestibular neurectomy on sensory and motor tests of human otolithic function. Acta Otolaryngol (Stockh) 1991;(suppl 481): 5–10. Dieterich M, Brandt T: Ocular torsion and tilt of subjective visual vertical are sensitive brainstem signs. Ann Neurol 1993;33:192–299. Dieterich M, Brandt T: Ocular torsion and perceived vertical in oculomotor, trochlear and abducens nerve palsies. Brain 1993;116:1095–1104. Ferman L, Collewijn H, Van den Berg V: A direct test of Listing’s law. I. Human ocular torsion measured in static tertiary positions. Vision Res 1987;27:929–938. Friedmann G: The influence of unilateral labyrinthectomy on orientation in space. Acta Otolaryngol 1971;71:289–298. Gibson E, Walk RD: The visual cliff. Contemporary psychology. Sci Am 1971:77–84. Graybiel A, Miller EF, Newson BD, Kennedy RS: The effect of water immersion on perception of the oculogravic illusion in normal and labyrinthine defective subjects. Acta Otolaryngol 1968;65: 599–610. Hubel DH, Wiesel TN: Receptive fields, binocular interaction and functional architecture in the cat’s visual cortex. J Physiol 1962;160:106–154. Lechner-Steinleitner S, Scho¨ne H: Hysteresis in orientation to the vertical (the effect of time of preceding tilt on the subjective vertical); in Hood JD (ed): Vestibular Mechanisms in Health and Disease. London, Academic Press, 1978, pp 326–331. Stoffregen TA, Riccio GE: An ecological theory of orientation and the vestibular system. Psychol Rev 1988;95:3–14. Van Nechel C, Toupet M, Bodson I: Are proprioceptive and oculomotor factors relevant in the assessment of the subjective visual vertical in healthy subjects. Submitted. Vibert D, Ha¨usler R, Safran AB: Subjective visual vertical in peripheral unilateral vestibular disease. J Vestib Res 1999;9:145–152. Yardley L: Contribution of somatosensory information to perception of the visual vertical with body tilt and rotating visual field. Percept Psychophys 1990;48:113–134. Ziyah M, Freda N: Dissociate contributions of the two cerebral hemispheres to judgments of the line orientation. J Intern Neuropsychol Soc 1996;2:335–339.

Dr. Ch. Van Nechel, IRON (Institut de Recherche en Oto-Neurologie), 10, rue Falguie`re, F–75015 Paris (France) Tel. +33 1 43 35 35 30, Fax +33 1 40 47 68 57, E-Mail [email protected]

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Clinical Application of the Off Vertical Axis Rotation Test (OVAR) Sylvette Wiener-Vacher Hoˆpital Robert-Debre´ Service ORL, Unite` d’Explorations Oto-neuroophtalmologiques, Paris (France)

Off vertical axis rotation with vestibulo-ocular responses (VOR) recordings is one of the few methods of vestibular evaluation of the otolith function currently available in medical practice. It provides a global assessment of the vestibular otolith system. Since 1991, we have applied this test to children with balance problems, deafness and delay in posturo-motor development and have demonstrated the value of this test for diagnosis in pediatrics practice. We have also used this test in normal children to study the maturation of the vestibular system. In adults we used it to study the processes of central compensation after surgical section of the vestibular nerve or to uncover possible otolith system disturbances in patients suffering from distortion of movement sensation.

What is the Off Vertical Axis Rotation Test? Methods and Principle of the OVAR Test The patients are seated in complete darkness, in a computer-controlled chair that rotates at a constant velocity rotation about an axis tilted with respect to the gravity vector (fig. 1). The apparatus we are using has been designed by Denise and Darlot [1] and already described in previous publications [2–5]. During OVAR, the head of the subject is rotated around a tilted axis relative to the gravity vector. The component of the gravity vector (G) which corresponds to the projection of G on the plane of the otolith organs, varies sinusoidally during rotation. The vector G sweeps the maculae alternatively rotating forward and backward during each half of one cycle of rotation [1].

Fig. 1. EVAR and OVAR tests: the rotation-tilt paradigm. First (A) the chair rotates about a vertical axis with an initial acceleration of 40º/s2 (EVAR) followed by a rotation at 60º/s. This induces a canal VOR (bottom traces column A). Since only the initial acceleration stimulates the canals, the canal VOR decays progressively (here in 20 s). Then the axis of the chair is tilted of 13º relative to vertical (B) while rotation continued at a constant velocity of 60º/s (OVAR). The horizontal and vertical components of the otolith VOR are recorded (bottom traces column B). These traces show the characteristic modulation of the eye movements synchronized to the position of the chair during the rotation. The black bands indicate the slow phases used for calculation of the velocities. The two graphs on the right of column B show the corresponding velocities of the horizontal (top) and vertical (bottom) eye movements recorded during 12 cycles of OVAR as a function of the orientation of the chair. The solid lines indicate the best-fitting sinusoid from which the bias was calculated. From Wiener-Vacher and Mazda [4].

This stimulation produces a constant sinusoidal variation of the direction of the gravity vector with respect to the head. The vestibulo-ocular responses (VOR) are recorded by electro-oculo-graphic electrodes in complete darkness. The rotation-tilt paradigm was chosen because it provides in the same session a canal testing with the earth vertical axis rotation as well as an otolith testing.

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The Vestibulo-Ocular Responses to OVAR The OVAR test produces a complex nystagmus as first described in humans by Guedry [6] and Benson and Bodin [7]. The ocular response evoked by the OVAR stimulation is composed of a bias (which corresponds to a mean slow phase velocity in a direction opposite to the rotation velocity of the head) and a sinusoidal modulation of the slow phase velocity with a periodicity identical to the period of the rotation (fig. 1). The amplitude of the response varies as a function of the angle of tilt of the rotation axis and the rotation velocity [1]. We chose for our OVAR paradigm a rotation velocity of 60º/s and 13º of tilt because this gives an optimal amplitude of the response without inducing discomfort of the subjects. Interpretation of the Responses to OVAR Guedry [8] in 1970 applied this stimulation to normal subjects as well as patients with vestibular bilateral deficits and observed the absence of coherent ocular responses in the case of vestibular lesions. Subsequent experiments in animals [9, 10] and observations in humans have shown that the principal target of this stimulation is in fact the otolith albeit with an excitation of some proprioceptive inputs (somesthesic, visceral). Specific lesions of the otolith system are considered to be responsible for disappearance of the responses to OVAR on the side of the lesion during the acute post-lesion phase [2, 9, 10]. While OVAR stimulates both sides of the otolith system, the stimulation is greater for the right otolith system when the rotation is applied clockwise and counterclockwise gives a stronger response from the left otolith organs. The production of the OVAR ocular response requires complex central processing of otolith signals in the brainstem vestibular nuclei where canal signals and somesthesic signals are also processed and oculo-motor responses generated. The vestibulo-ocular responses are also quite dependent on the integrity of the oculo-motor pathways and can be modified by lesions of these pathways. This explains why asymmetries observed in OVAR have to be interpreted carefully with other vestibular and ocular testing results. It also explains why the central compensation mechanisms are able to mask with time asymmetries of the responses to OVAR after unilateral vestibular lesion [2].

Role of the Vestibular System in the Posturo-Motor Development of Children The importance of the vestibular system in the posturo-motor development of children has been underestimated for a long time. The objectives of

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our study were to determine the respective roles played by canal and otolith vestibular information in the posturo-motor development of children and the repercussions of this for understanding certain pediatric pathologies. Our work was motivated by the fact that the vestibular system and particularly the otolith system were not being adequately tested in young children. This was due to the difficulties in motivating compliance by young children for testing. Factors contributing to this included unattractive and unfriendly clinical environments, but also the lack of available and practical otolith testing methods. For the last 9 years we have adapted for children a series of vestibular tests, and applied them to normal young volunteers as well as children referred to our department for balance problems. Most of our studies have focused on measuring vestibulo-ocular responses, which are recorded with adaptations of classic EOG (electro-oculographic) techniques (better accepted in our experience by very young subjects than video-oculo-graphic technics of recording). These tests include, for the canal function evaluation: the caloric test, pendular rotation, rotatory impulsion (earth vertical axis rotation or EVAR) and for otolith functional evaluations: off vertical axis rotation. More recently, we adapted other tests for otolith evaluation: measurements of the vertical subjective and myogenic evoked potentials from stimulation of the otolith organs by clicks applied to earphones. The various results obtained suggest that, as early as birth, vestibular information play a fundamental role for the postural motor control in children. But canal and otolith information does not have identical contributions. Children suffering a complete absence of vestibular information since birth invariably show severe delays for acquiring postural control of their head and trunk (for head holding, sitting, standing). Consequently, they are unable to achieve milestones of motor autonomy such as independent walking at normal ages [11, 12] (fig. 2). Functional deficiency of the canal vestibular system alone (as found in children with a congenital absence of semi-circular canals [5, 13]) does not seem as important as otolith information for acquiring the first levels of posturomotor control. The absence of semi-circular canals permits head holding, sitting, standing and walking with support to occur at normal ages, while it leads to substantial delays for the onset of independent walking [13]. This can be explained by a major contribution of the canal vestibular information at the onset of walking. This input is required to obtain a stabilization of gaze during the rapid movements of the head that occur at each step when walking and during orientation movements in space. Previous studies showed that there is a fine coordination between movements of the head and eyes, which involve particularly, canal vestibulo-ocular responses [14, 15]. This coordination is progressively accomplished in toddlers during their first years of walking [16–18].

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Fig. 2. Delays in independent walking (IW) are dependent on the degree of bilateral vestibular deficit. On the Y-axis is plotted a global index of otolith function (mean value of the VOR modulation to OVAR in both direction of rotation). On the X-axis is plotted a global index of the canal vestibular function (mean values of the amplitude of VOR in response to EVAR in both directions of rotation). Two population of children are compared: circles and squares represent young children showing no vestibulo-ocular responses in either sides to caloric tests (at 20 ºC) since an early age (=1 year of age), and triangles a group control of the same age at the time of the tests. Note that the children with the longest delay of IW are the ones which have the poorest canal and otolith responses (white circles). Note that children with no canal function but remaining otolith responses walk at a normal (or almost normal) age (respectively, black and gray squares). Note also that an absence of responses in the caloric test (20 ºC) can be associated with a residual canal function. From Wiener-Vacher et al. [submitted].

We studied the gait parameters as well as canal and otolith VOR during the periods preceding and following the acquisition of independent walking in a longitudinal study in children with normal vestibular function [19]. Otolith vestibulo-ocular responses showed characteristic changes correlated to the onset of independent walking while canal VOR did not change [3, 19]. These results suggest that the otolith system is essential for the timely acquisition of axial head and trunk postural control for this posturo-motor acquisition milestone. This hypothesis is supported by our observation that severe and early-acquired deficits of vestibular inputs in infants induce a severe hypotony and are correlated with a considerable delay in independent walking acquisi-

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tion. If the vestibular impairment is incomplete (with residual canal and otolith function) the posturo-motor control is acquired at normal ages. A recent study supports the hypothesis that children with residual otolith function have better posturo-motor control development than children with a remaining canal function in terms of posturo-motor control acquisition [13]. However, we have not yet found the pathological cases of complete deficits of otolith function coupled with normal canal function that would be necessary to confirm this hypothesis. Characteristics of the canal vestibulo-ocular responses change progressively over the years after the first steps of independent walking [3, 19]. This suggests that the canal vestibular system might be more involved in head rotation control after axial postural motor control is acquired. We know that gaze stabilization in space during walking requires accurate and fine control of the head displacements and eye movements. Head coordination during stepping in toddlers also develops progressively over the first years after acquisition of the first independent step [16, 17]. This pattern of development could correspond to the progressive changes observed in the canal VOR characteristics during the first years of life.

How Can the OVAR Test Be Used as a Diagnostic Tool? The OVAR Test during the Acute Phase of Vestibular Damage In our experience, the OVAR test can be useful during the acute phase after vestibular damage because the results can demonstrate signs of decrease or increase of excitability of the otolith system on the side sustaining damage. Within the year following a stable unilateral lesion of the vestibular system, the central nervous system compensates for most of the asymmetry of the vestibulo-ocular responses, a valuable indicator of the lesion side. However, if the lesion is progressive or fluctuating the vestibular function remains unstable and the central nervous system compensation processes are unable to correct the asymmetries of the vestibulo-ocular responses. A developing lesion of the inner ear, such as a labyrinthitis when fibrosis (and secondary bone) progressively invades the inner ear cavity, is a good example of such progressive lesion. As described in ‘Observation 1’ the OVAR responses show a permanent strong directional preponderance indicating that 1 year after the initial labyrinthitis, the vestibular deficit was not yet compensated. CT scan proved that there was an ossifying labyrinthitis. After cranial traumatism with a temporal bone fracture or in the case of a fluctuating hearing loss with suspicion of a congenital perilymphatic fistula, an OVAR test showing a strong directional preponderance toward the damaged

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ear, indicates a recent fluctuation and hyperexcitability of the vestibular receptors on the same side (see ‘Observation 2’). This was associated to the surgical discovery of active perilymphatic fistulae in all cases. When the directional preponderance is toward the side opposite to the lesion this indicates a recent lesion of the otolith system but does not necessarily evidence the existence of a fistula. In the case of unilateral vestibular neuritis the prognosis of functional recovery of the lesioned side over time is greater if the initial lesion is incomplete. For the initial vestibular functional testing the OVAR test permits an evaluation of the otolith function providing a more complete assessment of the extent of the lesion and thus a better appreciation of the prognosis (Observation 3). The Test OVAR during the Chronic Phase of Vestibular Damage During the chronic phase of vestibular impairments, the usefulness of the OVAR tests to localize the side of the lesion is more questionable. The mechanisms of compensation of a complete unilateral vestibular reduce or cancel with time the asymmetries of the vestibulo-ocular responses to most of the vestibular tests. Thus, the OVAR test may not be effective for diagnosing a partial or old unilateral otolith lesion. However, OVAR can be used for assessing complete vestibular bilateral deficit in the case of delays in posturo-motor acquisition and their vestibular origin. With a residual canal or otolith function a child without any other neurological problems is able to acquire all the milestones of the posturomotor development at a normal age (=19 months) (fig. 2). The detection of a remaining vestibular function in a child with severe delays in development indicates that problems other than a vestibular lesion are responsible for these delays (visual disorders, orthopedic disorders, and neurological disorders). The detection of a vestibular deficit in a child with other sensorimotor deficits is essential to permit prescription of a better adapted physicotherapy program [19], using the remaining sensorial information to compensate the other deficits. The OVAR tests have been used for detecting otolith system asymmetries in pathologies involving posturo-motor control for example in idiopathic scoliosis. Idiopathic scoliosis is a disorder, which is usually diagnosed during the period of rapid growth preceding the age of puberty. Various hypotheses have been proposed to explain the development of this progressive spine deformity. We discovered that more than 60% of the children with idiopathic scoliosis had an abnormal asymmetry of their vestibulo-ocular responses to OVAR while their canal vestibulo-ocular responses were normal [4]. These results bring new arguments to support the hypothesis of a central origin involving the otolith system for the development of scoliosis in young children.

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Observations Observation 1: Application of the OVAR Test in the Diagnostic of Unstable Developing Lesion of the Vestibule A 3-year-old boy suddently suffers violent abdominal pain, vomiting and ataxia 1 week after a tonsillitis. Two weeks later, the boy complains that he cannot hear the telephone with his left ear. He is referred to an Otorhinolaryngology department where audiometry testing reveals a complete sensorineural hearing loss in the left ear. No vestibular testing is done. But a CT scan is normal. Four months later, he is referred to our department for testing his hearing loss. A complete audio-vestibular examination confirms the sensorineural hearing loss on the left ear, but shows a deficit of the left vestibular receptors with no compensation (intense spontaneous nystagmus, intense directional preponderance toward the right side at all testing (canal and otolith VOR recordings). Thirteen months after the acute episode, compensation is still not achieved. This is very unusual in children of this age, who normally compensate very quickly. A CT scan and MRI are again performed. They show an ossifying labyrinthitis. Twenty months after this diagnosis the vestibular function will be completely destroyed and the compensation completed with a very discrete directional preponderance to the right side and a bilateral inhibition of the VOR measured by OVAR (as evidenced by very small modulation and almost zero bias). Observation 2: The Responses to OVAR Can Indicate an Abnormal Irritation of the Otolith Receptors on the Side of a Perilymphatic Fistula After falling from an elevated bed, a 7-year-old boy presents a cranial traumatism with a brief loss of consciousness, vertigo and unsteadiness and an hematic tympanic membrane in the right ear. The CT scan is normal. Ten days later the child is referred to our department because vomiting was occurring again without vertigo but with a right torticollis. The audio-vestibular testing shows a conductive and sensorineural hearing loss on the right side (with an averaged threshold at 30 dB HL). The stapedius reflex was not evoked on the right side by contralateral auditory stimulation. The evaluation of the vestibular function shows a quasi-areflexia on the right side with the caloric test but a very strong directional preponderance toward the right side at the OVAR test. The latter result was definitely interpreted as an indicator of irritation of the right vestibule organ and a sign of perilymphatic fistulae. Surgical exploration revealed a longitudinal fissure on the footplate of the stapes. A patch was installed on the oval window with aponeurosis and biologic glue. One and a half years after the surgery, the audio-vestibular testing showed a complete restitution of the hearing and the vestibular function. Observation 3: The OVAR Test Can Serve as a Prognosis Tool in Vestibular Neuritis, Helping to Complete the Evaluation of the Initial Vestibular Damage A 14-year-old girl is referred for audio-vestibular testing the fourth day after a sudden intense vertigo with vomiting and ataxia (a slight viral infection was reported 2 weeks earlier). Four days later, there is a typical right vestibular deficit syndrome and a complete areflexia on the right side in the caloric test. But the responses in the OVAR test are intense with a left directional preponderance. At day 10 the otolith VOR to the OVAR test is normal while

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the canal VOR is recovering. One month later the recovery is complete. The absence of an asymmetry to the test OVAR predicted an absence, or minor lesion of the otolith system and not a total complete loss of the right vestibular receptors or nerve.

Acknowledgments This work was supported by grants from : INSERM (No. 910207), CNES (No. 950322), DRC de l’Assistance Publique de Paris (No. 95108, No. 96156), Fondation pour la Recherche Me´dicale, Fondation de France, Fondation Reuter, Fondation Electricite´ et Sante´. Thanks to Franc¸oise Toupet for her technical help in testing young children and to Sidney Wiener for his helpful comments in the text.

References 1 2 3

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Darlot C, Denise P, Droulez J, Cohen B, Berthoz A: Eye movements induced by off vertical axis rotation at small angles of tilt. Exp Brain Res 1988;73:91–105. Darlot C, Toupet M, Denise P: Unilateral vestibular neuritis with otolith signs and off vertical axis rotation. Acta Otolaryngol (Stockh) 1997;117:7–12. Wiener-Vacher SR, Toupet F, Narcy P: Canal and otolith vestibulo-ocular reflexes to vertical and off vertical axis rotation in children learning to walk. Acta Otolaryngol (Stockh) 1996;116:657– 665. Wiener-Vacher SR, Mazda K: Asymmetric otolith vestibulo-ocular responses in children with idiopathic scoliosis. J Pediatr 1998;132:1028–1032. Wiener-Vacher SR, Amanou L, Denise P, Narcy P, Manach Y: Vestibular function in children with CHARGE Association. J Am Otolaryngol Head Neck Surg 1999;125:342–347. Guedry FE: Orientation of the rotation axis relative to gravity: Its influence on nystagmus and the sense of rotation. Acta Otolaryngol (Stockh) 1965;60:30–48. Benson AJ, Bodin MA: Interaction of linear and angular accelerations on vestibular receptors in man. Aerosp Med 1966;37:144–154. Guedry FE: Effects of concommittant styimulation of the semicircular canals and otoliths by ‘barbecue spit’ rotation, rotation about a tilted axis, and other forms of stimulation. Exerpta Med Int Congr Ser Amsterdam 1970, p 206. Cohen B, Suzuki J, Raphan T: Role of the otlith organs in generation of horizontal nystagmus: Effects of selective labyrinthine lesions. Brain Res 1983;276:159–164. Correira MJ, Money KE: The effect of blockage of all six semi-circular canal ducts on nystagmus produced by linear acceleration in the cat. Acta Otolaryngol 1970;69:7–16. Kaga K, Maeda H, Suzuki J: Development of righting reflexes, gross motor functions and balance in infants with labyrinth hypoactivity with or without mental retardation. Adv Otorhinolaryngol 1988;41:152–161. Tsuzuku T, Kaga K: Delayed motor function tests in children with inner ear anomalies. Int J Pediatr Otorhinolaryngol 1992;23:261–268. Abadie V, Wiener-Vacher S, Morisseau-Durand MP, Poree C, Amiel J, Amanou L, Peigne´ C, Lyonnet S, Manach Y: Vestibular anomalies in CHARGE syndrome: Investigations and consequences on postural development. J Eur Pediatr 2000; in press. Pozzo T, Berthoz A, Lefort L: Head stabilization during various locomotor tasks in humans. I. Normal subjects. Exp Brain Res 1990;82:97–106. Pozzo T, Berthoz A, Lefort L, Vitte E: Head stabilization during various locomotor tasks in humans. II. Patients with bilateral peripheral vestibular deficits. Exp Brain Res 1991;85:208–217.

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Ledebt A, Wiener-Vacher S: Head coordination in the sagittal plane in toddlers during walking: Preliminary results. Bull Brain Res 1996;40:371–373. Ledebt A, Bril B, Wiener-Vacher S: Trunk and head stabilization during the first months of independent walking. Neuroreport 1995;13:1737–1740. Assaiante A, Amblard B: Ontogenesis of head stabilization in space during locomotion in children: Influence of visual cues. Exp Brain Res 1993;93:499–515. Wiener-Vacher S, Ledebt A, Bril B: Changes in otolith VOR to off vertical axis rotation in infants learning to walk: Preliminary results of a longitudinal study. Ann NY Acad Sci 1996;781:709–712.

S. Wiener-Vacher, MD, Hoˆpital Robert Debre´, Service ORL, Unite´ d’Explorations Oto-neuro-ophtalmologiques, 48, Bld Se´rurier, F–75019 Paris (France) Tel. +33 1 40 03 2479, Fax +33 1 40 03 2202, E-Mail [email protected]

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Tran Ba Huy P, Toupet M (eds): Otolith Functions and Disorders. Adv Otorhinolaryngol. Basel, Karger, 2001, vol 58, pp 98–109

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VEMP Induced by High Level Clicks A New Test of Saccular Otolith Function Catherine de Waele Service ORL, Hoˆpital Lariboisie`re, et Laboratoire de Neurobiologie des Re´seaux Sensori-moteurs, CNRS-Paris V, Paris, France

Patients suffering from vertigo were most often investigated by caloric and horizontal rotatory tests. These tests are interesting but they appreciate the function of the horizontal canalar ampulla which are only one of the five pairs of vestibular sensors (three pairs of canals, two utricules and the two saccules). The function of the otolithic sensors remains elusive in most of these patients. This is a problem because the clinical syndromes resulting from removal of the otolith inputs are far from being neglectible. Fortunately, several new tests of the otolith functions have been made recently available to clinicians. The oculomotor syndrome induced by otolithic lesion is twofold. The static deficits include a skew deviation and an ocular cyclotorsion oriented towards the lesioned side. They are responsible for the vertical diplopia observed at the acute stage. These deficits can be precisely quantified by fundus photomicrographs, 3-D videonystagmography and by the measurement in darkness of the subjective visual horizontal and vertical. The dynamic deficits result from the changes of the dynamic properties of the maculo-ocular reflexes. They can be assessed by means of the off-axis vertical rotation (OVAR) test and by measuring the linear vestibulo-ocular reflex (LVOR). These tests give important information about the function of the otolith-ocular pathways. However, they have several limitations: first, they cannot differentiate between a utricular or a saccular lesion. Second, due to the vestibular compensation process, they can return to normal or subnormal values with time, which is a problem when patients are tested several months after the initial otolith trauma. Finally, apart from the test of the subjective visual horizontal and vertical, these tests require costly equipment which is not commonly available in ENT departments.

This explains why we have investigated whether routine recordings of the vestibular-evoked myogenic potential (VEMPs) evoked by high level clicks were useful to assess the otolith function in patients suffering from vestibular syndromes. This test, described in 1964 by Bickford et al. [1] and reintroduced later by Colebatch et al. [2] in 1994 presents two major advantages: (1) it selectively probes the function of each sacculus and of the sacculospinal pathways, and (2) it never compensates even after a long time following a peripheral vestibular lesion. Our 2 years’ study leads to the conclusion that VEMPs testing is relatively simple to use and has a triple diagnosis, prognostic and therapeutic interest. However, it should be stressed that, as useful as it is to investigate patients who complain of oscillopsia, movement illusions and ataxia, early VEMPs induced by high level clicks are the most informative when used in combination with some of the other otolithic tests quoted above. We will briefly report here some of the VEMPs data obtained in unilateral vestibular pathologies such as Menie`re’s disease, vestibular neuritis, acoustic neurinomas and bilateral canalar vestibular paresis.

Methods Patients suffering from different pathologies such as Menie`re’s disease, vestibular neuronitis, acoustic neurinoma, head trauma were tested by means of vestibular myogenic potentials test evoked on the ipsilateral sternomastoid muscle (SCM) by high-level clicks. The latency of the early P13/N23 waves and the amplitude of the P13/N23 peak relative to the SCM EMG activity were measured. Clicks Delivery Each ear was stimulated twice in a raw which led to four trials per patient (two trials on the left ear and two trials on the right ear). The test was performed as follows: stimulation of the left ear twice and then stimulation of the right ear twice. For each of the four trials, the EMG responses were averaged over a series of 512 clicks of 0.1 ms rarefactive square waves of 100 dB HL. The acoustic stimuli were delivered by calibrated TDH 39 headphones at a frequency of 6 Hz. EMG Recordings Surface EMG activity was recorded as previously described [3]. Briefly, skin electrodes were placed symmetrically on the upper half of each SCM. The reference surface and the ground electrode were located over the upper sternum and the central forehead, respectively. VEMP recordings were performed with a Nicolet Viking 4 with a 4-channel averaging capacity. The EMG from each side was amplified, bandpass filtered (10 Hz–1.6 kHz) and averaged using a sampling rate of 2.5 kHz for each channel. Patients were laid supine on a bed and were asked to raise their head straight-ahead off the bed to activate their SCM bilaterally and symmetrically. In this position, the EMG activity had a minimal root mean square (RMS) of 80 lV. Simultaneous average EMG of both SCM were collected from 20 ms

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before the clicks to 80 ms afterwards. Odd and even traces were stored and averaged separately. This allowed to compare the two averaged records at the end of each trial, which by definition had to be perfectly coincident to confirm their saccular origin. Data Analysis The mean peak latency (in ms) of the two early (P13 and N23) of the VEMP was measured. The peak to peak amplitude (in lV) was calculated for the P13/N23 waves and reported to SCM EMG activity. the SCM EMG activity (RMS) was measured before the first trial (first left ear stimulation) and after the last trial (last right ear stimulation). Indeed, the P13/N23 peak to peak amplitude has been previously shown to fluctuate with the SCM electromyographic amplitude [4].

Results Normal Subjects VEMP testing is now a well-established test to explore the sacculo-collic pathways in humans. Loud monaural clicks evoke an initial inhibitory potential in tonically contracted ipsilateral SCM. This potential is responsible for the early waves P13/N23 and has been demonstrated to be of saccular origin [2]: guinea pig saccular afferents [5–9] and vestibulo-spinal neurons of the lateral and of the descending vestibular nuclei [10], two nuclei mostly involved in the processing of otolithic inputs, were recently shown to respond to loud clicks. The P13/N3 potentials could be followed by additional late N34, P44 potentials which have been demonstrated to be of cochlear origin [2]. We have studied early VEMPs induced by high level clicks on the ipsi- and contralateral SCM in subjects with normal vestibular and auditory function. Subjects suffering from conductive hearing loss or abnormal acoustic reflexes were excluded since in these cases high-level clicks are unable to induce early VEMP due to the fact that the acoustic stimuli are not of sufficient amplitude to mechanically activate the sacculus [11]. 89% (n>33) of the age-matched controls displayed a short latency response in the SCM ipsilateral to the stimulated ear. Its mean latency was 11.2×1 ms (min. 9.08, max 14.8 ms) for the P13 wave and 19.4×2.4 ms (min. 14.3, max. 19.23 ms) for the N23 potential. The late response was found less frequently (50% of the subjects). When present, the latencies of the ipsilateral N34, P44 waves were 30.5×2.5 ms for N34 (min. 26 max. 38 ms) and 38.3×2.66 ms (min. 34 max. 45.4 ms) for P44. The absence of short latency response in the SCM ipsilateral to the stimulated ear in 11% of the controls was confirmed by testing these subjects on another day. The mean P13/N23 peak to peak amplitude was 67.9×52.6 lV (min. 10, max. 221 lV). It varied greatly from one subject to another and in the same

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Fig. 1. Left-hand side: Vestibular evoked myogenic potentials recorded on the sternomastoid muscles (SCM) in a healthy person. Traces 1 and 3 correspond to the evoked potentials obtained on the left (1) and the right (3) SCM when 100-dB clicks were delivered to the left ear (A). Traces 5 and 7 illustrate the evoked potentials obtained on the left (5) and right (7) SCM muscles when 100-dB clicks were delivered to the right ear (B). The VEMPs recorded on the muscle ipsilateral to the acoustic stimulation are composed of two early P13 and N23 potentials and of additional late N34 and P44 potentials (traces 1 and 7). Note the absence of crossed saccular responses in the SCM contralateral to the acoustic stimulation (traces 3 and 5). Right-hand side: Vestibular evoked myogenic potentials recorded from the sternomastoid muscles (SCM) of patient with right unilateral Menie`re’s disease. Traces 1 and 3 correspond to the evoked potentials obtained on the left and the right SCM when 100-dB clicks were delivered to the left ear (A). Traces 5 and 7 illustrate the evoked potentials obtained on the left and right SCM when 100-dB clicks were delivered to the right ear (B). These loud monaural clicks failed to evoke any early P13-N23 potentials on the right SCM when delivered on the right affected ear. In contrast, normal VEMP were observed in the left SCM muscle when loud clicks were delivered to the left intact ear. (Horizontal calibration: 10 ms/division. Vertical calibration: 20 lV/division.)

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subject between trials. However, it tended to increase, but not significantly, with the repetition of the trials: in the first trial, the mean was 63.6×54.4 lV and in the fourth trial 75.5×95.3 lV (p>0.45). The SCM RMS tends also to increase from 123.8×45.9 to 156.9×62.9 lV while the subject raised his head off the bed. However, this difference was not significant. The crossed response to the click stimulus was not investigated since it was observed in only 2/3 of the subjects. Its great variability suggests that it could not be readily used to explore the patient groups. Patients Suffering from Menie`re’s Disease This first study was designed to assess the saccular function of Menie`re’s subjects. Only the presence or the absence of the early VEMPs in the SCM ipsilateral to the stimulated ear (intact and affected one) and their latencies and amplitudes if present were analyzed for the following reasons: (a) the VEMPs evoked in the SCM muscle contralateral to the stimulated ear were variable in the control group; (b) as previously stated the late VEMPs have been shown to be of cochlear origin [2]. The aim was twofold: first, to detect potential dysfunction of the sacculocollic pathways which could explain the subjective problems of Menie`re’s patients with balance while standing and walking [12, 13]; second, to search for any correlation between the saccular deficit and three other variables: the degree of hearing loss, canal paresis and dynamic postural disorders. The uncrossed saccular response evoked by the stimulation of the affected ear was abolished in 32 of the 59 patients (54%). When present, the mean latency of the P13 potentials evoked by the stimulation of the affected ear in the ipsilateral SCM muscle was 11.3×1.3 ms (min. 8.9, max. 14.5) and that of the N23 potential was 18.8×2.0 ms (min. 14, max. 23.1), respectively. These values were not significantly different from those measured in the group of control subjects (ANOVA). In 27 Menie`re’s patients (46%), the P13 and N23 potentials persisted on the affected side. We therefore investigated whether their amplitudes differ from those of the control group. The mean P13/N23 peak to peak amplitude (left and right uncrossed SCM VEMP amplitude pulled together) in these 27 patients amounted to 63.8×62.6 lV (min. 11, max. 349 lV) which was not significantly different from the value recorded in the control group. Hence, when the P13 and N23 potentials persisted on the affected side of the Menie`re’s patients, their latencies and amplitudes did not differ from those of the similarly aged control group. In conclusion, the initial biphasic P13/N23 evoked potential was absent from the ipsilateral SCM in 54% of the Menie`re’s patients, which means that the endolymphatic hydrops can affect the response of the sacculus to clicks. Whether the otolithic sensors of these patients were also less sensitive to head

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tilt and vertical linear translations remains to be determined. However, this is most probably the case since some Menie`re’s patients have abnormal asymmetry of eye torsion in response to whole body roll towards the normal ear [14] and/or experience sudden falling spells [15]. These drop attacks are most probably triggered by stimulation of the otolithic membrane [16]. Therefore, our results predict that drop attacks of saccular origin should not occur in patients with abolished VEMP since their saccular sensory epithelium should be less or not sensitive to a brisk distention of the otolithic membrane. Relationship between VEMP and Hearing Loss. The low-frequency hearing loss of the affected ear was significantly greater in patients who did not exhibit ipsilateral VEMP than in patients who had intact VEMP (p>0.02). Following the stimulation of the affected ear, the 32 patients without VEMPs had a mean low-frequency hearing loss of 51.1×20 dB whereas the mean value was 39.4×16.5 dB in the 27 patients who had normal VEMP. Of the 49 patients with low-frequency hearing impairment ranging between 0 and 60 dB, the VEMP was intact in 26 (53%) and absent in 23 (47%). It was absent from the affected side in all patients with low-frequency hearing loss of more than 60 dB. In contrast, patients suffering from 4 to 8 kHz superior to 60 B can display normal P13/N23 potentials. In summary, low-frequency (250–1,000 Hz) but not high-frequency (4–8kHz) hearing loss correlated with VEMP loss. Absence of Relationship Between VEMP and Canal Paresis. Canal paresis could only be investigated in 52 of the 59 Menie`re’s patients because caloric testing had to be interrupted in 7 cases due to major neurovegetative signs. In these patients, we failed to find any correlation between saccular dysfunction and canal paresis. In the 30 (57.7%) patients with no VEMP following stimulation of the affected ear, the mean canal paresis was 32.8×32.7%. The mean value was 17.0×24.1% in the 22 patients (42.3%) who had intact VEMP following stimulation of the affected side. The difference was not significantly different (p>0.07). The ipsilateral early VEMP was absent from 48% of the 35 patients displaying a Jonkees index between 0 and 20% and from 76% of the 17 patients displaying greater canal paresis (between 20 and 100%). Some patients with canal paresis equal to or above 60% displayed intact saccular responses. Relationship between VEMP and Equitest Performances. Of the 39 patients undergoing dynamic computerized posturography tests, 22 did not display early VEMP following acoustic stimulation of the affected ear and 17 exhibited normal early VEMP. On the moveable platform, a larger than normal visual dependency was observed in some patients with absent saccular responses. They swayed more in conditions 3, 5 and 6, i.e. when visual references were either absent or stabilized. In accordance with a previous work [17], this difference was only significant for condition 5 (eyes closed) and was not related to the degree of canal paresis unlike other related findings [12]. This discrepancy

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could be due to a sample bias since all our patients were investigated during remission and not during acute phases [12]. It is intriguing that condition 5 was more destabilizing than condition 6 where the visual environment is present although it did not provide information about egomotion. Possibly, light has a nonspecific excitatory effect on these vestibular deficient patients. Conclusion. We have shown that a sizeable proportion of Menie`re’s patients present a saccular dysfunction. There was a clear relationship between the extent of the cochlear damage and the saccular impairment: patients with no VEMP had greater hearing impairment in the low-frequency range than patients with VEMP. Moreover, the sacculus was always dysfunctional when the hearing loss was greater than 60 dB. No such relationship was observed for high-frequency hearing loss and for horizontal canalar paresis as assessed by caloric testing. This result suggests that endolymphatic hydrops may principally affect cells which encode stimulation in the low frequency range. Finally, Menie`re’s patients with saccular impairments tended to become more dependent on vision than patients with intact saccular function to maintain an upright posture. Therefore, testing the VEMP and the dynamic control of posture could be of value for Menie`re’s patients. Indeed, subjects suffering loss of VEMP and with a strong visual dependency may be patients at risk, especially if they are aged. They would be good candidates for vestibular rehabilitation which has been shown to improve postural performance greatly. Patients Suffering from Menie`re’s Disease and Treated by Gentamicin Intratympanic Injections In most clinical studies on chemical labyrinthectomy induced by gentamicin intratympanic injections, investigations were restricted to caloric and/ or rotatory tests to monitor the functional impairment of the horizontal canal. Consequently, the toxicity of gentamicin to otolith sensors remains unknown. Only two studies on subjective visual vertical and horizontal [18, 19] and ocular torsion [18] suggest that otolithic deficits could indeed occur. We further investigated this issue by using VEMP evoked by high-level clicks (100 dB) to monitor saccular function in patients treated by gentamicin intratympanic injections on the hydropic ear. Our aim was twofold: (1) To assess the function of the sacculus and of the sacculo-collic pathways following the gentamicin injections and (2) to test for correlations between the saccular deficits and the degree of canal paresis. The relationship between hearing loss, dynamic postural disorders and early myogenic potentials evoked by high level clicks in these patients will be described in a pending publication. Two different injection protocols were investigated: a shotgun approach for inpatients in which gentamicin was delivered intratympanically over 4

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consecutive days [20] and a titration protocol in outpatients where single intratympanic doses of gentamicin were delivered weekly [21]. The main finding of this study was that early VEMPs were abolished 1 month after the gentamicin injections in 14/14 (100%) of the patients tested both before and after treatment and who had normal responses on both sides before gentamicin therapy. Six of the 14 patients were included in the shotgun protocol and 8 in the titration protocol. The absence of VEMPs on the injected side was confirmed six months and/or 1 year after the gentamicin treatment. Therefore, our results suggest for the first time that gentamicin injections render the sacculus less sensitive to high level clicks. Whether this finding results from a complete or a partial lesion of the sacculus and/or from a lesion of the saccular nerve remains to be determined. Indeed, degenerative changes, which could result from a direct ototoxic effect of gentamicin, have been observed in guinea pig vestibular ganglion cells 4 weeks after gentamicin injections into the middle ear [22]. Preliminary results using short-duration glavanic stimulation and recordings of VEMPs on the sternomastoid muscles in gentamicin-treated patients suggest that the same is likely to occur in humans. Finally, no correlation could be detected between vertigo control (observed in 71% of the patients) and saccular damage. In contrast, only 58% if our patients exhibited unilateral abolition of caloric response 1 month after intratympanic injections. We did not find any correlation between control of vertigo and the abolition of the caloric response. Variable thickness of the round window, mechanical obstructions due to adhesions in the round window niche, the eustachian tube function and also genetic predisposition to ototoxicity [23] could explain this result. The aminoglycosides have been demonstrated to be ototoxic not only in hair cells [24] but also in endolymphsecreting dark cells [24, 25]. Since these cells have been shown to play a key role in the active ion transport involved in endolymph production, it was suggested that gentamicin may control the endolymphatic hydrops. This would explain why the treatment can be effective even when not abolishing caloric responses or producing an acute vestibular deafferentation syndrome. Gentamicin has a biphasic effect: initially, it induces a reversible blockage of transduction channels and of calcium channels causing a competitive displacement of divalent cations (calcium and magnesium). Later, it causes irreversible destruction of hair cells due to their energy-dependent competitive uptake of polyamines, their polyphosphoinobiphosphate binding and interference with intracellular second-messenger systems. It has also been reported that gentamicin can cause mistranslation of mitochondrial complex-1 genes, leading to oxidative damage to mitochondria and cell death [26]. In summary, intratympanic gentamicin injections induced saccular dysfunction in all patients who had normal VEMPs before the treatment. There-

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fore, although it cannot predict the efficacy of gentamicin on vertigo control, VEMP testing is useful to detect its early effects. The saccular dysfunction did not depend on the protocol and was not related to the number of injections and to the degree of gentamicin-induced horizontal canalar paresis. A gentamicin-induced saccular dysfunction was always observed in our patients whereas a unilateral abolition of the horizontal canal function was detected in only 58% of our gentamicin-treated patients. This suggests that the sacculus is more sensitive than the horizontal semicircular ampulla to ototoxic effects of intratympanic gentamicin injections.

Patients Suffering from Vestibular Neuronitis Among the 72 patients tested, 60 were tested during the acute state, i.e. during the first 2 weeks following the initial rotatory vertigo. The aim of our study was to try to determine whether the whole vestibular nerve or only its superior branch was lesioned in this pathology. In 47 patients (65%), early uncrossed VEMPs were detected at a normal latency and amplitude on the SCM ipsilateral and contralateral to the lesioned side. This result supports the conclusion of a previous study. Using the 3-D components of the ocular nystagmus, it was shown that the saccular nerve and most probably the inferior vestibular nerve could be spared in vestibular neuronitis [27]. On the other hand, in 15 of the 72 patients (20.8%), stimulation of the affected ear evoked no P13/N23 responses in the ipsilateral SCM whereas stimulation of the intact ear resulted in a normal ipsilateral P13/N23 response. In 10 patients (13.8%), there was no VEMP in the ipsilateral SCM following stimulation of either the affected or intact ears. Therefore, the uncrossed saccular response evoked by the stimulation of the affected ear was abolished in 25 of the 72 patients (34.7%). When present, the mean latency and amplitude of the P13 and N23 potentials evoked by the stimulation of the affected ear in the ipsilateral SCM muscle were unchanged compared to ones measured in normal subjects. In 10 patients, a bilateral abolition of VEMPs was observed during the acute stage of vestibular deafferentation. Normal VEMPs reappeared on the intact side after 1 month in all of these patients. This indicated that contralesional central vestibular neurons may have changed their sensitivity to high level clicks. Similar data [28] have been reported following caloric tests: the caloric responses decreased on the contralesional side over a period of 1 year following vestibular neurotomy. In accordance with a previous study [10], we observed that none of the patients with absent uncrossed VEMPs on the lesioned side developed benign paroxysmal positioning vertigo (BPPV) in the first 2 years following the beginning of the disease. This indicates that posterior semicircular canal-type BPPV

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could not develop in neuronitis patients which exhibit a lesion of the inferior vestibular nerve. In conclusion, VEMP test has confirmed that in most cases (two thirds of the patients) the viral lesion spared the saccular nerve and most probably the inferior part of the vestibular nerve. However, one third of the patients presented a clear sign of saccular nerve lesion. In addition, the VEMP test has a prognostic value since it can predict whether patients suffering from vestibular neuritis will develop delayed positioning vertigo. Patients Suffering from Other Vestibular Pathologies In patients suffering from an acoustic neurinoma, VEMP test could be normal or abnormal. It depends greatly on the size and extension of the tumor on the inferior and on the superior branch of the vestibular nerve. It could help the diagnosis when associated with other audiometric, vestibular tests and MRI of the cerebellopontine angle. Preoperatively, it is useful to evaluate the importance of the symptoms (skew deviation, ocular cyclotorsion) the patient will suffer at the acute stage due to otolith deafferentation. They are obviously less pronounced when the otolithic sensors are lesioned before the neurectomy, leaving time for the compensation process to occur before the surgery. The VEMP test could also bring important information in patients suffering from delayed vertigo after head trauma. These patients may exhibit normal caloric and rotatory tests if the lesion has spared the horizontal ampulla. They could also exhibit normal visual subjective horizontal or vertical tests if the lesion had occurred several months after vestibular testing because of the vestibular compensation process. The same holds true for the OVAR test. The maculo-ocular reflex may have recovered normal dynamic properties. In these cases, only VEMP testing may indicate whether the head trauma had induced an otolithic lesion. Indeed, once the sacculus is lesioned, the P13/N23 potentials never reappear even after a long delay following the lesion. Finally, some patients suffering from disequilibrium and oscillopsia exhibit bilateral dysfunction of the horizontal semicircular ampulla as assessed by caloric or rotatory testing. The problem is then to determine whether these patients present partial or complete loss of the vestibular function. Indeed, depending on the pathology and the subject, the otolithic function can be preserved or not. In that context, VEMP testing can detect a residual saccular function. This is important on two grounds. From a clinical point of view, it helps to assess the functional status of the vestibular system and it may be useful to guide vestibular rehabilitation. In addition, it is clear that a precise assessment of the vestibular function is required when patients accept to be tested to investigate the role of the vestibular system in gaze and postural control or cognitive tasks. In that regard, it can be questioned whether the

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numerous ‘bilabyrinthectomized patients’ used in the past 20 years in many of these studies were truly deprived of vestibular function or were still endowed with residual otolithic functions.

Conclusion VEMP testing is a reliable, non-nauseogenic and a noninvasive test of human saccular function. (1) It has a diagnostic value in unilateral (Menie`re’s disease, vestibular neuronitis, acoustic neurinoma) and bilateral vestibular pathologies to detect a potential lesion of the sacculus of the sacculo-spinal pathways. (2) It also has a prognostic interest in some pathologies. In vestibular neuronitis it is useful to predict the possible occurrence of positional vertigo at late stages after the initial rotatory vertigo. Before surgery of acoustic neurinoma, it is useful to inform the patient if he will suffer from symptoms such as diplopia and deviation of the visual vertical subjective resulting from the otolith deafferentation of the extraocular motoneurons. (3) Finally, its therapeutic interest is evident in bilateral horizontal vestibular loss to guide the vestibular rehabilitation and in Menie`re’s patients treated by unilateral injections of gentamicin to detect early effects of gentamicin. New tests using the evoked potentials method and stimuli such as short tone bursts or short latency galvanic currents are now currently performed in our department to investigate in greater details the function of the sacculus and of the vestibular nerve.

Acknowledgements The author thanks Franck Zamith, Nelly Bellalimat and The´re`se Dabbadie for their excellent technical assistance and their help in preparing the manuscript. She would like also to thank the Nicolet Biomedical Society and the Biodigital Society for the help in setting up the software.

References 1 2 3

Bickford RG, Jacobson JL, Cody DTR: Nature of average evoked potentials to sound and other stimuli in man. Ann NY Acad Sci 1964:204–223. Colebatch JG, Halmagyi GM, Skuse NF: Myogenic potentials generated by a click-evoked vestibulocollic reflex. J Neurol Neurosurg Psychiatry 1994;57:190–197. de Waele C, Tran Ba Huy P, Diard JP, Freyss G, Vidal PP: Saccular dysfunction in Menie`re’s disease. Am J Otolaryngol 1999;20:223–232.

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Lim CL, Clouston P, Sheean G, Yamikas C: The influence of voluntary EMG activity and click intensity on the vestibular click evoked myogenic potential. Muscle Nerve 1995;18:1210–1213. Didier A, Cazals Y: Acoustic responses recorded from the saccular bundle on the eighth nerve of the guinea pigs. Hear Res 1989;37:123–128. McCue MP, Guinan JJ: Acoustically responsive fibers in the vestibular nerve of the cat. J Neurosci 1994;14:6058–6070. McCue MP, Guinan JJ: Spontaneous activity and frequency selectivity of acoustically responsive vestibular afferents in the cat. J Neurophysiol 1995;74:1563–1572. McCue MP, Guinan JJ: Sound-evoked activity in primary afferent neurons of a mammalian vestibular system. Am J Otol 1997;18:355–360. Murofushi T, Corthoys IS, Gilchrist DP: Responses of guinea pig vestibular neurons to clicks. Exp Brain Res 1995;111:149–152. Murofushi T, Halmagyi MG, Yavor RA, Colebatch JG: Absent vestibular evoked myogenic potentials in vestibular neurolabyrinthitis: An indicator of inferior vestibular nerve involvement? Arch Otolaryngol Head Neck Surg 1996;122:845–848. Halmagyi GM, Colebatch JG, Curthoys IS: New tests of vestibular function. Baillie`res Clin Neurol 1995;3:485–500. Black FO: Vestibular function assessment in patients with Menie`re’s disease: The vestibulo-spinal system. Laryngoscope 1982;92:1419–1436. Van de Heyning PH, Wuyts FL, Claes J, Koekelkoren E, Van Laer C, Valke H: Definition, classification and reporting of Menie`re’s disease and its symptoms. Acta Otolaryngol [suppl] (Stockh) 1997; 526:5–9. Kingma H, Wuyts FL, Boumans L: Clinical testing of the statolith system in patients with Menie`re’s disease. Acta Otolaryngol [suppl] (Stockh) 1997;526:24–26. Tumarkin A: Otolithic catastroph: A new syndrome. BMJ 1936;ii:175–177. Baloh RW, Jacobson K, Winder T: Drop attacks with Menie`re’s disease syndromes. Ann Neurol 1990;28:384–387. Morrison G, Hawken M, Kennard C, Kenyon G: Dynamic platform sway measurement of Menie`re’s disease. J Vestib Res 1994;4:409–419. Robertson DD, Garber LZ, Ireland DJ: Ocular torsion monitoring in chemical labyrinthectomy. J Otolaryngol 1996;25:171–177. Tribukait A, Bergenius J, Brantberg K: Subjective visual horizontal during follow-up after unilateral deafferentation with gentamicin. Acta Otolarungol (Stockh) 1989;118:479–487. Nedzelski JM, Schessel DA, Bryce GE, Pfleiderer AG: Chemical labyrinthectomy: Local application of gentamicin for the treatment of unilateral Menie`re’s disease. Am J Otol 1992;13:18–22. Toth AA, Parnes LS: Intratynpanic therapy for Menie`re’s disease: Preliminary comparison of two regimens. J Otolaryngol 1995;24:340–344. Harada Y, Sera K, Ohya T, Tagashira N, Suzuki M, Takumida M: Effect of gentamicin on vestibular ganglion. Acta Otolaryngol (Stockh) 1991;481:135–138. Chen JM, Williamson PA, Nedzelski JM, Cortopassi GA: Topical gentamicin-induced hearing loss: A mitochondrial ribosomal RNA study of genetic susceptibility. Am J Otol 1996;17:850–852. Pender DJ: Gentamicin tympanoclysis: Effects on the vestibular secretory hair cells. Am J Otol 1985;6:358–367. Bagger-Sjoback D, Bergenius J, Lundberg AM: Inner ear effects of topical gentamicin treatment in patients with Menie`re’s disease. Am J Otol 1990;6:406–410. Hutchin T, Cortopassi G: Proposed molecular and cellular mechanism for aminoglycoside ototoxicity. Antimicrob Agents Chemother 1994;38:2517–2520. Fetter M, Dichgans J: Vestibular neuritis spares the interior division of the vestibular nerve. Brain 1996;119:755–763. Fisch U: The vestibular response following unilateral vestibular neuronectomy. Acta Otolaryngol (Stockh) 1973;76:229–238.

Dr. Catherine de Waele, Service O.R.L., Hoˆpital Lariboisie`re, CNRS Paris, 2, rue Ambroise Pare´ F–75475, Paris ce´dex 10, (France)

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Tran Ba Huy P, Toupet M (eds): Otolith Functions and Disorders. Adv Otorhinolaryngol. Basel, Karger, 2001, vol 58, pp 110–127

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Peripheral Disorders in the Otolith System A Pathophysiological and Clinical Overview Patrice Tran Ba Huy a, Michel Toupet b a b

Hoˆpital Lariboisie`re, et Centre d’Explorations Fonctionnelles Oto-Neurologiques, Paris, France

During recent years, better understanding has emerged of the role of utricle and saccule in stabilizing both the head and vision thanks to advances in fundamental vestibular physiology. Nevertheless, the semiology of otolith disorders remains largely misdiagnosed by ENT clinicians, in part due to the lack of specificity of the tests currently available to them. The aim of this chapter is to provide an overview of current pathophysiological, clinical and therapeutic advances which have been developed in the previous chapters.

Structure and Function The Otolith Organs Two parts of the labyrinth sense inertial forces arising from head movements as well as forces due to gravity. The semicircular canals are primarly concerned with rotational accelerations while the otolith organs, the utricle and the saccule, transduce linear acceleration and are sensitive to static head position. Both of these organs contain a sensory epithelium, the macula, which is composed of three layers [1; see chapter by A. Sans, this vol.]. (i) A cellular layer consists of supporting cells and sensory hair cells of types I and II. At the apical face of each hair cell resides a bundle of hairlike processes containing a few hundred stereocilia graded in height, with the taller ones being closest to a kinocilium. This arrangement defines an axis

of symmetry which, in turn, defines the functional polarization of the cell. Filamentous structures link the tips of adjacent stereocilia. (ii) A gelatinous layer overlies the tip of the hair bundle. (iii) An otolithic membrane contains embedded otoconia. These crystals of calcium carbonate make the mass of the otolithic membrane markedly denser than the surrounding endolymph. Two structural features have important physiological implications: (1) The two maculae have different spatial orientations. Thus, the utricle is oriented in approximately the same plane as the lateral semicircular canal while the saccule is oriented perpendicular to it, in an approximately parasagittal plane. Furthermore, the surfaces of the maculae are curved rather than planar. (2) A central line of demarcation named the striola divides each macula into two parts. In each hemimacula, hair bundles are arranged in opposite senses so that in the utricle, kinocilia are oriented toward the striola while in the saccule, kinocilia are directed away from it. Also of functional importance is the fact that saccular and utricular maculae on the left side are mirror images of those in the right vestibule. Moreover, the axis of symmetry, as defined by the orientation of the kinocilia with respect to the row of stereocilia, varies continuously. The overall result of these principles of anatomical and functional organization is that otolith organs respond to translations and tilts in all directions.

Stimulus and Transduction The otolith organs are sensitive to three types of motion: (i) linear acceleration of the head along the roll, pitch and yaw axes; (ii) static displacement of the head by tilting about these three axes; (iii) the force of gravity, which acts downwards but is equivalent to an acceleration in the upward direction. All of these stimuli are transduced through shearing forces on the hair bundles. When the head translates in space, the inertia of the endolymph creates a force that moves the gelatinous layer in the opposite direction (this encodes linear acceleration). This movement is enhanced by the density of the overlying otolithic membrane (this encodes gravity and static motion, i.e. force due to the tilt of the head relative to the vertical force of gravity). Displacement of the hair bundle towards the kinocilium opens cation-selective transduction channels and depolarizes the hair cell, while movements towards the shortest stereocilia close the channels and lead to hyperpolarization. The ultrastructural features of the otolith organs have several functional implications:

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(1) Their spatial orientation and disposition confers on the utricular and saccular maculae sensitivity for horizontal and vertical displacements, respectively. (2) The surface curvature of each hemimacula as well as the opposing and varying polarization of the hair cells allows that any linear acceleration, regardless of direction, will excite a distinct subset of cells at specific orientations along its axis. (3) Each hemimacula acts in concert with a counterpart located in the contralateral vestibule so that, for example, the right lateral hemimacula works with the left medial hemimacula. (4) The final response corresponds to a push and pull mechanism: some cells on one side are stimulated while symmetrically opposite cells are inhibited, thus amplifying the overall receptor signal. (5) Furthermore, backward or forward head tilts provide the same signal as forward directed linear acceleration or deceleration, respectively [2].

Vestibular Nerve and Central Pathways The utricular and saccular fibers run though the superior and inferior branches of the vestibular nerve, respectively. Once the two branches gather in the cerebellopontine angle, their exact position is not well defined within the VIIIth nerve. Electrophysiological studies show that these fibers normally display a spontaneous firing rate. A given movement induces phasic-tonic or tonic changes in the steady discharge rate. This allows the fibers to encode either linear acceleration or absolute head tilt [3]. The responsivity range of the nerve is such that it may encode a very wide band of accelerations as detailed in the chapter by M. Gresty [this vol]. The fibers then project into the lateral and medial vestibular nuclei located in the inferior part of the brainstem [3]. These vestibular nuclei transmit descending outputs via the lateral and medial vestibulospinal tracts to control neck and leg muscles. Their projections toward the extraocular muscles pass via the medial longitudinal fasciculus. Cortical projections are multiple and dispersed, mainly in parietal and temporal areas [4]. However, other areas have also been demonstrated in humans by electrical stimulation of the vestibular nerve during surgery [5]. These cortical projections are likely to provide information for perception of self-motion and spatial orientation. However, it must be stressed that visual and somatosensory inputs also reach the brainstem vestibular nuclei, so the existence of a primary vestibular cortex exclusively devoted to vestibular function is questionable. The exploitation of functional

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MRI and PET scan techniques will hopefully provide further knowledge in the near future.

Reflexes and Function Stimulation of the otoliths triggers reflexes which normally stabilize posture and gaze during static tilt or dynamic translations of the head. Similar to canal reflexes, there are two types of otolith reflexes. Maculo-Spinal Reflexes Otoliths contribute to maintenance of postural balance though vestibulospinal reflexes. Several experiments suggest that this is based on a threeneuron reflex arc. This accounts for the rapid muscular responses which are necessary to counteract perturbations of body equilibrium [6]. Moreover, Brandt [7] has shown that otolith stimulation triggers different patterns of antigravity muscle activation, depending on the current posture. His observations of surprisingly short latencies in a case of Tullio phenomenon are likely to correspond to a required capacity for humans. In day-to-day experience, these reflexes are evidenced by the compensatory movements displayed by standing passengers when their train starts or stops suddenly. From a clinical standpoint, these otolith responses are tested by the clickevoked potentials in sterno-cleido-mastoid muscles [see chapter by C. de Waele, this vol]. Maculo-Ocular Reflexes These reflexes take into account both dynamic translational and static (gravitational) forces and act to stabilize gaze during any movement of the head by inducing compensatory movements of the eyes [8]. Four types of movements can be identified: Translational (T ) or linear (L) reflexes are triggered when the head, or more precisely, the orbits translate. The resulting rotation of the globe is inversely proportional to the distance of gaze fixation: the nearer the target, the greater the rotation. The gain is low in darkness. If the target is located lateral from the midline, a disconjugate movement of the eyes must take place. This T- or L-VOR occurs at short latencies (15–60 ms). Rotational otolith VOR occurs when the head rotates along an axis tilted with respect to the earth-vertical (off-vertical axis rotation). In this paradigm, the otoliths are stimulated continuously by the cyclic changes in the relative orientation of gravity vector associated with the rotation of the head [see chapter by S. Wiener-Vacher, this vol.]. The resulting nystagmus is sustained

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and polymorphic. It persists after the disappearance of the horizontal nystagmus induced by the canal response to the initial rotatory acceleration. Modulation of spontaneous and induced nystagmus can be induced by otolith stimulation. Changes in static otolith inputs influence the direction and duration of caloric, rotatory and postrotatory nystagmus. Tilt of the head may also modify spontaneous nystagmus so that a downbeat nystagmus may be converted to an upbeat nystagmus. Ocular counterrolling occurs when the head is tilted laterally, that is, in the frontal plane (about the roll axis). In this situation, the globes counterroll to reorient the horizontal meridians of the retinae toward the earth horizontal plane. These compensatory movements are of utricular origin and result from a contraction of the superior and inferior oblique muscles. Thus an inclination of the head to the right stimulates the left superior and right inferior oblique muscles. The gain of this reflex is low (0.1). Similarly, when the head is tilted forward or backward, that is in the sagittal plane (about the pitch axis), the eyes rotate in the opposite direction (‘baby doll eyes’). Other functions are also attributed to the otolith system such as hemodynamic and respiratory adaptation to postural changes, determining visual subjective vertical, mental representations of the body, detection of changes in spatial orientation, evaluation of displacements, etc.

Pathophysiology Dysfunctions of the otoliths alter the transduction of linear acceleration forces, including gravity. As a result, the physical forces which act permanently on any moving individual are no longer adequately sensed. The otoliths then provide erroneous information for the control of posture and eye-head coordination as well as sensation of upright posture, self-motion, and awareness of the body. This may lead the patient to describe strange feelings of disorientation, detachment or instability even causing psychological disturbances such as anxiety and panic. Various etiologies can be put forward such as infection, trauma, degenerative disorders, etc. However, some intrinsic factors may account for the development of an otolith disorder. Intrinsic Predisposing Factors While the particular organization of the hair cells facing each other in each hemi-macula amplifies the signal by a push-pull mechanism, it also renders the system fragile. By way of comparison, in the cristae, all of the hair cells are organized with their kinocilia pointing in the same direction: utriculopetal in the lateral canal, utriculofugal in the anterior and posterior

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canals. Thus, the entire population of sensory cells is depolarized when the cupula moves in the appropriate direction. On the contrary, hair cells in the saccular and utricular maculae are polarized in many directions permitting them to signal tilt or linear acceleration in all directions. However, for any given direction of the linear force only a small fraction of the cells are appropriately aligned and optimally stimulated. In other terms, otolith transduction from normal stimuli relies on only a limited number of cells. Moreover, the push-pull mechanism induces pairs of opposite signals making the coding more complex than in the canals. Within the maculae, the anatomical distribution of type I hair cells (more central) and type II hair cells (more peripheral) recalls the organization of cones and rods in the retina [see chapter by A. Sans, this vol.]. This may explain why localized and patchy lesions of the receptor surface will not necessarily affect overall otolith function but rather cause only minor and discrete symptoms requiring highly sophisticated investigative approaches to identify them. Other complications arise from the fact that the position of the macular fibers within the vestibular nerve is not well defined. Thus, identification of these fibers during vestibular neurotomy is uncertain – this may account for the persistence of symptoms of dizziness in some patients since a complete section is often difficult to ascertain. Vestibular nuclei receiving otolith inputs are situated low in the brainstem. This explains the lateropulsions observed in caudal lesions such as Wallenberg’s syndrome. Interacting Factors The otolith system interacts with several sensory and motor systems. This explains why the clinical features of otolith disorders frequently overlap with various manifestations of other origins. Thus pure otolith syndromes are rare. As will be seen below, semiology should be interpreted in light of several factors: (1) Similar or complementary information is also provided by other sensorimotor inputs, especially proprioceptive inputs. It is well known that sensitive information coming from the back and lower trunk are of primary importance in sensing displacement in seated patients. This observation is exploited in physical therapy for rehabilitation. (2) Canal and otolith organs are often stimulated simultaneously – this is because purely linear or angular accelerations of the head are extremely rare. (3) Further ambiguity derives from the organizational principle of mirror symmetry between the maculae of both sides. Hence, a unilateral impairment is compensated by the contralateral macula which still possesses a population of sensory cells capable of signaling stimulation in all directions.

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These interacting factors account for the fact that otolithic symptoms are often difficult to identify and become apparent when visual or proprioceptive functions are defective.

Symptoms Dysfunction of the otolith system results in three types of symptoms: visual, postural and perceptual. Other signs related to neurovegetative and autonomic functions are also suggestive of otolith disorders [2, 9]. All these symptoms share the following features: (i) they are triggered by linear or static displacements; (ii) they become evident when visual and proprioceptive pathways are also disturbed; (iii) they vary greatly in intensity and frequency among patients. Visual Symptoms Accurate and precise VORs are necessary to maintain stable images on the retina. Vergence, calculation of viewing distance and disconjugate eye movements are required for this system to be efficient. In other terms, it may be said that the otolith system acts as the autofocus of a camera. Accordingly, otolith dysfunction will lead to complaints of poor vision experienced while the patient is moving, such as trouble focussing, difficulty with reading, altered depth perception, etc. Among the major symptoms are oscillopsia, vertical and oblique diplopia, and altered perception of verticality. The latter is manifested by difficulty in correctly aligning objects on a wall, especially when viewed from nearby, i.e. when visual orienting references in the environment are out of view. Perceptual Symptoms As described above, otolith dysfunction may lead to erroneous perceptions of the relation between environment and self as well as the patient’s perception of his body. This leads to seemingly strange complaints such as abnormal sensations of levitation, translation or tilt. The patient may report inappropriate sensations of moving up and down, the illusion of standing on the deck of a moving ship or walking on soft or inclined ground, the sensation of falling, lateropulsions, etc. Illusory self-motion, erroneous internal representations, permanent and severe disorientation, feelings of dissociation and hallucinations are also frequently reported by patients. Facing such symptoms, the clinician should first investigate the possibility of otolith pathology before invoking functional or psychiatric disorders.

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Postural Symptoms The loss or impairment of otolith function produces a decrease in resting activity of the graviceptive pathways. This precipitates an imbalance in tonus which compensating oculomotor and postural reactions act to minimize. Perhaps the most spectacular postural example of this is illustrated by the ocular tilt reaction (OTR) described by Brandt [this vol.]. In the case of a peripheral deficit, this consists of ipsilateral head tilt, skew deviation (vertical divergence of the eyes) and ocular torsion. Body lateropulsion may also be associated. Other Symptoms Otolith organs partly control some autonomic functions such as blood pressure, volume distribution, and cardiorespiratory parameters [see chapter by M. Gresty, this vol.]. In orthostatic hypotension, encoding by the otolith organs of the movement of the patient standing up is dissociated from adequate control of blood pressure by baroreceptors, giving rise to a pseudo-vertiginous feeling. In mal de de´barquement (post-seasickness), nausea and vomiting, bradycardia, and hypotension could be due to excessive stimulation of the utricular and saccular maculae by prolonged linear stimulation due to the rocking motion of the ship. In motion sickness, changes in blood pressure could be secondary to abnormal stimulation of the otolith system. The motorcyclist has learned to tilt his head forward during accelerations: this orients the otolith organs in the direction of the vector sum between the horizontal linear acceleration and the upward gravity vector [see Gresty, this vol.]. However, the passenger who does not anticipate the acceleration and permits his head to tilt backwards will complain of a brief sensation of nausea and lipothymia.

Peripheral Otolith Syndromes The few proven otolith syndromes are described in detail by Brandt [this vol.] and his textbook [7]. In the following sections, we will review their main clinical features and add some personal comments in light of our daily clinical experience. Post-Benign Paroxysmal Positioning Vertigo Syndrome Benign paroxysmal positioning vertigo (BPPV) is the most frequent cause of peripheral vertigo in France [10]. Its semiology is characterized by brief attacks of rotatory vertigo and concomitant nystagmus. It is elicited when the patient is in a given attack-precipitating position. Its pathogeny – cupulo- or

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most probably canalo-lithiasis principally of the posterior semicircular canal – are well known [7, 11]. However, it must be stressed that BPPV is not an otolithic syndrome but rather a neo-otolithic one since the cupula and/or the canal are the structures affected by the otoconial debris and these are not otolith organs per se. Actually, the otolith component of the syndrome may sometimes become evident after the acute phase has subsided spontaneously, or following physical therapy including positional exercises or maneuvers disengaging the debris. At this point it is not uncommon to see patients complaining of symptoms suggestive of an otolith disorder such as unsteadiness, visual blurriness when walking, etc. These symptoms are likely to arise from abnormal utricular function on the side of the BPPV – this would be due to the decrease in density of the otolith membrane from the dislodged otoconia. The Tumarkin Crisis The vestibular symptoms which characterize a typical attack of Menie`re’s disease are highly suggestive of involvement of all three semicircular canals. An otolithic component is seen only in the ‘vestibular drop attack’ described by Tumarkin [12] in 1936. Without any prodrome, the patient feels abruptly forced to the ground and falls. The attack is so sudden that the patient has no time to interrupt his current activity, stop his car, to sit or to lie down. Severe head trauma and bony fractures of the nose are not uncommon. In our experience, this ‘otolithic catastrophe’ occurs only at a late stage of the disease. The lack of warning symptoms and fear of further unpredictable accidents leads patients to seek radical treatment. As preventive pharmacological treatment is ineffective, we have tried using trans-tympanic instillation of gentamicin in such cases. While this consistently suppressed myogenic evoked potentials, suggesting successful abolition of saccular function, we found that some patients were still incapacitated by recurring crises. Therefore, surgery would seem to be the only reliable modality of treatment. Post-Traumatic Vertigo Patients may complain of a very wide range of symptoms having only one factor in common, a head trauma in their recent past. The reported signs can include disorientation, illusions of motion, gait ataxia, sensations of falling, blurring of vision, etc. – these are often imprecise and variable so that a specific clinical picture cannot be described. A perilymph fistula is frequently evoked. However, when results are all normal from neuro-otological examination, current vestibular tests and complete radiological evaluation, the organic nature of the disease is frequently questioned. Thanks to the development of new objective tests capable of

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revealing alterations of the subjective visual vertical or disappearance of evoked myogenic potentials on one side, it is now possible to unequivocally demonstrate the origin in the otolith system. Considering the major forensic and financial implications, otolith testing (discussed below) should be included in the routine examination of any posttraumatic vertigo. Otolith and Perilymph Fistula (PLF ) Leak of perilymph through the oval or round windows, or promontory dehiscence may be congenital or acquired. It induces vestibular symptoms by inadequate transfer of pressure changes to macular receptors. As emphasized by Brandt, head movements are much better tolerated than linear accelerations. In our experience, PLF is not uncommon after head or barotrauma, violent implosive or explosive forces from the middle to the inner ear or from the CSF to the middle ear, respectively, or erosion by cholesteatoma [13]. In these circumstances, diagnosis is usually made on the basis of clinical and radiological arguments. Surgery confirms the fistula, and various techniques of successful repair have been described [14]. On the contrary, spontaneous PLF seems rare if not exceptional and should be seriously questioned when considering: (i) the marked discrepancies among authors, some reporting impressive numbers of surgical cases while others (like us) still desperately trying to find even a single case; (ii) the lack of universally accepted tests for diagnosing PLF; (iii) the highly debatable (and surprising to us) criteria advocated by some authors who do not require the presence of a fluid leak at the time of exploratory tympanotomy for establishing a diagnosis of PLF; (iv) the positive results reported after prophylactic grafting, even in the absence of well-defined and well-localized fistula. Therefore, preoperative criteria should be extremely strict including: (i) association of cochleo-vestibular symptoms, i.e. brief and transient episodes of ataxia, fluctuating aural fullness, tinnitus and sensorineural hearing loss; (ii) symptom-provoking circumstances should include situations where intracranial pressure is increased, such as strenuous activities and rising from a sitting position; (iii) the various pressure or vascular tests should give unequivocally positive results. If these criteria are fulfilled and conservative treatment has failed, this could justify exploratory tympanotomy. But the diagnosis of PLF should not be accepted until a perilymph leak is clearly evidenced. Postoperative OTR Syndrome An ipsiversive OTR syndrome may be observed after a peripheral vestibular lesion [7]. The most frequent circumstances are a vestibular neurotomy or after removal of an acoustic neuroma (provided that vestibular function was

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Fig. 1. Postoperative OTR syndrome in a right vestibular neurotomy patient who had complained of diplopia upon awakening from anesthesia. The bedside examination was performed at 7 p.m. On the left, the patient first looks at the blue cross with his right eye. When opening the left eye, he draws the cross above and to the left of the first drawing. On the right, the patient looks at the blue cross with his left eye. When opening the right eye, he draws the cross above and to the right. The next morning these symptoms had disappeared.

still present prior to surgery). The sudden imbalance of tone of the VOR due to reduced utricular inputs yields an oculo-cephalic response toward the affected ear. This consists of head tilts, skew deviation with ipsilateral eye undermost, and cyclotorsion (fig. 1). This syndrome is short-lasting and usually subsides within a few hours. The Otolith Tullio Phenomenon This rare condition was precisely identified and described by Dieterich et al. [9] in 1992. It is manifested by attacks of oscillopsia and postural imbalance which are elicited by loud sounds applied to the affected ear [see chapter by T. Brandt, this vol.]. The detailed ocular and postural movements observed in this tonic paroxysmal OTR syndrome include contralateral head tilt, skew deviation with ipsilateral hypertropia greater than the contralateral hypertropia (both eyes are upward deviated), ocular torsion (the incyclotropia of the ipsilateral eye is more pronounced than the exocyclotropia of the con-

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tralateral eye), and increased body sway. In contrast with the postoperative OTR syndrome described above, the ocular and head postural deviations are due to pathological stimulation of the utricle. Various etiologies have been reported, all of which include either a perilymph fistula or a contiguity between the ossicular chain and the membranous labyrinth so that loud acoustic stimulation is directly transmitted to the otolith structures. In our experience, the most frequent circumstance is encountered after stapedectomy, especially when a graft interposition has been placed over the oval window. Indeed, some successfully operated patients complain of brief gait disturbances or lateropulsion, and tilt of the visual scene when exposed to traffic or industrial noise, music at concerts or headphones. In two recent cases observed in our institution, the mechanism was likely the development of a postinflammatory fibrosis within the vestibule. In the early postoperative period, both patients developed an acute labyrinthitis with sensorineural hearing loss and vertigo. Once the acute episode subsided, the patients recovered their hearing and balance, but developed tonic OTR. The first patient, a professional clarinet player, complained of otolith symptoms each time he played his instrument, once falling on the shoulder of his colleague while playing a Bruckner symphony. Steroids and topical vasoconstrictors were given and alleviated the symptoms in a few days (fig. 2). The second patient presented the same types of signs while listening to headphones. Although in this case the treatment with medications failed, insertion of a ventilating tube relieved the symptoms. Other possible surgical techniques include section of the stapedial muscle or removal of the piston. Presbyvestibulopathy and Ototoxicity Numerous experimental and histopathological studies have shown bilateral and progressive otolith lesions secondary to aging or after aminoglycoside intoxication [15]. Loss of hair cells and primary neurons as well as degeneration of the otoconia are well-documented features which can easily account for the symptoms so frequently reported in elderly patients, i.e. unsteadiness, gait disturbance, and oscillopsia. However, tests of otolith function may reveal normal responses.

Evaluation of a Patient with a Possible Otolith Disorder Any patient presenting signs of an otolith disorder should undergo complete neuro-otological evaluation. However, the clinician must keep in mind that the typical signs of vestibular disease, such as spontaneous nystagmus,

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Fig. 2. Otolith Tullio phenomenon in a patient operated for right stapedectomy 3 weeks earlier. The CT scan shows a granuloma filling the oval window niche.

or abnormal caloric or rotatory responses are likely to be absent. A major achievement in recent years has been the development of tests investigating otolith function. It must be stressed, however, that the specificity of these tests is weakened by the multisensory contributions to sensing linear acceleration from the translations and the force of gravity [16]. Moreover, a single otolith organ is able to signal adequately motion in all directions due to the bidirectional polarization of hair cells (see above). In other terms, unilateral dysfunction is compensated by the mirror symmetry of the otolith organs. With these caveats, the following procedures may be used by clinicians to demonstrate impairment or loss of otolith function. Ocular Counter-Rolling This ocular reaction represents the unique manifestation of utricular function that can be directly observed in healthy subjects following stimulation. As noted above, this is evidenced by a compensatory movement which orients the horizontal meridian of the retinae toward the perpendicular to the vertical. In this test, the head of the patient is tilted laterally (in the frontal plane) toward the right then left shoulders by about 30º. In the normal subject, the eyes rotate about the roll axis in the direction opposite the applied tilt with

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no delay. However, this ocular movement, called ‘counter-rolling’ (‘contrerotation’ or ‘Gegenrolung’) is rarely very informative since it is relatively insensitive. The problem is that a head inclination of 90º yields an eye rotation of only 6º (the equivalent of the movement of the minute hand of a clock after only 1 min!) Instrumental measurements of torsional nystagmus by videonystagmography will undoubtedly provide greater sensitivity for this simple test. The Subjective Visual Vertical Test Because otolith organs play a major role in sensing verticality and upright posture, this test is a sensitive and very easily administered tool for assessing otolith function [17; see also chapter by C. Van Nechel, this vol.]. The patient is placed in complete darkness and asked to orient a fluorescent bar vertically or horizontally. In the immediate postoperative period of vestibular neurotomy or acoustic neuroma surgery, these estimates may be deviated by up to 15º towards the operated side, being more pronounced if only the ipsilateral eye is used. Longterm follow-up of these patients shows that the pathological deviation may last for months after surgery. Ongoing debates concern the correlation between the degree of ocular torsion and the perceptual deviation. Although not exclusively specific for otolith dysfunction, the simplicity and cost-effectiveness of this test render it quite useful. Evoked Myogenic Potentials Recording vestibular evoked myogenic potentials (VEMPs) evoked in the sterno-cleido-mastoid muscles (SCMs) by loud clicks is a reliable and noninvasive test of saccular function in humans [6, 18; see also chapter by C. de Waele, this vol.]. The subject lies supine on a bed and is asked to lift only his head up in order to activate the SCMs bilaterally and symmetrically. The clicks consist of 0.1 ms rarefactive square waves of 100 dB HL delivered by calibrated TDH 39 headphones. They are delivered at a frequency of 6 Hz and their amplitude is 145 dB SPL. Surface EMG activity is recorded by means of skin electrodes placed symmetrically on the upper half of each SCM and amplified, bandpass filtered (8–1,600 Hz) and averaged using a sampling rate of 2.5 kHz for each channel. The mean peak latency of the two early potentials and of the late evoked potential of the VEMP is measured. The response consists of an initial positive potential at 10 ms, and negative potentials at 20 and 30 ms. The main advantage of this test is that it permits each saccule to be investigated independently and objectively.

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Other Tests Other tests permit testing of otolith function, but their high levels of sophistication render them more difficult to administer. Off-Vertical Axis Rotation (OVAR). In this test, the patient is seated on a rotatable chair and eye movements are measured by electro-oculography. After an initial acceleration to a constant velocity (60 deg/s), the rotating chair is tilted by 13º with respect to gravity. Sessions are conducted with clockwise and counter-clockwise rotations to permit functional investigation of the right and left otolith systems, respectively. This test takes advantage of the fact that the semicircular canal responses rapidly habituate to the constant velocity rotation. Thus, any resulting ocular nystagmus is strictly due to otolith system activation [19; see also chapter by S. Wiener-Vacher, this vol.]. This test can detect dysfunctions of the otolith system as well as functional asymmetries between the left and right sides. The Eccentric Rotating Chair or the Carousel Test. In this test the patient is seated on a chair mounted 1 m from the axis of rotation. The patient is rotated in darkness clockwise and counterclockwise, facing forward in either case. He is requested to align either vertically or horizontally a luminous bar located 60 cm in front of him. The combination of the forces of the applied angular and horizontal acceleration as well as gravity preferentially stimulates the more eccentrically positioned utricle. This perturbs the perception of horizontal and vertical such that responses can deviate by as much as 20º relative to the true orientation. This angle is the resultant of the axis of horizontal centripetal acceleration and that of gravity. The response angle varies as a function of the velocity of rotation. In cases of unilateral lesions, ¨ dkvist, asymmetric responses are observed [20; see also chapter by L. O this vol.]. While this test is more sensitive than ocular counter-rotation, the apparatus is more costly. The Tilt Suppression Test. This test takes advantage of the propensity for otolith stimulation to modulate secondary instrumental nystagmus [8, 21]. In this test, the patient is seated in a chair without being attached, rotated for ten turns (at a velocity of 120º/s). After coming to an abrupt stop, the slow phase velocity is measured for 5 s with the eyes open, then again after tilting the head forward. In normal subjects, or in cases of functional impairments of individual semicircular canals, the nystagmus is dramatically reduced after the tilt. However, if the cerebellar nodulus or otolith organs are affected, the nystagmus remains after the forward tilt (fig. 3).

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a

b

c Fig. 3. Post-rotatory nystagmus (10 rotations in 60 s). The head is tilted forward (a). This induces a marked reduction of the nystagmus (b). Such a decline is not observed in cases of lesion of cerebellar flocullus or in cases of otolith disorder (here a post-BPPV syndrome) (c).

Treatment Peripheral problems in the otolith system will normally disappear rapidly. Within a few weeks central compensatory mechanisms alleviate the vestibular deficit and most patients require no particular treatment. However, it must be noted that the pharmaceutical treatments currently prescribed for acute and complete peripheral vestibular damage (both canalar and macular) assist or accelerate the typically spontaneous recovery.

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Further treatment only becomes necessary in cases where symptoms persist beyond 1 or 2 months. This consists primarily of rehabilitative therapy where the patient is trained to use the remaining otolith function maximally and to depend more on visual and proprioceptive informations. For example, typical exercises can include: (a) The patient jumps on a trampoline with eyes first open, then closed. (b) The subject walks in place on an inflated mattress or a mobile platform, eyes open, then closed. (c) The latter exercises are repeated while tilting the angle of the head (hence varying the direction of the gravity vector). (d) The subject performs calisthenics, first on two legs, then on one. This is done facing a mirror marked with vertical and horizontal bars to provide visual reference cues. (e) Rapid translations are applied to a mobile platform on which the subject is standing. The aim here is to make the patient lose equilibrium, and thus learn new postural reflexes. (f ) The patient reads from a stationary text which is then moved slowly. This helps develop slow visual pursuit. This is then repeated rapidly, then with random movements in order to develop visually guided saccades. The same exercise is also repeated while the subject makes horizontal, then linear head movements. (g) The patient is subjected to optokinetic stimulation in the frontal or sagittal planes at increasing velocities. This obliges him to break free of his dependence on visual input and to emphasize the importance of the (remaining) otolith information. The vestibular exercises must exclude any type of rotatory stimulation of the canals. It is recommended to also include orthoptic therapy with, for example, the use of ocular prisms correcting for vertical divergence. Psychological counselling is also advised in order to reduce the strain and suffering that accompanies equilibrium disorders. These diverse exercises requiring the use of the otolith will reinstate the appropriate circuits in the brain and bring about motor learning which the patient will be able to apply on a daily basis. Should the patient show no improvement, and if the otolith damage is unilateral, a chemical labyrinthectomy may be performed by trans-tympanic instillation of aminoglycosides. The outcome can then be measured by myogenic evoked potentials. If this is ineffective, and, moreover, the symptoms are truly incapacitating, vestibular neurotomy via retro-sigmoid or middle fossa approaches would then become necessary. The efficacy of this is unquestionable, but it is rarely indicated.

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References 1 2 3 3a 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Lindeman HH: Anatomy of the otolith organs. Adv Oto-Rhino-Laryngol 1973;20:405–433. Gresty MA, Bronstein AM, Brandt T, Dieterich M: Neurology of otolith function: Peripheral and central disorders. Brain 1992;115:647–673. Baloh RRW, Honrubia V: Clinical Neurophysiology of the Vestibular System, ed 2. Philadelphia, Davis, 1990. Gacek RR: The course and central termination of first order neurons supplying vestibular endorgans in the cat. Acta Otolaryngol (Stockh) 1969;254:1–66. Lobel E, Kleine JF, Bihan DL, Leroy-Willig A, Berthoz A: Functional MRI of galvanic vestibular stimulation. J Neurophysiol 1998;80:2699–2709. Vidal P-P, de Waele C, Baudonnie`re PM, Lepecq JC, Tran Ba Huy P: Vestibular projections in the human cortex. Ann NY Acad Sci 1999;871:455–457. Colebatch JG, Halmagyi GM, Skuse NF: Myogenic potentials generated by a click-evoked vestibulocollic reflex. J Neurol Neurosurg Psychiatry 1994;57:190–197. Brandt T: Vertigo: Its Multisensory Syndromes, ed 2. London, Springer, 1999, 503 pp. Zee DS, Hain TC: Clinical implications of otolith-ocular reflexes. Am J Otol 1992;13:152–157. Dieterich M, Brandt T, Fries W: Otolith function in man. Brain 1989;112:1377–1392. Toupet M: Evolution a` long terme de 168 vertiges paroxystiques positionnels be´nins traite´s par la maneuvre; in: Vertige 93. Paris, Arnette & Duphar-Solvay, 1994, pp 55–90. Schuknecht HF: Pathology of the Ear. Cambridge, Harvard University Press, 1974. Tumarkin A: The otolithic catastrophe: A new syndrome. Br Med J 1936;175–177. Tran Ba Huy P: Physiopathology of peripheral non-Menie`re’s vestibular disorders. Acta Otolaryngol (Stockh) 1994;(suppl 513):5–10. Guyot JP (ed): Perilymphatic Fistula: A Controversial Issue. Otorhinolaryngol Nova 1998;8:169–212. Anniko M: The aging vestibular hair cell. Am J Otolaryngol 1983;4:151–160. Gresty MA, Bronstein AM: Testing otolith function. Br J Audiol 1992;26:125–136. Bo¨hmer A, Rickenmann J: The subjective visual vertical as a clinical parameter of vestibular function in peripheral vestibular disease. J Vestib Res 1995;5:35–45. de Waele C, Tran Ba Huy P, Diard JP, Freyss G, Vidal P-P: Saccular dysfunction in Menie`re’s disease. Am J Otol 1999;20:223–232. Wiener-Vacher SR, Toupet F, Narcy P: Canal and otolith vestibulo-ocular reflexes to vertical and off vertical axis rotation in children learning to walk. Acta Otolaryngol (Stockh) 1996;116:657–665. Odkvist LM, Gripmark MA, Larsby B, Ledin T: The subjective horizontal in eccentric rotation influenced by peripheral vestibular lesion. Acta Otolaryngol 1996;116(2):181–184. Van Der Stapen A, Wuyts FL, Van de Heyning P: Influence of head position in the vestibuloocular reflex during rotational testing. Acta Otolaryngol (Stockh) 1999;119:892–894.

Prof. Patrice Tran Ba Huy, Hoˆpital Lariboisie`re, Service d’Oto-Rhino-Laryngologie, 2, rue Ambroise-Pare´, F–75475 Paris (France) Tel. +33 1 49 95 80 57, Fax +33 1 49 95 80 63

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Subject Index

Acoustic neuroma, vestibular-evoked myogenic potential 106, 107 Autonomic function, otolithic control 26–28, 117 Benign paroxysmal positioning vertigo clinical presentation 38, 117, 118 diagnosis 39 etiology 38, 39 horizontal canalolithiasis 39 physical therapy 39 subjective visual vertical 78 Blood pressure, otolithic control 26, 28, 29, 117 Calbindin, expression in utricle 6 Calcitonin gene-related peptide, expression in utricle efferent system 8 Calretinin, expression in utricle 6, 8, 11 Cerebral cortex areas involved in vestibular processing during galvanic stimulation 56, 57 vestibulular fields 54–56 Cranio-facial asymmetry anatomic findings anteroposterior asymmetry 60, 61 asymmetries of orientation 61 asymmetry in torsion 61 lateral asymmetry 61 vertical asymmetry 61 magnetic resonance imaging 60 ocular torsion examination 62–64

overview of symptoms and otolith dysfunction 58, 59 spinal column and posture tests 64, 65 videonystagmography 65 visual acuity findings 62 Eccentric rotatory testing clockwise direction testing 70 equipment 70, 71 head tilt 69, 70 protocol 71–73, 124 Electromyography, see Vestibular-evoked myogenic potential Endolymph, specific weight 68 Eye movement reflexes, see also Eccentric rotatory testing, Off-vertical axis rotation test, Subjective visual vertical counter-rolling 22, 24, 69, 114, 122, 123 cyclo-torsion and visual vertical in unilateral otolithic lesions 24 linear movement in horizontal and vertical planes lesion effects 20–22 rapidity of response 20 linear reflexes 113 oscillopsia 24, 25 rotational reflexes 113, 114 subjective visual horizon test no rotation test 73 tilting chair 73 translational reflexes 113

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Galvanic vestibular stimulation cortical areas involved in vestibular processing 56, 57 imaging 57 overview 56 Gentamicin Me´nie`re disease treatment and vestibular-evoked myogenic potentials 104, 105, 108 ototoxicity mechanisms 121 vestibular drop attack induction 37 Hair cells functional polarization 111, 114, 115 function in otolith unit 17, 110, 111 predisposing factors in otolith dysfunction 114, 115 saccule 4–6, 12 stimuli 111 utricle 4–6, 8, 11, 12 Head direction cell system 57, 58 LED bias bar test clockwise direction testing 70 equipment 70, 71 head tilt 69, 70 protocol 71–73 subjective visual horizon test no rotation test 73 tilting chair 73 Linear motion simulator 18, 19 thresholds 18 Maculo-ocular reflexes, see Eye movement reflexes Maculo-spinal reflexes, otoliths 113 Malaise, pathophysiology with vestibular disorders 26–28 Mal de de´barquement, otolith role 117 Me´nie`re disease eccentric rotatory test 74 vestibular-evoked myogenic potential canal paresis 103 equitest performance relationships 103 gentamicin-treated patients 104, 105, 108

Subject Index

hearing loss relationship 102, 103 saccular function 74, 101–103 visual dependence of patients 103, 104 Motion sickness otolith role 117 prevention in ambulance transport 28–30 Neurokinin A, expression in utricle afferent system 11 Ocular counter-rolling, testing 22, 24, 69, 114, 122, 123 Off-vertical axis rotation test interpretation of responses 90 perilymphatic fistula, abnormal irritation of otolith receptors 95 principle and methodology 88, 89, 124 vestibular damage diagnostics acute phase of damage 93, 94 chronic phase of damage 94 unstable developing lesions 95 vestibular neuritis prognostic testing 95, 96 vestibular system role in posturo-motor development of children 90–93 vestibulo-ocular responses 88–90, 92, 95, 96 Orthostatic hypotension, otolith role 117 Oscillopsia 24, 25, 116, 107 Otoconia density 68 function 111 Otoconial membrane function 1, 111 scanning electron microscopy of ultrastructure 2, 3 Otolithic calnolithiasis, see Benign paroxysmal positioning vertigo Parvalbumin, expression in utricle 6, 11 Perilymph fistula clinical presentation 41, 42 diagnosis 119 etiology 41, 119 otolith types 41, 42 preoperative criteria 119 Tullio phenomenon 42

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Perilymphatic fistula, off-vertical axis rotation test 95 Positional vertigo, see Benign paroxysmal positioning vertigo Postoperative ocular tilt reaction syndrome 119, 120 Postural symptoms, otolith dysfunction 117 Posturo-motor development 90–93

clinical types 43 otolith case reports 44, 45 clinical manifestations 43, 44, 120, 121 etiology 121 ocular tilt reaction 43, 44, 120 pathology 42 Tumarkin otolithic crisis 35, 37, 118

Quix, F.H., contributions to otolith dysfunction evaluation 15, 17, 25

Upright orientation, sensitivity 18, 19 Utricle afferent system glutamate as neurotransmitter 8 neurokinin A expression 11 substance P expression 11, 12 calcitonin gene-related peptide expression in efferent system 8 calcium-binding protein expression calbindin 6 calretinin 6, 8, 11 parvalbumin 6, 11 function 1, 68, 69, 111, 112 hair cells 4–6, 8, 11, 12 scanning electron microscopy of ultrastructure 2, 3

Rehabilitative therapy, otolith disorders 39, 126 Saccule function 1, 68, 69, 111, 112 hair cells 4–6, 12 scanning electron microscopy of ultrastructure 3 Semicircular canal otolith function overlap 34, 52–54, 115, 116 vertigo 34, 35 Spatial orientation, perception 18, 19 Startle response, vestibular origins 25 Striola, orientation 111 Subjective visual vertical definition and overview 77 instrumentation for measurement 86 monocular vs binocular testing 84, 85 otolithic disorder deviations 78, 79, 123 stages of measure comparison process 82, 83 subjective vertical reference somatosensory inputs 81, 82 vestibular contribution 81 visual contribution 81 visual input 79–81 stimulus methodology 83, 84 subject placement 85 Substance P, expression in utricle afferent system 11, 12 Tilt suppression test 124 Traumatic otolithic vertigo 37, 38 Tullio phenomenon

Subject Index

Vertigo benign paroxysmal positioning 38, 39 cerebral cortex areas involved in vestibular processing during galvanic stimulation 56, 57 vestibulular fields 54–56 cognitive contribution of otoliths to spatial orientation and movement perception ambiguity of perception 48, 49 imagination modification of subjective vertical perception 49, 50 interaction between canals and otoliths for two-dimensional displacement trajectory perception 52–54 perception and memory of pure angular or linear motion 50, 51 cranio-facial asymmetry patients, see Cranio-facial asymmetry definition 48 head direction cell system 57, 58

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Vertigo (continued) otolithic syndromes, overview 35 perilymph fistulas 41, 42 semicircular canal vertigo 34, 35 tilt perception in otolithic disease 19, 20 traumatic otolithic vertigo 37, 38, 45, 107, 118, 119 Tullio phenomenon 42–45 vestibular drop attacks 35, 37 vestibular syndromes affecting otolith function 35, 36 Vestibular drop attacks 35, 37 Vestibular exercises, rehabilitative therapy 126 Vestibular nerve firing rate 112 projections 112, 113 Vestibular neuritis caloric testing 74, 75 off-vertical axis rotation test 95, 96 otolithic and semicircular canal contributions 34 subjective visual vertical 77 vestibular-evoked myogenic potentials 105, 106

Subject Index

Vestibular-evoked myogenic potential acoustic neuroma 106, 107 advantages over other tests 98, 99, 123 applications 74, 75, 99, 107, 108 Me´nie`re disease canal paresis 103 equitest performance relationships 103 gentamicin-treated patients 104, 105, 108 hearing loss relationship 102, 103 saccular function 74, 101–103 methodology clicks delivery 99 data analysis 100 electromyography 99, 100 overview 73, 74, 123 normal subject results 100, 101 oscillopsia 107 traumatic vertigo 107 vestibular neuritis 105, 106 Vestibulo-spinal function, clinical test 25, 26 Visual acuity cranio-facial asymmetry findings 62 otolith dysfunction 116 Wallenberg syndrome 34

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