Vestibular Dysfunction and Its Therapy (Advances in Oto-Rhino-Laryngology, Vol. 55)

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Advances in Oto-Rhino-Laryngology Vol. 55

Series Editor

KARGER

W Arnold, Munich

Basel· Freiburg· Paris· London· New York· New Delhi· Bangkok· Singapore· Tokyo· Sydney

Vestibular Dysfunction and Its Therapy

Volume Editor

U Battner, Munich

28 figures. 3 in color and 10 tables. 1999

KARGER

Basel· Freiburg· Paris· London· New York· New Delhi· Bangkok· Singapore· Tokyo· Sydney

Prof. Dr. med. U. Buttner Department of Neurology Klinikum GroBhadem Ludwig Maximilians University Marchioninistrasse 15 D-81366 Munich (Germany)

Library of Congress Cataloging-In-Publicatlon Data Vestibuiar dysfunction and its therapy / voiume editor, U. Bottner. (Advances in oto-rhlno-Iaryngology; vol. 55) Includes bibliographical references and indexes. I. Vestibular apparatus - Diseases - Treatment. 2. Labyrinth (Ear) - Diseases - Treatment. 3. Nystagmus - Treatment. 4. Meniere's disease - Treatment. 5. Vertigo - Treatment. I. BLittner, U. II. Series. [DNLM: J. Labyrinth Diseases - therapy 2. Vestibular Diseases - therapy.

3. Vestibular Diseases - physiopathology. 4. Vestibule - physiopathology. WI AD701 v. 55 1999/ WV 255 V5826 19991 RF16.A38 vol. 55 [RF2601 617.51 s-dc21 [617.8821 ISBN 3-8055-6702-2 (hardcover: alk. paper)

Bibliographic Indices. This publication is listed In bibliographic services, including Current Contents Index Medlcus.

and

Drug Dosage. The authors and the publisher have exerted every e ort 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. Lncluding photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.

Copyright 1999 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland) Printed In Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3-8055-6702-2

Contents

~Preface

C!::: Brainstem and Cerebellar Structures for Eye Movement Generation Horn, A.K.E.; Buttner, u.; Buttner-Ennever, JA. (Munich) [26 Intrinsic Physiological and Pharmacological Properties of Central Vestibular Neurons Vidal, P-P; Vibert, N. (Paris); Serafin, M. (Geneva); Babalian, A. (Paris); MOhlethaler, M. (Geneva); de Waele, C. (Paris) 82] Vestibular Compensation Curthoys, 1.S. (Sydney); Halmagyi, G.M. (Camperdown)

~

Vestibular I\leuritis Strupp, M.; Brandt, T. (Munich)

[1371 Meniere's Disease Hamann, K.-F.; Arnold, W (Munich)

11691 Benign Paroxysmal Positioning Vertigo Brandt, T. (Munich) 1195' Drug Therapy of Nystagmus and Saccadic Intrusions Buttner, u.; Fuhry, L. (Munich)

[228

Nonpharmacological Treatment of Nystagmus Leigh, R.J (Cleveland, Ohio)

1241J Subject Index

Preface

Vertigo and dizziness are one of the most common complaints of patients consulting a doctor. These symptoms can be very disturbing to the patient, but a precise diagnosis is often di cult to make and, in many instances, satisfying therapy is lacking. The diagnostic approach has to be multidisciplinary including otolaryngology, ophthalmology and neurology. In November 1996 an international conference on 'Therapy of ocular motility and related visual disturbances' was held at Case Western Reserve University, Cleveland, Ohio, and was organized by H.]. Kaminiski and R.J Leigh [conference summary see, Neurology 1997;48:1178-1184]. At this conference it became quite clear that impressive progress has been made on the basic neurophysiological and neuropharmacological mechanisms of ocular motility over the last 10 years, and has resulted in a number of successful therapeutical studies. However, it was also obvious that more research and clinical studies are required. Particularly in the field of drug therapy, the number of patients investigated in double-blind controlled studies is still very small. Over the last years the basic mechanisms of benign paroxysmal positioning vertigo (BPPV), one of the most common causes of vertigo, have successfully been worked out. The correct application of these findings to physical therapy has led to impressive, often astonishing results. With a single maneuver lasting less than 5 min patients who had su ered from vertigo for many years can often be cured. The chapters in this book present the current state of research and clinical studies in this widely relevant field. They are aimed at the basic scientist wUI'king in the field uf neuruphysiulugy and neurupharmacolugy uf the vestilmlar and oculomotor system, who wishes to become more familiar with the clinical aspects and therapy. They are also aimed at clinicians interested in neuro-otology and neuro-ophthalmology, providing both information about the neuropharmacological and neurophysiological basis and, in addition, the

Contents

VII

clinical and therapeutic approach to patients with vestibular and ocular motility disorders. The book is divided into eight chapters. The first two chapters provide an overview of the structures in the brainstem and cerebellum involved in oculomotor and vestibular control with the main emphasis on neuropharmacological aspects. The chapter by Vidal et al. covers the vestibular nuclei, and the contribution of Horn et at. other brainstem and cerebellar structures. Peripheral vestibular disorders are treated in the fol1owing chapters by Curthoys and Halmagyi (Vestibular compensation), Strupp and Brandt (Vestibular neuritis), Brandt (Benign paroxysmal positioning vertigo) and Hamann and Arnold (Meniere's disease). The last two chapters address central eye movement disorders (nystagmus, saccadic intrusions) and their pharmacological (Buttner and Fuhry) and non-pharmacological treatment (Leigh). The aim of this book is to aid the diagnosis and treatment of patients with vestibular and oculomotor disorders, and it will also perhaps stimulate research for better therapy. Ulrich Battner Munich, August 1998

Preface

VIII

Btittner U. (ed): Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger, 1999, vol 55, pp 1-25

Brainstem and Cerebellar Structures for Eye Movement Generation AKE. Horn a , U Battner b, JA Battner-Ennever a a b

Institute of Anatomy, Ludwig Maximilians University, Munich and Department of Neurology, Klinikum Grosshadern, Munich, Germany

Over the last years much progress has been made in the identification and characterization of functional cell groups of the premotor system for eye movements in the brainstem and cerebellum of the monkey. In parallel, attempts have been made to identify the homologous cell populations in humans, which now can be analysed at a cellular level with postmortem examinations uf brains with eye movement uisun.lers [Hum et aI., 1996], With the uevelupment of immunocytochemical techniques and the improvement of tract -tracing methods, the histochemical properties and the neurotransmitter profile of some populations have been studied in mammals. The knowledge about the chemical properties of the functional cell groups for eye movement generation is a prerequisite for the development of possible pharmaceutical therapies in patients. The current state of research excluding the vestibular nuclei [see Chapter by Vidal et al.] is reviewed in the present chapter.

Rostral Interstitial Nucleus of the Medial Longitudinal Fascicle

Structure and Function I The rostral interstitial nucleus of the medial longitudinal fascicle (riMLF)1 is essential for the generation of vertical and torsional saccades [Buttner et a1., 1977; Vilis et aI., 1989; Crawford and Vilis, 1992]. The riMLF lies in the mesencephalic reticular formation and forms the rostral medial part of thel fields of Forel. In transverse sections the riMLF appears as a wing-shaped

Supported by the Deutsche Forschungsgemeinschaft (SFB 462).

nucleus below the thalamus, dorsomedial to the red nucleus, dorsally bordered by the posterior branch of the thalamosubthalamic artery. From the caudaUy adjacent interstitial nucleus of Cajal (iC) the riMLF is roughly separated by the traversing fibres of the tractus retroflexus and the rostral end is formed by the traversing fibres of the tractus thalamosubthalamicus [Bottner-Ennever and Bottner, 1988J. The riMLF contains medium-lead burst neurons that discharge with highfrequency bursts 8-15 ms before and during vertical and torsional saccades. The right riMLF contains up- and down-burst neurons with a clockwise torsional component, and the left riMLF up- and down-burst neurons with a counterclockwise torsional component [Vilis et aI., 1989J. In primates, upand down-burst neurons are intermingled [Bottner et aI., 1977; Moschovakis et aI., 1991a, b; Horn and BClttner-Ennever, 1998], although in cats a tendency of upward neurons lying more caudally than downward neurons was observed [Wang and Spencer, 1996]. Within the small to medium-sized neurons of the riMLF, the saccadic premotor burst neurons belong to the medium-sized cell population (mean diameter 22 m) and contain the calcium-binding protein parvalbumin, which is present in neurons with high-firing activity [Bairnbridge et aI., 1992; Horn and Bottner-Ennever, 1998J.

A erent and E erent Connections The burst neurons project monosynaptically to the motoneurons of the vertical pulling extraocular eye muscles in the oculomotor and trochlear nuclei providing the premotor signal for the saccadic eye movement [Moschovakis et aI., 1991a, b; Horn and Bottner-Ennever, 1998]. There are additional connections of the riMLF to the contralateral riMLF via the ventral commissure, to the iC, the paramedian tract (PMT) neurons and sparsely to the spinal cord [Moschovakis et aI., 1991a, b; Wang and Spencer, 1996; Holstege and Cowie, 1989]. The burst neurons in the riMLF receive a strong input from the inhibitory saccadic omnipause neurons within the paramedian pontine reticular formation (PPRF) [Horn et aI., 1994J. In addition, the riMLF receives a erents from neurons in the iC that are not oculomotor-projecting premotor neurons [Moschovakis et aI., 1991b], but perhaps the saccade-related burst neurons [Helmchen et al., 1996], and the superior colliculus [Nakao et aI., 1990]. A minor projection from the medial vestibular nucleus targets mainly the mediocaudal part of the riMLF, and might derive from secondary vestibular neurons [Buttner-Ermever and Lang, 1981; Matsuu et aI., 1994]. Transmitters Anatomical studies in the riMLF of the cat revealed the presence of inhibitory premo tor burst neurons using GABA as transmitter. These

HornlBottner/Bottner-Ennever

GABA-immunoreactive neurons are concentrated in the dorsomedial part of riMLF [Spencer and Wang, 1996J. In contrast, the riMLF of the monkey contains only few small GABA-immunoreactive neurons, presumably local interneurons, which are not premotor burst neurons. So far there is no evidence for the presence of GABAergic premotor burst neurons in the monkey [Carpenter et a!., 1992; Horn, pel's. observationsJ. Microinjections of muscimol, a GABA agonist, into the riMLF result in similar deficits as those observed after kainic acid lesions: a loss of the torsional component to the ipsilateral side after unilateral injections. This indicates the presence of GABAA receptors on premotor burst neurons [Vilis et aI., 1989; Suzuki et aI., 1995; Crawford et a!., 1992]. Immunocytochemical studies showed that the premotor saccadic burst neurons in the riMLF receive a strong innervation of GABA- and also glycine-immunoreactive terminals [Horn et a!., 1994; Horn, pers. observations). Possible sources of the GABAergic a erents are the saccade-related burst neurons in the iC, which might provide an inhibitory feedback signal to the riMLF [Moschovakis et aI., 1996; Helmchen et aI., 1996], or collaterals of the vestibula-oculomotor connection, which is GABAergic for the vertical system [Spencer et aI., 1992J. Glycinergic a erents arise from the saccadic omnipause neurons in the PPRF [Horn et aI., 1994]. There are limitations using immunocytochemlcal techniques for the detection of amino acid transmitters in cell bodies. Whereas GABA and glycine are thought to occur in high concentrations exclusively in the neurons, which use them as transmitters, glutamate and aspartate are metabolic products as well. Almost all neuronal somata express more or less glutamate- and aspartate-immunoreactivity [Yingcharoen et a!., 1989J. Only careful studies applying the appropiate antibody dilutions with additional quantitative measurements of the staining intensity at the ultrastructural level may di erentiate between transmitter pools and metabolic pools. This distinction is easier in nerve terminals, of which for example the glutamatergic were shown to contain 2-3 times the average level of glutamate [for review, see Storm-Mathisen et aI., 1995J. In the vestibula-oculomotor system such quantitative studies were performed only in cats so far and revealed glutamate- and aspartate-positive neurons that project to the motoneurons in the oculomotor and trochlear nucleus, suggesting that glutamate and aspartate are the transmitters of excitatory premotor burst neurons in the riMLF in this species [Spencer and Wang, 1996J. This study did not show whether aspartate and glutamate are culucalized in the same neuruns, !.Jut !.Juth transmitter populations, e.g. aspartate and glutamate, had di erent ultrastructural and synaptic features (synaptic vesicle shape, degree of postsynaptic specializations) , which indicates that aspartate and glutamate are released from di erent terminals [Spencer and Wang, 1996].

Brainstem and Cerebellar Structures for Eye Movement Generation

3

Interstitial Nucleus of Cajal

Structure and Function As the riMLF, the iC is related to vertical and torsional eye movements, but more involved in the integration of eye-velocity into eye-position signals [Fukushima et aI., 1992] and eye-head coordination [Fukushima, 1987], rather than in the generation of vertical saccades [Helmchen et aI., 1998]. The iC lies within the medial longitudinal fascicle lateral to the rostral pole of the oculomotor nucleus. In humans its rostral border to riMLF is di cult to define, because both nuclei have a similar cellular appearance in Nissl-stained sections. The distinction between both is made easier with histochemical markers, such as the immunostaining pattern for the calciumbinding protein parvalbumin [Horn and Bottner-Ennever, 1998J. The iC is a rather compact nucleus consisting of small to medium-sized neurons with few large-sized polygonal neurons interspersed [Bianchi and Gioia, 1991]. Recording experiments in alert cats and monkeys revealed several functional cell groups within the iC: (1) Burst-tonic and tonic neurons encode the eye position and they are involved in the vertical integrator function [review in Fukushima et aI., 1992]. Accordingly, a lesion of the posterior commissure, which contains the crossing fibres of the burst-tonic and/or tonic neurons, results in the inability to hold eccentric gaze after vertical saccades [Partsalis et aI., 1994J. (2) Approximately one third of the eye movement-related neurons are saccade-related burst neurons with a similar firing pattern as premotor burst neurons in the riMLF [Helmchen et al., 1996]. Since they do not project to the eye muscle motoneurons but send collaterals back to the riMLF, they are thought to be part of an inhibitory feed back system carrying eye displacement information [Moschovakis et aI., 1996J. This hypothesis is supported by the observation that only the saccade amplitude was reduced after muscimol injections into the iC, but not the saccade velocity [Helmchen et aI., 1998J. (3) In the cat another group of neurons was identified, classified as bursterdriving neurons (BONs) or 'vestibular plus saccade' neurons that discharge a burst of spikes shortly before (but with longer lead time of 34 ms than medium-lead burst neurons in the riMLF) and during downward saccades. During the upward slow phase of vestibular stimulation the BONs discharged at gradually increasing firing rates [Fukushima et al., 1991, 1995]. Vertical BONs were also identified in and around the iC in monkeys [Kaneko and Fukushima, 1993]. A erent and E erent Connections There are three main e erent projection systems leaving the iC [Kokkoroyannis et aI., 1996]: the ascending system has strong projections to the ipsilat-

HornlBottner/Bottner-Ennever

eral mesencephalic reticular formation including riMLF and zona incerta, weaker projections to the ipsilateral centromedian and parafascicular thalamic nuclei and bilateral to the mediodorsal, central medial and lateral nuclei of the thalamus. The descending system projects through the medial longitudinal fascicle to innervate the ipsilateral oculomotor and trochlear nucleus, the ipsilateral PPRF, the rostral cap of the abducens nucleus (VI) as part of the PMT cell groups [Bottner-Ennever, 1992), the vestibular nuclei, the nucleus prepositus hypoglossi, the gigantocellular portion of the reticular formation, the inferior olive and the ventral horns of Cl up to C4. The commissural system projects via the posterior commissure to the nucleus of the posterior commissure bilaterally, the contralateral iC and the contralateral oculomotor and trochlear nuclei to innervate monosynaptically the motoneurons of vertical pulling extraocular eye muscles [Kokkoroyannis et aI., 1996J. This system arises from medium-sized, presumably burst-tonic and/or tonic neurons, which contain the calcium-binding protein parvalbumin [Horn and Bottner-Ennever, 1998J. Saccade-related burst neurons appear not to project to eye muscle motoneurons, but have recurrent collaterals to the riMLF [Moschovakis et aI., 1996J. The iC receive inputs from premotor neurons that encode eye- or head-velocity signals: via collaterals from secondary vestibulo-ocular neurons, excitatory signals from the contralateral side and inhibitory signals from the ipsilateral side [Iwamoto et aI., 1990] and from the y-group of the vestibular nuclei [Fukushima et aI., 1986J. Most probably the burst-tonic and tonic neurons receive a erents from the saccadic burst neurons in the riMLF [Moschovakis et al.. 1991 a, bJ. TransmHlers

Up to date there is no systematic study about the transmitter profile in the ie. There is some evidence that the iC contains small and medium-sized GABAergic neurons, but their connectivity has not been studied yet [Horn, pers. observations]. These neurons could comprise inhibitory premotor neurons projecting to the oculomotor and trochlear nucleus [Nakao et al.. 1990; Nakao and Shiraishi, 1985; Schwindt et aI., 1974], or they form part of the inhibitory feedback system to riMLF as suggested by Moschovakis et aI., [1996J (see above). The presence of symmetric synaptic profiles at the somata of all neuron types, but predominantly at large neurons, indicate monosynaptic inhibitory a erents to iC [Bianchi and Gioia, 1995J. The iC contains numerous GABA-irIlInunoreactive terminals, in part uutlining neuronal sumata [Hum, pers. observationsJ. The source of these inputs has not been studied yet, but part of them could arise from collaterals of inhibitory secondary vestibulooculomotor projections from the ipsilateral superior vestibular nuclei, which were shown to be GABAergic [Wentzel et aI., 1995; De la Cruz et aI., 1992].

Brainstem and Cerebellar Structures for Eye Movement Generation

In the monkey, unilateral microinjections of the GABAA-receptor agonist muscimol result in a torsional and vertical spontaneous nystagmus (torsional fast phases always toward the lesion), a severe gaze-holding deficit for vertical and torsional saccades, and a tonic torsional eye-position shift to the contralesional side [Crawford and Vilis, 1992; Helmchen et al., 1998]. So far nothing is known about the nature of excitatory neurons that drive oculomotor neurons. Weakly choline acetyltransferase (Chat)-positive neurons were found in the iC of humans [Juncos et aI., 1991], which appear not to be premotor neurons projecting to the oculomotor nucleus [Carpenter et aI., 1992]. Only a weak innervation by cholinergic a erents is reported in cats, whose origin is unknown [Kimura et aI., 1981].

Paramedian Pontine Reticular Formation

Structure and Function The PPRF was introduced as a functional term as the site where lesions produce a horizontal gaze palsy [Cohen and Komatsuzaki, 1972]. Anatomically the PPRF extends from rostral to caudal from the trochlear to the abducens nucleus and includes the nucleus reticularis pontis oralis (NRPO) , the nucleus reticularis pontis caudalis (NRPC) with corresponding midline structures, and the nucleus paragigantocellularis dorsalis (PGD) [Bottner-Ennever and Buttner, 1988; Hepp et aI., 1989]. There are several classes of eye movement-related neurons within the PPRF: Excitatory burst neurons (EBNs) lie as a compact group withln the dorsomedial part of the NRPC just rostral to the saccadic omnipause neurons (OPNs) [Strassman et aI., 1986a; Horn et aI., 1995J. Inhibitory burst neurons (lENs) are located in the PGD just beneath the rostral pole of the abducens nucleus [Strassman et aI., 1986b; Horn et aI., 1995]. Both, the EBNs and lENs form populations of medium-sized neurons within the NPRC and PGD, respectively, and contain the calcium-binding protein parvalbumin [Horn et aI., 1995J. The EBNs and lENs exhibit a high-frequency burst during horizontal saccades and are otherwise silent. OPNs lie within a distinct nucleus between the traversing fibres of the abducens nerve at the midline, which was named nucleus raphe interpositus [Bottner-Ennever et aI., 1988]. In monkeys the OPNs lie in two compact cell columns, which appear more scattered around the midline in humans [Hurn et aI., 1994]. The medium-sized OPNs are hurizontally oriented with their long dendrites reaching across the midline. They contain the calcium-binding protein parvalbumin and a high level of cytochrome oxidase activity, which is presumably related to the high-firing activity [Buttner-Ennever et aI., 1988; Horn et aI., 1994]. Saccade-related long-

HornlBottner/Bottner-Ennever

6

lead burst neurons (LLBNs) exhibit an additional irregular low frequency activity before the saccade-related burst and they are thought to activate premotor medium-lead burst neurons. LLBNs are found at several locations in the brainstem and can be divided into several groups on the basis of their location and their projection targets [Moschovakis et al., 1996]: pontine LLBNs lie witWn the NRPC, intermingled with EBNs, and more rostrally in the NRPO and nucleus reticularis tegmenti pontis (NRTP) [Kaneko et a!., 1981; Hepp and Henn, 1983; Scudder et a!., 1996J and in the PGD intermingled with IBNs [Scudder et al., 1988J. One class of LLBNs, reticulospinal neurons, were first described in the cat as neurons with long-lead burst activity related to eye-neck (head) movements, which lie either rostrally or ventrally to the abducens nucleus [Grantyn et a!., 1987J. During fixation and slow eye movements the OPNs exert monosynaptically a tonic inhibition onto premotor EBNs and IBNs in the riMLF and NRPC. During saccades the OPNs are inhibited by polysynaptic inputs possibly via LLBNs - from the superior colliculus. A erent and E erent Connections EBNs project directly to the motoneurons and internuclear neurons in the abducens nucleus thereby activating the ipsilateral lateral rectus muscle and the contralateral medial rectus muscle. In addition, the EBNs send an ipsilateral projection to the IBNs, thereby inhibiting the contralateral abducens nucleus and preventing the contralateral lateral rectus muscle from abduction during saccades [Strassmann et al., 1986a]. The OPNs send direct projections to the vertical premotor burst neurons in the riMLF, and the horizontal EBNs and IBNs in the NRPC and PGD [Ohgaki et a!., 1989; Strassman et aI., 1987J. Single-cell reconstructions of identified LLBNs in the NRPO of the monkey revealed projections to the dorsomedial part of the NRPC (EBN region), the PGD (IBN region), the NRTP and the nucleus reticularis gigantocellularis (NRG) [Scudder et aI., 1996J. In the cat, reticulospinal neurons were shown to project to the abducens nucleus, the facial nucleus, the medial and lateral vestibular nuclei and the nucleus prepositus hypoglossi [Grantyn et al., 1987]. Only recently, identified reticulospinal neurons in the monkey were shown to project to the spinal cord giving 0 collaterals to the PGD, the caudal half of the nucleus prepositus hypoglossi, but none to the abducens or facial nucleus, indicating that the contwl uf eye and head movements is mediated by mUI'e separated pathways in primates than in cats [Robinson et aI., 1994; Scudder et al., 1996J. Recent work in monkeys showed that the IBNs and EBNs receive via the predorsal bundle a strong a erent input from the intermediate layers of the superior colliculus motor map mediating large horizontal saccades, but

Brainstem and CerebelJar Structures for Eye Movement Generation

7

not the OPNs [Bottner-Ennever et aI., 19971. A strong a erent input to the somata of OPNs was observed from the superior colliculus motor map representing small horizontal saccades and fixation, whereas the EBN and IBN areas receive only a weak innervation [Bottner-Ennever et a!., 1997; Everling et al., 1998]. TransmHlers

The IBNs use glycine as transmitter [Spencer et a!., 1989], whereas the transmitter of the EBNs is not known yet. The OPNs are glycinergic as well, and they receive a similar strong input of glycine- and GABA-immunoreactive terminals on their somata and proximal dendrites [Horn et aI., 1994], which appear the most likely source for providing the brisk inhibition of the tonic activity during saccades. However, it is not clear why in the cat the iontophoretic application of glycine showed none and that of G ABA only a weak suppression of the firing activity of OPNs [Ashikawa et aI., 1991]. So far the origin of these inhibitory inputs is not known. Glycinergic inputs can theoretically derive from glycinergic neurons within the neighbouring formatio reticularis, which lie within reach of the descending projection fibres of the predorsal bundle from the 'small- and large-horizontal-saccade zone' of the superior colliculus motor map [Bottner-Ennever et aI., 1997]. The strong supply with glutamate-immunoreactive terminals on the proximal dendrites of the OPNs [Horn et a!., 1994] might derive from the 'rostral pole' of the superior colliculus, mediating fixation [Munoz and Wurtz, 1993; Pare and Guitton, 1994; BottnerEnnever et a!., 1997]. Cortical projections from the frontal and supplementary eye fields could be another source of glutamatergic a erents to OPNs [Shook et a!., 1988; Stanton et aI., 1988]. The systemic or local iontophoretic application of serotonin results in a complete suppression of the tonic firing rate of OPNs, which can be abolished by a prior intravenous injection of methysergide, a serotonin blocker, as shown in the cat [Furuya et a!., 1992]. So far, nothing is known about the nature of the transmitters used by LLBNs including reticulospinal neurons, and whether they are excitatory or inhibitory.

Paramedian Tract Neurons

Structure

i:lIJ(.l

FunctiuIJ

PMT neurons are defined as groups of cerebellar-projecting neurons that lie around the midline fibre bundles of the pons and medulla. The PMT cell groups have been brought to the attention of oculomotor neuroanatomists on account of their projection to the flocculus and ventral paraflocculus region

Horn/Buttner/Buttner-Ennever

8

[Sato et a!., 1983; Blanks et al. 1983; Langer et a!., 1985; Blanks, 1990]. The PMT cell groups could provide the flocculus and ventral paraflocculus of the cerebellum and other areas of the brain with a motor e erence copy ofthe oculomotor output signal. Damage could lead to a disturbance in gaze-holding [Bottner et al. 1995]. There are at least six relatively separate 'PMT cell groups' scattered in the medial longitudinal fascicle, rostral to, and even within, the abducens nucleus, and continuing back to the level of the hypoglossal nucleus. In the cat, rat and monkey they have been given di erent names by di erent investigators: we use the individual terms introduced by Langer and colleagues, 1985. The use of the nomenclature 'medial' and 'caudal interstitial nuclei of the MLF' for the PMT cell groups rostral or caudal to the abducens nucleus appears less satisfactory (as well as unwieldy), partly because they overlook fine di erences in the cell grouping at least in the primate, and also because often the prefix medjalor caudal is dropped and then there is total confusion with the vertical premotor neurons of the riMLF and iC (see above). A erent and E erent ConnecUons Aside from their projection to the flocculus and ventral paraflocculus, the PMT neurons receive an a erent input from all premotor brainstem nuclei known to project to oculomotor motoneurons [Buttner-Ennever and Buttner, 1988; Bottner-Ennever et al.. 1989; Bottner-Ennever, 1992]. TransmHters The transmitter content of the PMT cell groups is unknown: however, we have found that the cell somata are not serotoninergic, or catecholaminergic [pers. observation]. In addition, the PMT cell groups contain high levels of cytochrome oxidase and acetylcholinesterase. The neurons are chromophilic, medium-sized cells that lie immediately lateral to the smaller-celled raphe nuclei. The di erence between them is easily demonstrated by immunocytochemical stainings with serotonin antibodies: the raphe nuclei are labelled, but the PMT cells are not.

Abducens Nucleus

Structure am} FUIlcUun The abducens nucleus (VD contains at least three functional cell groups: (1) motoneurons innervating the lateral rectus muscle; (2) internuclear neurons, and (3) floccular-projecting neurons in the rostral cap, which belong to the PMT neurons (see above) [Buttner-Ennever, 1992]. Motoneurons and internuclear neu-

Brainstem and Cerebellar Structures for Eye Movement Generation

9

rons exhibit the same burst-tonic firing pattern during eye movements. However, only the motoneurons carry conjugate- and vergence-related signals, whereas internuclear neurons do not carry vergence-related signals [Delgado-Garciaet aI., 1986a, b; Zhou and King, 1998J. The motoneurons contain the calcium-binding protein parvalbumin, but in the cat at least 80% of the internuclear neurons contain a di erent calcium-binding protein, calretinin, which could serve as a histological marker for internuclear neurons [De la Cruz et aI., 1998].

A erent and E erent Connections The internuclear neurons project to the motaneurons of the medial rectus muscle in the contralateral oculomotor nucleus, thereby forming the anatomical basis for conjugate eye movements [Bottner-Ennever and Akert, 1981]. The motaneurons and internuclear neurons receive bilateral a erents from secondary vestibula-ocular neurons in the medial vestibular nuclei, the nucleus prepositus hypoglossi (PPH), the excitatory and inhibitory saccadic burst neurons in the NRPC and PGD and from internuclear neurons of the oculomotor nucleus [Evinger, 1988J. Transmitters In contrast to the cholinergic motoneurons, identified internuclear neurons are not cholinergic [Spencer et aI., 1986; Carpenter et aI., 1992], but appear to use glutamate and aspartate as transmitter [Nguyen and Spencer, 1996]. In cats, serotonin-immunoreactive synaptic contacts were disclosed at the dendrites of abducens neurons, but the serotoninergic dorsal raphe nucleus lying above the caudal oculomotor nucleus was shown not to be the source of these a erents [May et aI., 1987]. The abducens nucleus receives a strong supply of glycinergic inhibitory a erents, which originate from IBNs in the contralateral PGD, the PPH and the ipsilateral medial vestibular nucleus [Spencer et al., 1989J. Anatomical studies revealed a rather weak GABAergic input to the abducens nucleus with a slight tendency of motoneurons being more heavily contacted than internuclear neurons [De la Cruz et aI., 1992; Lahjouji et al., 1995J. Combined tracer and immunocytochemical studies revealed a GABAergic input from internuclear neurons in and above the oculomotor nucleus, which project to the abducens nucleus [De la Cruz et aI., 1992].

Oculomotor and Trochlear Nucleus

Structure and Function The oculomotor nucleus contains the motoneurons innervating the ipsilateral inferior rectus (IR), inferior oblique (10) and medial rectus (MR) muscle

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and those for the contralateral superior rectus (SR) muscle organized in a topographic map [Evinger, 1988]. In primates there are three clusters of MR motoneurons, ventral the A group, dorsolateral the B group and medially at the border of the oculomotor nucleus the C group, consisting of smaller motoneurons [Bottner-Ennever and Akert, 1981]. These MR-motoneuron subgroups presumably have di erent functions as indicated by a selective input from the pre tectum to only the C group [Bottner-Ennever et a!., 1996]. Several popu lations of internuclear neurons within and around the oculomotor nucleus were identified, which di er in their projection targets: the spinal cord, the cerebellum, the abducens nucleus [for review, see Evinger, 1988J. SO far little is known about the physiology and their function. The trochlear nucleus contains only motoneurons of the contralateral superior oblique muscle.

A erent and E erent Connections The MR subgroup in the oculomotor nucleus receives a erents via the medial longitudinal fascicle from the internuclear neurons of the contralateral abducens nucleus [Bottner-Ennever and Akert. 1981J and from the ipsilateral ventral part of the lateral vestibular nucleus via the ascending tract of Deiters, a pathway presumably involved in the control of vergence [Baker and Highstein, 1978]. Secondary vestibula-oculomotor projections target on the motoneurons of vertical pulling eye muscles, Le. IR, 10, MR and SR, via excitatory fibres from the superior and medial vestibular nuclei from the contralateral side, and via inhibitory fibres from the superior vestibular nucleus of the ipsilateral side [for review, see Bottner-Ennever, 1992J. The motoneurons of vertical pulling eye muscles in the oculomotor and trochlear nuclei receive bilateral projections from the iC (see above), and predominantly ipsilateral projections from the riMLF [Horn and Bottner-Ennever, 1998]. Transmitters The motoneurons in the oculomotor and trochlear nuclei are cholinergic [Spencer and Wang, 1996] and express parvalbumin-immunoreactivity [De la Cruz et a!., 1998]. In contrast to the abducens nucleus, the motaneurons of vertical pulling eye muscles in the oculomotor and trochlear nuclei receive a strong GABAergic, but a rather weak glycinergic input [De la Cruz et a!., 1992; Spencer et a!., 1992]. Anatomical studies in the rabbit showed that glycine-immunoreactive terminals were evenly distributed throughout the uculumutor nucleus, amI they were preduminantly fuund at proximal and distal dendrites of motoneurons, and only a few at the somata [Wentzel et aI., 1993J. The authors showed in neighbouring ultrathin sections that all glycineimmunoreactive terminals in the oculomotor nucleus contain GABA as well, whereas only a small fraction of GABA-positive terminals express glycine-

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immunoreactivity [Wentzel et aI., 1993]. The function ofthis colocalization is not clear yet, and it cannot be excluded that glycine is only metabolic. Glycine is also known as coactivator of N-methyl-D-aspartate (NMDA) receptors to potentiate the response to glutamate [Johnson and Ascher, 1987]. GABAergic a erents to the oculomotor and trochlear nucleus originate from inhibitory secondary vestibula-ocular neurons in the ipsilateral superior vestibular nucleus [rabbit: Wentzel et aI., 1995; cat: De la Cruz et aI., 1992] and, at least in the cat, from the riMLF (see above) [Spencer and Wang, 1996]. Possible GABAergic projections from the iC have not been proven yet. There are conflicting reports about a strong GABAergic input to medial rectus motoneurons mediating horizontal eye movements: some authors did not see an obvious di erence of the supply with GABA-immunoreactive terminals at MR motoneurons compared to other motoneuron subgroups in rabbits and cats [De la Cruz et aI., 1992; Wentzel et aI., 1996], whereas a much weaker innervation by GABAergic terminals was observed in cats and monkeys [Spencer et aI., 1992; Horn, pers. observations]. A possible source for GABAergic a erents to MR motoneurons are small GABAergic interneurons scattered in and above the oculomotor nucleus [De la Cruz et aI., 1992]. The contralateral excitatory a erents from secondary vestibula-ocular neurons in the medial and superior vestibular nuclei most probably use glutamate as transmitter [De memes and Raymond, 1982]. Recent anatomical studies in the cat indicate that excitation to MR motoneurons from the internuclear neurons of the contralateral abducens nucleus is mediated by glutamate and aspartate, whereas the a erents from the ascending tract of Deiters use only glutamate as transmitter [Nguyen and Spencer, 1996].

Cerebellum

Structure and Function The cerebellum can be divided into ten lobules, according to Larsell; the median part of each lobule forms the vermis, and the lateral regions - the hemispheres [for reviews, see Voogd et aI., 1996; Berry et aI., 1995]. The cerebellum refines, modifies and coordinates all types of movement, including eye movements. The areas of the cerebellar cortex involved in eye movements are (1) the floccular region, (2) nodulus/uvula and (3) the dorsal vermis. Lesions in each structme lead tu specific eye movement deficits. The fluccular regiuIJ consists of the flocculus and parts of the ventral paraflocculus (part of the tonsilla in man) [Buttner and Buttner-Ennever, 1988]. Lesions here cause a smooth pursuit eye movement (SPEM) deficit, which is more pronounced to the ipsilateral side [Zee et aI., 1981; Leigh and Zee, 1991]. Since the same

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Purkinje cells in the floccular region are involved in SPEM and the visual suppression of the vestibula-ocular reflex (VOR-supp) [Bottner and Waespe, 1984], the SPEM deficit is always combined with impaired VOR-supp [Zee et aI., 1981; Leigh and Zee, 1991; Bottner and Grundei, 1995]. In addition, lesions of the floccular region lead to gaze-evoked nystagmus, whose intensity is highly correlated with the SPEM deficit [Bottner and Grundei, 1995]. Common features are also downbeat and rebound nystagmus, particularly with bilateral lesions [Zee et aI., 1981; Leigh and Zee, 1991]. Pulse-step mismatch dysmetria as seen with lesions of the floccular region causes a postsaccadic drift, since the neural command for the saccade (pulse) and the following new eye position (step) do not match [Leigh and Zee, 1991 J. A characteristic feature of a nodulus/ uvula lesion is periodic alternating nystagmus (PAN), which is known to cause disturbing oscillopsia [Halmagyi et al., 1980; also see Chapter by Bottner and Fuhry]. The nodulus has an inhibitory e ect on the 'velocity storage' mechanism in the vestibular nuclei. Consequently, lesions of the nodulus/uvula lead to prolonged time constants of the postrotatory vestibular nystagmus. They also a ect the 'dumping' of vestibular nystagmus by otolith stimulation and cause spontaneous nystagmus in the dark [Waespe et aI., 1985J. It has also been implicated in the generation of motion sickness [Money, 1970J. Lobulus VI and VII of the posterior vermis are considered as the oculomotor vermis [Yamada and Noda, 1987]. Lesions here lead to saccadic step-size error dysmetria and SPEM deficits [Vahedi et aI., 1995; Takagi et aI., 1996J. In contrast to lesions of the underlying fastigial nuclei, which lead to hypermetric saccades [Buttner and Straube, 1995], oculomotor vermis lesions cause hypometric saccades [Vahedi et al., 1995J. The cerebellar cortex has a homogenous histological architecture in terms of the arrangement of the input, output, and interneuronal elements (fig. 1).

A erent and E erent Connections The cerebellum has di erent types of input fibres: (a) The mossy fibres, which comprise all the cerebellar a erents from the brain except those from the inferior olivary nucleus. Mossy fibres are a heterogeneous group of fibres, that converge on granular cells in the granular layer of the cerebellum, forming glomerular synapses 'rosettes' with a variety of morphologies in association with Golgi cells IMugnaini et a1., 1974]. The information is transferred to Purkinje cells via the granular cell axon, the parallel fibres, synapsing on dendritic spines (fig. 1). (0) Climoing fiores, which arise exclusively frum the inferior olive and provide the Purkinje cells with an important excitatory input (fig. 1). They may control the access of mossy fibre inputs to the Purkinje cells. (c) Fine beaded fibres: Some a erent fibres, described in the reviews above, are not typical mossy fibres. They are fine and beaded (varicose), and

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terminate in all layers, the molecular, the Purkinje cell and granular layers (fig. 1). They could be considered as a third category of cerebellar a erents [Hokfelt and Fuxe, 1969]. The Purkinje cells provide the only output from the cerebellar cortex: their axons enter the cerebellar white matter and terminate in the cerebellar or vestibular nuclei. Thus the cerebellar nuclei form the main output of the cerebellum: the lateral or dentate nucleus carrying information from the lateral cerebellum, the hemispheres: the nucleus emboliformis and globosus (nucleus interpositus) from the intermediate hemispheres, while the fastigial nucleus receives e erents from the vermis. The flocculus, ventral paraflocculus and nodulus project directly to the vestibular nuclei. A erents and e erents of the cerebellum travel in the three cerebellar peduncles: the superior cerebellar peduncle is almost exclusively an e erent pathway: only the ventral spinocerebellar tract enters the cerebellum via this route. The brachium conjunctivum is the main e erent tract within the peduncle. The superior cerebellar peduncle decussates in the caudal mesencephalon and provides cerebellar inputs to the regions around the oculomotor nucleus, the red nucleus and the ventrolateral and intra laminar thalamic nuclei. The middle cerebellar peduncle is exclusively a erent, carrying the axons from the pontine nuclei and nucleus reticularis tegmenti pontis (also called nucleus papillioformis) to the cerebellum. While the interior cerebellar peduncle (restiform body and juxtarestiform body) carries a erents and e erents from the spinal cord and brainstem structures [Voogd et a!., 1996], the flocculonodular lobe (lobule X) receives a major input from the vestibular nuclei and is often referred to as the vestibulocerebellum. Its organization has been recently reviewed by Voogd et a!. [1996]. Transmitters The chemical substances used in the cerebellum for fast neurotransmission or neuromodulation have been recently reviewed [Otterson, 1993; Tohyama and Takatsuji, 1998]. Purkinje cells have long been suspected of using GABA as their neurotransmitter. However, the large cell bodies do not stain with GABA antibodies, because the transmitter is quickly transported to its ter-

Fig 1. The main transmitters and input-output pathways of the cerebellum: mossy fibres, from heterogeneous sources with eli erent transmitters, drive glutaminergic granule cells (Gr). Climbing fibres utilize L-glutarnate: both pathways provide an excitatory input to GABAergic Purkinje cells (P). GABAergic interneurons, such as stellate (S), Golgi (Go) and basket cells (B), modulate the signals. The Purkinje axons form the only cerebellar cortex output, and they control the cerebellar and vestibular nuclei. ACH Acetylcholine, ASP aspartate, DA dopamine, ENK enkephalin, 5HT serotonin, GABA -aminobutyric acid, GLU L-glutamate, GLY glycine, NA noradrenaline.

HornlBottner/Bottner-Ennever

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Molecular

layer

Purk;r.rje cell fayer

Granular"

fDyer

- -G"kBA,- - - -5"1,' laltJri II

DA ' N~

"

GILU

GLUI

ACH

White

(ASP)

matte".

GABA

:CH

110

t

Fl II rl;l 10

I

Inferior (nive I

Brainstem and Cerebellar Structures for Eye Movement Generation

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minals, where it is easily demonstrated. Similar results were observed with antibodies against the synthesizing enzyme glutamate decarboxylase (GAD), and somatal staining could only be achieved by prior injections of colchicine, which interrupts the intra-axonal transport [Mugnaini and Oertel, 1985J. The messenger RNA for GAD is confined to the soma of GABAergic cells and was clearly detected in the Purkinje cells using in situ hybridization methods [Wuenschell et a!., 1986]. Taurine is also present in the Purkinje cell terminals, but its role is unclear [Otterson, 1993J. In addition, the Purkinje ce]]s contain the calcium-binding proteins parvalbumin and calbindin [Andressen et a!., 1993]. The interneurons of the cerebellum, stellate and basket cells in the molecular layer, and the Golgi cells in the granular layer, are also inhibitory and use GABA as their transmitter. The majority of Golgi cells colocalize GABA and glycine and might corelease both transmitters, as indicated by in vitro studies [see Ottersen, 1993J. The basket and stellate cells contain parvalbumin, whereas the Golgi cells lack parvalbumin [Andressen et a!., 1993J. Although Golgi cells are considered as inhibitory neurons, a recent report in humans demonstrates that most of the Golgi cells in the vermis, flocculus and tonsilia are Chat-immunopositive, a marker for acetylcholine, but the function of the transmitter here is not clear yet [De LacalJe et al. 1993J. Glutamate is the most likely neurotransmitter in climbingfibres, although earlier studies had suggested aspartate could playa role as well [see Ottersen, 1993]. The mossy fibre excitation of the granule cells has been considered to utilize glutamate in a large proportion ofthe fibres, including spinocerebe]]ar, pontinocerebellar and vestibular nerve a erents [for reviews, see Otterson and Laake, 1992; Ji et a!., 1991; Barmack et a!., 1992c; Otterson, 1993J. Two subpopulations of mossy fibres, one GABAergic and one glutamatatergic, originate from the cerebellar nuclei and ascend to the cerebellar cortex [Batini et a!., 1992J. In several species including monkeys, Barmack and colleagues found that all lobules of the cerebellum received a di use cholinergic a erent projection, but particularly dense projections were detected in the vestibulocerebellum in three areas: (a) the uvula-nodulus (lobules IX and X), (b) the flocculus and ventral paraflocculus, and (c) lobules I, II and III of the anterior vermis [compare, rat: Barmack et a!., 1992a, b; with cat: Ikeda etal., 1991J. Similar results were reported for the human [De Lacalle et al. 1993J. In the rat, the cholinergic projection to the uvula and nodulus originated mainly in the caudal medial vestibular nuclei and to a lesser extent in nucleus prepositus hypoglossi [Barmack et a!., 1992bJ. In the light of this stIUng chulinergic mussy fibre input tu the vestibulucerebellum, alung with its association with motion sickness, it is of interest that the most e ective antimotion sickness agents are antimuscarinic. Certain populations of mossy and climbing fibres also contain peptides, such as corticotrophin-releasing factor, in addition to the amino acid transmit-

HornlBottner/Bottner-Ennever

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tel'. They are considered to facilitate the neuronal response to the transmitter [King et aI., 1992J. The simultaneous stimulation of climbing and parallel fibres leads to a depression in the synaptic e cacy of the parallel fibres for long periods. This phenomenon is called long-term depression, and is considered to reflect cerebellar regulatory mechanisms. Nitric oxide plays a neuromodulatory role in this process [Dawson et aI., 1992; Holschner 1997J. Adenosine modulates the parallel fibre-Purkinje cell transmission [Cuenod et aI., 1989]. The fine-beaded, or varicose, fibres form a thick plexus of fibres terminating in all layers of the cerebellar cortex (fig. 1). They were thought to constitute the monoaminergic input to the cerebellum carrying either serotonin, noradrenaline or possibly dopamine [Ito, 1984], but Barmack et a1. [1992aJ report the presence of cholinergic beaded a erents as well. Thin varicose fibres immunopositive for serotonin could be found in all parts of the cerebellum except the lobule X in cats [Kerr and Bishop 1991], but they are more evenly distributed in the rat [Tohyama and Takatsuji. 1998]. The serotoninergic a erents do not arise from the raphe nuclei, as usually supposed, but from more lateral parts in the reticular formation. and the lateral tegmental field [Kerr and Bishop, 1991J. The well-known raphe input to the cerebellum originates most probably from the PMT celJ groups, which utilize a transmitter other than serotonin (see above). The fine noradrenergic fibres to the cerebellum arise from locus coeruleus, and a distinct dopamlnergic input arises from the A8, A9 and AID cell groups of the mesencephalon [see Otterson, 1993]. The presence of scores of peptides and transmitter-binding sites have been documented within the lobules of the cerebellar cortex by Tohyama and Takatsuji [1998]. There are only two receptors not evenly distributed: one is the dopamine receptor which is concentrated in lobule X (the flocculus), the second are the nicotinic acetylcholine receptor-binding sites, which are concentrated in the ventral cerebellar lobules (the vestibulocerebellum including lobule I).

Fastigial Nucleus

Structure and Function The fastigial nucleus (FN) is the most medial deep cerebellar nucleus. Through a erent and e erent connections it is intimately related to the vestibular nuclei [Noda et aI., 1990J. It also receives a major input from the Purkinje cells of the overlying cerebellar vermis. which is topographically mganized. The anterior vermis (lobules I-V) projects to the rostral FN and the posterior vermis to the caudal FN. Functionally the anterior vermis is part of the spinocerebellum and is involved in the control of posture, gait and neck movements. In contrast, lobules VI and VII of the posterior vermis receive a

Brainstem and CerebelJar Structures for Eye Movement Generation

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major pontine input, they are classified as pontocerebellum and playa role in oculomotor functions [Yamada and Noda, 1987]. A similar division is also present in the FN. Neurons in the rostral FN are modulated during vestibular stimulation [Siebold et a1., 1997], but not with individual eye movements. Unilateral lesions cause a falling tendency to the ipsilateral side [Kurzan et a1., 1993; Thach et a1., 1992]. In contrast, neurons in the caudal FN are modulated with individual eye movements, either saccades [Helmchen et aI., 1994; Fuchs et a1., 1993] or smooth pursuit eye movements [Buttner et a1., 1991; Fuchs et a1., 1994J. Accordingly the caudal FN has been termed fastigial oculomotor region [Yamada and Noda, 1987]. Lesions in the caudal FN lead to step-size error dysmetria, with saccades to visual targets either too large (hypermetric) or too small (hypometric) [Buttner et a1., 1994; BOttner and Straube, 1995; Robinson et a1., 1993J. Smooth pursuit eye movements can have a reduced gain (cogwheel smooth pursuit) [Kurzan et aI., 1993; Robinson et aI., 1997]. In an earlier experimental study spontaneous nystagmus in the dark was observed after cooling of the FN [Vilis and Hore, 1981]. This, however, could not be confirmed in recent studies, and the involvement of adjacent structures (nodulus, uvula, pathways to the vestibular nuclei) must be considered as a cause. Lesions to the nodulus/uvula region are known to cause spontaneous nystagmus in the dark [Waespe et a1., 1995]. In clinical studies macrosaccadic oscillations have been related to disturbed visually guided saccades and deep cerebellar nuclei lesions [Selhorst et a1., 1976J. However, it is quite clear from clinical as well as experimental lesion studies in FN that severe saccadic dysmetria can occur without macrosaccadic oscillations [Buttner et a1., 1994; Robinson et a1., 1993J.

A erent and E erent ConnecUons The FN receives an ipsilateral input from the vermis. Lobules I-V project to the rostral FN and lobules VI-IX to the caudal FN [Noda et a1., 1990]. Also, the nodulus Oobule X) projects to the FN aside from its major projection to the vestibular nuclei [Wylie et aI., 1994]. Collaterals ofmossy fibers generally originate bilaterally from the brainstem. They derive from all vestibular nuclei (except the lateral vestibular nucleus), nucleus prepositus hypoglossi, dorsolateral and dorsomedial pontine nuclei and nucleus reticularis tegmenti pontis [Noda et a1., 1990J. A erents from climbing fibers terminate in the deep cerebellar nuclei [Van der Want et al., 1989J. Manye erent projections from the FN go to the same structures in the orainstem, fwm which the FN receive a erents, uften un the cuntralateral side (nucleus reticularis tegmenti pontis, dorsomedial and dorsolateral pontine nuclei and perihypoglossal nuclei). Projections to the vestibular nuclei are mainly contralateral, but also ipsilateral [Noda et a1., 1990J. Some deep cerebellar nuclei including FN neurons project to the cerebellar cortex [Batini et a1., 1989].

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Transmitters The FN, as all deep cerebellar nuclei, consists of heterogeneous groups of excitatory and inhibitory projection neurons and interneurons. The excitatory projection neurons are general1y larger and use glutamate as their transmitter, while the smal1er inhibitory neurons mostly use GABA as their transmitter. The GABAergic (inhibitory) neurons project mainly to the inferior olive [Fredette and Mugnaini, 1991], but some might also project to the cerebellar cortex [Batini et aI., 1989] and the pontine nuclei [Aas and Brodal, 1990J. Interneurons within the deep cerebellar nuclei probably use glycine as an inhibitory transmitter. It is well established that Purkinje cells projecting onto deep cerebellar nuclei neurons use GABA as a transmitter [Ito, 1984J. Individual Purkinje cells can innervate both inhibitory (GABA-ergic) and excitatory (non-GABAergic) neurons [De Zeeuw and Berrebi, 1995J. They also project to the (inhibitory) glycinergic interneurons [De Zeeuw and Berrebi, 1995]. The GABAinduced inhibition was thought to involve only GABA A and not GABA B receptors [Bmard et aI., 1993J. However, recently also the presence of GABA B receptors on terminals of Purkinje cells on deep cerebel1ar nuclei has been demonstrated in vitro [Mouginot and Gahwiler, 1996J. Other inputs to the deep cerebellar nuclei derive from collaterals of mossy fibres and climbing fibres. Both are excitatory and in most instances glutamate is used as a transmitter.

Outlook

The growing knowledge about the histochemistry and transmitters of the functional cell groups of the eye movement system leads not only to a better understanding of the function of the neuronal elements, but also opens the possibility to develop pharmacological treatments for eye movement disorders. There is a qUickly expanding literature on the chemical control of the cerebellum and brainstem, and it will take many more years of research to understand their interactions.

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Baimbridge KG, Celio MR. Rogers JH: Calcium-binding proteins in the nervous system. Trends Neurosci 1992; 15:303-308. Baker R, Highstein SM: Vestibular projections to medial rectus subdivision of oculomotor nucleus. J Neurophysiol 1978;41: 1629-1646. Barmack NH, Baughman R\N, Eckenstein FP: Cholinergic innervation of the cerebellum of rat, rabbit, cat, and monkey as revealed by choline acetyltransferase activity and immunohistochemistry. J Comp Neural 1992a;317:233-249. Barmack NH, Baughman RW, Eckenstein FP: Cholinergic innervation of the cerebellum of the rat by secondary vestibular a erents. Ann NY Acad Sci 1992b;656:566-579. Barmack NH, Baughman RW, Eckenstein FP, Shojaku H: Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers. J Comp Neurol 1992c;317:250-270. Batini C. Buisseret-Delmas C, Compoint C, Daniel H: The GABAergic neurones of the cerebellar nuclei in the rat: Projections to the cerebellar cortex. Neurosci Lett 1989;99:251-256. Batinl C, Compoint C, Buissert-Delmas C, Daniel H, Guegan M: Cerebellum nuclei and the nucleocortical projections in the rat: Retrograde tracing coupled to GABA and glutamate immunohistochemistry. J Comp Neurol 1992;315:74-84, Berry MM, Standring SM, Bannister LH: Cerebellum; in Gray's Anatomy (ed): Nervous System. London. Churchill Livingstone, 1995, pp 1027-1065. Bianchi R, Gioia M: Accessory oculomotor nuclei of man. 2. The interstitial nucleus of Cajal - A Nissl and Golgi study. Acta Anat 1991;142:357-365. Bianchi R. Gioia M: Fine structure of the interstitial nucleus of Cajal of the cat. J Anat 1995; 187: 141-150. Billard JM, Vigot R, Batini C: GABA, THIP and baclofen inhibition of Purkinje cells and cerebellar nuclei neurons. Neurosci Res 1993; 16:65-69. Blanks RHI: A erents to the cerebellar flocculus in cat with special reference to pathways conveying vestibular, visual (optokinetic) and oculomotor signals. J Neurocytol 1990;19:628--£42. Blanks RHI, Precht W, Torigoe Y: A erent projections to the cerebellar flocculus in the pigmented rat demonstrated by retrograde transport of horseradish peroxidase. Exp Brain Res 1983;52:293306. BUttner U, Buttner-Ennever JA: Present concepts of oculomotor organization, Rev Oculomot Res 1988; 2:3-32. BOttner U. BOttner-Ennever JA. Henn V: Vertical eye movement related activity in the rostral mesencephalic reticular rormation of the alert monkey. Brain Res 1977;130:239-252. BOttner U, Fuchs AF, Markert-Schwab G, Buckmaster P: Fastigial nucleus activity in the alert monkey during slow eye and head movements. J Neurophysiol 1991;65:1360-1371. Buttner U, Grundei T: Gaze-evoked nystagmus and smooth pursuit deficits: Their relationship studied in 52 patients. J Neurol 1995;242:384-389. BOttner U. Helmchen C, Buttner-Ennever JA: The localizing value of nystagmus in brainstem disorders, Neuroophthalmology 1995; 15:283-290. BOttner U, Straube A: The e ect of cerebellar midline lesions on eye movements. Neuraophthalmology 1995; 15:75-82. I3tittner U, Straube A, Spuler A: Saccadic dysmetria and 'intact' smooth pursuit eye movements after bilateral deep cerebellar nuclei lesions. J Neurol Neurosurg Psychiatry 1994;57:832-834. Btittner U, Waespe W: Purkinje cell activity in the primate flocculus during optokinetic stimulation, smooth pursuit eye movements and VOR-suppression. Exp Brain Res 1984;55:97-104. Btittner-Ennever JA: Patterns of connectivity in the vestibular nuclei. Ann NY Acad Sci 1992a;656: 363-378. Btittner-Ennever JA: Paramedian tract cell groups: A review of connectivity and oculomotor function; in Shimazu H, Shinoda Y (eds): Vestihular and Brain Stem Control of Eye, Head and Body Movements. Basel, Japan Scientific Societies Press/Karger. 1992b, pp 323-330. BOttner-Ennever JA, Akert K: Medial rectus subgroups of the oculomotor nucleus and their abducens internuclear input in the monkey. J Comp Neural 1981;197:17-27. BOttner-Ennever JA, Buttner U: Neuroanatomy of the oculomotor system. The reticular formation. Rev Oculomot Res 1988;2: 119-176.

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Blittner U. (ed): Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger, 1999, vol 55, pp 26-81

Intrinsic Physiological and Pharmacological Properties of Central Vestibular Neurons Pjerre-Paul VMaJ", Njcolas Vjber(", Mauro Serafin b, Alexander BabaJjan a, Mjchel A1{jhlethalerb, Catherjne de Waele a a b

Neurobiologie des Reseaux Sensorimoteurs, CNRS UPRES-A 7060, Paris, France et Departement de Physiologie, Centre Medical Universitaire, Geneve, Suisse

Introduction

Oculomotor and postural stabilizing responses result from a complex multisensory integration, which can be defined as the process of matching multiple internal representations of an external event (head and/or body movement) obtained through di erent sensory modalities (visual, vestibular and proprioceptive) , into a unique, intrinsic frame of reference in which appropriate motor commands can be coded. It is therefore not surprising that such complex sensorimotor transformations are disturbed by aging, by pathological damage to the inner ear or eye muscles, by excessive natural stimulation and/or by exposure to conflicting sensory perceptions. Hence, to be accurate enough to provide a correct estimation of body position and self-motion during the whole life span, the stabilizing, oculomotor and postural responses must display a high degree of plasticity. We are therefore dealing here with a model involving the maintenance of a stable, internal representation of self-motion by the central nervous system (eNS) in a continually changing internal and external environment. From an experimental point of view, several characteristics of the motor synergies stabilizing gaze and posture make them suitable for neurophysiological studies: these reflexes have a well-defined goal, and require computation of the parameters underlying self-motion. Moreover, both the inputs (retinal slip of the visual world detected by the eyes, velocity of the head given by the vestibular system, etc....) and the static and dynamic motor responses to these inputs (eye and head movements, changes in skeletal geometry) are quantifiable with great precision IVibert et al., 1997J.

As a result, the neuronal operations underlying gaze and postural control have been intensely scrutinized for the past 30 years using electrophysiological recordings as well as morphological and electroanatomical methods [for reviews, see Baker et aI., 1981; Berthoz, 1989], which led to the elaboration of realistic models describing the underlying neuronal computations. Amongst other examples, it was shown that the central vestibular networks could integrate (in the mathematical sense of the term) a velocity signal into a position signal, and that they were segregated in frequency-tuned channels. In addition, the gains of vestibula-ocular and vestibulospinal pathways have been shown to change according to vigilance and following learning; the dea erented vestibular neurons are even able to recover a normal resting discharge in a few days following labyrinthine dea erentation [for reviews, see Berthoz, 1985; Smith and Curthoys, 1989; Cohen et al.. 1992; Kawato and Gomi, 1992; Barnes, 1993; Curthoys and Halmagyi, 1995; Dieringer, 1995; du Lac et a!., 1995J. All these remarkable features are extremelyinteresting in one vital respect:

these complex neuronal operations can be very precisely related to behavior. The neuronal computations underlying gaze and postural control will be, as all operations in the CNS, the by-product of both the emerging properties of the vestibular networks and the individual properties of their components, i.e. the neurons. This chapter deals with the individual properties of central vestibular neurons, which can be broadly segregated in two categories. First, in vitro studies have demonstrated that all vertebrates' neurons are endowed with specific nonlinear, intrinsic membrane properties, which confer to them complex integrative capabilities [Llinas, 1988]. Second, multiple pre- and postsynaptic receptors responding to various neurochemical compounds have been shown to influence the time course and the nature of the response of any given neuron to its main synaptic inputs. The membrane properties and neuropharmacological profile of neurons have been investigated both in vivo and in vitro using electrophysiological recordings. However, these methods have their limitations. Action potentials are all-or-none phenomena in a neuron, but they can be generated by a variety of di erent mechanisms. Furthermore, molecular biology has revealed the existence of various subclasses of the main neurotransmitter receptors expressed by vestibular neurons. These di erent subclasses can have markedly di erent distributions, and their activation often induces distinct electrophysiological or biochemical responses in di erent subsets of neurons. However, few specific ligands have yet been described for most of these receptors, which precludes the use of electrophysiological methods to study their involvement in vestibular-related computations. On the other hand, recent morphological methods such as in situ hybridization, which detects the expression of messenger RNAs leading to the synthesis of receptors, can be used in various behav-

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ioral contexts. Therefore, to understand how the emerging properties of the vestibular network combine with the physiological and pharmacological properties of its constituent elements to stabilize gaze and posture requires the use of complementary neurobiological methods, in several types of in vivo and in vitro preparations. Needless to say, such investigations pave the way for new pharmacological treatments of vestibular syndromes, and could have even wider clinical applications since vestibular compensation has been shown to be a valuable model of postlesional plasticity in the CNS.

Physiological Properties of Central Vestibular Neurons

This part of the chapter presents our current knowledge of the individual membrane and discharge properties of vestibular nuclei neurons. Indeed, these properties deeply constrain how these neurons process the information they receive from their various a erences, which include visual, vestibular, and proprioceptive pathways, as well as cerebellar and cortical inputs [for reviews, see Highstein and McCrea, 1988; Berthoz, 1989; Schor et aI., 1992; Shinoda et aI., 1993J. In addition, these properties of central vestibular neurons can be strongly modulated by various neurotransmitters and neuromodulators, as described in the next part of the chapter.

Scientific Context

Most studies have focused on medial vestibular nucleus neurons (MVNn). As an example, we will mainly describe the results we obtained using intracellular recordings in guinea pig brainstem slices [Serfin et aI., 1991a, bJ and in the isolated whole brain [Babalian et aI., 1997J which can be compared with the results of the various studies made in the same species, in either acute or awake preparations. The functional anatomy [Curthoys et al.. 1975; Vidal et aI., 1986; de Waele et aI., 1989b; Graf et aI., 1995a, bJ and performance [Gresty, 1975; Pettorossi et aI., 1986; Mirenowicz and Hardy, 1992; Escudero et aI., 1993; Escudero and Vidal, 1996; Vi bert et aI., 1993] of the guinea pig's oculomotor system have been well described. Morphological and electrophysiological in vivo studies have unraveled the main structural and physiological characteristics of its central vestibula-ocular networks [Azzena et aI., 1976; Curthoys, 1982; Gstoettner and Burian, 1987; Smith and Curthoys, 1988; Yagi and Ueno, 1988; de Waele et aI., 1988; Marlinsky, 1992; Ris et aI., 1995; Murofushi et aI., 1996J.

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28

Finally, the intrinsic membrane properties of MVNs will be compared with those of two other classes of cells involved in postural and oculomotor control, the reticular neurons of the gigantocellular nucleus, and the prepositus hypoglossi nucleus neurons [Serafin et aI., 1996a, b].

MVN Neurons Physiological Properties: In vivo Recordings We tried to investigate the functional significance of the intrinsic membrane properties of vestibular neurons in two ways: by quantifying the discharge of these neurons in vivo, and by recording them in a preparation of isolated, in vitro whole brain to try to correlate the results of slice recordings with in vivo data. The activity of identified, second-order vestibular neurons was recorded at rest and during horizontal sinusoidal head rotations in the head-fixed, alert guinea pig. At rest, second-order MVNn formed a continuum between regularly and irregularly discharging cells [Serafin et aI., 1994: Ris et al., 1995], as already described in other species [Precht and Shimazu, 1965; Shimazu and Precht, 1965]. Their mean coe cient of variation (CV) amounted to 0.50, and their mean discharge rate to about 30 Hz. These two variables were highly correlated. During natural vestibular stimulation, second-order MVNn coded head velocity. Some of them were sensitive to the horizontal component of eye position, and half of these cells displayed some modification of their firing rate during the qUick phase of vestibular nystagmus. They decreased their discharges during quick phases oriented towards the side ipsilateral to their soma, and generated a burst of impulses during quick phases towards the contralateral side. Altogether, these firing characteristics are very similar to those of the horizontal, second-order vestibular neurons observed in cats and monkeys [Berthoz et aI., 1989; Scudder and Fuchs, 1992J. The regularity of the resting discharge of both first- and second-order vestibular neurons in vivo has been used as a convenient marker of their dynamic properties. Very approximately (since regular and irregular cells actually form a continuum), tonic, regular primary a erents tend to have a lower gain and a slower conduction velocity than the irregular, phasic cells [Goldberg and Fernandez, 1971; Yagi et al., 1977; Goldberg et al., 1984J. What are the functional implications of that segregation? One hypothesis states that the tonic first- and second-order vestibular neurons would mainly encode low-frequency head movements, and would be mostly involved in static postural and oculomotor control. The kinetic cells would in contrast encode high-frequency stimuli, and would playa major role in the stabilization of gaze and posture during fast, transient postural perturbations. According to

Intrinsic Properties of Central Vestibular Neurons

29

several authors, the whole vestibular network controlling gaze and posture would actually be organized in frequency-tuned channels [Baker et aI., 1981; Godaux et ai., 1983; Lisberger et ai., 1983]. Indeed, the inputs of regular and irregular, first -order vestibular neurons remain partly segregated at the level of second-order vestibular neurons [Goldberg et ai., 1987; Highstein et aI., 1987; Sato and Sasaki, 1993]. On the other hand, the oculomotor plant has widely di erent biomechanical properties from the other mobile segments of the body (neck, trunk, limbs). Therefore, it has also been proposed that the tonic MVNn would mostly control the oculomotor system, while the kinetic cells would be more involved in vestibulospinal synergies [Highstein et aI., 1987; Iwamoto et aI., 1990; Boyle et ai., 1992]. In alert guinea pigs, the irregular second-order MVNn that we have recorded did not have a higher sensitivity to vestibular stimulation than the regular ones. However, we have been unable to record these irregular cells at frequencies higher than 3 Hz, which is probably insu cient to reveal the di erent dynamic sensitivities of these two types of cells. An opposite hypothesis [Angelaki and Perachio, 1993] would be that the irregular a erents are mainly used to modulate VOR amplitude during constant velocity rotations. They would specifically input the velocity storage integrator included in the vestibula-ocular network, which improves the compensatory properties of the VOR at low frequency and in response to longduration, step changes in angular velocity.

MVN Neurons Intrinsic Membrane Properties: Slice Recordings Oi erent Types of MVN Neurons Intracellular recordings in guinea pig's brainstem slices [Serafin et ai., 1991a, b] led us to define two main classes of MVNn, according to their intrinsic membrane properties. Similar properties have been observed for rat and chick MVNn [Gallagher et aI., 1985; Outia et ai., 1995; du Lac and Lisberger, 1995]. It should be emphasized however that, as pointed out by du Lac and Lisberger [1995], this segregation in two subclasses is somewhat artificial, in the sense that the membrane properties of MVNn are actually distributed as a continuum in between the two stereotyped schemes corresponding to canonical A and B cells (see the intermediate types classified as type C neurons in Serafin et al. [1991a, b]). Type A MVNn (about 30% of recorded cells) are characterized by wide action potentials ( 1 ms at threshold) followed by a deep, single afterhyperpolarization (AHP). They also exhibit a transient rectification due to the activation

VidaINibertiSerafin/Babaiian/Miihlethaler/de Waele

30

of an lA-like, 4-aminopyridine-resistant conductance. Finally, type A MVNn display small, high-threshold calcium spikes potentiated by barium. Type B MVNn (about 50% of recorded cells) are in contrast characterized by thinner action potentials, and a double-component AHP including a first, fast and small component followed by a delayed and slower one. The overall amplitude of this AHP is lower than for type A MVNn. Type B MVNn also displays large, high-threshold calcium spikes and prolonged, calciumdependent plateau potentials, as well as a persistent, subthreshold sodium conductance. Finally, about one quarter of B MVNn, namely type B LTS MVNn, displayed low-threshold calcium spikes (LTS) that confer to them bursting properties. All types of MVNn display a spontaneous, regular discharge in slices (mean frequency of about 10 Hz) which persists when synaptic transmission is blocked, leading to the hypothesis that their resting activity may partly rely on pacemaker properties of the membrane of these cells [for review, see Darlington et aI., 1995].

Rhythmic Activity in Type B MVN Neurons In rare cases, type B MVNn neurons can spontaneously display an oscillatory discharge with regular bursts of two or more action potentials. On the other hand, this rhythmic activity could be elicited very easily by perfusing various pharmacological compounds in the bath. The frequency and duration of these oscillatory discharges were always voltage-dependent. The three following types of oscillations were observed: Addition of2.10 4 MN-methyl-D-aspartate (NMDA) in the bath induced a long-lasting oscillatory behavior in type B cells (but not in type B LTS MVNn) hyperpolarized (by 10-30 mY) from their resting membrane potentia] [Serafin et aI., 1992aJ. These membrane potential oscillations were tetrodotoxin (TTX)-resistant, and could be suppressed by APV, a specific NMDA antagonist, or by replacing sodium with choline. Perfusion ofthe slice with a low Ca 2 Ihigh Mg 2 -containing solution (which suppresses synaptic transmission) also triggered a rhythmic discharge [de Waele et aI., 1993] in slightly hyperpolarized type B MVNn (but not in the B LTS ones). This behavior was APV-resistant, but could be suppressed by TTX. M apamin, a selective blocker of one type of calcium-dependent potassium conductance (the SK channels), induced rhythmic burst firing on slightly hyperpolarized cells of the Band B LTS subtypes [de Waele et aI., 1993J. This oscillatory behavior was APV-resistant, but could be abolished by TTX or with ouabain, a specific antagonist of the active sodium pump.

Intrinsic Properties of Central Vestibular Neurons

31

Neuronal oscillations are by no mean restricted to vestibular neurons. NMDA-induced oscillations were observed in abducens motoneurons [Durand, 1993], in the spinal cord, the caudate nucleus, the cortex [for review, see Serafin et al., 1992a], and in cholinergic nucleus basalis neurons of the basal forebrain [Khateb et aI., 1995]. In vitro recorded thalamocortical cells can display either a tonic firing mode or an oscillatory discharge, and can switch from one to the other in response to various modulatory transmitters [for review, see McCormick, 1992].

MVN Neurons Intrinsic Membrane Properties: Recordings in the in vitro Whole Brain The overall viability of the vestibula-ocular network in the isolated whole brain preparation (IWB) has been precisely assessed in a recent study [Babalian et al., 1997]. The advantage of the IWB preparation is that, since the connectivity of the brain is preserved, stable intracellular recordings revealing the intrinsic membrane properties of neurons can be made in functionally identified groups of cells. Field potential recordings can be used in association with stereotaxic atlases [Gstoettner and Burian, 1987] to localize unambiguously small brain regions like the abducens nucleus ( 1 mm~. The abducens nucleus was then used as landmark to localize other neighboring structures such as the medial vestibular nucleus, the prepositus hypoglossi nucleus and to characterize the recordings obtained in the reticular formation. The four known types of medial vestibular nucleus neurons (types A, B, B LTS and C) were recorded in the isolated brain, with similar membrane properties than on slices (fig. 1). This means that this classification was not an artifact of the slice preparation. 80-85% of the MVNn recorded in the IWB could be identified as second-order cells, in which stimulation of the stump of the ipsilateral vestibular nerve evoked monosynaptic, excitatory postsynaptic potentials (EPSP). This proportion did not vary Significantly among the MVNn cell types. Stimulation of the contralateral vestibular nerve evoked di- or trisynaptic inhibitory postsynaptic potentials (IPSP) in about 75% of these second-order neurons, in accordance with previous in vivo studies [Shimazu and Precht, 1966; Precht et al., 1973]. The mean resting discharge of second-order MVNn amounted to about 10 Hz, similar to that found in slices or in anesthetized guinea pigs [Smith and Curthoys, 1988] but lower than the average 36 Hz obtained in the alert guinea pig [Ris et aI., 1995]. A crucial di erence was that second-order MVNn, which all discharged regularly on slice, displayed highly variable spontaneous activities in the IWB, like in vivo (fig. 2). Whereas type A cells had regular

Vidal/Vibert/SerafinlBabalian/Muhlethaler/de Waele

32

3

2

A

B

4

-l,- >~_) tlLUJ 16

-L,- 14- illlli ~ >

'[T~~ l

lliL1l1~, Iwm' lOOms

Fig J. Identification of three distinct cell types in the region of the MVN of isolated whole brains [reprinted with perrrtission from Babalian et aI., 19971. Intracellular recordings from individual type A (first row), type B (second row) and type B LTS (third row) vestibular neurons at resting potentials of 66, 64 and 58 mY, respectively. Column I: Individual spikes shOWing the single component AHP (arrow) of type A neurons and the double component AHP (single and double arrows) of type Band B LTS neurons. Column 2: Response of neurons to current pulses passed through the intracellular electrode. Arrowheads indicate the level of the resting membrane potential. The dot shows the slowing down of the repolarization of a type A neuron after a hyperpolarizing pulse, possibly due to an IA like rectifying current. Depolarizing pulses applied from a hyperpolarized level of membrane potential produce an LTS-like response with superimposed spikes (asterisk) in B LTS neurons, but ordinary spikes in B neurons. Column 3: Spontaneous discharge of the three neurons. Column 4: Monosynaptic activation of the neurons by stimulation of the ipsilateral vestibular nerve.

firing rates, type Band B LTS cells could present very irregular patterns of spontaneous activity. More precisely, while type B MVNn tended to be more irregular than type A neurons, they actually displayed a wide range of CVs (from 0.09 to 0.77), with the more regular type B MVNn being as regular as type A cells. Basically, the regularity of type B MVNn seems to depend on the amount of spontaneous synaptic activity reaching each neuron, whereas type A MVNn would be less sensitive to synaptic inputs. The type A and type B (including B LTS) MVNn identified in vitro in the IWB appeared

Intrinsic Properties of Central Vestibular Neurons

33

~ type A VNn

1O

•

CIl

c:

2:::l

8

'"c:

6

"-'

type B VNn

0

....

4

E :::l

2

15 c:

0

a

N.

"l. v.

0

0

0

"'0

"'. "". 0

0

<Xl. 0

"'.

A

-.

q

0

N.

"l. v.

CV

c: 0

.

•

0,8

c

":;l

'" "@ ....>0 i:

0,2

'"0 U

0,0

i:B

•

0,4

'"

"C

•

0,6

type A type B type B+LTS

B 15

1O

5

20

25

AHP (mV)

•

15 CIl

c:

2:::l

....'"c:

extracell ular

10

0

....

'"

.0

E :::l

c:

0

N

C')

V

Ll)

a a a a a

"'. "". 0

0

a:>.

0

"'. 0

e o.

~.

"!. "l. v.

CV

Fig 2. Characteristics of the spontaneous discharge of second-order VNn in the isolated whole brain [reprinted with permission from Babalian et aI., 19971. A Histogram showing the distribution of cae cients of variation for spontaneous discharges of type A (gray columns) and type B (black columns) cells" B Diagram displaying the relationship between AHP amplitudes (abscissa) and CVs (ordinate) for type A (open squares), type B (dots), ilnd type B LTS (fiJled squilres) neurons. The slope of the regression line is 0.018. e Distribution of CVs for spontaneous discharges of extracellularly-recorded units.

Vidal/Vibert/SerafinlBabalian/Muhlethaler/de Waele

34

therefore to correspond to the regular and irregular second-order vestibular neurons described in vivo. Note that in both cases, we are dealing with a continuum. In addition, stimulation of the ipsilateral eighth nerve could often trigger, in type B MVNn, long subthreshold plateau potentials on top of the monosynaptic evoked EPSP, sometimes following evoked action potentials. Similarly, the eighth nerve shock could induce low-threshold spikes with superimposed bursts in second-order, type B LTS neurons maintained slightly hyperpolarized. These nonlinear responses were obtained without any pharmacological manipulation, which supports the hypothesis that the membrane properties of MVNn described on slices could have a functional significance in the behaving animal.

Oscjllatory Behavior of MVN Neurons: Functional Speculations Up to now, there is no direct experimental evidence of a functional relevance of the MVNn oscillations. The simplest hypothesis would be that these oscillations are just a side e ect of the artificial MVNn exposure to exogenous, biologically-active compounds. For instance, apamine perfusion would be e ective because it completely blocks part of the Ca 2 -dependent K channels, which are indeed the target of various endogenous neuromodulators [for reviews, see Nicoll et ai., 1990; McCormick, 1992J. The neuronal oscillations observed in slices, the head oscillations induced by unilateral infusion of apamin into the vestibular complex of alert guinea pigs [de Waele et aI., 1993J would be the consequence of a nonphysiological blockade of these Ca 2 dependent conductances. The same reasoning could apply to NMDA-triggered oscillations, which could be a side-e ect of a nonphysiological, massive activation of all the NMDA receptors present on the MVNn membranes. Another pOSSibility would be that the MVNn oscillations result from an inherent instability of these cells, a side e ect due to the particular set of membrane conductances they have to express in order to properly encode head velocity in space. In that context, the periodic discharges recorded in vitro would be functionally irrelevant. Nevertheless, it could reveal a tendency of MVNn to oscillate in some unusual contexts, leading in vivo to pathological syndromes. Very prolonged exposures to conflicting sensory information [Collewijn, 1979; de Waele et aI., 1989a] led for instance to long-lasting oscillations of the rabbit and guinea pig oculomotor system, in the absence of any sensory activation. Similarly, the mal de debarquement syndrome, or some of the vertigoes of central origin, could be related to such putative, pathological oscillations of the MVNn in vivo.

Intrinsic Properties of Central Vestibular Neurons

35

During locomotion, vestibular neurons discharge rhythmically in phase with extensor limb activity in cat [Orlovsky, 1972J and guinea pig [Marlinsky, 1992J. Moreover, NMDA-induced oscillations in spinal motoneurons induce fictive swimming in the lamprey spinal cord preparation [Headley and Grillner, 1990; Hochman et al., 1994]. Therefore, the activation of the MVNn NMDA receptors during locomotion could help these neurons to sustain an oscillatory mode of activity. Finally, both NMDA receptors and neuronal oscillations such as the rhythm [Larson et aI., 1986; Steriade et aI., 1993] have been involved in CNS plasticity. Given the extremely developed adaptive properties of vestibuloocular and vestibulocollic synergies, MVNn oscillations might contribute to plastic modifications of the vestibular network. Some of the MVNn, playing a key role in these plastic processes, the so-called floccular target neurons, receive a powerful inhibitory drive from the cerebellum which could initiate the oscillatory behavior. More generally, several authors suggested that oscillations are used as a tool by the CNS to synchronize populations of neurons [for review, see Steriade et aI., 1993J. In invertebrates [for review, see Meyrand et aI., 1994], switching neurons to an oscillatory mode of firing allows to reconfigure complex neuronal networks according to the behavioral context.

MVN Neurons Intrinsic Membrane Properties: Functional Speculations We and others [Gallagher et aI., 1985; Dutia et aI., 1995; du Lac and Lisberger, 1995] have compared the physiological characteristics of MVNn in vivo and in vitro to search whether the heterogeneous, highly nonlinear membrane properties of these neurons may have a functional relevance. It must be stressed first that these membrane properties are not artifacts ensuing from the slicing procedure. Indeed, the same nonlinear responses could be recorded both in the IWB and on slices. This is quite reassuring in the sense that in the IWB, MVNn keep their normal connections; their axonal and dendritic trees are preserved. Moreover, LTS and plateau potentials were obtained without any pharmacological manipulation. Not surprisingly, our results confirm that the regularity ofMVNn is linked with their intrinsic membrane properties. In vivo, the regularity of the resting discharge has been used as a convenient marker of the dynamic properties of first- and second-order vestibular neurons: regular and irregular MVNn could correspond to tonic and phasic neurons, respectively. Therefore, the regular, tonic MVNn in vivo would correspond, in vitro, to the regular, type A MVNn. The irregular phasic MVNn in vivo would correspond in vitro to the irregular, type B MVNn. The membrane properties would then contribute to determine

Vidal/Vibert/SerafinlBabalian/Muhlethaler/de Waele

36

the dynamic properties ofMVNn. We have seen that the inputs of the regular and irregular, first -order vestibular neurons remained partly segregated at the level of second-order vestibular neurons, which would lead to the segregation of the vestibular networks in frequency-tuned channels. This segregation might therefore rely on the distinct membrane properties of the neurons involved in these di erent channels. In these schemes, MVNn having the same connectivity should altogether display a whole range of widely di erent membrane properties. In line with that hypothesis, the study of du Lac and Lisberger [1995J demonstrates that the cellular properties of MVNn indeed contribute to the processing of temporal information in VOR pathways. Our own model of intracellularly-recorded MVNn also indicates that their membrane properties are strong determinants of their dynamic properties [Av-Ron and Vidal, 1997J. On the other hand, our results in the guinea pig do not fit with the hypothesis that the regular and irregular vestibular neurons would correspond to the vestibula-ocular and vestibulospinal neurons, respectively [Highstein et aI., 1987; Iwamoto et a!., 1990; Boyle et aI., 1992J. In the IWB, a similar proportion of regular and irregular neurons were identified as vestibulospinal neurons by their antidromic activation from the cervical spinal cord [Babalian et aI., unpubl. observationsJ. The subthreshold plateau potentials evoked in the second-order (irregular) type B MVNn by orthodromic stimulation of the eighth nerve in the IWB raise the question of the capability of these neurons to 'store' information transmitted by the sensory vestibular a erents. For example, temporal summation of these long-lasting plateau potentials could be one of the neuronal mechanisms underlying the velocity storage system included in vestibuloocular networks [Raphan et a!., 1979J. This would fit well with the hypothesis of Angelaki and Perachio [1993] stating that irregular neurons would specifically input the velocity storage integrator. The plateau potentials of type B MVNn could also playa role in the transformation of the head velocity signal into a position signal by the so-called neuronal integrator [for reviews, see Fukushima et aI., 1992; Anastasio, 1994] localized in the prepositus hypoglossi nucleus (PHN) and the medial vestibular nucleus [Baker et a!., 1981; Fuchs, 1981; Godaux et aI., 1993J. In this respect. it is interesting to note that the type B neurons recorded in the PHN exhibit the same plateau potentials as type B MVNn [Serafin et aI., 1996b]. Finally, we would like to ask what could be the functional correlate(s) of the low-threshold spikes recorded in B LTS MVNn? We have proposed that these LTS could participate in vivo to the burst of discharge recorded in second-order MVNn during the fast phases of nystagmus [Serafin et aI., 1990]. However, irregular B LTS MVNn represented only 10-15% of all MVNn recorded in the IWB, whereas studies in the alert guinea pig have shown that

Intrinsic Properties of Central Vestibular Neurons

37

at least 50% of MVNn bursted during fast phases, whatever the regularity of their resting discharge. Hence, LTS was clearly not a prerequisite for this phasic activity to occur. The functional relevance of LTS remains therefore to be determined.

Membrane Properties of Other Types of Neurons Participating in Gaze Control. Towards a Unifying Scheme?

Assuming that the intrinsic membrane properties of the MVNn could help to specify the various dynamic properties of these neurons, and assuming that the existence of frequency-tuned channels are a valid hypothesis, then other types of neurons which participate in gaze and postural control should display the same type of various membrane properties as the MVNn. We have tried to answer that question by exploring the membrane properties of the gigantocellular reticular nucleus neurons (GCRNn) and of the prepositus hypoglossi nucleus neurons (PHN n). GCRNn have been mainly involved in locomotion, respiration and stabilization of gaze and posture [for reviews, see Vertes, 1979; Peterson, 1984; Grantyn and Berthoz, 1987]. They are input by visual, vestibular and somatosensory a erents, and are under both tectal and cortical control. GCRNn are organized in a somatotopic way, and project onto motoneurons at every level of the spinal cord [for reviews, see Peterson, 1979, 1984]. In guinea pig's brainstem slices [Serafin et aI., 1992b, 1996a], we have shown that they were endowed with intrinsic membrane properties which were strikingly similar to those of MVNn. GCRNn could indeed be subdivided in the same type A and type B cells, even if no B LTS neuron could be found in this nucleus. It is noteworthy, however, that pontine reticular neurons probably involved in gaze control [Vidal et aI., 1983; Grantyn and Berthoz, 1987] displayed LTS in vitro [Greene et aI., 1986]. Both regular and irregular GCRNn were found in vivo [Siegel, 1979; Vertes, 1979; Steriade et aI., 1984] and in the isolated whole brain [Serafin et al., 1992b]. As a first approximation, the regular neurons recorded in the IWB tend to be mostly type A cells, whereas the majority of type B neurons seem to have an irregular resting discharge. As mentioned above, the PHNn playa major role in oculomotor control: in close association with MVNn, they transform a velocity signal arising from the MVN into a position signal necessary to control the eye movements. We are currently investigating the intrinsic membrane properties of PHNn on guinea pig's brainstem slices [Serafin et aI., 1996b]. Again, these neurons are endowed with intrinsic membrane properties strikingly similar to those of MVNn and GCRNn. Type A, type B and type B LTS neurons could be

VidaINibertiSerafin/Babaiian/Miihlethaler/de Waele

38

found in the PHN. A fourth, distinct type of neurons displayed subthreshold oscillations and spontaneous clusters of spikes in addition to a strong, lA-like current. This last cell type is very similar to cells recorded within the basal forebrain, a structure of the diencephalon known to be strongly involved in cortical activation across the sleep-waking cycle [Khateb et at., 1995). Given the tight dependency of oculomotor behavior on the vigilance level [MelvillJones and Sugie, 19721, these cells might be involved in some of the interactions between the neuronal structures underlying gaze control and those setting the level of vigilance. Finally, both in vivo and in vitro intracellular recordings revealed that the membrane properties of abducens motoneurons, which display highly phasic firing patterns in vivo, were rather similar to those of type B MVNn [Durand, 1989; Babalian et al., 1997J. In summary, the description of intrinsic membrane properties of other types of brainstem neurons also involved in gaze control tend to support the hypothesis that: (a) these membrane properties contribute to shape the dynamics of responses of any given class of neurons; (b) they could participate in the segregation of neuronal networks controlling gaze and posture in frequency-tuned channels. Such concepts could also apply to the networks controlling respiration, locomotion, etc. However, a large part of these nonlinear membrane properties could also contribute to other aspects of neuronal processing, such as integration. Finally, the functional relevance of some of the characteristics of the recorded brainstem neurons still remain unknown.

Neurotransmitters and Neuromodulators of the Vestibular Neurons

We will subdivide the neurotransmitters acting on central vestibular neurons in three main groups. The excitatory and inhibitory amino acids, which include aspartate, glutamate, GABA and glycine, mediate fast synaptic events by acting mainly on postsynaptic, ionotropic receptors. The five monoamines (histamine, dopamine, serotonin, noradrenaline, and adrenaline) constitute a second category, together with acetylcholine. They have more di use and moderate e ects on vestibular neurons. Most of them activate only metabotropic receptors acting through second messenger systems, and have therefore much slower actions on the neuronal activity [Hille, 1992). Finally, several neuroactive peptides have been shown to be e cient on vestibular nuclei neurons. A brief technical comment: both in case of in vivo microiontophoretic applications, or of in vitro bath application on slice, the e ects of a tested

Intrinsic Properties of Central Vestibular Neurons

39

compound on any given neuron normally represent the summation of the direct e ect of the drug on the recorded cell combined with the action of the drug on the inhibitory and excitatory (inter)neurons contacting the neuron under scrutiny. On slice and in the IWB, synaptic transmission can be blocked by perfusing a high Mg 2 low Ca 2 solution, or adding TTX to the bath. It is therefore possible to isolate the e ect of the drug on the recorded neuron, and to record it independently of the rest of the network.

The Excitatory and Inhibitory Amino Acids in Vestibular Networks The excitatory and inhibitory amino acids (EAA and IAA) include aspartate and glutamate on one side, and GABA and glycine on the other side. Glutamatergic receptors can be subdivided into ionotropic and metabotropic receptors, named after their main specific agonists [for review, see Nakanishi, 1992]. The ionotropic receptors include the AMPA/kainate and NMOA receptors, while the eight distinct metabotropic receptors sensitive to trans-ACPO can be divided into three main groups [Pin and Ouvoisin, 1995).

Excitatory Amino Acid (EAA) Receptors of the Vestibular Nuclei Neurons Anatomical studies have revealed the presence of all types of EAA receptors in the vestibular nuclei [for reviews, see Raymond et aJ., 1988; de Waele et aI., 1995; Vidal et aI., 1996). including metabotropic receptors of the mGluRl, mGluR2, mGluR5 and mGluR7 subtypes [Shigemoto et aI., 1992; Ohishi et aI., 1995; Neki et aI., 1996]. In situ hybridization techniques have also revealed some of the subunits which compose ionotropic EAA receptors in the vestibular nuclei: high densities of the four subunits of the AMPA receptors (GluRl, GluR2/3, GluR4), and of the Rl and R2C subunits of the NMOA receptors were detected, whereas the R2B and R20 subunits were expressed at lower levels [Petralia and Wenthold, 1992; de Waele et aI., 1994; Watanabe et aI., 1994]. These anatomical data fit with numerous in vitro, electrophysiological studies which demonstrated that vestibular neurons are responsive to both agonists and antagonists of the AMPAIkainate, NMOA and trans-ACPO receptors [for reviews, see Gallagher et aI., 1992; Smith et aI., 1992; de Waele et aI., 1995; Vidal et aI., 1996). Moreover, most MVNn are depolarized by AMPA, kainate, NMOA and trans-ACPO [Vibert et aI., 1992, 1994), whatever their intrinsic membrane properties (table 1). Given the persistence of these

VidaINibertiSerafin/Babaiian/Miihlethaler/de Waele

40

Table 1. E ects of excitatory amino acids on MVNn recorded in slices: the nature and number of e ects obtained with six agonists of the excitatory amino acid receptors on the various parameters characterizing intracellularly-recorded MVNn are given for type A. type B and type B LTS neurons

Experimen tal conditions

Control

potential and discharge

Type A neurons

20

Type B neurons

20

Type B LTS neurons

TTX

NMOA

AMPA

121

(95%)

120

resistance

13

114

potential and discharge 22

124

(93%)

(92%)

8

31

18

135

Control

17

120

180

(88%)

(85%)

(56%)

14

26

8

117

126

(82%)

(100%)

(25%)

10

4

13

4 15

8

6

(80%)

(100%)

110

(100%)

12

14

(100%)

112

114

(93%)

31

(100%)

20

131

13

(100%) /14

120

14

18

(19%)

113

(100%)

250/31

150/18

(81%)

(83%)

16

/]4

116

(100%)

(100%)

(100%)

Kainate

Quisqualate

Glutamate

potential and discharge 6

Type B neurons

8

Increase;

18

resistance

(89%)

Type A neurons

Type B LTS neurons

7

potential and discharge

(100%)

14

Experimen tal conditions

resistance

(100%)

(100%)

Synaptic uncoupling

Trans-ACPO

resistance

16

6

(100%)

19

(89%) 3

resistance

16

14 115 (93%)

13

5

15

(100%) 3

13

(100%)

potential and discharge

12

113

(92%)

5

16

4 18 (50%)

(83%)

I

II

(100%)

no e ect.

Intrinsic Properties of Central Vestibular Neurons

resistance

4 15 (80%)

(100%)

(100%)

decrease; 0

potential and discharge

41

responses both during bath application of TTX and in a high Mg 2 flow Ca 2 -containing solution, all these responses are at least partly mediated by postsynaptic receptors [see also Darlington and Smith, 1995J. As mentioned above, long-term NMDA perfusion can generally induce a long-lasting oscillatory behavior in type B MVNn [Serafin et aI., 1992a]. There is now a general agreement that an excitatory amino acid like glutamate and/or aspartate mediates synaptic transmission between first- and second-order vestibular neurons [for reviews, see Raymond et aI., 1988; Gallagher et aI., 1992; de Waele et aI., 1995; Yamanaka et aI., 1997J. Also, at least in the frog, several groups of a erents to the vestibular nuclei such as the proprioceptive fibers originating in the spinal cord and the excitatory commissural pathways linking together the two vestibular complexes use glutamate and/or aspartate as transmitter [Cochran et aI., 1987; Dieringer, 1995J. Finally, the excitatory second-order vestibular neurons which input the contralateral abducens motoneurons and some of the spinal motoneurons involved in postural stabilization are also believed to release excitatory amino acids [for reviews, see Raymond et aI., 1988; de Waele et aI., 1995; Dieringer, 1995J.

Pharmacological Analysis of EAA-Mediated Synaptic Transmission in the MVN The contribution of NMDA receptors to the synaptic transmission between first- and second-order vestibular neurons [for reviews, see de Waele et aI., 1995; Dieringer, 1995; Vidal et aI., 1996J has been a matter of debate. It was first believed that the monosynaptic input of vestibular a erents was only mediated through non-NMDA receptors [Cochran et aI., 1987; Lewis et aI., 1989; Doi et aI., 1990J. Subsequent slice studies indicated that it might not be the case [Kinney et aI., 1994; Takahashi et aI., 1994; Straka et aI., 1995bJ. In slices, however, isolated electrical stimulation of the first-order vestibular neurons has been di cult to obtain. We therefore recorded the field potentials evoked in the MVN, and the monosynaptic EPSPs evoked in second-order MVNn following single-shock stimulation of the vestibular nerve in the IWB of guinea pig [Babalian et aI., 1997J. Our data confirmed that this transmission was mediated by EAA. Perfusion of CNQX (an antagonist of AMPA/kainate receptors) suppressed a major part of the field potentials and EPSPs evoked following the stimulation of the stump of the eighth nerve. In about 50% of the cases, perfusion of APV (an antagonist of NMDA receptors) subsequently abolished a small and variable part of field potentials or EPSPs which persisted following CNQX perfusion. The results obtained with APV demonstrated that NMDA receptors

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42

contributed to the transmission between first- and second-order MVNn in mammals. However, this was the case in only 50% of the recorded neurons, and this NMDA contribution was highly variable. Such conclusions were in agreement with a previous study by Straka et a!. [1995bJ in the isolated frog's brainstem, which demonstrated in addition that only the thickest vestibular a erents (presumably the kinetic neurons) would activate NMDA receptors on second-order vestibular neurons. In both studies, it was clear that NMDA receptors were involved in the direct, monosynaptic transmission linking the sensory a erents to the second-order vestibular neurons. The low amplitude of the CNQX-insensitive, APV-sensitive component of the EPSP evoked by stimulation of the eighth nerve does not mean that NMDA-mediated transmission is of minor importance in vivo. NMDA receptors are subjected to a voltage-dependent block by extracellular Mg 2 [Ascher and Nowak, 1988], and a quantitative assessment of the NMDA-mediated transmission in a totally dea erented brain was therefore irrelevant. It should also be noted that we found a CNQX- and APV-resistant component in the transmission between sensory vestibular a erents and second-order MVNn. This component could result from the activation of the postsynaptic, metabotropic glutamate receptors present on most MVNn, or from the involvement of another transmitter like acetylcholine. Finally, it is noteworthy that in the frog, disynaptic IPSPs seem to be often superimposed upon the monosynaptic EPSPs elicited in vestibular neurons by stimulation of the ipsilateral vestibular nerve [Straka and Dieringer, 1996J. Presynaptic EAA receptors could also regulate glutamate release by the glutamatergic a erents reaching vestibular neurons. Presynaptic NMDA and trans-ACPD receptors are present on the terminal arborization ofaxons in the vestibular nucleus [Gallagher et a!., 1992; Kinney et a!., 1993J. In particular, they may be localized on the synaptic endings of the first-order neurons since several NMDA and trans-ACPD receptor subunits are expressed by vestibular ganglion cells [Doi et a!., 1995; Safieddine and Wenthold, 1997].

Functional Roles of NMDA Receptors in the Vestibular Nuclei: Correlation with in vivo Data Chronic, unilateral perfusion of APV in the vestibular complex of aler guinea pigs induced a massive postural and oculomotor syndrome, similar to! the one observed following ipsilateral, acute vestibular dea erentation [de Waele et a!., 1990J. Perfusion ofCNQX, in contrast, failed to induce any static postural syndrome or eye deviation. This experiment demonstrated that (a) the cation channels associated with NMDA receptors were open in the alert animal;

Intrinsic Properties of Central Vestibular Neurons

43

(b) they were absolutely essential to maintain a normal resting discharge ofneurons in the vestibular nuclei, which was not the case for AMPA/kainate receptors. This result was quite interesting, because it linked in an intimate way the static control of posture to the NMDA subtype ofEAA receptor. In addition, the long duration of the NMDA-mediated EPSPs might facilitate the summation of synaptic potentials [Mettens et aI., 1994b], and NMDA receptors could therefore be involved in the integration of the velocity signal encoded by the first-order vestibular neurons into a position signal necessary to stabilize the eyes: in the alert cat indeed, APV perfusion in the central part of the medial vestibular nucleus induced important gaze-holding failures [Mettens et aI., 1994a]. The absence of the voltage-dependent block of the NMDA receptors of the central vestibular neurons by Mg 2 in alert animals is explicable. First, many of their a erent fibers have high, spontaneous firing rates. For instance, first-order neurons have a mean resting discharge of about 30-40 spikes/so This presumably maintains the membrane potential of vestibular neurons at a su ciently depolarized level to prevent the Mg 2 block. Second, glYCine, an inhibitory transmitter acting on strychnine-sensitive receptors [for review, see Betz et aI., 1994], is also a coagonist of glutamate at a strychnine-insensitive site of the NMDA receptors [for review, see Wood, 1995]. It turns out that in frog and rat, glycine is colocalized with glutamate in the largest, sensory vestibular neurons [Reichenberger and Dieringer, 1994], precisely those which trigger in vitro NMDA-mediated responses in vestibular neurons [Straka et aI., 1995a]. Hence, corelease of glutamate and glycine by these fibers could potentiate postsynaptic I\lMDA receptors, and contribute to decrease the Mg 2 block. The functional relevance of the glycinergic modulation of NMDA receptors is unclear. It was even stated that it might not operate in normal conditions, since it has been suggested that the strychnine-insensitive site may be saturated in vivo [Wood, 1995]. In order to investigate that problem, we have checked on slices that MVNn NMDA receptors were sensitive to bath application of a specific agonist (D-serine) and antagonist (7 -chlorokynurenate) of the strychnine-insensitive binding site of NMDA receptors [Lapeyre and Benazet, unpub!. results]. Both compounds were then chronically perfused unilaterally in the vestibular complex of alert, unrestrained guinea pigs [Benazet et aI., 1993]. D-Serine induced an asymmetry of the HVOR, and a reversible postural syndrome consistent with a hyperactivity of vestibular neurons on the perfused side. In contrast, 7-chlorokynurenate induced the same syndromes in the opposite direction, revealing a hypoactivity of vestibular neurons. These results demonstrated that, in vivo, the vestibular NMDA receptors could be modulated through their glycinergic site. The extent to which this may be of functional importance remains to be clarified.

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EAA Receptors and Vestibular Plasticity NMDA receptors have been shown to play a key role in di erent types of synaptic plasticity [for review, see Nakanishi, 1992], which raised the question of their involvement in vestibular plasticity. Postlesional Plasticity Vestibular compensation after unilateral labyrinthectomy is considered as an excellent model of plasticity of the adult CNS [Llinas and Walton, 1979J. Indeed, the postural and oculomotor syndromes observed at the acute stage largely disappear over time in all species of vertebrates studied [for review, see Schaefer and Meyer, 1974). The static syndromes observed at the acute stage result from an asymmetry of the resting discharges between the intact and dea erented vestibular nuclei: immediately following the lesion, the dea erented MVNn are silent, whereas the spontaneous activity of the contralateral medial vestibular neurons is increased [for review, see Smith and Curthoys, 1989J. At the compensated stage, the dea erented vestibular neurons recover a quasinormal resting activity [for review, see Ris et a!., 1995). As a result a new, symmetrical pattern of resting activity is restored between the intact and the dea erented vestibular complexes; the emergence of this new balance plays an essential role in the compensation process. Since we have shown that NMDA receptors were essential for the maintenance of the resting discharge of central vestibular neurons, we suggested that they could be strongly involved in the recovery of resting discharge after lesion. This was tested by comparing the e ects of APV perfusion in the vestibular complex of normal and compensated, unilaterally labyrinthectomized guinea pigs [de Waele et a!., 1990J. APV induced similar postural and oculomotor syndromes in intact and lesioned animals, which indicated that, indeed, a denervation supersensitivity of the vestibular NMDA receptors present on the dea erented vestibular neurons could contribute to vestibular compensation. To check that hypothesis, the distribution of mRNAs coding for the NMDA R1 subunit in the two vestibular nuclei were investigated in both intact and compensated rats [de Waele et a!., 1994). On both sides of the brain, the mean density of mRNA coding for the NMDA R1 subunit in the MVN decreased by 20% just after the lesion. Three days later, the intensity of labeling was back to normal. Hence, unilateral labyrinthectomy induced a transient decrease of the NMDA receptor synthesis in both vestibular nuclei, which disappeared during compensation. This result is compatible with the postulated denervation supersensitivity of NMDA receptors. Other studies support that hypothesis [for reviews, see Smith et a!., 1992; de Waele et al., 1995; Vidal et al.,

Intrinsic Properties of Central Vestibular Neurons

45

1996]. Systemic injections of MK-801, another NMDA antagonist, impaired compensation in the guinea pig [Smith and Darlington, 1988; Pettorossi et aI., 1992; Kitahara et aI., 1995]. However, studies in the frog did not find any evidence for an NMDA supersensitivity [Knopfel and Dieringer, 1988; Dieringer, 1995]. More studies are needed to ascertain whether modifications of the NMDA receptors occurring during vestibular compensation are causally related to the behavioral recovery.

Functional Plasticity Habituation and adaptation of the vestibulo-ocular and vestibulospinal reflexes are well-known illustrations of the functional plasticity of the central vestibular system. They are believed to rely on long-term modifications of synaptic strengths occurring at di erent levels of vestibulo-ocular and/or vestibulospinal pathways [for reviews, see Kawato and Gomi, 1992; Cohen et aI., 1992; du Lac et aI., 1995]. Based on extracellular field recordings, the occurrence of such long-term synaptic modulations, and the concomitant involvement of the NMDA receptors appeared likely at the level of the vestibular nuclei [Racine et aI., 1986; Capocchi et aI., 1992; Grassi et aI., 1995]. However, our intracellular recordings of MVNn, either in vivo or in the IWB, have failed up to now to detect long-term potentiation and/or long-term depression phenomena at the level of vestibular neurons.

Inhibitory Amino Acid (IAA) Receptors of the Vestibular Nuclei Neurons

Anatomical Studies GABA and glycine are the main inhibitory transmitters in the CNS [Sivilotti and Nistri, 1991; Sato et aI., 1991]. Vertebrates' GABA receptors can be of two types: The ionotropic GABA A receptors include chloride ion channels [for review, see Kaila, 1994]. The GABA s metabotropic receptors activate second messenger systems [for review, see Misgeld et aI., 1995]. Glycine receptors are ionotropic receptors quite similar to the GABA A ones [for review, see Betz et aI., 1994]. Anatomical studies have revealed a dense innervation of all vestibular nuclei by GABAergic and glycinergic a erent fibers [for reviews, see Raymond et aI., 1988; de Waele et al.. 1995; Rampon et aI., 1996; Reichenberger et aI., 1997]. In situ hybridization and immunocytochemical techniques have demonstrated that vestibular neurons were endowed with GABAA , both pre- and postsynaptic GABA s receptors [Holstein et aI., 1992], and glycinergic receptors. 30% of MVNn were shown to be GABAergic neurons expressing glutamate decarboxylase (GAD), the specific enzyme for GABA synthesis [de Waele

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et a1., 1994; Holstein et a1., 1996]. These cells would correspond to the inhibitory intemeurons previously described in the MVN [Shimazu and Precht, 1966; Nakao et a1., 1982] and to the inhibitory, second-order MVNn projecting to extraocular andfor spinal motoneurons [for reviews, see de Waele et aI., 1995; Graf et aI., 1997]. Electrophysiological Studies In vitro studies confirmed the importance of inhibition in the processing of egomotion information in the vestibular nuclei. In slices, extracellularlyrecorded MVNn were inhibited by GABA through both GABA A and GABA B receptors [Smith et a1., 1991; Dutia et aI., 1992]. Intracellular recordings [Vibert et aI., 1995a, c] in a high Mg 2 flow Ca 2 solution, or in presence of TTX, confirmed that all types of MVNn were directly hyperpolarized and inhibited (table 2) by GABA, muscimol (a specific GABA A agonist), and baclofen (a specific GABA B agonist). However, in normal medium, while many MVNn were still hyperpolarized by bath application of GABA and muscimol, others could be depolarized. MVNn which were depolarized in control conditions were always hyperpolarized by muscimol when TTX was added in the bath. These results indicated that (a) local inhibitory intemeurons were spontaneously active in the slice and often exerted a tonic inhibition on the recorded neurons; (b) bath application of GABA and muscimol inhibited these interneurons, interrupting the tonic inhibition they exerted on the recorded cell and often leading to its disinhibition in normal medium; (c) this disinhibition could supersede the direct inhibition induced by bath application of GABA and muscimol on the recorded MVNn, which provoked the apparent depolarizing e ects observed with these compounds. Ultimately, this suggests that both the recorded MVNn and the local inhibitory interneurons present in the vestibular nuclei are endowed with postsynaptic, GABA A receptors. This hypothesis is strengthened by a recent morphological study [de Zeeuw and Berrebi, 1996], which demonstrated that indeed, individual Purkinje cell axons (which use GABA as their main transmitter) terminate on both inhibitory and excitatory neurons in the vestibular nuclei. Bath application of glycine produced a dose-dependent decrease in the MVNn resting discharge [Lapeyre and de Waele, 1995]. This inhibitory action was suppressed by strychnine, and persisted in a high Mg 2 flow Ca 2 -containing solution, which indicated that MVNn display postsynaptic, strychninesensitive glycinergic receptors. Therefore, glycine can modulate the MVNn at two levels: it might potentiate the depolarizing action of glutamate through the glycinergic, strychnine-insensitive modulatory site of NMDA receptors, but can also have a hyperpolarizing e ect by acting on their strychnine-sensitive receptors.

Intrinsic Properties of Central Vestibular Neurons

47

Table 2. E ects of inhibitory amino acids on MVNn recorded in slices: the nature and number of e ects obtained with three agonists and one antagonist of the GABA receptors on the various parameters characterizing intracellularly-recorded MVNn are given for type A, type B and type B LTS neurons (bicuculline is a specific antagonist of GABA A receptors)

<

0: Ol

~

5'

"~

Experimental conditions

E ects of GABA

E ects of muscimol

E ects of baclofen

Bicuculline

potential

discharge

resistance

potential

discharge

resistance

potential

discharge

resistance

potential and discharge

resistance

11 /23 (48%)

22 /23 (96%)

22 /36 (61%)

36 /36 (100%)

14 /16 (88%)

30 /34 (88%)

31 /34 (91%)

8 /12 (67%)

5 /25 (20%) 1 /6 (17%)

21 /25 (84%) 6 /6 (100%)

6 /8 (75%) 9 /9 (100%) 2 /2 (100%)

17 /38 (45%) 4 /17 (24%)

38 /38 (100%) 17 /17 (100%)

13 /14 (93%) 7 17 (100%)

23 /25 (92%) 13 /13 (100%)

25 /25 (100%) 12 /13 (92%)

120/16 (75%) 40/6 (67%)

8 /9 (89%) 7 17 (100%) 1 /1 (100%)

7 /7 (100%) 7 /7 (100%) 1 /1 (100%)

3 /3 (100%)

15 /15 (100%)

10 /10 (100%)

8 /8 (100%)

3 /6 (50%)

6 /8 (75%)

3 /5 (60%)

8 /10 (80%)

30/3 (100%)

30/3 (100%)

CIl

~

"'coOl

CT

g. "'3: c'

0-

" "i l

8Ol-

" ~

""

Control Type A neurons Type B neurons Type B LTS neurons TTX

7 17 (100%)

Synaptic uncoupling

6 /6 (100%)

2 /2 (100%)

23 /24 (96%)

6 /6 (100%)

15 /15 (100%)

Inhibition of muscimol e ects by bicuculline: 9 out of 9 cases in control medium, lout of 1 case in TTX, 3 out of 3 cases in synaptic uncoupling conditions. Increase; decrease; 0 no e ect.

.,. 00

FuncUonal Roles of VesUbular IAA Receptors Glycine and GABA has been shown to be involved in four types of synapses in the vestibular nuclei: (1) Purkinje cells, which project onto the vestibular complex, use GABA as their main neuromediator [for review, see Sato and Kawasaki, 1991]. (2) The commissural inhibition linking the two medial vestibular nuclei in mammals is mediated by local inhibitory interneurons (the type II neurons) activated by contralateral MVNn [Shimazu and Precht, 1966; Nakao et a!., 1982J. These intemeurons are both GABAergic and glycinergic [Precht et a!., 1973; Furuya et a!., 1991]. (3) A direct GABAergic projection originating from the contralateral inferior olive might reach the vestibular complex [Matsuoka et a!., 1983]. (4) Glycine would be colocalized with glutamate and/or aspartate in some of the large-diameter, first-order vestibular neurons, at least in the frog and the rat [for review, see Straka et aI., 1995a]. The sensitivity of all MVNn to GABA A and GABA s agonists certainly plays a key role in the processing of information in the vestibular nuclei [for reviews, see Straube et a!., 1991; Reber et a!., 1996J. It is noteworthy that cerebellar Purkinje cells, which are strongly involved in adaptation and habituation of the HVOR, use GABA as their main transmitter. The GABAergic regulation of the interneurons which mediate commissural inhibition (see above) could be used to modulate the velocity storage integrator included in vestibulo-oculomotor pathways, and more generally in the control of HVOR gain [Galiana and Outerbridge, 1984; Katz et aI., 1991]. In vivo indeed, perfusions of the vestibular nuclei with agonists or antagonists of the GABA A or GABA s receptors can induce postural and oculomotor asymmetries, or mOdify the gain of the HVOR. Furthermore, systemic injections of baclofen, a GABA s agonist, strongly impaired the velocity storage integrator [Cohen et a!., 1987; Niklasson et a!., 1994J.

Cholinergic Influences on VesUbular Networks Two main types of cholinergic receptors have been distinguished in the CNS: the nicotinic and the muscarinic receptors. The nicotinic receptors are ionotropic receptors which include a cation channel, whereas the metabotropic, muscarinic receptors act through G proteins and second messenger systems. Molecular biology studies have further revealed the existence of several di erent subtypes of both the nicotinic and muscarinic receptors [for reviews, see Hosey, 1992; Clarke, 1995].

Intrinsic Properties of Central Vestibular Neurons

49

Anatomical Evidence Only few intrinsic cholinergic neurons have been detected in mammals within the boundaries of the vestibular nuclei [for review, see de Waele et aI., 1995]. In the monkey, choline acetyl-transferase (ChAT)-immunoreactive cells were localized in the caudal medial vestibular nucleus and in the dorsal, inferior vestibular nucleus. The presence of cholinergic neurons in the medial vestibular neurons was confirmed in rats, gerbils and rabbits [de Waele et al., 1995; Lan et aI., 1995; Zanni et aI., 1995]. In rabbits, these cholinergic, second-order vestibular neurons encoding egomotion-related information have been shown to project to the flocculus, the nodulus and the dorsal cap of the inferior olive. Other cholinergic cells projecting to the spinal cord have been detected in the rat vestibular complex, mostly in the lateral vestibular nuclei [Jones et aI., 1986J. On the other hand, nicotinic and muscarinic cholinergic receptors have been detected in all vestibular nuclei, and particularly in the medial vestibular nucleus [for reviews, see de Waele et aI., 1995; Zanni et aI., 1995]. Moreover, vestibular nuclei neurons were labeled by monoclonal antibodies raised against specific subunits of the nicotinic acetylcholine receptors [Dominguez del Toro, 1994; de Waele et aI., 1995J. Finally, all vestibular nuclei have been shown to display ChAT activity, the highest activity being recorded in the medial vestibular nucleus [Burke and Fahn, 1985]. The identity of the cholinergic neurons innervating the vestibular nuclei remains to be determined. They could be localized within the vestibular nuclei or in several structures including the pedunculopontine formation, the tegmental dorsal nuclei neurons and/or the contralateral inferior olive [for review, see de Waele et aI., 1995J.

Electrophysiological Evidence In vitro studies on slices demonstrated that both nicotinic and muscarinic, cholinergic agonists could depolarize MVNn. This depolarization could be reversibly suppressed by nicotinic or muscarinic antagonists [for reviews, see Darlington et aI., 1995; de Waele et aI., 1995]. These e ects are mostly due to the activation of postsynaptic receptors, since they persist in the presence of TTX, or while perfusing a low Ca 2 /high Mg 2 -containing solution. While Ujihara et al. [1989J have proposed that the MVNn spontaneous activity on slices was mostly regulated via muscarinic receptors, Phelan and Gallagher r1992J showed that both muscarinic and nicotinic receptors were important. This discrepancy could be due to the rapid desensitization exhibited by nicotinic receptors. In vivo, both systemic injections and microiontophoretic studies have demonstrated that the lateral and medial vestibular neurons were excited

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by acetylcholine, physostigmine (an inhibitor of acetylcholine esterase) and muscarinic agonists [for review, see de Waele et aI., 1995]. These e ects were at least partly mediated by muscarinic receptors, because they were often antagonized by atropine and scopolamine, two muscarinic antagonists. The vestibular field potential evoked by ipsilateral vestibular nerve stimulation in the medial and lateral vestibular nuclei is composed of a presynaptic P wave, followed by the mono- and polysynaptic waves N 1 and N 2 • The N 1 wave is potentiated by intrasystemic injection of physostygmine, an anticholine esterase drug, and decreased by scopolamine, an antimuscarinic drug [Matsuoka et al., 1985]. Therefore, it was concluded that the synaptic transmission between the first-order and second-order vestibular neurons was facilitated by cholinergic agonists and disfacilitated by muscarinic antagonists. Finally, the inferior olive stimulation evoked monosynaptic EPSP in lateral vestibular neurons which were suppressed following systemic injection of atropine, a muscarinic antagonist [Matsuoka et al., 1985].

Behavioral Evidence Several in vivo experiments indicated that cholinergic modulation of the vestibular system was indeed functionally relevant [for review, see de Waele et aI., 1995]. Unilateral perfusion of muscarinic agonists into the vestibular nuclei of intact animals has been shown to induce a postural deficit which is the mirror image of the postural syndrome induced by unilaterallabyrinthectomy. The central cholinergic system could accordingly be involved in vestibular compensation. Following unilateral labyrinthectomy, systemic injection of acetylcholine esterase or cholinergic antagonists induced postural deficits which are the mirror image of those previously induced by the first lesion and decrease the slow-phase eye velocity of postlesional nystagmus. In contrast, injections of cholinomimetics or of anticholinesterase drugs induces the reappearance of the postural syndromes in compensated animal (postural decompensation). Belladonna alkaloids, which have anticholinergic properties, are the oldest agents used for the prophylaxis of motion sickness [de Waele et aI., 1995]. The existence of cholinergic second-order vestibular neurons projecting to the cerebellum might explain the e ciency of antimuscarinic drugs in the symptomatic treatment of motion sickness, since the uvula-nodulus has been reported to be strongly involved in the triggering of this syndrome. Muscarinic receptors would also be involved in the cerebellar control of the vestibulospinal reflex gain [Andre et aI., 1995]. In summary, there is good evidence that the cholinergic modulation of central vestibular neurons plays an important role in gaze and posture stabiliza-

Intrinsic Properties of Central Vestibular Neurons

51

tion. The fact that second-order vestibular neurons can be either glutamatergic or cholinergic opens intriguing questions concerning the functional relevance of that segregation.

Modulation of Central Vestibular Neurons by Monoamines The three catecholamines (dopamine, noradrenaline, and adrenaline) are synthesized from the amino acid tyrosine, whereas serotonin comes from tryptophan and histamine is produced by a decarboxylation of histidine. Each monoamine is synthesized by well-localized, small populations of neurons which give rise to extremely di use axonal arborizations extending to almost every structure of the CNS. Each monoaminergic transmitter activates several types of receptors on target neurons, which explain why each monoamine can have various e ects in any particular brain structure, depending on the nature of the activated receptors and on their localization at the cellular level. There is no need to insist on the important role of monoaminergic modulations in the CNS. Monoamines have been shown to significantly modulate the activities of large CNS structures, particularly in relation with the di erent behavioral states of the animal. In addition, several major neurological disorders like schizophrenia or Parkinson's disease are linked to dysfunctions of the aminergic systems. Therefore, the importance of monoaminergic modulation of the vestibular system should not be underestimated. The turnover rates of monoaminergic metabolites in the vestibular complex strongly suggest that significant monoaminergic activity exists in these nuclei ICransac et a!., 1996]. Furthermore, various agonists and antagonists of the monoaminergic receptors are successfully used in clinic to obviate vertigo and motion sickness [for review, see Rascol et a!., 1995], or to improve vestibular compensation following vestibular neurectomy [Smith and Darlington, 1994; Tighilet and Lacour, 1997]. An in-depth understanding of the monoaminergic modulation of the vestibular system will hopefully pave the way to new, more e cient clinical treatments.

The Histaminergic System

Central Histaminergic Pathways In mammals, histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus. These cells innervate almost every structure of the CNS, with the noticeable exception of the cerebellum. Hista-

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minergic receptors are localized on neurons, but also on astrocytes and blood vessels. The histaminergic system has been strongly involved in the regulation of vigilance, which explains why many antihistaminergic drugs induce somnolence. It also intervenes in neuroendocrinian control, and in the regulation of internal temperature and cerebral blood flow. Altogether, since all these fields deeply depend on the day-night altemance, histamine probably plays an essential role in the definition and control of circadian rhythms [for review, see Onodera et aI., 1994]. Up to now, three types of metabotropic receptors to histamine have been described. Postsynaptic H] and Hz receptors are positively coupled to phospholipase C and adenylate cyclase, respectively. Activation of these two receptors mainly leads to neuronal excitation. H 3 receptors are often presynaptically localized on histaminergic terminals. In that case, they exert a negative feedback on hlstamine synthesis and release. They may also inhibit the release of other transmitters at nonhistaminergic axon terminals [Arrang et aI., 1995].

Histaminergic Modulation of the Vestibular System Anatomical evidence has first indicated that the activity of vestibular neurons could be modulated by the histaminergic system. The histaminergic neurons of the posterior hypothalamus have been shown to project onto the entire vestibular complex [Takeda et aI., 1987] with a predominance for the medial and superior nuclei [Tighilet and Lacour, 1996]. Autoradiographic and in situ hybridization studies have disclosed the presence of many H] and Hz binding sites in all vestibular nuclei [Bouthenet et aI., 1988; Vizuete et aI., 1997]. In vitro electrophysiological recordings on slice have confirmed that histamine mostly depolarizes MVNn [phelan et aI., 1990; Wang and Dutia, 1995]. Using intracellular recordings, we demonstrated that the three types of MVNn (A, B, and B LTS neurons) were equally sensitive to histamine [Serafin et aI., 1993]. In guinea pig slices, the depolarizing e ect of histamine was mediated by Hz receptors. Neither mepyramine (a selective H] antagonist) nor methylhistamine and thioperamide (respective H 3 agonist and antagonist) modified the MVNn responses to histamine. In contrast, in rat slices [Wang and Dutia, 1995], the excitatory responses of MVNn to histamine could be partially antagonized by triprolidine, a specific H[ antagonist. In vivo electrophysiological recordings have further demonstrated the sensitivity of lateral and medial vestibular nuclei neurons to histamine. These neurons could be both inhibited or excited by histamine or histaminergic agonists [for review, see de Waele et aI., 1995]. Presynaptic H 3 receptors are di cult to detect on slices, because of their localization on histaminergic terminals which are severed during the slicing procedure. We have therefore perfused one vestibular complex of alert, unrestrained guinea pigs with either

Intrinsic Properties of Central Vestibular Neurons

53

-methylhistamine or thioperamide, which are respective agonists and antagonists of the H 3 receptor [Yabe et a1., 1993J. The oculomotor and postural syndromes induced by unilateral perfusion of the H 3 agonist strongly suggest that the histaminergic fibers reaching the vestibular nuclei carry presynaptic H 3 autoreceptors regulating histamine release. The fact that the observed syndromes mimicked the one induced by unilateral labyrinthectomy indicated that in the awake guinea pig, the vestibular nuclei neurons are submitted to a tonic excitatory drive from histaminergic fibers. Histaminergic ligands have been successfully used in humans for the symptomatic treatment of vertigo and motion sickness. First, histaminergic drugs may have an indirect influence on vestibular syndromes through the well-known e ect of these compounds on vigilance. The vestibular system is indeed very sensitive to the state of alertness [Melvill-Jones and Sugie, 1972J. Therefore, it cannot be excluded that decreasing the level of vigilance may be helpful by itself to obviate the vestibular syndromes. Second, histaminergic drugs have direct actions in the eNS, including on the vestibular nuclei neurons as described above [for review, see Fischer, 1991J. Because of its vasodilating properties, histamine has been proposed as a treatment of inner ear dysfunctions of vascular origin. Other histaminergic ligands like betahistine (which is both a partial HI agonist and an H 3 antagonist) probably act through a direct action on central vestibular structures. Antihistaminergic drugs like cinnarizine have also been extensively used to treat vestibular-related disorders, despite their sedative properties [Rascal et aI., 1995J.

Summary Altogether, histamine seems to have a clear excitatory e ect on vestibular neurons. This e ect is mediated by postsynaptic HI and/or Hz postsynaptic receptors, and a tonic release of histamine in the vestibular nuclei is apparently controlled through presynaptic H 3 receptors. Interestingly, modulations of the whole histaminergic system seem to be triggered when the information concerning egomotion is suddenly modified, following for instance unilateral labyrinthectomy [Horii et al., 1993], or during multisensory conflicts inducing motion sickness [Takeda et a1., 1993J. Hence, in clinical practice, administration of histaminergic ligands could just mimic a physiological response to stress. One remaining problem is that very often, drugs given against vertigo and motion sickness induce drowsiness as a side e ect. In that respect, H 3 antagonists may be useful in the future. Betahistine, already used in clinic, acts as a partial antagonist of the H 3 receptors. Moreover, our group has recently shown that in the guinea pig, the gain of the horizontal vestibulo-ocular reflex was depressed following intraperitoneal injection of the potent H 3 antagonist thioperamide. We think therefore that one could e ciently modulate the sensitivity

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54

of the vestibular system through H 3 antagonists. What makes this perspective so attractive is the fact that thioperamide, in contrast to standard histaminergic agents, does not induce drowsiness. In contrast, it has been reported to rise the level of vigilance [Lin et aI., 1990].

The Serotoninergic System

Central Serotonjnergjc Pathways The serotoninergic cells are clustered in eight separate groups within the brainstem reticular formation, and their di use projections extend over all the eNS. The serotoninergic system has been shown to modulate arousal, feeding behavior, nociception, thermoregulation, sexual activity, and more generally the regulation of emotional states [Bonate, 1991J. At least ten serotoninergic receptor subtypes have been individualized up to now [for review, see Zifa and Filion, 1992]. They have been classified in four groups, which include three groups of metabotropic receptors (5-HT 1, 5-HTz, and 5-HTJ and one group of ionotropic receptor (5-HT 3). The three subtypes of 5-HT 1 receptors (5-HT 1A , 5-HT 1B , and 5-HT iD) have the highest a nity for serotonin, and are negatively coupled with adenylate cyclase. The three subtypes of 5-HTz receptors (5-HT zA , 5-HTzB , and 5-HTzcl are positively coupled with phospholipase C. Their activation increases the intracellular calcium concentration. The 5HT 1 and 5-HTz receptors can be both pre- and postsynaptically localized. The 5-HT4 receptors are positively coupled to adenylate cyclase, and would be mostly localized postsynaptically. The 5-HT3 receptors include a cation-selective channel, induce short-lasting depolarization and would be mainly localized presynaptically. They are believed to facilitate the release of various neurotransmitters, including serotonin itself. Serotoninergjc Modulation of the Vestibular System Immunocytochemical studies have demonstrated a rich innervation of all vestibular nuclei by serotoninergic fibers [for review, see de Waele et aI., 1995J, most probably issued from the dorsal raphe nucleus [Giu rida et al., 1991J. In addition, autoradiographic and in situ hybridization studies have demonstrated the presence of 5-HT 1A , 5-HT 1B and 5-HT z receptors in the vestibular complex [Pazos and Palacios, 1985; Wright et al., 1995; Kia et aI., 1996J. In vitro extracellular recordings in slices [Johnston et aI., 1993J have shown both excitatory and inhibitory e ects of serotonin on the MVNn spontaneous activity, but with a predominance ofexcitatory actions. Our intracellular recordings (table 3) in guinea pig brainstem slices [Vibert et aI., 1994] revealed that 80% of the MVNn were depolarized by serotonin, the type Band B LTS neurons

Intrinsic Properties of Central Vestibular Neurons

55

Table 3. E ects of serotoninergic compounds on MVN n recorded in slices [reprinted with permission from Vibert et al .. 1997]: the nature and number ofe ects obtained with four serotoninergic agonists on the various parameters characterizing intracellularly-recorded MVNn are given for type A and type B neurons (8-0H-DPAT. -methylserotonin and 2-methylserotonin are respectively selective agonists of the 5-HT 1A • 5-HT, and 5-HT3 serotoninergic receptors)

Experimental conditions

Control Type A neurons

Type B or B LTS neurons

Serotonin

-Methyl-5-HT

8-0H-DPAT

2-Methyl-5-HT

potential resisand tance discharge

potential and discharge

potential and clischarge

7 /8 (87%)

4 /4 (100%)

1 /1 (100%)

30/3 (100%)

40/4 (100%)

14 /15 (93%)

12 /12 (100%)

2 /2 (100%)

60/8 (75%)

50/7 (72%)

potential resisand tance discharge

25 /37 (68%) 8 /37 (21%) 48 /54 (89%) 6 /54 (11%)

TTX or synaptic uncoupling' 3 /16 lYpe A (19%) neurons 120/16 (75%) 15 /20 lYpe B (75%) or 10 /10 20/20 (100%) B LTS (10%) neurons Increase; - decrease; 0 no e ect. In 4 cases out of 4 (100%). the hyperpolarizing e ects of serotonin obtained in control medium persisted in TTX or synaptic uncoupling conditions (on 1type A and 3 type B neurons). 1

being more sensitive than the type A neurons. Moreover. serotonin directly activated postsynaptic receptors on type B MVNn, whereas excitation of type A MVNn was indirect. As previously shown [Johnston et aI., 1993], -methylserotonin (a specific agonist of 5-HTz receptors) reproduced the depolarizing e ects ofserotonin. which were however only partly blocked by ketanserin (an antagonist of 5-HTz receptors). Moreover. these e ects were associated with decreases of the membrane resistance. which is not typical of 5-HTz receptors activation. Indeed. 5-HT receptors usually induce a resistance increase linked with the inactivation of potassium conductances [Bobker, 1994]. Similar depolarizations, ac-

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companied by a decrease of membrane resistance, had already been observed in the CNS with serotonin, but the serotoninergic binding site involved remains to be determined [Andrade and Chaput, 1990]. In 15% of both type A and type B cells, bath application of serotonin induced a hyperpolarization, which should be mediated through 5-HT 1A receptors according to the available literature. In vivo studies concerning modulation of the vestibular system by serotonin have been very sparse. Microiontophoretical studies in the rat [for review, see de Waele et aI., 1995J have shown that the lateral vestibular nucleus neurons react to the application of 5-HT serotonin by a short hyperpolarization, followed by a large depolarization. MVNn and superior vestibular nuclei neurons could display excitatory responses probably mediated through 5-HT2 receptors, inhibitory responses mediated through 5-HT 1A receptors, or biphasic responses. Finally, intracerebroventricular injection of serotonin increased the gain of the horizontal vestibula-ocular reflex in the rat [Ternaux and Gambarelli, 1987J.

Summary Our actual knowledge on the serotoninergic modulation of the vestibular system is very poor. 80% of the MVNn appear to be excited by serotonin, probably through the activation of a still undefined binding site, a '5-HTr like' receptor. The only clear result of our study was a predominance of the impact of 5-HT on type B MVNn, which could indicate that this neuromodulator is more involved in tuning the dynamic responses of vestibular neurons than aimed at regulating the static reflexes. In that regard, the serotoninergic receptors can be opposed to NMDA receptors, which appear to mainly settle the resting discharge of vestibular neurons and would therefore more deal with static oculomotor and postural control.

The Doparninergic System

Central Dopaminergic Pathways Numerous studies have been devoted to the physiology of central dopaminergic pathways. Indeed, dopaminergic disorders underlie several well-known neurological pathologies, including Parkinson's disease, Huntington's chorea, and progressive supranuclear palsy. Three main dopaminergic pathways have been described in the CNS [for review, see Civelli et aI., 1993J: (1) The nigrostriatal fibers originate in the substantia nigra, and play an essential role in the control of locomotion and movement. (2) The mesocorticolimbic pathway includes dopaminergic neurons of the ventral tegmental area, and innervates all limbic structures (hippocampus, entorhinal cortex). These dopaminergic cells appear to be essentially involved in the regulation of emotional states. (3) The tuberoin-

Intrinsic Properties of Central Vestibular Neurons

57

fundibular pathway originates from dopaminergic neurons located in the hypothalamus, and participates in the control of hypophyseal activities. This dopaminergic system regulates prolactin concentration in the blood, and would strongly influence the hormonal control of reproductive activities. Some smaller dopaminergic cell groups, with more restricted projection sites, have been furthermore identified in various brain structures. Dopaminergic neurons have been localized for instance in the olfactory bulb, the retina, the thalamus, and the dorsal motor nucleus of the vagus nerve. Since 1979 [Kebabian and Caine, 1979), two main types of dopaminergic receptors (the D 1 and D z ones) were classically described. Recent studies, however, have shown that dopamine could actually activate at least five distinct subtypes of metabotropic receptors [for review, see Civelli et a1., 1993). These five receptors can be grouped in two classes, according to their pharmacological and structural homologies with the prototypical D 1 and D z binding sites defined in 1979. The 'D1-like' receptors include the D 1and D s subtypes. They are generally positively coupled with adenylate cyclase, and can be both preand postsynaptically localized. In presynaptic position, they mostly stimulate the release of various transmitters. The 'Dz-like' receptors include the D z, D 3 , and D 4 subtypes. In most cases, they seem to be negatively coupled with adenylate cyclase, and can be both pre- or postsynaptically located. The presynaptic ones apparently inhibit the release of various neurotransmitters in many di erent structures. On the other hand, postsynaptic 'Dz-like' receptors generally hyperpolarize neurons by activating some of their potassium conductances [Vallar and Meldolesi, 1989).

Dopaminergic Modulation of the Vestibular System Anatomical studies have not demonstrated any dopaminergic innervation of the vestibular nuclei [Kohl and Lewis, 1987J. On the other hand, two studies using in situ hybridization and autoradiographic methods have revealed the presence of dopaminergic D z receptors in the vestibular complex of the rat, mostly in the MVN [see de Waele et aI., 1995; Yokoyama et aI., 1994). In view of these results and those of electrophysiological studies (see below), the absence of dopaminergic innervation is surprising. This negative result could be due either to technical limitations or to the little attention paid to any specific innervation of the vestibular system. Indeed, in vitro studies on slices have unambiguously demonstrated a depolarizing action of dopamine on intracellularly-recorded, medial vestibular neurons in rat [Gallagher et aI., 1992J. In the guinea pig, our own study [Vi bert et aI., 1995bJ confirmed that result (table 4): dopamine depolarized about 75% of the recorded MVNn in normal Ringer, whatever their type (A, B, or B LTS MVNn). This depolarization was accompanied by an increased membrane

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"

§. ~.

Table 4. E ects of dopaminergic compounds on MVNn recorded in slices: the nature and number of e ects obtained with four dopaminergic agonists on the various parameters characterizing intracellularly-recorded MVNn are given for type A and type B neurons (SKF-38393 is a selective agonist of D\-like dopaminergic receptors, while piribedil and quinpirole are selective agonists of Dz-like receptors; SCH-23390 and sulpiride are respective, selective antagonists of the D\-like and Dz-like receptors)

'U

a

'U

'" ::+

[f o ....,

Experimental conditions

Dopamine (1 mAt)

eo.

~

5' E.

Control Type A neurons

'" a iii

Type B or B LTS neurons

TTX

Synaptic uncoupling

Quinpirole

SKF-38393

discharge

resistance

potential

discharge

resistance

potential

potential

discharge

potential and discharge

19 /30 (63%)

13 (68%) 4 (21%) 20(11%) 24 (71%) 8 (24%) 20(5%)

7 /12 (59%)

13 /16 (81%)

6 /9 (67%)

4 /10 (40%)

3 /3 (100%)

3 /3 (100%)

20/2 (100%)

12 /22 (55%)

23 /30 (77%)

5 (38%) 4 (31%) 40(31%) 10 (43%) 9 (39%) 40(18%)

17 /20 (85%)

4 /9 (44%)

7 /8 (87%)

5 (72%) 1 (14%) 10(14%)

80/8 (100%)

30/5 (60%)

6 /8 (75%)

e;

z

DA(IOO At)

potential

n

'~"

Piribedil

34 /41 (83%)

7 /13 (54%) 8 /10 (80%)

3 /3 (100%)

6 17 (86%)

not tested not tested

Inhibition of dopamine e ects by sulpiride: 5 out of 5 cases in control medium, 2 out of 2 cases in synaptic uncoupling conditions. Absence of inhibition of dopamine e ects by SCH-23390: 5 out of 5 cases in control medium. DA Dopamine; increase; decrease; 0 no e ect.

OJ">
resistance, and mediated through 'Dz-like' receptors. This result was rather unusual in the sense that activation of postsynaptic 'Drlike' receptors is generally reported to be associated with a decrease of the cell's membrane resistance [Vallar and Meldolesi, 1989J. It turned out that the depolarization was actually due to an indirect, presynaptic e ect: when synaptic transmission was blocked (in presence of a high Mg Z flow Ca 2 -containing solution), dopamine had a weak postsynaptic, hyperpolarizing action on all types of MVNn mediated by postsynaptic, 'Drlike' receptors. Our interpretation of these data was that dopaminergic agonists, by acting on presynaptic 'Dz-like' receptors, could inhibit in the slices a spontaneous, TTX-resistant, tonic release of an inhibitory transmitter like GABA. Several experimental results supported that view: (a) as stated above in the section on IAA, the vestibular nuclei contain GABAergic interneurons, which would mediate commissural inhibition, as well as numerous GABAergic terminals; (b) spontaneous GABA release takes place in the vestibular nuclei in vitro (also see above); (c) during continuous perfusion of bicuculline in the bath, the depolarizing e ects of dopamine were suppressed, and replaced by hyperpolarizing e ects as in synaptic uncoupling conditions; (d) similar presynaptic, inhibitory e ects of dopaminergic agonists on the release of various neurotransmitters have already been reported in several structures of the CNS [for instance, see Starke et aI., 1987J. In vivo studies on animals have demonstrated that the resting activity of vestibular neurons increased following systemic injections of L-DOPA (one of the metabolic precursors of dopamine), and that microiontophoretic ejections of dopamine modulate the discharge of these cells. Dihydroergocristine, a nonspecific dopaminergic agonist, reduces the nystagmus following unilateral labyrinthectomy in the guinea pig, which fits with the finding that vestibular compensation was improved foJJowing systemic injections of 'D z-Iike' dopaminergic agonists [for review, see Vibert et aI., 1995b]. These data therefore tend to show that dopaminergic modulation of the vestibular system could be used to treat the vestibular syndromes. Indeed, piribedil (Trivastal ), a specific agonist of 'Drlike' receptors, is currently used to obviate some of the age-related cochleovestibular syndromes in humans [Dourish, 1983; Vibert et aI., 1995bJ.

Summary Dopamine apparently acts on MVNn at both pre- and postsynaptic levels through 'Drlike' receptors. The dopaminergic inhibition of GABA release in the MVN opens the intriguing possibility that the e ciency of the inhibitory commissural connections could be modulated by dopamine, which could lead [Galiana and Outerbridge, 1984; Katz et aI., 1991J to a modulation of the

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gain and the time constant of the horizontal vestibulo-ocular reflex. Such modulation could be physiologically relevant, and could explain the clinical impact of dopaminergic drugs.

The Noradrenergic System Central Noradrenergic Pathways Most noradrenergic neurons are localized in the locus coeruleus. These cells project to the forebrain. the cerebellum, and the dorsal half of the brainstem. In a more ventral position, other groups of noradrenergic neurons project to the ventral brainstem and the hypothalamus. Noradrenaline acts both at pre- and postsynaptic levels through metabotropic receptors. It is supposed to increase the signal-to-noise ratio of amino acid-mediated synaptic transmission [Woodward et al.. 1991J and to regulate vigilance and selective attention by modulating thalamocortical activation processes. together with acetylcholine and serotonin [McCormick and Wang. 1991]. Ten types of adrenergic receptors have been defined, which can mostly be localized both at the pre- and postsynaptic levels. They are classified in three distinct groups, i.e. the 1, 2 and receptors [Bylund et aI., 1994; Nicholas et al.. 1996J. The 1 class includes four subtypes of receptors ( lA to 10); their activation results in an increase of the intracellular calcium concentration through activation of phospholipase C. In a postsynaptic situation, they also inactivate voltage-dependent potassium channels [McCormick and Wang. 1991], which increases the excitability of the target cell. The 2 receptors' class includes three subtypes of receptors, which are negatively coupled with adenylate cyclase. While presynaptic 2 receptors decrease transmitter release, the postsynaptic ones activate potassium channels. thus decreasing neuronal activity. Finally, the receptors class includes three subtypes of receptors ( 1 to 3) positively coupled with adenylate cyclase. In a presynaptic position, they stimulate transmitter release. whereas activation of postsynaptic receptors generally depolarizes the neurons [for reviews, see Bylund et al.. 1994; Starke et al.. 1987]. Noradrenergic Modulation of the Vestibular System Immunohistochemical studies have revealed two sets of noradrenergic fibers, issued from the locus coeruleus, which project over all the vestibular complex, and particularly towards the superior and lateral vestibular nuclei [Schuerger and Balaban. 1993J. Autoradiographic and immunocytochemical studies have demonstrated that vestibular neurons were endowed with and 2 receptors [for review, see de Waele et aI., 1995J. While receptors are

Intrinsic Properties of Central Vestibular Neurons

61

Table 5. E ects of noradrenergic compounds on MVNn recorded in slices: the nature and number of e ects obtained with four noradrenergic agonists on the various parameters characterizing intracellularlyrecorded MVNn are given for type A and type B neurons (clonidine, isoproterenol and L-phenylephrine are respective, selective agonists of the z, and 1 noradrenergic receptors)

Experimental conditions

Control Type A neurons

Noradrenaline

Clonidine

potential and discharge

resistance

potential and discharge

resistance

potential and discharge

res istance

potential and discharge

resistance

5 /6 (83%)

4 17

1 /1

6

2 /2

(100%)

(60%)

1 /1 (100%)

3

(57%)

(67%)

11

(79%)

9 /15 (60%)

3 /5

9

15 /24 (63%)

4 /4 (100%)

20 /44 (45%) 9 /44 (21%)

Type B or B LTS neurons

35

/10

/5

(60%)

(100%)

10

3

/52 /52

/14

(60%)

/17

(59%)

/4 (75%)

(17%)

TTX

1 17

8

4

/4

(100%)

11

/18

(61%)

6

/8

(75%)

/8

(63%)

4 /20

(72%)

(20%)

decrease; 0

/15

(33%)

5

5 17

Increase;

5

/20 (40%)

(14%)

Synaptic uncoupling

L- P henylephrine

Isoproterenol

4 /15 (27%)

3 (33%) 3 (33%) 30(33%)

no e ect.

numerous in the lateral and superior subnuclei, 2 receptors are mainly localized in the MVN [Rosin et aI., 1996; Talley et aI., 1996J. In addition, ), 2A and 2C receptor subtypes have been described in all vestibular nuclei using in situ hybridization techniques [for review, see de Waele et 31., 1995J. The results of our in vitro experiments in guinea pig brainstem slices (table 5) are in good agreement with these anatomical data [Vibert et a1., 1994]. 55% of MVNn were depolarized by bath application of noradrenaline, while their membrane resistance decreased. Type A MVNn (excited in about 40% of the cases) tended to be less sensitive than type B or B LTS MVNn (excited in about 65% of the cases). 20% of the MVNn were in contrast hyperpolarized by bath application of noradrenaline, with no di erence between type A and type B cells. Isoproterenol, (a receptor agonist) depolarized about 60% of MVNn while decreasing their membrane resistance. L-Phenylephrine (an I receptor agonist) also depolarized about 60% of MVNn but, in

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62

contrast to isoproterenol, while increasing their membrane resistance. Finally, clonidine (an 2 receptor agonist) hyperpolarized most MVNn, while decreasing their membrane resistance. This e ect of clonidine was direct, because it persisted in conditions of synaptic uncoupling. On the other hand, a large proportion of the depolarizing responses were indirect, since they were modified when synaptic transmission was interrupted in the slices. Further studies should be done to clarify these points. l-mediated e ects were never found in synaptic uncoupling conditions: in the vestibular nuclei, these receptors are probably localized presynaptically, as the H 3 histaminergic receptors. In vivo, microiontophoretic injections of noradrenaline in the vestibular nuclei of cerebellectomized cat led to an increased activity of lateral vestibular nucleus neurons, and to a decrease of MVNn activity [see de Waele et aI., 1995J. In contrast, the rat lateral and superior vestibular nuclei neurons were found to be inhibited by noradrenaline, an e ect mediated by 2 receptors [Licata et ai., 1993J. From a functional point of view, it is well established that the activity of the locus coeruleus neurons is modulated by vestibular and cervical, proprioceptive stimulations [Pompeiano et aI., 1990]. Furthermore, noradrenergic compounds tend to alter the dynamic properties of the vestibulospinal and vestibula-ocular reflexes [for review, see Pompeiano, 1989; Pompeiano et aI., 1994]. The noradrenergic modulation of vestibular neurons could therefore be essential to regulate the adaptive capabilities of these reflexes [McElligott and Freedman, 1988J.

Summary A fair amount of experimental data now supports the hypothesis that the noradrenergic system integrates visual, vestibular. and proprioceptive information at the level of the locus coeruleus, and can very e ciently modulate the activity of vestibular nuclei neurons through all the three main classes of noradrenergic receptors. Type B neurons display a higher sensitivity to noradrenaline than type A cells. This makes sense if the type B cells really correspond to the so-called 'kinetic' neurons in vivo, since noradrenaline was indeed shown to modulate the dynamic vestibular reflexes. When contradictions arise between the visual, proprioceptive and vestibular information, noradrenaline could trigger and/or facilitate the plastic changes which underlie adaptation of the vestibula-ocular and vestibulospinal reflexes.

Conclusion on the Monoaminergic Systems Let us briefly summarize our very speculative suggestions concerning the respective contribution of each monoaminergic system to gaze and postural

Intrinsic Properties of Central Vestibular Neurons

63

control. On one hand, histamine and dopamine have the same impact on type A and B MVNn. Histamine could regulate the activity of vestibular neurons according to the main circadian rhythms. Dopamine seems to be able to control the tonic, inhibitory drive a ecting vestibular neurons, and may be specifically involved in the coordination of the two vestibular nuclei. On the other hand, serotonin and noradrenaline mainly act on type Band B LTS neurons. Therefore, they could mostly modulate the dynamic properties of the vestibular system. Serotonin apparently increases the responsiveness of the vestibular system to external stimulations, which is reminiscent of general arousal. Noradrenaline could playa key role in the adaptive processes which continuously tune the vestibula-ocular and vestibulospinal synergies with the ever-changing conditions of our environment, or following the aging process.

NeuropepUdes in Central Vestibular Networks Several neuropeptides are known to act as neuromodulators on central vestibular neurons through specific, metabotropic receptors [for reviews, see Balaban et aI., 1989; de Waele et aI., 1995]. The most important ones include somatostatin (or SRIF), the opioid peptides, adrenocorticotropin (ACTH) and substance P. On the other hand, vestibular neurons have also been shown to be sensitive to specific growth factors, even in adult animals. It is noteworthy, however, that large species di erences were demonstrated among mammals in the anatomical and functional repartition of many neuropeptides and neuropeptide receptors in the brain. What holds true for guinea pigs might be for instance very di erent in rats [see Gehlert and Gackenheimer, 1997J.

Somatostatin

J

Somatostatin functions as a neurotransmitter in the CNS, with main e ects on locomotor activity and cognitive functions. Five distinct types 0 somatostatin receptors, SST H , have been cloned and functionally identified. They modulate neuronal activity through a decrease of cAMP activity, or through a G protein-mediated e ect on Ca 2 and/or K channels [for review, see Reisine and Bell, 1995J. Somatostatin-immunoreactive cell bodies and fibers have been described within the vestibular nuclei, with the highest density of terminals in periventricular regions of the medial vestibular nuclei [de Waele et aI., 1995]. Moderate to high concentrations of high a nity somatostatin binding sites have also been detected in all vestibular nuclei, with a predominance in the medial

Vidal/Vibert/SerafinlBabalian/Muhlethaler/de Waele

64

I

vestibular nucleus. In situ hybridization studies have revealed that they corresponded to SST3 receptors [Thoss et aI., 1995J. Intraventricular injection of somatostatin was shown to induce a postural imbalance reminiscent of the one observed following unilateral labyrinthectomy, i.e. bilateral limbs extension and body rotations about the longitudinal axis (called barrel rotations or barrel turning by neuropharmacologists). This postural reaction could be blocked by intrasystemic injection of antimuscarinic drugs, suggesting that the e ect of somatostatin was indirect. In addition, in vivo microiontophoretic application of somatostatin has been shown to depress the resting discharge of rabbit lateral vestibular neurons. Since these neurons were inhibited by somatostatin-immunoreactive, vermal Purkinje cells, it was hypothesized that somatostatin might be released together with GABA from the cerebellovestibular pathways [for reviews, see Balaban et aI., 1989; de Waele et aI., 1995J. On the other hand, Won et a1. [1996J have recently found in the rabbit somatostatin-immunoreactive neurons in the vestibular ganglion, which suggests that this neuropeptide might be involved in the modulation of sensory transmission from the labyrinth.

Opioid Peptides Three classes of endogenous opioid peptides have been individualized: the enkephalins, the -endorphins and the dynorphins. Each group of peptides preferentially interact with one of the three types of metabotropic, opioid receptors which have been defined. The (OP l ) , (OP 2) and (OP 3) receptors are preferentially activated by the enkephalins, the dynorphins and -endorphins, respectively. In the brain, opiate receptors generally activate inwardlyrectifying potassium channels, following adenylate cyclase inhibition. In some cases, they have also been shown to block voltage-dependent calcium channels. Altogether, the functional e ects of opiates in the CNS seem to be mostly inhibitory ones [for review, see Dhawan et aI., 1997]. Both enkephalin-immunoreactive cell bodies and enkephalin terminal endings have been detected within the vestibular nuclei [for reviews, see de Waele et aI., 1995; Zanni et aI., 1995]. Preproenkephalin (the precursor of met- and leu-enkephalin) mRNA-positive cells were also observed within the medial and lateral vestibular nuclei. Interestingly, the medial vestibular nucleus contains the highest density of enkephalinergic neurons among all the structures of the CNS. Dynorphin-immunoreactive sites have also been detected in the lateral and medial vestibular nuclei. Accordingly, central vestibular neurons are endowed with both and receptors, but only few receptors [Mansour et aI., 1994; Zastawny et aI., 1994; de Waele et aI., 1995].

Intrinsic Properties of Central Vestibular Neurons

65

In vitro studies on slices [Carpenter and Hori, 1992; Lin and Carpenter, 1994J have shown that morphine (which is a selective agonist of receptors), met-enkephalin and [D-Ala2]leu-enkephalin (a selective agonist of receptors) excited about 30% ofMVNn spontaneous activity by direct actions on postsynaptic receptors. Naloxone (a specific antagonist of and receptors) not only blocked these excitatory e ects, but also the increase of spontaneous discharge rate induced by bath application of acetylcholine. Therefore, these authors suggested that cholinergic and opioid receptors could interact on vestibular neurons through some yet unknown cellular mechanism. In vivo, microiontophoretic injections of morphine and enkephalins have also been shown to mainly increase the discharge of medial vestibular neurons [Iasnetsov and Pravidvtsev, 1986]. In contrast, leu- and met-enkephalin have been shown to decrease the resting discharge of lateral vestibular nuclei neurons. The decrease mediated by met-enkephalin was dose-dependent, suggesting that this peptide could be used as a neurotransmitter in the cerebellovestibular pathways (like somatostatin). On the other hand, the leuenkephalin e ect was more complex, suggesting that leu-enkephalin mainly is a neuromodulator of vestibular function [for review, see de Waele et aI., 1995J. Why the medial vestibular nucleus contains the highest density of enkephalinergic neurons in the CNS remains unexplainable in the absence of further data on the functional role of these neurons. They could be involved in the control of the vestibula-ocular and vestibulospinal reflexes, but we suggest that they could also be part of a built-in defense system against motion sickness and vertigo, since naloxone (an opiate antagonist) enhances the incidence of motion sickness [for review, see de Waele et aJ., 1995J.

Substance P and the Tachykinins Three types of endogenous tachykinins have been identified in the CNS: substance P, neurokinin A and neurokinin B. Each of these three compounds preferentially activates one of the three identified types of tachykinin receptors, Le. the NK j , NK z and NK 3 receptors, respectively. All of them belong to the G protein-coupled receptors family, and their a ects are likely to be mediated through activation the phosphatidylinositol-Ca z second-messenger system [for review, see Regoli et aI., 19941. Substance P-immunoreactive fibers and terminal endings (as well as a few immunoreactive neurons) have been identified within the vestibular nuclei, particularly in the caudal medial vestibular nucleus and in the inferior vestibular nucleus [for reviews, see de Waele et aI., 1995; Vibert et aI., 1996]. These

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Table 6. E ects of substance P on MVNn recorded in slices: the nature and number of e ects obtained with substance P on the various parameters characterizing intracellularlyrecorded MVNn are given for type A. type B and type B LTS neurons

Experimental conditions

Control Type A neurons

Substance P potential and discharge

resistance'

19 /49 (39%)

8 /12 (67%)

4

2

/49

(8%)

Type B neurons

Type B LTS neurons

TTX

Synaptic uncoupling

Agonists

46

GR-73632

/2

E ects of various tachykinin receptor agonists on neurons depolarized by substance P

neurons hyperpolarized by substance P

120/14 (86%)

3

80/8

1

(100%)

(100%)

/3

(100%)

(100%) /67

16

/25

Sar Met-SP

/1

(69%)

(64%)

6 /67 (8%)

(100%)

Pro-substance

3

P

20/2 (100%)

not tested

II

not tested

/18

I

/1 /6

2

(61%) /18

1 /l

Neurokinin

50/5

(12%)

(100%)

A

(100%)

16

6

GR-64349

50/5

/23

(50%)

/7

(86%)

(70%) 3 /23

2

(13%)

(100%)

6

not tested

(100%)

/2

Senktide

70/7

not tested

(100%)

/8

(75%)

2

/8

(25%)

2

/2

(100%)

Substance

60/6

2

P,-,

(100%)

(100%)

/2

SP Substance P: increase; decrease; 0 no e ect. J Resistance modifications were separated for depolarizing versus hyperpolarizing e ects of substance P.

fibers could originate from the brainstem reticular formation. and from the vestibular nerve itself. Indeed, a sizable (but highly species-dependent) proportion of sensory vestibular neurons are substance P-immunoreactive in frog. rabbit. guinea pig. cat. sqUirrel monkey and man [Felix et al.. 1996J. These a erent fibers are of utricular and saccular origin in rabbits, and innervate the base of the ampullar crests and the peripheral part of the otolithic maculae in guinea pigs. These data suggest that substance P could be colocalized with

Intrinsic Properties of Central Vestibular Neurons

67

Fig 3. Summary diagram of the neurochemistry of vestibulo-oculomotor and vestibulospinal pathways [reprinted with permission from de Waele et a!., 1995]. Ach Acetylcholine; G Fct growth factors; GLU glutamate; GLY glycine; HIS histamine; HOR VOR horizontal vestibulo-ocular reflex; 5-HT serotonin; LDT laterodorsal tegmentum; Op opioid peptides; PPT pediculopontine tegmentum; SP substance P; ST somatostatin; VCR vestibulocollic reflex; VER VOR vertical vestibulo-ocular reflex; VSR vestibulospinal reflex.

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glutamate in part of the thinnest sensory vestibular a erents [Usami et aI., 1993J. Why some of these a erents only release glutamate, whereas others display a colocalization of glutamate with glycine (see above) or substance P remains to be explained. These anatomical results contrast with in situ hybridization studies, which have demonstrated only few, typical NK-1 receptors in the medial vestibular nucleus of rats [Maeno et aI., 1993J. It is noteworthy, however, that unidentified 'substance P receptors' were detected in all vestibular subnuclei using immunohistochemical techniques [Nakaya et aI., 1994). In accordance with this result, we have recently shown that in guinea pig brainstem slices (table 6), substance P depolarized about 70% of medial vestibular neurons by activating atypical, postsynaptic substance Preceptors [Vibert et al., 1996J. In vivo, intrasystemic injection of substance P has been shown to accelerate the recovery from postural deficits following unilateral labyrinthectomy.

Adrenocorticotropin (ACTH) Very few data are available on the mode of action of this peptide on central vestibular neurons. An in vitro slice study has shown that ACTH depressed the resting discharge of medial vestibular neurons. In vivo, intrasystemic injections of ACTH accelerate the recovery of the postural and oculomotor syndromes following unilateral labyrinthectomy [for reviews, see de Waele et aI., 1995; Darlington et aI., 1996J. The fragment 4-9 could be responsible for what appears to be due to a direct action of ACTH on the ipsilateral vestibular nucleus [Gilchrist et aI., 1996).

Growth Factors Neurotrophic peptides like the nerve growth factor (NGF) were first mostly described as regulatory factors for the survivaL di erentiation, and subsequent maintenance of functions of a specific population of neurons. There is, however, increasing evidence that these neurotrophins are also involved in common processes of neuronal plasticity [for review, see Thoenen, 1995J. In this context, it is interesting to note that moderate densities of specific NGF receptors have been detected in the medial and spinal vestibular nuclei, mostly at the borders of the prepositus hypoglossi nucleus [Sobreviela et aI., 1994; Sukhov et aI., 1997). The exact role(s) subserved by these receptors in adult animals is unknown.

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Other Neuropeptides Apart from the five families of neuropeptides detailed above, some other neuropeptides or neuropeptide receptors have been detected in neurons and/ or terminals within the boundaries of the vestibular nuclei. In particular, fibers positive for neuropeptide Y, neurotensin, vasoactive intestinal peptide (VIP) and cholecystokinin seem to reach the medial and spinal vestibular nuclei, whereas thyrotropin-releasing hormone (TRH) and neurotensin receptors have been described in these two regions [for reviews, see Balaban et a1., 1989; de Waele et a1.. 1995; Zanni et a1., 1995].

Presence of Purine Receptors in the Vestibular Nuclei Adenosine 5 -triphosphate (ATP) is a well-known provider of energy to cells and neurons. In addition, ATP interacts with several types of specific, membrane receptors to modulate physiological responses. Seven subtypes of ionotropic receptors (the P 2X receptors), and six subtypes of metabotropic receptors (the P 2Y receptors) activated by ATP have been described up to now. In addition, several subtypes of PI receptors sensitive to adenosine, the ultimate breakdown product of ATP, have been identified. As a rule, ATP was found to have excitatory e ects on neurons in several sensory nuclei and autonomic ganglia [for review, see Chessell et al., 1997]; it would elicit glutamate release from sensory neuron synapses in the spinal cord [Gu and MacDermott, 1997]. Two in vitro studies have demonstrated that MVNn neurons were sensitive to ATP, and were endowed with P2X and P 2Y purine receptors [for review, see Chessell et al., 1997]. In particular, bath application of P 2 receptor agonists induced a dose-dependent increase in the spontaneous discharge of 35% of extracellularly-recorded MVNn on rat brainstem slices. Bath application of P2 antagonists suppressed these responses. Further studies should be undertaken to obtain an idea of the functional relevance of these receptors.

Conclusion

As stated in the introduction, the stabilizing oculomotor and postural responses emerge from a complex multisensory integration, which must show a high degree of plasticity. We also pointed out that the neuronal computations underlying gaze and posture control would be a by-product of both the emerging properties of vestibular networks and the individual properties of each

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of their components, Le. the neurons. Therefore, we have tried to describe in this chapter how various neurobiological methods were combined in di erent types of in vivo and in vitro preparations to take into account these two complementary aspects of neuronal processing in the vestibular nuclei. Needless to say, this combined approach has created more questions than it has solved. Furthermore, similar studies are still just beginning for the many other structures of the CNS involved in gaze and postural control. Nevertheless, it clearly appears that the wealth ofdata brought by the molecular biology methods and in vitro recordings will have to be replaced and interpreted in a functional frame if one wants to understand their' raison d' etre' , and ul timately to figure au t how the brain works. We also hope to convince the reader that such investigations pave the way for new treatments of vestibular syndromes and could lead to wider clinical applications. Indeed, vestibular compensation and vestibular adaptation have now been shown to be valuable models to study the postlesional plasticity and adaptive capabilities of the CNS.

Acknowledgements This work was supported by grants from the Swiss NSF, the Sandoz and Roche Foundations, the Centre National de la Recherche Scientifique (CNRS-DRCI), the Centre National d'Etude Spatiales (CNESJ, and the French Ministere des A aires Etrangeres (Programme International de Cooperation with M. Muhlethaler). N. Vibert was awarded postdoctoral fellowships from the French Ministere de l'Enseignement Superieur et de la Recherche, and from the Fondation pour la Recherche Medicale (FRM). We thank Mrs. D. Machard, Mr. M. Ehrette, Mr. M. Loiron and Mr. G. Krebs for their excellent technical assistance. We would like to thank Prof. IS Curthoys for his critical reading of the manuscript.

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Dr. Pierre-Paul Vidal, Neurobiologie des ResealLX Sensorimoteurs, CNRS UPRES-A 7060, 15, rue de I'Ecole de Medecine, F-75270 Paris, Cedex 06 (France) Tel. 33 1 43296154, Fax 331 44073681, E-Mail [email protected]

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Buttner U. (ed): Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger, 1999, vol 55, pp 82-110

Vestibular Compensation Ian S. Curthoysa, G. Mjchael Halmagyjb a b

Department of Psychology, University of Sydney, N.S.W, and Eye and Ear Research Unit, Neuro-otology Department, Royal Prince Alfred Hospital, Camperdown, N.S.W, Australia

Introduction

If a normal healthy person suddenly loses all peripheral vestibular function on one side they show a distinct pattern of oculomotor, postural and sensory symptoms. Typically these are: (1) A vigorous ocular nystagmus consisting of rhythmic, mainly horizontal, eye movements with qUick phases directed away from the a ected ear. This spontaneous nystagmus is present even in light but is much more vigorous in total darkness. (2) Postural symptoms, such as falling to the a ected side, di culty standing and walking. (3) Strong sensations of vertigo - the sensation that the person, or the room, or both are turning. Within the space of about 1 week, these symptoms usua]Jy diminish or disappear entirely, even without any medical intervention. In fact, medical intervention during this critical early stage may have deleterious e ects on recovery, especially long-term recovery. Over the next few weeks and months the person returns to their usual lifestyle - walking, running, playing tennis as if they had never su ered the loss. This quite miraculous recovery of apparently normal function is called vestibular compensation and it has been the subject of intense study because of its intrinsic interest. its clinical significance and its potential value as a model for understanding the neural mechanisms responsible for such rapid behavioral changes. We will use the term UL (for unilateral vestibular loss) to refer to a person with partial or complete luss uf vestibular a erent input frum une labyrinth. Not all UL patients show this very rapid recovery. After apparently identical losses some patients may show permanent adverse e ects whereas others seem to recover completely. In such poorly compensated patients after the initial decline of the symptoms, the person continues to experience sensations

of postural unsteadiness as if they are on a constantly moving surface, like the deck of a ship in rough seas. They have di culty walking. They report that their vision during walking or driving may be so poor they have di culty recognizing friends or reading street signs. Nothing is fixed or stable - it is as if they have no 'anchor'. Their visual world appears to move as they move. Their 'postural world' is also unstable in the sense that they are unsteady at rest and during walking and they find this visual and postural instability very disturbing. Many of these poorly compensated patients lead a miserable life and may be incapacitated. Some are labelled neurotic because of this apparently unusual combination of symptoms. It appears that for this group of patients the process of vestibular compensation has not taken place or has relapsed (decompensated). A very rough estimate is that around 70% of patients are well compensated and around 30% are poorly compensated. The crucial question of course is: What is the di erence between wellcompensated and poorly-compensated patients? Some preliminary questions and answers: (1) Is there really a di erence between the two groups? Perhaps both groups of patients experience the same symptoms and the same sensations but the poorly compensated patients complain more? It is very di cult to obtain empirical evidence on such a question. At best we can say that clinical experience with many patients shows that although a complaint factor does operate to some extent with some individuals, such a 'complaint factor' is not the reason for the di erence between the groups. (2) Do the two groups really have equivalent vestibular losses? We have found that patients with apparently identical peripheral vestibular losses can compensate either well or poorly. The extent and the speed of vestibular loss are not clear-cut factors responsible for the di erence: some patients in whom the whole vestibular nerve has been removed may compensate well, others may compensate poorly. (3) Are there objectively measurable di erences between the two groups in some of the responses generated by vestibular stimulation? Could such response di erences explain the di erence between groups? We have yet to find such a consistent response di erence between the groups in over 15 years of research on this question. Furthermore, if such a response di erence were to be found would it be the cause of the di erence between the two groups or simply caused by whatever mechanism is responsible for the di erence. (4) Are there pre-existing di erences in vestibular functiun between the labyrinths on the two sides? Could it be that the labyrinth on the presumed 'normal' side of poorly compensated patients is also a ected or diseased so that when one labyrinth is removed the remaining labyrinth cannot take over and restore normal function? This may account for the results in some patients.

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(5) Do the poorly compensated patients tend to be older? It seems that there is a tendency for young patients to compensate more quickly and for older patients to fall into the poorly compensated group. But robust evidence on age as a factor in the quality of human vestibular compensation is lacking. Some poorly compensated patients are relatively young. From the above it is clear that there is no simple answer to this perplexing puzzle [see also Black et aI.. 1996; Blakley et aI., 1989a, bJ. In this chapter we seek to clarify this matter by briefly reviewing the behavioral and physiological mechanisms of vestibular compensation in more detail and also considering matters apart from the sensory and motor changes which take place during compensation. For other recent reviews, see Curthoys and Halmagyi, 1992, 1995; Dieringer, 1995; de Waele et aI., 1994; Vibert et aI., 1997; Schaefer and Meyer, 1974; Smith and Curthoys. 1989; Lacour et aI., 1989; Precht, 1986; Precht and Dieringer. 1985; Vidal, 1998. Vidal, this volume. In this chapter we have tried to keep references to a minimum and those recent compendious reviews should be consulted for a full list of the references. This chapter is a 'metareview' which encompasses the major findings in those previous reviews and refers to more recent developments. We will refer to both animal and human data almost interchangeably since many of the mechanisms for vestibular compensation seem to be similar across species. The major di erence is that the time course is faster in some species. The results from animal work are crucial since it is only by experimental studies of vestibular compensation in animals that it wiJ] be possible to understand the complex interdependent neural physiological processes which take place during vestibular compensation. Vestibular compensation gives the appearance of being a simple process where the remaining labyrinth assumes the function for both labyrinths. That appearance is misleading. The seemingly simple process is in fact composed of a number of processes which are seamlessly intertwined to provide the basis for a continuum of recovery. The diverse symptoms themselves - oculomotor responses. postural responses and perceptual responses - show how basic the vestibular sensory information is for so many di erent systems. Gaze control and posture control and perception all rely heavily on vestibular input for their usual operation and unilateral vestibular loss severely disrupts all systems. There are probably di erent neural mechanisms for recovery in di erent systems. Even in well-compensated patients some vestibular-controlled functions never recuver whereas uthers du (table 1).

Djrect and Indjrect Consequences of Unilateral Loss In addition to the direct consequences of vestibular loss there are secondary consequences which are additional sensory consequences resulting from

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Table 1. Clinical feature as related to physiological mechanisms Clinical feature

Spontaneous nystagmus With head stationary there is a vigorous rhythmic nystagmus with mainly horizontal components. The quick phases are directed away from the a ected ear. The nystagmus strength decreases over the following days. Visual stimuli suppress this spontaneous nystagmus so Frenzel lenses or equivalent means are necessary for observing it.

Asymmetrical horizontal VOR response Reduced or absent eye movement response to sudden unpredictable horizontal head movements towards the lesioned ear. Slightly reduced response for head movements towards the intact side.

Maintained rolJed ocular torsional position After UL both eyes are rolled around the visual axis towards the lesioned side. This is large (around 9-10°) shortly after the lesion and decreases over the first weeks after UL. There is a corresponding perceptual deviation: short lines in an otherwise darkened room appear to be roll-tilted by the same amount as the ocular torsion [Curthoys et a1., 19911.

Probable physiological mechanism

The UL results in loss of semicircular canal input to one vestibular nucleus resulting in a large imbalance in activity between the average neural resting discharge between the two vestibular nuclei. Such a neural imbalance would occur during a very large angular acceleration in the horizontal plane and horizontal eye movement is the appropriate response to such a stimulus.

During horizontal head accelerations to the ipsilesional side the relatively weak disinhibition relayed from the intact labyrinth is the only source of oculomotor drive. For rotations to the contralesional side the usual facilitation takes place. Brief natural head accelerations reveal this asymmetry - slow unnatllfal sinusoidal stimuli do not. Absence of otolithic and vertical canal input produces an imbalance in resting discharge between the two vestibular nuclei, eqUivalent to the imbalance during a maintained roll-tilt to the intact side in a healthy person.

the inadequate motor response to the vestibular stimulus. The following elaborates this. Vestibular loss may cause two types of error: Errors may occur because either the sensors themselves (or their a erent neurons) signal stimuli which are not physically present. For example, if the neurons in the semicircular canal system signal that the head is undergoing angular rotation, the person will experience rotation sensations even when physically statiunary. Similarly if neurons in the utulith system signal that the head is undergoing linear acceleration, the person will experience tilting or falling sensations when they are upright and stable. In both cases the brain cannot distinguish between neuronal activity caused by appropriate stimuli from aberrant firing patterns.

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But other secondary or indirect errors will occur if the response to the sensory input is not adequate. For example, a patient with poor semicircular canal function will have vestibular-induced eye movements which do not compensate adequately for normal head movements. Consequently in such a patient the image falling on the retina will be smeared during head movement, causing the person to experience a combination of degraded and distorted visual input due to the inadequate sensorimotor response in addition to the erroneous sensory experience from the inadequate semicircular canal signal. The vestibular loss is responsible for both errors.

The Recovery Process Closer examination shows that even amongst well-compensated patients there is great variability in recovery of specific symptoms after UL. One vestibular response - spontaneous nystagmus (SN) - shows very fast and almost complete recovery after loss. Another response - the vestibula-ocular reflex response to natural head angular accelerations towards the lesioned side - shows little recovery. We consider these so-called static and dynamic aspects of recovery separately below. In doing so it should be remembered that there can be very di erent neural mechanisms responsible for each behavior. Only by experimental challenges is it possible to determine if the behavior has a single cause. For example, the decrease in SN appears to be caused by a simple physiological process such as neural adaptation very early in the compensation process but is probably maintained by more robust neural mechanisms involving anatomical changes, such as axonal sprouting, later in compensation. In such a case the one behavior, the decrease in SN, appears to be caused by very di erent neural processes early and late in vestibular compensation (table 2).

Static Symptoms

Spontaneous Nystagmus Immediately after UL there is a sustained horizontal ocular nystagmus with quick phases directed away from the a ected side, and slow phases directed toward the a ected side. It is the direction of the quick phases which is apparent to the observer and so the patient's eyes appear to be beating away fwm the a ected side. Such a nystagmus pattern wuuld be ubtained in a healthy person or animal during a large maintained horizontal angular acceleration directed towards the intact side. The loss of input has mimicked the neural imbalance during such a natural stimulus and the nystagmus and other perceptual responses are appropriate for such a natural stimulus.

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Table 2. Some vestibular controlled behaviors which compensate and some which do not

Behavior

Before UL

Acutely after UL

Long term after UL

Recovery?

Horizontal eye position

Midposition

Horizontal nystagmus to the intact side

Nystagmus disappears

Yes

Torsional eye position

Upright

Both eyes roll to the lesioned side

Eye torsion decreases

Yes

Sensation of felt body position

Upright and stable

Sensation of turning (vertigo)

Vertigo disappears

Yes

Dynamic horizontal VOR

Compensates for head rotation in both directions

Inadequate for ipsilesional rotations; VOR gain asymmetry

VOR gain asymmetry persists

No

Axis of eye rotation

Aligned with axis of head rotation

Eye axis is misaligned

Misaligned

No

Posture

Normal

FaIJs to the a ected side

Posture is normal

Yes

Gait

Normal

Ataxic and turns to the a ected side

Gait returns to normal

Yes

Figure 1 shows the neural equivalence of UL-induced SN and rotationinduced nystagmus, based on the known anatomical and physiological connections of the horizontal semicircular canal system. After a few days, the intensity of the SN reduces and thereafter may only be observed when visual fixation is completely excluded. The time required for the disappearance of SN in light varies according to species from an hour for the goldfish [Ott and Platt, 1988J to a few days for man. Although there is variability between species, the recovery rate for di erent animals of the one species is similar, suggesting that a common neural mechanism is in operation.

Ocular THt Reaction ~ UL results in maintained posture of the head and eyes called the ocula tilt reaction. The head has a roll-tilt towards the lesioned side, both eyes adop a maintained torted position (rolled around the optic axis toward the lesione side) and there is a skew deviation (hypotropia) toward the lesioned side (Le. the eye on the a ected side moves down in the orbit relative to the position of the eye on the intact side) [Halmagyi et a!., 1979, 1993; Curthoys et a!., 1991; Wolfe et a!., 1993]. The change in ocular torsion position is accompanied by a corresponding change in the perception of the orientation of visual lines

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Fjg 1. The equivalence of horizontal head rotation (A) and unilateral loss (B) in generating horizontal nystagmus. The neural connections have been established by anatomical and physiological studies in cats and monkeys. MVN type I neurons receive peripheral a erent input and are excited by ipsilateral angular accelerations. Type II neurons are driven indirectly via the opposite labyrinth and hence have a mirror-image response: they are excited by contralateral rotations and silenced during ipsilateral rotations. Type II neurons are inhibitory neurons (closed circles) so their reduced inhibition during an ipsilateral rotation tends to disinhibit the type I neurons and thus tends to enhance the ipsilateral a erent input to type I neurons. During yaw angular acceleration to the left, primary a erents from the left horizontal semicircular canal are activated whereas primary a erents from the right horizontal canal are silenced. The solid lines indicate ceUs whose firing increases and the dashed lines indicate those whose firing decreases. After UL on the right (B), primary a erents on the right side are silenced, resulting in an imbalance ofresting activity between the two VN similar to that shown (A). The circuitry responsible for quick phase generation is triggered by this imbalance in both cases but the connections oftms quick phase circuit are still not fully known. It should be noted that many other projections are activated either directly or indirectly by vestibular a erent input and these other pathways are not shown in this very simplified illustration [for references, see Wilson and MelviH Jones, 1979; Highstein and McCrea, 1988; Nakao et aI., 1982; Shimazu and Precht. 1965, 1966; Shimazu, 1983; Precht et aI.. 1966; Precht and Shimazu, 1965; Ried et aI.. 1984; Smith and Curthoys, 1988a, b; Newlands and Perachio, 1990a, b; Ris et aI.. 1995, 1997; Markhametal., 1977,19781.

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in reduced viewing conditions. A short visible line in an otherwise darkened room appears to be rotated down on the a ected side by the extent of the ocular torsion [Curthoys et aI., 1991; Friedmann, 1970, 1971]. So if the person has had a right vestibular loss it appears to them that a truly horizontal line is rotated right-side down (clockwise from the observer's point of view). The ocular torsion and perceptual changes both decrease over time so that at testing 1 month after UL they are about half the values measured at 1 week after UL. There is also a decrease in sensitivity to roll-tilt so that roll-tilts of the body towards the operated side are underestimated [Dai et aI., 1989; Halmagyi et aI., 1993J.

Restoration of Static Equilibrium Animal studies have shown that compensation of the static symptoms proceeds normally even in the absence of vision [Smith et aI., 1986J or of the occipital cortex [Fetter and Zee, 1988; Fetter et aI., 1988J or of the cerebellum [Haddad et aI., 1977J. However, somatosensory and proprioceptive inputs are important for the compensation of static symptoms because if these sensory inputs are withheld, compensation takes longer or is incomplete: guinea pigs and monkeys deprived of visual input take longer for roll-head tilt to recover [Lacour et aI., 1976, 1979; Xerri and Lacour, 1980]. On the basis of evidence such as tills, it is suggested that after UL, patients should be encouraged to become active and mobile as quickly as possible. The diminution of nystagmus and reduction in ocular torsion that takes place over the first weeks is substantial but it is probably never complete [Curthoys et aI., 1991J. Similarly in some patients even years after UL, a low velocity (1-2°/s) horizontal SN can still be detected in darkness and measures of ocular torsion and perception likewise show a small residual ocular torsion. The Bechterew Phenomenon Studies on animals show that long-lasting changes in the brainstem, probably predominantly in the vestibular nuclei, are likely responsible for the recovery of static symptoms. If the remaining labyrinth is removed a few days or weeks after a UL, the animal shows a near-complete pattern of behavioral responses, just as if this second labyrinthectomy were the first labyrinthectomy on a normal animal [Bechterew, 1883]. There is SN, head roll-tilt, static eye deviation all towards the most recently operated side. This behavioral pattern is called the Bechterew phenomenon and it is held to constitute strong evidence that neural rebalancing in both oculomotor and postural control systems must have taken place in the interval between the two labyrinthectomies. The rebalanced system is the 'unbalanced' again by the second labyrinthectomy so that although there are no vestibular inputs present at all after the second

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labyrinthectomy, the animal still displays symptoms which appear to be due to strong vestibular stimuli. Studies of the Bechterew phenomenon show that multiple mechanisms must operate during vestibular compensation. In guinea pigs the SN has substantially decreased and almost disappeared by day 1 but there is no Bechterew phenomenon in guinea pigs at day 1 post-UL. By day 3 the Bechterew phenomenon is fully present. This absence of the Bechterew phenomenon very early in compensation shows that the process responsible for the early disappearance ofSN must be di erent from the processes responsible for the absence of nystagmus at later times after UL. This seamless intertwining of di erent neural processes responsible for the same behavior must be borne in mind in considering the neural mechanisms of vestibular compensation.

Dynamic Responses

Rotational Tests Objective measures of purely vestibular dynamic response (Le. eye movements during the first 100 ms of an abrupt unpredictable passive horizontal head rotation) show there is little recovery of purely vestibular function, even years after the loss [Halmagyi and Curthoys, 1988; Halmagyi et aI., 1990; Aw et aI., 1995, 1996a, b; Cremer et aI., 1998]. This eye movement response to passive head rotation and variations on it are widely used to indicate vestibular function and the response is called the vestibulo-ocular response (VOR). A measure of VOR performance is gain; the ratio of the eye velocity response to a given head velocity stimulus. In normal subjects, VOR gain is around 1.0 during movements in the natural range of head angular accelerations: in other words the eye moves to compensate for the head movement so that the image stays relatively fixed on the fovea during normal head movements [Grossman et al., 1989; Grossman and Leigh, 1990]. During the first week after UL, if the patient's VOR is tested by passive head rotations, then it is found that the eye velocity responses for yaw head rotations in both directions are decreased. In addition there is an asymmetry in the gain of the horizontal VOR: there is a slower eye velocity response (smaller VOR gain) for horizontal head rotations directed to the lesioned side than fur identical head rotatiuIlS directed tu the intact side. During rotatiuns to the operated side the VOR gain falls to 0.4. Rotations towards the healthy side show a higher gain (around 0.7) although it is still significantly 1.0. Both low-acceleration sinusoidal rotations and high-acceleration impulsive angular accelerations show this VOR gain asymmetry but it is more apparent

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with brief stimuli which have accelerations in the natural range (i.e. above about 1,0000/s/s) [Fetter and Zee, 1988; Wolfe and Kos, 1977; 1st! et aI., 1983; Olson and Wolfe, 1984; Jenkins, 1985]. There is likewise an asymmetry in the roll VOR where roll-head movements to the a ected side show smaller gain than roll-head movements to the intact side. In pitch, the VOR gain for both upward and downward head movements is decreased. Head impulses in the plane of the semicircular canals show the losses with remarkable specificity: the loss of a single canal can be detected by the particular asymmetry [Cremer et aI., 1998]. It should be stressed that these are tests of high frequency (and high acceleration) dynamic vestibular function to passive vestibular stimuli. Our recent results from tests where the person actively turns their head, show higher VOR gains than during passive rotations. The inadequate VOR gain during horizontal head movements means that the retinal image must be smeared across the retina during passive head movements, with greater retinal smear during head movements to their a ected side. This permanent VOR dysfunction gives us some indication of why poorly compensated patients experience a shifting visual world - the visual image is moving across the retina during head movements. The puzzle is that our measures have shown the VOR is just as inadequate in well-compensated patients and poorly compensated patients. The dynamic VOR of some patients may show some small recovery over time after loss - others do not. On average there is no functionally e ective recovery of VOR dynamic response to natural head accelerations.

The VOR Time Constant Another means of testing the VOR is by measuring the eye velocity response either to an abrupt stop from constant velocity rotation (an impulse of angular acceleration) or to the onset or 0 set of a long duration constant angular acceleration (a step of angular acceleration). Such large unidirectional stimuli allow the calculation of the time constant of the semicircular canal system. (The simple head turns described above do not allow this calculation since they consist of an acceleration in one direction, followed a few hundred milliseconds after by an acceleration in the opposite direction.) For horizontal angular accelerations around an earth-vertical axis the decay time constant of the monkey horizontal canal primary a erents is around 5-6 s whereas the decay time cunstant uf munkey and human horizuntal nystagmus tu cumparable stimuli is far longer at around 20 s. The prolongation of the nystagmus time constant relative to the primary a erent time constant is held to be due to the operation of brainstem neural circuitry referred to as the velocity storage integrator [Cohen et aI., 1977; Raphan et aI., 1979]. It appears that this

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brainstem neural mechanism is severely disabled after UL since the decay time constant of horizontal nystagmus falls from around 20 s to 10 s [Blakley et aI., 1989a, b; Hain and Zee, 1992]. Responses to Oto]jthic Stimulation Probably the simplest linear acceleration stimulus is that occurring during a simple roll-tilt of the head. If the head is maintained in a rolled head position (for example ro]]ed so that it is towards the left shoulder) then the action of the linear acceleration of gravity on the inner ear is di erent to that with head vertical. Ocular counterrolling (OCR) - the torsion of the eyes in response to a roll-tilt stimulus around a naso-occipital (X) axis - is one of the few accepted measures of otolith operation [Diamond and Markham 1981, 1983]. They showed that UL does not appear to produce consistent changes in the amplitude of OCR during roll-tilt towards the a ected or to the intact ear. There have been few reports of comparable measurements of OCR before and after UL. Briefimpulsive linear accelerations directed along an interaural axis generate a horizontal eye velocity response (an otolith-ocular reflex). This response is equal in magnitude for accelerations directed to either side. There have been reports that there is a smaller response for linear accelerations directed to the intact ear than accelerations directed to the operated ear in post-UL patients but the response asymmetry declines within a few weeks [Lempert et aI., 1997; Bronstein et aI., 1991]. Recently we have shown that there is another way of assessing the function of one part of the otoliths - the saccule. High intensity auditory clicks delivered by a headphone to one ear cause short latency inhibition of the ipsilateral sternocleidomastoid neck muscles. This response is referred to as the vestibular evoked myogenic potential (VEMP). Averaging responses to repeated clicks in subjects who are tensing their neck muscles shows this short latency ( 11 ms) response. Data from control patients shows that this is not an auditory response: most convincingly by the fact that subjects who are totally deaf can show such a VEMP [Colebatch et aI., 1992, 1994]. Experiments on guinea pigs have shown that these clicks activate receptors on the macula of the saccule [Murofushi et aI., 1995, 1996; Murofushi and Curthoys, 1997J. UL abolishes this otolithic response. E ects uf UL UIl Pusture aIld Gait Black et a1. [1989J have reported that in the Sensory Organization Test which measures postural stability by means of a posture platform with varying visual and postural feedback, all post-UL patients tested in the acute postoperative period had abnormal postural control in conditions where the move-

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ment of the visual and somatosensory stimuli was locked to the patients sway. Well-compensated patients have scores in the normal range on such testing by about 4 weeks after UL.

Dynamic Compensation and VOR Plaslicity The permanent dynamic VOR deficit of UL patients is in sharp contrast to the relative ease with which VOR gain can be changed in normal subjects. For example, many reports have shown that healthy subjects who wear magnifying spectacles show significant increases in VOR gain after wearing the magnifying spectacles for just a few hours [Berthoz and Melvill Jones, 1985; Lisberger, 1988J. After wearing 2 magnifying lenses the gain of the VOR (measured in darkness without spectacles) increases Significantly beyond its usual gain of around 1.0. Similarly, after wearing 0.5 minifying lenses the gain of the VOR decreases significantly below 1.0. In both cases the change in VOR gain is symmetrical and acts to maintain a stable retinal image and to minimize retinal smear during head movement. This rapid VOR gain change shows that in normal humans the VOR is highly modifiable ('plastic'). It is commonly presumed that this plasticity of the VOR should transfer and assist the recovery of the dynamic VOR in patients after unilateral loss. However, the objective measures of the VOR shows that this transfer just does not happen. Post-UL patients show substantial permanent deficits in dynamic vestibular function to natural head accelerations despite the existence of such VOR-adaptive processes which apparently should assist them in overcoming their deficits [Halmagyi et al., 1990; Cremer et al., 1998J. On the other hand, our measures show there is no functionally e ective recovery in the VOR in either well-compensated or poorly-compensated postUL patients. Why does VOR plasticity apparently not assist the process of vestibular compensation? Closer analysis shows that there are substantial di erences between normal subjects and post-UL patients: (1) In UL patients the entire vestibular a erent input from one side has been removed, whereas in normal subjects both labyrinths send a erent input to the brainstem. (2) The challenge for the VOR after UL is very di erent from any challenge yet imposed on normal subjects by magnifying spectacles. After UL the VOR must generate an asymmetrical response - with di erent gains for horizontal head rotation to each side. All spectacle studies to date have reqUired symmetrically increased UI' decreased VOR. (3) UL not only removes the sensory input from the periphery but also disrupts the central processing of vestibular and other sensory information. This loss e ectively disables the brainstem velocity storage integrator and so a ects the processing of many long duration vestibular signals. It may be that

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this central mechanism is important for mediating some of the rapid plastic changes in the VOR. There is one further and possibly crucial di erence. We have recently shown that when exact measures are taken of the full three-dimensional components of the eye movement response (horizontal, vertical and torsional eye movement components of the human VOR) after UL, there are even more serious VOR deficits than had been believed. During head rotation towards the a ected side there are permanent deficits not only in eye velocity but also in the axis around which the eye rotates [Aw et aI., 1996a, b; Cremer et aI., 1998J. For the retinal image to remain stable during a head movement, the eye velocity must be equal and opposite to the head velocity, but in addition the axis of eye rotation must match the axis of head rotation. Our measures show that both are permanently impaired by UL. The eye rotates at an inadequate velocity and it rotates around an incorrect axis. Both of these errors are due to the UL and will act to smear the retinal image across the retina during normal head movements. The challenge of trying to repair both eye velocity and the axis of eye rotation may be too great for mechanisms of vestibular plasticity to overcome (fig. 2). Our present position is that it appears that well-compensated patients learn to use other behavioral strategies to bypass the impact of these permanent eye velocity and axis deficits so they do not experience the retinal smear yielded by their inadequate VOR. That position is not consistent with the conclusion from studies of the recovery of dynamic vestibular VOR using low-frequency sinusoidal horizontal rotations. Results from such tests apparently show substantial recovery of VOR function: they seem to show that one labyrinth is almost as good as two in generating dynamic VOR responses [Baloh et aI., 1984; Paige 1989; Takahashi et aI., 1984; Olson and Wolfe, 1984; Jenkins, 1985J. However, lowfrequency sinusoidal rotation is not an adequate test of normal vestibular function. Other sensory input (such as somatosensory input) can be used to generate an eye movement response to such low-frequency stimuli. We have shown that patients with no vestibular function after bilateral vestibular neuroma removal can show good performance on such low-frequency sinusoidal rotation tests [Halmagyi and Curthoys, 1987J. With the natural head accelerations used in the head impulse test and the exact measures of eye movement using three-dimensional scleral search coils, our research has repeatedly shown that there is little impwvement in uynamic VOR uver time: fur heau wtatiuns towards the operated side the dynamiC VOR appears to be permanently highly compromised both for eye velocity gain and axis of eye rotation. So how do patients deal with the smeared and twisted retinal image which our VOR measures show they should receive during head movements? One way appears

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A

Fig 2. A In a normal healthy person during head rotation, the velocity of eye rotation is equal and opposite to the head rotation. The axes of both eye and head rotation are parallel. B In a patient after unilateral vestibular loss the eye velocity is less than head velocity and in addition, the axis of eye rotation is not parallel to the axis of head rotation. Both the decreased eye velocity and the nonparallel axes of rotation will cause the retinal image to be smeared.

B

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to be by eliminating it; a well-timed blink during a head movement will e ectively prevent the retinal image from being smeared - during the blink there will be no retinal image [R.A. Black et aI., unpubi. observations]. Our recent measures have confirmed that during natural head movements, blinks are common even in healthy subjects during large eye-head refixations. Experimental studies tend to ignore these blinks by forcing subjects to keep their eyes open during such large refixation movements, forcing subjects and patients to suppress the natural blink response. Rehabilitation It is clear that post-UL rehabilitation is e ective in increasing the speed with which post-UL recovery takes place. Cawthorne [1946] and Cooksey [1946] originally developed a series of exercises which were reported to assist the recovery of post-UL patients and a number of authors have modified and extended these exercises. There is now abundant evidence for the e cacy of some of these treatments in some patients. There is also animal evidence supporting this idea. For example, squirrel monkeys given exercise each day after UL returned to pre- UL performance levels on a balancing task faster than animals without exercise. In complementary fashion, post-UL sensorimotor restriction slowed the return of other animals to pre- UL levels of performance. The evidence of adaptive plasticity of the VOR in normal healthy subjects is frequently used to support the value of vestibular rehabilitation programs. We concur about the value of such rehabilitation programs especially early after UL (cf. Telian and Shepard, 1996; TeHan et aI., 1990; Igarashi et aI., 1975; Shumway-Cook and Horak, 1990J. We disagree as to what is being changed. Our evidence has shown conclusively that after UL there are only modest gain changes in the dynamic VOR so that large, permanent VOR gain asymmetries remain even in well-compensated patients. If VOR-adaptive plasticity operates, then it does not restore VOR gain or remove VOR asymmetry. Possibly other central neural mechanisms (such as the velocity storage integrator) may be changed by such a rehabilitation program, since our own unpublished evidence has confirmed that there is an increase in the time constant of the VOR during rehabilitation. Understanding that post-UL patients probably rely more on learning other behavioral responses (such as blinks) than on potentiation of VOR gain, has profoundly important implications for diagnosis and rehabilitation [Zennou-Azogui et aI., 1994, 1996; Xerri amI Zermuu, 1989; Lacuur et aI., 1989; Xerri et aI., 1983J. When the appropriate tests of purely vestibular function are carried out after UL, there is only modest recovery in purely vestibular control of gaze. There are many changes in the behavioral response of patients after UL and it seems that most of these changes take the form of learning new behavioral

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strategies or boosting the relative weights of inputs in the gaze control system (and probably also the postural control system) rather than some restoration of purely vestibular function. The final result is that the performance and lifestyle of well-compensated post-UL patients is almost indistinguishable from that of a normal healthy individuaL we contend by virtue of this increased role of extravestibular mechanisms. When specific tests of purely vestibular function, using passive head rotation stimuli, are performed, the unilateral loss of vestibular function is very clearly demonstrated in all post-UL patients. One possible reconciliation is that during natural active head movements the patients may be better able to coordinate the eye-head movement - all of our VOR tests to date have used passive head movements to attempt to minimize any role for prediction or preprogramming by the patient but it may be that the essential ingredient of successful vestibular compensation is to learn how such preprogramming functions. There appears to be a 'critical period' for substitution processes during vestibular compensation: it is the first few weeks immediately after the vestibular loss [Horn and Rayer, 1978J. This is the very time which patients find most distressing and seek medication to suppress the unpleasant symptoms. However, the Bechterew phenomenon shows that this is a crucial time to establish long-term neural changes. Medication at this time, even just tranquilizers, may interfere with the rapid neural changes which are occurring in this critical period and may not be in the best long-term interests of the patient. The following sections explore in more detail some of the neural changes which have been shown to take place during vestibular compensation.

Neural Correlates of Vestibular Compensation

Resting ActMty After UL, neurons in the vestibular nucleus on the lesioned side (the ipsilesional VN), will receive no input from the periphery, so they will be deprived of both the resting activity and the modulation in response to vestibular stimulation of the angular acceleration sensors - the horizontaL anterior and posterior semicircular canals and the linear acceleration sensors - the otolithic receptors on the utricular and saccular maculae. This loss of input from the periphery has dramatic e ects on neurons in the vestibular nuclei. To um.lerstam.l these e eets it is neeessaly tu um.lerstam.l sume general principles uf operation of vestibular sensors and the integration of their activity. Peripheral vestibular a erents have a high resting discharge rate: some a erents in monkeys have resting activity as high as 100 spikes/s even when the head is motionless and in its normal upright position. Since there are

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roughly 18,000 vestibular a erents from each human labyrinth, UL will at once remove a massive a erent neural flux projecting from the dea erented labyrinth to the ipsilesional VN. The corresponding VN on the intact side (the contralesional VN) will continue to receive its usual a erent bombardment. UL thus results in a large imbalance in average resting activity between the two VN, just as occurs during a prolonged angular acceleration (fig. 1). This imbalance in neural activity a ects many brain regions as shown by studies of brain changes after UL using 2-deoxyglucose and c-fos which show substantial asymmetry of neural activity in various brain regions after UL [Llinas and Walton, 1979; Cirelli et aI., 1996; Patrickson et aI., 1985].

Neurons Responding to Horizontal Angular Accelerations Two types of neurons are found in the medial vestibular nuclei (MVN). Type I neurons increase their firing when the head is rotated in a horizontal plane around an earth-vertical axis in the ipsilateral direction (Le. towards the side on which the neuron is being recorded) and decrease their firing when the head is rotated in the opposite direction. Type II neurons respond in a mirror-image fashion. The reason why type I and type II neurons respond oppositely is that type I neurons are excited by ipsilateral horizontal canal primary a erent neurons whereas type II neurons are driven indirectly from the opposite labyrinth. Type II neurons are inhibitory so the ipsilateral head rotation causes two complementary e ects; the direct excitation from ipsilateral primary a erents, complemented by the reduction in inhibition from the reduced activity of the inhibitory type II neurons (fig. 1). Some type I neurons drive the horizontal VOR by excitatory projections to contralateral lateral rectus motoneurons in the contralateral abducens nucleus. Other type Is send inhibitory projections to ipsilateral lateral rectus motoneurons in the ipsilateral abducens nucleus. In the horizontal semicircular canal system, the functionally inhibitory interaction between the two VN by means of the interconnecting commissural fibers generates the smooth symmetrical bidirectional oculomotor response of normal individuals to horizontal angular accelerations (fig. 1). Immediately post-UL there is a large imbalance in the resting activity of the two VN: type I neurons in the VN on the intact side fire at high rates whereas type I neurons in the VN on the lesioned side (the ipsilesional side) fire at very low rates. This early imbalance in resting discharge between the two MVN has also been shown with other indicators of neural response: 2deuxyglucose and more recently c-fus. For neurons in the horizontal semicircular canal system of normal animals a similar imbalance in neural firing occurs during a large maintained ipsilateral horizontal angular acceleration (fig. 1). In healthy alert animals such a large horizontal acceleration causes horizontal nystagmus with quick phases in the

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direction of the acceleration, which corresponds to the direction of the VN with the larger average firing rate. After UL, the neural imbalance generates quick phases towards the intact side (the SN). which again is toward the VN which has the larger average firing rate. However. unlike any natural acceleration. the neural imbalance following UL is e ectively maintained continuously for hours and days. In guinea pigs the SN gradually disappears over the course of 1-2 days and recordings from guinea pig single VN neurons during this time show a return of resting activity in the guinea pig MVN. Initially the ipsilesional VN is virtually devoid of type I neurons but within a few hours there is a progressive return of resting activity in these neurons. Type I neurons can be found, with resting rates similar to those in normal animals, as soon as 52 h after operation [Smith and Curthoys. 1988a. b]. Ris et al. [1995. 1997J have confirmed this pattern of early recovery in single neuron recordings from alert guinea pigs but they have noted a dissociation here: that SN may be abolished whilst there is still a substantial asymmetry of average resting activity between the two vestibular nuclei. UL not only causes a decrease in the prevalence of type I neurons in the ipsilesional VN but also the average sensitivity (or gain) of those neurons which do respond to 0.2 Hz horizontal angular acceleration stimulation is significantly less at 52 h after UL than comparable neurons recorded preoperatively. The low average gain persists for the next year - there is very little if any recovery of gain on average over the following 12 months [Smith and Curthoys. 1988a. bJ. There may be some small neural dynamic compensation but it is only measurable at accelerations so low that the contralesional VN neurons are not driven to silence. The lower neuronal gain of type I neurons at 52 h in the ipsilesional VN compared to the neuronal gain in the VN of normal animals is not surprising. After UL the only way type I neurons in the ipsiIesional VN can respond to rotation is by means of modulation in disinhibition mediated by commissural fibres from the contralesional VN. In order to respond to horizontal semicircular canal stimulation, these ipsilesional type I VN neurons must be driven indirectly via the disfacilitation of the contralesional semicircular canal primary a erents which in turn disfacilitate the contralesional VN neurons and so result in a modulated disinhibitory drive via the commissural5bres (fig. 1). This modest source of drive may be adequate to generate responses to very luw angular acceleratiun rotatiuns. Once the angular acceleratiun attains a value in the natural range, the neurons will be driven to silence since they will be saturated by larger angular accelerations. In summary: the normal dynamic vestibular neuronal response is due to the combined e ect of both excitation from the ipsilateral periphery and

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disinhibition from the contralateral side. The consequence of UL is that for rotations to the lesioned side there is no ipsilateral excitatory drive from the periphery. only the disinhibition from the contralateral side and the inadequate horizontal VOR for ipsilesional rotations is due to this substantially reduced source of activation.

Otolithic Input UL will also silence otolithic primary a erents. resulting in an imbalance between the total neural activity of the two lateral vestibular nuclei (LVN) [pompeiano et aI., 1984; Xerri et aI., 1983]. The consequence will be that with head erect the average neural activity of the contralesional LVN will be greater than the average activity of the ipsilesional LVN, corresponding we suggest, to the neural imbalance that occurs during roll-tilt towards the intact ear in a normal animal. The Return of Resting Activity After UL Exactly what causes the resting activity to reappear in the ipsilesional VN is still not known and is a source of intense interest. If this return of resting activity could be accelerated it may be possible to accelerate the rebalancing of activity between the VN and probably the rehabilitation of post-UL patients. There may be multiple mechanisms at work here: possibly an early mechanism initiating the neural changes and a later mechanism for maintaining the changes. The extremely rapid abolition of SN in some species e ectively rules out some mechanisms proposed to account for the early return. One of the hypotheses to explain the return of resting activity in the vestibular neurons on the Jesioned side is that axons sprout into the synaptic contacts vacated by the degenerating axons. Axonal sprouting has been demonstrated in the mammalian central nervous system in response to axonal injury, but the process of degeneration and sprouting seem to be just too slow to account for the early return of vestibular neural activity. However, such a process probably has a role in the maintenance of compensation since anatomical studies suggest such changes do take place over a longer time period. The evidence from studies of axonal sprouting and the development of function of these newly sprouted axons in other neuronal assemblies. indicates that sprouting is just coming into operation at 2-3 days after UL. Whilst anatomical changes such as sprouting cannot explain the initial return of activity, major anatumical changes du take place in the VN in respunse tu UL and these anatomical changes probably determine the long-term stability ofthe recovery [Gacek et al.. 1988, 1989. 1991; Gacek and Schoonmaker, 1997; Guyot et aI., 1995; Raymond et al., 1991; de Waele et al., 1996].

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Another possible mechanism is denervation sensitivity: that the cells in the MVN which have been deprived of a massive amount of peripheral input by the UL become more sensitive to the transmitter from which they have been deprived. Other neurons synapsing on VN neurons probably also release this same transmitter. so the modest input from these other cells may become much more significant perhaps acting to return resting activity. The speed of compensation is also against this proposal: the evidence is that denervation sensitivity is much too slow to be responsible for the initial restoration of activity. Another contender is neural adaptation. UL causes a large increase in the resting discharge of type I neurons in the contralesional VN because they have been released from the tonically acting commissural inhibition. The increased discharge ofthese contralesional type I cells will act to exert even more inhibition on the type I neurons in the ipsilesional MVN, thus acting to silence type I cells in the ipsilesional VN even further. If the rapidly firing type I neurons in the contralesional MVN adapt, then there will be a progressive reduction in commissural inhibition from these neurons resulting in a reduction in inhibition which may be su cient to allow cells in the ipsilesional MVN to resume firing. A related possibility is that descending cerebellar input may act to 'shut down' vestibular nucleus activity [McCabe and Ryu, 1969; McCabe et aI., 1972J. The very rapid recovery in some species (only 1 h in goldfish [Ott and Platt, 1988; Weissenstein et aI., 1996]) points towards such a simple physiological process being responsible for the initiation of compensation which may be supplemented at later stages by other slower acting processes (such as axonal sprouting).

Spinal Input The activity in the descending projections from the vestibular nuclei to the spinal cord is disrupted by UL, resulting in significant static postural changes. But those postural changes will themselves alter the spinal a erent input to the VN because of the ascending projections from the spinal a erents back to the VN. The 'weighting' of spinal a erent input to the VN changes during compensation: there is anatomical evidence for increased spinal a erent projections to the VN following UL [Dieringer et al.. 1984J. The cervicalspinal a erent input, accompanying the characteristic body flexion of UL, may act to restore the balance in the resting discharge between the two VN. Overview Probably a number of mechanisms operate at di erent times and to di erent extents during compensation. Some of the potential mechanisms such as synaptogenesis simply do not have time to operate during the crucial early phase of compensation (the first 24-48 h) but clearly do operate over longer

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intervals and probably ensure the permanence of the recovery. Of the shortterm mechanisms responsible for the return of resting activity in the ipsilesional VN, adaptation or cerebellar inhibition of the contralesional type I neurons at present seems to be the likely possibility.

Models of Vestibular Compensation Some of the physiological evidence has been incorporated into neural network models of the VOR which have attempted to account for the static and dynamic symptoms after unilateral loss and vestibular compensation (e.g. Caliana et aI., 1984]. Recently neural network models constrained to be consistent with established anatomical and physiological results, and trained on actual eye movement data from guinea pigs have produced results which account for vestibular compensation [Cartwright and Curthoys, 1996]. Such models pinpoint the neurons of greatest importance in this circuit and in the simplified neural circuits studied, the type I neurons on the intact side are the cells whose gain changes most. This may be the clue to understanding the mechanisms responsible for compensation - that it is changes in these type I neurons on the intact side which should be studied in greatest detail. or particular importance is that although these models were trained only on the dynamic eye movement data before and after unilateral loss, the neural changes which take place in the artificial network also produce the imbalance between the two abducens nuclei which corresponds to SN. That suggests that the static and dynamic symptoms of UL are much more closely related than the empirical data implies. Another approach has been to use neural network models with 'hidden units' to produce the behavioral results with little relationship to what is known about the physiology of the vestibulo-ocular pathways [Anastasio, 1992; Weissenstein et aI., 1996]. The physiologically realistic models result in predictions for some specific aspects of compensation (e.g. the consequences of unilateral canal blocking) but application of the models to these specific experimental situations has not yet been fully tested. Neurochemjstry Neurons in the VN receive many di erent sources of input using many di erent transmitters and the internal neuronal circuitry of the nuclei is complex. Some of the transmitters in the vestibulo-ocular pathway have been identified [fur reviews, see Raymond et aI., 1988; Smith et aI., 1991; de Waele et aI., 1995; Vidal this volume]. The development of the brainstem slice preparation of the vestibular nuclei has resulted in very active research on neurotransmitters in the vestibular oculomotor system [Serafin et aI., 1991a, b; Cameron and Dutia, 1997]. The

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new guinea pig isolated whole brain preparation allows even more comprehensive physiological studies [Babalian et aI., 1997; Vibert et aI., 1997]. There are significant problems in relating this work to vestibular compensation in living animals, not the least of which is that the very process of preparing the slice or brain requires both vestibular nerves to be cut, i.e. bilateral dea erentation of the VN. Recently, Vidal's group in Paris has identified that the Bechterew phenomenon may solve this problem [Vibert et aI., 1998, in preparation]. Rather than studying the properties of the slice or isolated whole brain which has been removed a short time after unilateral loss, this group first carries out a UL, waits some days for compensation to occur, and then removes the brain. Removal requires cutting the remaining vestibular nerve and so the removal is equivalent to the second labyrinthectomy in the Bechterew phenomenon described above. This approach allows detailed study of the asymmetry between the two vestibular nuclei. Both slice and isolated whole brain show the major asymmetries of neural activity between the two MVN which have been recorded in both anesthetized and awake guinea pigs post-UL. It is the side of the first vestibular nerve section which shows the higher activity of the two nuclei. Some studies have directly measured the neurochemical changes in the VN which accompany vestibular compensation [see Cransac et aI., 1996; Smith and Darlington, 1991; de Waele et aI., 1994, 1995; Li et aI., 1996; Henley and Igarashi, 1991, 1993; Flohr et aI., 1985]. For example, immediately after UL there is an increase in GABA in the ipsilesional LVN and a decrease in the contralesional LVN. However, in the long term after UL, there is a decrease in GABA bilaterally. Most neurochemical studies have tested substances which a ect the time course of vestibular compensation: usually the disappearance of SN or the change in posture [Flohr and Luneberg, 1982; Gilchrist et aI., 1990, 1993, 1996]. Any substance which alters, however indirectly, the delicate balance of neural activity between the vestibular nuclei wi1l result in behavioral manifestation of vestibular symptoms such as nystagmus, vertigo and ataxia, and thus appear to a ect compensation. The vestibular nuclei contain neurons with cholinergic, glutaminergic, dopaminergic and GABAergic receptors so that substances which a ect any of these transmitter systems will appear to a ect vestibular compensation, whether those transmitter systems are directly involved in the recovery process or not.

Swnmary The word 'balance' is a common term which is used to describe the function of the vestibular system itself but that word also applies to the neural mechanism of vestibular operation. Unilateral loss or disease causes a massive

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disruption to this nicely balanced system and the behavioral symptoms are the manifestations of this imbalance. As the balance in neural activity between the two VN returns. behavioral symptoms such as nystagmus, disappear. Concurrently other behavioral mechanisms probably substitute for those a ected by the aberrant vestibular function. The UL disrupts the neural equilibrium in both the MVN and the LVN with consequences for both static head and eye position and for the dynamic response of both the canal and the otolithic systems to imposed stimuli. The major question which is still unanswered is the cause of the return of firing of neurons in the ipsilesional VN. The answer may be found by studies of the neurochemistry of the vestibular nuclei using the brain slice or isolated whole brain preparations.

Conclusion

For convenience we have considered separately the various vestibular functions a ected by UL. However, the vestibular system is an integrated system. both anatomically and physiologically. and the physiological state of one part of the labyrinth can influence responses from other sensory regions. For example, concurrent otolithic stimulation modulates nystagmus produced by semicircular canal stimulation. This close interrelationship is of direct clinical importance since patients may have malfunction in one part of their labyrinth which will influence the operation of other parts of this complex interdependent system. Our interpretation is in sharp conflict with the interpretation that vestibular compensation is a process of complete restoration of pre- UL behavior and perception. Vestibular compensation shows how a brain can deal with information from a damaged and disabled sensory system and cope quite remarkably well with this disrupted source of information. A vestibular system with input from only one labyrinth does not provide a faithful record of head movement or head position. Furthermore. there are additional errors resulting from the sensory consequences of the inadequate responses. Most patients learn to deal with the inadequate and erroneous information but some do not. It still remains to be uncovered why some patients fail to compensate but by putting the question in terms of the very complex multidimensional challenge to be overcome when one labyrinth is lost. we may perhaps discover answers. Acknowledgments The preparation of this review and much of our research in this area has been supported by the National Health and Medical Research Council of Australia and the Garnet Passe

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and Rodney Williams Foundation and we are grateful for their past and continuing support. The work has also been supported (in part) by research grant No.5 ROI DC 02372-02 from the National Institute on Deafness and Other Communication Disorders, US National Institutes of Health.

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Li H, Godfrey TG, Godfrey DA, Rubin AM: Quantitative changes of amino acid distributions in the rat vestibular nuclear complex after unilateral vestibular ganglionectomy. J Neurochem 1996;66: 1550-1564. Lisberger SG: The neural basis for learning of simple motor skills. Science 1988;242:728-735. Llinas R, Walton K: Vestibular compensation: A distributed property of the central nervous system; in Asanuma H, Wilson VJ (eds): Integration in the Nervous System. Tokyo, Igashu-Shoin, 1979, pp 145-166 Markham CH, Curthoys IS, Yagi T: The influence of the contralateral labyrinth on static and dynamic properties of brainstem vestibular neurons in the cat, guinea pig and rat; in Hood JH (ed): Vestibular Mechanisms in Health and Disease. London, Academic Press, 1978, pp 86-94. Markham CH, Yagi T, Curthoys IS: The contribution of the contralateral labyrinth to second order vestibular neuronal activity in the cat. Brain Res 1977;138:99-109. McCabe BF, Ryu JH: Experiments on vestibular compensation. Laryngoscope 1969;79:1728-1736. McCabe BF, Ryu JH, Sekltani T: Further experiments on vestibular compensation. Laryngoscope 1972; 82:381-396. Murofushi T, Curthoys IS: Physiological and anatomical study of click-sensitive primary vestibular a erents in the guinea pig. Acta Otolaryngol 1997; 117:66-72. Murofushi T, Curthoys IS, Gilchrist DP: Response of guinea pig vestibular nucleus neurons to clicks. Exp Brain Res 1996;111:149-152. Murofushi T, Curthoys IS, Topple AN, Colebatch JG, Halmagyi GM: Responses of guinea pig primary vestibular neurons to clicks. Exp Brain Res 1995; 103: 174-178. Nakao S, Sasaki S, Schor RH, Shimazu H: Functional organization of premotor neurons in the cat medial vestibular nucleus related to slow and fast phases of nystagmus. Exp Brain Res 1982;45: 371-385. Newlands SO, Perachio AA: Compensation of horizontal canal related activity in the medial vestibular nucleus following unilateral labyrinth ablation in the decerebrate gerbil. I. Type [ neurons. Exp Brain Res I990a;82:359-372. Newlands SO, Perachio AA: Compensation of horizontal canal related activity in the medial vestibular nucleus following unilateral labyrinth ablation in the decerebrate gerbil. H. Type H neurons. Exp Brain Res 1990b;82:373-383. Olson JE, Wolfe JW: Responses to rotational stimulation of the horizontal canals from patients with acoustic neuromas. Acta Otolaryngol Suppl (Stockh) 1984;406:203-208. Ott JF, Platt C: Early abrupt recovery from ataxia during vestibular compensation in goldfish. J Exp Bioi 1988; 138:345-357. Paige GO: Nonlinearity and asymmetry in the human vestibulo-ocular reflex. Acta Otolaryngol (Stockh) 1989; 108: 1-8. Patrickson JW, Bryant HJ, Kaderkaro M, Kutyna FA: A quantitative 14C-2-deoxy-D-glucose study of brain stem nuclei during horizontal nystagmus induced by lesioning the lateral crista ampullaris of the rat. Exp Brain Res 1985;60:227-234. Pompeiano 0, Xerri C, Gianni S, Manzoni 0: Central compensation of vestibular deficits. II. Influences of roll tilt on di erent-size lateral vestibular neurons after ipsilateral labyrinth dea erentation. J Neurophysiol 1984;52: 18-38. Precht W: Recovery of some vestibuloocular and vestibulospinal functions following LUlilaterallabyrinthectomy. Prog Brain Res 1986;64 :381-389. Precht W, Dieringer N: Neuronal events paralleling functional recovery (compensation) fOllowing peripheral vestibular lesions. Rev Oculomot Res 1985; I:251-268. Precht W, Shimazu H: Functional connections of tonic and kinetic vestibular neurons with primary vestibular a erents. J Neurophysiol 1965;28: 10 14-1028. Precht W, Shimazu H, Markham CH: A mechanism of central compensation of vestibular function following hemilabyrinthectomy. J Neurophysiol 1966;29:996-10 I O. Raphan T, Matsuo V, Cohen B: Velocity storage in the vestibulo-ocular reflex arc (VOR). Exp Brain Res 1979;35:229-248. Raymond J, Dememes D, Nieoullon A: Neurotransmitters in vestibular pathways. Prog Brain Res 1988; 76:29-43.

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Raymond J, Ez-Zaher L. Dememes D, Lacour M: Quantification of synaptic density changes in the medial vestibular nucleus of the cat following vestibular neurectomy. Rest Neurol Neurosci 1991;3: 197-203. Ried S, Maioli C, Precht W: Vestibular nuclear neuron activity in chronically hemilabyrinthectomized cats. Acta Otolaryngol (Stockh) 1984;98:1-13. Ris L, Capron B, de Wade C, Vidal PP, Godaux E: Dissociations between behavioural recovery and restoration of vestibular activity in the unilabyrinthectomized guinea-pig. J Physiol 1997;500:509522. Ris L, de Waele C, Serafin M, Vidal PP, Godaux E: Neuronal activity in the ipsilateral vestibular nucleus following unilateral labyrinthectomy in the alert guinea pig. J Neurophysiol 1995;74:2087-2099. Schaefer KP, Meyer DL: Compensation of vestibular lesions; in Korohuber HH (ed): Handbook of Sensory Physiology. Berlin, Springer, 1974, vol VI, part 2, pp 463-490. Serafin M, de Wade C, Khateb A, Vidal PP, Muhlethaler M: Medial vestibular nucleus in the guineapig. I. Intrinsic membrane properties in brainstem slices. Exp Brain Res 199Ia;84:417-425. Serafin M, de Waele C, Khateb A, Vidal PP, Milhlethaler M: Medial vestibular nucleus in the guineapig. II. Ionic basis of the intrinsic membrane properties in brainstem slices. Exp Brain Res 1991 b; 84:426-433. Shimazu H: Neuronal organization of the premotor system controlling horizontal conjugate eye movements and vestibular nystagmus. Adv Neurol 1983;39:565-588. Shimazu H, Precht W: Tonic and kinetic responses of cat's vestibular neurons to horizontal angular acceleration. J Neurophysiol 1965;28:991-1013. Shimazu H, Precht W: Inhibition of central vestibular neurons from the contralateral labyrinth and its mediating pathway. J Neurophysiol 1966;29:467-492. ShLUTIway-Cook A, Horak FE: Rehabilitation strategies for patients with vestibular deficits. Neurol Clin 1990;8:441-457. Smith PF, Curthoys IS: Mechanisms of recovery following unilateral labyrinthectomy: A review. Brain Res Rev 1989;14:155-180. Smith PF, Curthoys IS: Neuronal activity in the contralateral medial vestibular nucleus of the guinea pig following unilateral labyrinthectomy. Brain Res 1988a;444:295-307. Smith PF, Curthoys IS: Neuronal activity in the ipsilateral medial vestibular nucleus of the guinea pig following unilateral labyrinthectomy. Brain Res 1988b;444:308-319. Smith PF, Darlington CL: Neurochemical mechanisms of recovery from peripheral vestibular lesions (vestibular compensation). Brain Res Rev 1991;16:117-133. Smith PF, Darlington CL, Curthoys IS: The e ect of visual deprivation on vestibular compensation in the guinea pig. Brain Res 1986;364: 195-198. Smith PF, de Waele C, Vidal PP, Darlington CL: Excitatory amino acid receptors in normal and abnormal vestibular function. Mol Neurobiol 1991;5:369-387. Takahashi M, Uemura T, Fujishiro T: Recovery of vestibulo-ocular reflex and gaze disturbance in patients with unilateral loss of labyrinthine function. Ann Otol Rhinol Laryngol 1984;93: 170-175. Telian SA, Shepard NT: Update on vestibular rehabilitation therapy. Otol Clio North Am 1996;29: 359-371. Telian SA, Shepard NT, Smith-Wheelock M, Kemink JL: Habituation therapy for chronic vestibular dysfunction: Preliminary results. Otolaryngol I lead Neck Surg 1990;103:89-95. Vibert N, de Waele C, Serafin M, Babalian A, Muhlethaler M, Vidal PP: The vestibular system as a model of sensorimotor transformations. A combined in vivo and in vitro approach to study the cellular mechanisms of gaze and posture stabilization in mammals. Prog Neurobio11997;51 :243-286. Vidal PP, de Waele C, Vi bert N, Miihlethaler M: Vestibular compensation revisited. Otolaryngol Head Neck Surg 1998;119, in press. Weissenstein L, Ratnam R, Anastasio T J: Vestibular compensation in the horizontal vestibulo-ocular reflex of the goldfish. Behav Brain Res 1996;75:127-137. Wilson Vj, Melvill Jones G: Mammalian Vestibular Physiology. New York, Plenum Press, 1979. Wolfe GL Taylor CL. Flamm ES, Gray LG, Raps EC, Galetta SL: Ocular tilt reaction resulting from vestibuloacoustic nerve surgery. Neurosurgery 1993;32:417-420. Wolfe JW, Kos CM: Nystagmic responses of the rhesus monkey to rotational stimulation following uoilaterallabyrinthectomy: Final report. Trans Am Acad Ophthalmol Otolaryngol 1977;84:38-45.

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Xerri C, Gianni S, Maozoni D, Pompeiano 0: Central compensation of vestibular deficits. I. Response characteristics of lateral vestibular neurons to roll tilt after ipsilateral labyrinth dea erentation. J Neurophysiol 1983;50:428-448. Xerri C, Lacour M: Compensation deficits in posture and kinetics following unilateral vestibular neurectomy in cats. The role of sensorimotor activity. Acta Otolaryngol (Stockh) 1980;90:414-424. Xerri C, Zennou Y: Sensory, functional and behavioural substitution processes in vestibular compensation; in Lacour M, Toupet M, Denise P, Christen Y (eds): Vestibular Compensation: Facts, Theories and Clinical Perspectives, Paris, Elsevier, 1989, pp 35-58, Zenoou-Azogui Y, Xerri C, Harlay F: Visual sensory substitution in vestibular compensation: Neuronal substrates in the alert cat. Exp Brain Res 1994;98:457-473.

Dr. IS Curthoys, Department of Psychology, University of Sydney, Sydney, NSW 2006 (Australia) Tel. 61 2 9351 3570, Fax 61 2 9351 2603, E-Mail [email protected]

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Buttner U. (ed): Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger, 1999, vol 55, pp 111-136

Vestibular Neuritis Michael Strupp, Thomas Brandt Department of Neurology, Ludwig-MaximlJJians Unlversltat Munchen, Klinikum Grosshadern, Munich, Germany

Vestibular neuritis (VN), also known as acute unilateral (idiopathic) vestibular paralysis or vestibular neuronitis, is the third most common cause of peripheral vestibular vertigo (the first is benign paroxysmal positioning and the second, Meniere's disease). Its annual incidence is about 3.5/100,000 population [71J. It was first described by Ruttin [64) in 1909 and later by Nylen [59) in 1924. The term 'vestibular neuronitis', coined by Hallpike [28) in 1949 and Dix and Hallpike [20J, should be replaced by 'vestibular neuritis', because there is strong evidence that the ganglion cells themselves are not primarily inflamed, but rather parts of the nerve, I.e., the neurite. The chief symptom is the acute/subacute onset of prolonged severe rotational vertigo, associated with spontaneous horizontal-rotatory nystagmus, postural imbalance, and nausea without concomitant auditory dysfunction. Caloric testing invariably shows ipsilateral hypo- or nonresponsiveness (as a sign of horizontal semicircular canal paresis). Epidemic occurrence of the condition, the frequency of preceding upper respiratory tract infections, a small number of postmortem studies that found cell and axon degeneration of one or more vestibular nerve trunks, and the demonstration of latent herpes simplex virus type I in human vestibular ganglia - all suggest that the cause may be a viral reactivation in the vestibular ganglia, similar to those producing Bell's palsy and sudden sensorineural hearing loss. VN is most likely a partial rather than a complete vestibular paresis, with predominant involvement of the horizontal and anterior semicircular canals (sparing the pusterior semicircular canal) and the utricle. The cunditiun mainly a ects adults, ages 30-60, and has a natural history of gradual recovery within 1-6 weeks. Recovery is a product of combined (1) peripheral restoration of labyrinthine function (frequently incomplete); (2) contralateral vestibular, somatosensory, and visual substitution for the unilateral vestibular deficit, and

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Fig 1. Ocular signs, perception (vertigo, subjective visual vertical, and subjective straight ahead), and posture in the acute stage of right-sided vestibular neuritis. Spontaneous vestibular nystagmus is always horizontal-rotatory away from the side of the lesion (best observed with Frenzel's glasses). The initial perception of apparent body motion (vertigo) is also directed away from the side of the lesion, whereas measurable destabilization (Romberg fall) is always toward the side of the lesion. The latter is the compensatory vestibulospinal reaction to the apparent tilt.

(3) central compensation of the vestibular tone imbalance (aided by physical exercise). Diagnosis of VN is based on the simple assessment of an acute vestibular tone imbalance associated with a unilateral peripheral vestibular loss (bedside testing of high-frequency vestibular ocular reflex; caloric testing) after clinical exclusion of a central neurological disorder. As this diagnostic procedure lacks selectivity, pathological processes other than VN which also cause an acute unilateral loss of peripheral labyrinthine function may be wrongly labeled. Thus, the term VN does not describe a well-defined clinical entity, but rather a syndrome in which peripheral vestibular paralysis can have a number of possible causes (usually viral, less often vascular). Some authors have proposed uther sites fur the lesiun: peripheral labyrinth ur the insertiun site uf the rout of the eighth nerve into the ponto-medullary brainstem (here an MS plaque can mimic VN). Di erential diagnosis includes all other causes of acute loss of peripheral labyrinthine function. For a more detailed presentation, see Brandt [6].

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The Clinical Syndrome

Key signs and symptoms of VN (fig. 1) are an acute onset of sustained (1) rotatory vertigo (contraversive) with pathological adjustments of perceived straight-ahead and subjective vertical (ipsiversive); (2) postural imbalance with Romberg fall and past-pointing (ipsiversive); (3) horizontal-rotatory spontaneous nystagmus (contraversive) with oscillopsia, and (4) nausea and vomiting. Ocular motor evaluation reveals apparent horizontal saccadic pursuit, gazeevoked nystagmus toward the fast phase of the spontaneous nystagmus, and a directional preponderance ofoptokinetic nystagmus (contraversive to the lesion), all of which are secondary to the spontaneous nystagmus indicating vestibular tone imbalance in yaw and roll planes. Hearing loss is not a typical feature of the condition, and the detection of any neurological deficit beyond the above indicated signs and symptoms should raise doubts about the diagnosis ofVN. A suspected diagnosis can be hardened by demonstrating a unilateral deficit in vestibulo-ocular reflex bedside testing and, more definitively, hypoor unresponsiveness in bithermal caloric testing (fig. 2; horizontal semicircular canal paresis of the labyrinth opposite to the fast-phase of the spontaneous nystagmus). There is, however, no pathognomonic test or sign for VN as a clinical entity. In a strict sense, only an acute unilateral peripheral vestibular hypofunction with horizontal semicircular canal paresis can be diagnosed by the proposed procedure. The thus defined group has many of the clinical features described below in common and does not require further apparative or invasive diagnostics, although some patients may have a di erent etiology.

Vertigo and Posture

In VN the fast phase of the spontaneous rotatory nystagmus (fig. 1) and the initial perception of apparent body rotation are directed away from the side of the lesion, and the postural reactions initiated by vestibulospinal reflexes are usually opposite to the direction of vertigo. These result in both the Romberg fall and in past-pointing toward the side of the lesion. Patients with this type of vertigo often make confusing and contradictory statements about the directionality of their symptoms. In actual fact, there are two sensations of opposite directions, and the patient may be describing one or the other. The first is a purely sulJjective sense of self-motion in the direction of the nystagmus fast phases, which is not associated with any measurable body sway. The second is the compensatory vestibulospinal reaction resulting in objective, measurable destabilization and a possible Romberg fall in the direction opposite to the fast phases [9]. Subjective straight-ahead and tilts of perceived

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Fjg 2. Eye signs in the acute stage of right VN (arrow). Spontaneous VN is always horizontal-rotatory away from the side of the lesion. It is best observed with Frenzel's glasses (top), since fixation largely suppresses nystagmus. With lateral gaze and fixation of a stationary target, spontaneous nystagmus is inhibited when gaze is directed toward the a ected ear and increased when gaze is directed toward the una ected ear (middle). Thermic irrigation of the external auditory canal (caloric test) demonstrates unresponsiveness of the a ected right horizontal semicircular canal but normal responses in the left horizontal semicircular canal (bottom). Spontaneous vestibular nystagmus to the left causes a directional bias of the recorded eye movements during thermic irrigation [from 61.

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vertical can be determined psychophysically as the perceptual consequence of vestibular tone imbalance in yaw (horizontal semicircular canal) and roll (anterior semicircular canal). The direction of pathological deviation - as adjusted by the patient - and the Romberg faJl are ipsiversive to the lesioned ear. The severity of tone imbalance can be measured in degrees; it is thus possible to assess quantitatively the recovery of spatial disorientation during the course of the illness. Furthermore, the e cacy of physical and medical treatment of the condition can also be measured in this way [78J.

Eye Movements

The nystagmus is always rotatory-horizontal (beating clockwise-left or counterclockwise-right). The nystagmus is typically reduced in amplitude by fixation (fixation suppression) and enhanced by eye closure or Frenzel's (high plus) lenses. According to Alexander's law, amplitude and slow-phase velocity are increased with gaze shifts toward the fast phase, and decreased with gaze shifts toward the slow phase of the nystagmus. This may mimic unilateral gaze-evoked nystagmus in a patient with moderate, spontaneous nystagmus that is completely suppressed by fixation straight ahead but still present with the gaze directed toward the fast phase. Using a motor-driven 3-D rotating chair, Fetter and Dichgans [22] studied 3-D properties of the vestibula-ocular reflex in 16 patients in the acute stage of VN. Their measurements support the view that VN is a partial rather than a complete unilateral vestibular lesion [12J and that this partial lesion a ects the superior division of the vestibular nerve including the a erents from the horizontal and anterior semicircular canals and the utricle [22J: 'In all patients, spontaneous nystagmus axes clustered between the direction expected with involvement of just one horizontal semicircular canal and the direction expected with combined involvement of the horizontal and anterior semicircular canals on one side. Likewise, dynamic asymmetries were found only during rotations about axes that stimulated the ipsilesional horizontal or ipsilesional anterior semicircular canals. No asymmetry was found when the ipsilesional posterior semicircular canal was stimulated.' This analysis was based on physiological data that electrical stimulation of single semicircular canal nerves elicits eye movements in the plane of the canal and that combinations of canal lesions should result in a direction uf spuntaneuus nystagmus, which reflects the weighted vector sum uf the axes of the involved canals. A significant directional preponderance of optokinetic nystagmus (OKN) may be another consequence of the peripheral lesion, and not a result of involvement of the brainstem or cerebellum. These vestibularly induced di erences in OKN slow-phase velocity can be as large as 70%, and

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Day:1O Fig 3. Fundus photograph of the left eye of a patient with VN on the left side showing 20° cyclorotation toward the left (excyclotropia, torsion of the papilla-fovea line clockwise from the viewpoint of the observer) on day 3 after symptom onset. On day 30 the ocular torsion was within the normal range ( 2 so: -1 to 11.5°) [from 781.

are due to enhancement toward the side of the lesion and depression in the opposite horizontal direction [8J. The interaction is not purely additive or subtractive; a feed-forward optokinetic gain control of the vestibular component (multiplication) is involved before the two signals are combined. Ocular torsion (fig. 3) and perceived tilts of visual vertical have been described in most patients with VN [5). In some patients with acute VN, skew deviation (ipsilesional eye undermost) with vertical and oblique diplopia has also been found [65, 85). Skew deviation, however, is very rare in VN, and one should first exclude a central lesion before assuming that VN is the cause. These signs indicate a vestibular tone imbalance in the roll plane induced by involvement of the anterior semicircular canal, otolith function, or both. The superior division of the vestibular nerve innervates not only the cristae of the horizontal and anterior semicircular canals but also the maculae of the utricle and the anterosuperior part of the saccule. It is possible that a lesion of only the superior division results in ocular torsion and tilts of the visual vertical, whereas a lesion of both the superior and the inferior divisions of the eighth nerve results in ocular torsion, tilts of visual vertical, and skew deviation. We have seen evidence for the latter in a patient with herpes zoster oticus, which manifested with skew torsion and showed a contrast enhancement of the superior and inferior parts of the eighth nerve on MRI [2).

Caloric Testing

The principal diagnostic marker of the disease is an initial paresis of the horizontal semicircular canal on the a ected side; this can be demonstrated by

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caloric tests (fig. 2). Meran and Pfaltz [561 reported that 2 weeks after onset of vestibular neuritis, 66% of patients did not respond to thermal irrigation of the external auditory canal, and 34% showed reduced responses. Two years later, however, 72% had normal reactions, 12% showed reduced responses, and 16% did not respond. They found complete recovery of semicircular canal function in two-thirds of the patients. In a more recent study, Okinaka et al. [62J found that caloric responses normalized in only 25 (42%) of 60 patients. Horizontal semicircular canal paresis was found in about 90% 1 month after onset, and in 80% after 6 months. The di erent results in these two studies may be due to di erent criteria for defining a pathological unilateral hyporesponsiveness. Caloric hypoexcitability may be defined as a maximum slow-phase velocity (MSPV) during caloric irrigation with 30° warm and 44° hot water for 2-3°/s on the a ected side [81J. Since there is a large intersubject variability, JongKees' 'vestibular paresis formula' [37] is also very useful: {[(R 30° R 44°) (L 30° L 44°)J/(R 30° R 44° L 30° L 44°)} 100, where, for instance, R 30° is the MSPV during caloric irrigation with 30°C warm water. According to Hornrubia [37], vestibular paresis is defined as 25% asymmetry between the right-sided and the left-sided responses. The precise measurement of vestibular hypofunction, however, may be di cult in the early stage of the disease due to intense spontaneous nystagmus.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) has become increasingly important for detecting labyrinthine or eighth nerve disorders [45] such as vestibular paroxysmia, Cogan's syndrome [32], leptomeningeal carcinomatosis, or meningitis. Due to recent MRI advances it is now possible to demonstrate facial nerve enhancement in Bell's palsy and cochlear enhancement in sudden hearing loss. However, to date, attempts to image lesions of the vestibular nerve or ganglion in patients with cryptogenic VN have failed [31, 82J (fig. 4).

High-Frequency Defect of Vestibula-Ocular Reflex (VOR) in Permanent Peripheral Vestibular Lesion

It is possible to demonstrate a permanent, direction-specific, high-frequency defect of the VOR in patients whose semicircular canal function is not restored. Ewald's second law [21], which states that horizontal canal function has a directional asymmetry, predicts this: ampullopetal stimulation (cupula deflection toward the utricle) during ipsiversive head rotation is more

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A

B

Fig 4. MRIs of a patient with a left VN (and persisting caloric unresponsiveness) which were made 20 days after symptoms began. A Axial Tlweighted 2-D FLASH sequence with gadoliniwnDTPA: the facial nerve (short, large arrow). the superior part of the vestibular nerve (long. large arrow), the cochlear nerve (long. small arrow). and the inferior part of the vestibular nerve (short, small arrow) can be delineated. No contrast enhancement is visible. B Axial T2-weighted 3-D CISS sequence: no thickening of the superior part of the vestibular nerve (long arrow) is seen; the facial nerve (short arrow) is also shown. C Axial T2-weighted 3-D CISS sequence: no thickening of the inferior part of the vestibular nerve (long arrow) is seen; the cochlear nerve is indicated by the short arrow [from 82].

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b Fjg 5. Clinical testing of the horizontal VOR (Halmagyi-Curthoys test [29]). Fast rotations of the head toward the side of the lesion show the dynamic VOR deficit. In contrast to the healthy control (A), the patient is not able to generate a fast contraversive eye movement and has to perform a saccade to fixate the target (B) [from 80J. (C) Method illustrating how to examine the patient.

e ective than ampullofugal stimulation (cupula deflection away from the utricle) during contraversive head rotation. Electrophysiological studies of primary vestibular a erents in the monkey during constant angular accelerations have confirmed the law [26J. Gain asymmetries have been demonstrated in humans after acute unilateral peripheral vestibular lesions, showing that rotation toward the side with the lesion (ampullopetal stimulation of the remaining intact labyrinth) resulted in lower gain than rotation away from the side with the lesion. Unpredictable, passive rotational head impulses with accelerations up to 4,0000/S2 demonstrated considerable asymmetries in VOR gain even 1 year after a unilateral peripheral vestibular lesion [30J. That there is no central cumpensatiun uf the directiunal asymmet:.ry uf high-frequency canal functiun was also demonstrated by Halmagyi and Curthoys [29] using a simple VOR bedside test (fig. 5). When the head was rapidly rotated toward the side with the lesion, all 12 patients who had undergone unilateral vestibular neurectomy made clinically evident, oppositely directed, compensatory reflxation saccades.

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This indicates a unilateral high-frequency deficiency of VOR, produced by functional asymmetry of the remaining labyrinth. Furthermore, the wellknown clinical method for provoking spontaneous nystagmus (passive head shaking while the patient wears Frenzel's glasses [46]) reveals a unilateral labyrinthine loss, even if it is apparently compensated centrally, i.e., it persists for life in most cases. Hain et al. [27J were able to show that horizontal head shaking in yaw elicits horizontal nystagmus with slow phases that are initially directed toward the side of the lesion and upward (fast phases directed toward the una ected ear). They assume that 'head-shaking nystagmus is generated by the combination of a central velOcity-storage mechanism, which perseverates peripheral vestibular signals, and Ewald's second law, which states that highvelocity vestibular excitatory inputs are more e ective than inhibitory inputs'. Head-shaking nystagmus as a bedside test allows not only clinical detection of a centrally compensated unilateral peripheral vestibular loss, but also stage assessment of the spontaneous course of VN [55].

Differential Diagnosis of Vestibular Neuritis

When based on careful history-taking and clinical evaluation, di erential diagnosis is determined by two elementary questions: (1) Is the clinical syndrome compatible with only peripheral vestibular loss or are there any central neurological deficits incompatible with VN? (2) Are there any signs, symptoms, or clinical indications for a specific etiology of an acute unilateral. partial, or complete vestibular loss? If central, there is only a small area in the lateral medulla including the root entry zone of the vestibular nerve and the medial and superior vestibular nuclei, which is critical to avoid confusion with peripheral vestibular nerve or labyrinthine lesions. We have seen several patients su ering from multiple sclerosis with pontomedullary plaques at the root entry zone of the eighth nerve which mimic VN (fig. 6) [19]. Small brainstem infarctions have also been reported to mimic VN, e.g., in the form of a local brainstem syndrome of rotational vertigo with masseter paresis [38]. Electrophysiological measures such as auditory-evoked potentials or masseter reflex and MRI [23, 38] may help to identify brainstem disorders with few symptoms. The di erential diagnosis between central and peripheral causes of unilateral vestibular loss is simple, if the patient presents with oovious additional orainstem signs. All patients we observed with central lesions mimicking VN had some additional ocular motor signs (such as saccadic vertical pursuit, direction-changing positional nystagmus) which were detected by careful neuro-ophthalmological examination. A central cause was always suspected prior to MRI. The two

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Fig 6. Fascicular and nuclear lesion of the vestibular nerve due to an MS plaque, mimicking VN (TZ-weighted MRI from Jager et al. [45]). This patient complained of rotatory vertigo and had a horizontal-rotatory nystagmus (fast phase) to the right. Caloric irrigation revealed an incomplete 'peripheral' deficit.

disorders most relevant to the present discussion are multiple sclerosis and small brainstem infarctions. Hemorrhages (cavernomas) or tumors rarely manifest with purely acute rotational vertigo and horizontal semicircular canal paresis. Acoustic neurinomas, which mostly arise from the vestibular part of the eighth nerve, produce such a gradual reduction in vestibular brainstem input from the end-organ on the side of the tumor that central compensation is capable of preventing vertigo. However, acute rotational vertigo and semicircular canal paresis may rarely be the first manifestation of a rapidly growing and larger tumor of the cerebellapontine angle. Then the critical site of the lesion is peripheral, even though larger tumors compress the brainstem and the flocculus. The di erential diagnosis of peripheral labyrinthine and vestibular nerve disorders mimicking VN includes numerous rare conditions. Nevertheless, extensive laboratory examinations, lumbar puncture, and CT/MRI are not part uf the IUutine tliagnustics uf VN fur twu reasuns: (1) the rareness uf these disorders and (2) typical additional signs and symptoms indicative of other disorders. For example, the combination of vestibular with auditory symptoms suggests herpes zoster oticus, if the ear is painful and blisters are observed in the external auditory canal; or Cogan's syndrome, if inflammatory eye symp-

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toms are found; or Lyme borreliosis [44], if the patient reports a recent tick bite or an erythema migrans. Thus, any further diagnostic procedures in patients with VN are usually prompted and guided by the unusual presentation of the syndrome, an atypical course, or additional signs and symptoms. An initial monosymptomatic vertigo attack in Meniere's disease or basilar artery migraine without headache can be confused with VN in a patient admitted to hospital in an acute stage, since these disorders can also cause intense rotatory vertigo with a horizontal-rotatory nystagmus. The shortness of the attack and the patient's rapid recovery, however, allow di erentiation.

Etiology and Pathomechanism

In our dizziness unit, VN is the third most common cause of peripheral vestibular disorders ((1) benign paroxysmal positional vertigo, (2) Meniere's disease) and accounts for about 5% of the patients [40). Its usual age of onset is between 30 and 60 years [18], and age distribution plateaus between 40 and 50 years [71]. There is no significant sexual di erence, although Meran and Pfaltz [56] found a peak for females in the fourth decade and males in the sixth decade [56). VN is relatively rare in children, but it has repeatedly been reported to occur in children aged 3-15 years, obViously a ectlng boys more frequently than girls [73, 83). VN in children seems to di er from VN in adults in the fo]]owing three aspects: (1) a higher frequency of preceding upper respiratory tract infections; (2) a more rapid recovery from vertigo and nystagmus, and (3) a better prognosis as to the recovery rate of labyrinthine function assessed by follow-up caloric testing [71, 73, 83).

Pathophysiology

Normal vestibular end-organs generate an equal resting-firing frequency, which is the same on both sides. This continuous excitation (resting discharge rate in monkey 100 Hz [26); 18,000 vestibular a erents for each labyrinth [4]) is transmitted to the vestibular nuclei via vestibular nerves. Pathological processes a ecting an end-organ alter its firing frequency, thereby creating a tone imbalance (in most cases the firing frequency is lowered; only in Meniere's disease it may transiently increase due to potassium-induced membrane depolarization). This imbalance causes most of the manifestations of the vertigo syndrome: perceptual, ocular motor, postural, and vegetative (nausea). As distinct from bilateral vestibulopathy, unilateral semicircular canal paresis can be largely substituted for by the redundant canal input from the

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una ected labyrinth. Angular head accelerations are detected by three pairs of semicircular canals and linear head accelerations by two pairs of otoliths. These sensors induce compensatory eye movements (slow phases) in the opposite direction to head acceleration and transduce the sensation of head motion. Sensorimotor transformation proceeds via canal planes to planes of eye movements so that the neurons always contact their two respective extraocular muscles. This means that a lesion of a single semicircular canal induces a spontaneous nystagmus with slow phases in the '0 -direction' of that canal. If multiple canals are lesioned, the slow phases should be in a direction that is a weighted vector sum of the axes of the involved canals [22). The direction of head rotation is sensed by corresponding on-and-o modulation of the resting activity (on: 100 500 Hz; 0 : 100 a Hz) of the right and left canals, corroborating in pairs for the particular plane of motion (yaw horizontal semicircular canals, right and left). Loss of function in the on-direction (head rotation to the right with right horizontal semicircular canal paresis) is still sensed by the opposite canal, which is stimulated (inhibited) in its 0 -direction. Modulation of the neuronal activity in the a -direction is limited, and as the speed of head rotations increases, the firing rate of the neurons will reach zero; this is also called Ewald's second law [21) (see also High-Frequency Defect of VOR). Vertigo, spontaneous nystagmus with oscillopsia, and postural imbalance in VN are the appropriate stimuli to promote central vestibular compensation and vestibular substitution by visual and somatosensory input. Since vestibular compensation is less perfect than generally believed, especially for dynamic conditions, further mechanisms such as sensory substitution by vision or proprioception in part replace the missing vestibular input [11). There is, for example, a measurably increased influence of cervical proprioception on spatial orientation and gaze in space ipsilateral to a peripheral vestibular lesion [79). Vestibular exercises and pharmacological substances may facilitate these processes [78) (see below).

Vestibular Neuritis - Not a Total But a Partial Unilateral Vestibular Loss

Does VN produce a complete or a partial unilateral vestibular paralysis? The coexistence of a complete VN and benign paroxysmal positioning vertigo (due to canalolithiasis of the posterior semicircular canal) in the same individual, in the same ear, at the same time seems impossible, for this implies the simultaneous function and loss of function of one labyrinthine structure. The repeated clinical observation of this apparently paradoxical coincidence led us to draw the following conclusions [12). VN a ects only part of the

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Fig 7. VN. a partial labyrinthine lesion with horizontal semicircular ca-

Vasculature

Innervation

nill

piln~sis:

Vilsflllilr or virill p.tiology?

A theoretical explanation is that only the anterior vestibular artery (AVA) is a ected, sparing the posterior branch which supplies the posterior canal (top). The more likely explanation is a viral etiology a ecting parts of the vestibular nerve (VN) , in particular the horizontal ampullary nerve, but sparing the inferior division. the functioning of which is necessary for the simultaneous occurrence of VN and benign paroxysmal positioning nystagmus on the same side. AC Anterior canal; HC horizontal canal; PC posterior canal [from 6].

vestibular nerve trunk, usually the superior division (horizontal and anterior semicircular canals. maculae of the utricle and anterosuperior part of the saccule). which has its own path and ganglion [52. 66]. whereas the inferior part (posterior semicircular canal) is spared (fig. 7). This hypothesis of partial involvement of the vestibular nerve is supported by findings of temporal bone pathology [69] and also by the histopathology of a case of herpes zoster oticus [63J. In the latter case the otolith apparatus and the posterior semicircular canal remained intact. The earlier hypothesis of Lindsay and Hemenway [SOJ, on the other hand, convincingly explained the coexistence of VN and benign paroxysmal positioning vertigo as due to a vascular pathogenesis. If an ischemic event invulves unly the anterior vestibular artery. it wuuld cause a cuntraversive horizontal nystagmus in the acute stage with no ipsilateral response to thermic irrigation of the horizontal canal; it could also promote cupulolithiasis of otoconia by ischemic degeneration of the utricular macula. Histologic investigations by these authors found degeneration of the nerve fibers leading to the

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horizontal and the anterior semicircular canals and the utricle, whereas the posterior ampullary nerve appeared intact. Schuknecht and Kitamura [69] favored a viral etiology and, in order to disprove a vascular etiology, even tried to declare that Lindsay and Hemenway's case was of viral origin. Recently, analysis of 3-D properties of the vestibular ocular reflex in patients with VN clearly demonstrated that the vectors of the spontaneous nystagmus clustered between the expected directions for lesions of either the horizontal or a combined lesion of the horizontal plus the anterior semicircular canals [22J. These data strongly support lesion of the superior division of the vestibular nerve, sparing the inferior division.

Viral or Vascular Etiology?

Historical Discussion In the past, two main causes were proposed: either inflammation of the vestibular nerve [20, 59. 64J or vascular disturbance, which could be due to labyrinthine ischemia [50] or even infection-induced microvascular disturbances [56]. The histologic findings in single cases reported by Hilding et a1. [34J suggest an infectious pathogenesis. On the basis of a few autopsy studies, in which the pathological findings were similar to those occurring with known viral disorders, Schuknecht and Kitamura [69] deduced that typical VN is in fact a viral neuritis ofthe superior vestibular nerve trunk (fig. 8). Schuknecht and Witt [70] distinguished between acute viral labyrinthitis (cochlear and/or vestibular). acute viral neuritis, and delayed endolymphatic hydrops as the sequel to labyrinthitis. Similarly, viral cochleitis is a convincing explanation for sudden idiopathic sensorineural hearing loss (without vertigo). a conclusion supported by findings of temporal bone pathology [68]. Finally. acute bilateral sequential VN has been described by Schuknecht and Witt [70] and by Ogata et a1. [60]. This condition has a poor prognosis. with permanent but somewhat lessening disequilibrium arising from a bilateral partial loss of vestibular function. Herpes zoster oticus is considered an entity separate from VN if it manifests with auditory and vestibular symptoms [51. 63J. The mumps virus can cause not only deafness but also vertigo and impairment of caloric responses [41]. Arguments for Viral Etiology The must pupular theury is that uf viral etiulugy. but tile evidence fm it remains circumstantial [57, 84J. The following arguments are presented to support a viral etiology: (1) VN shows an epidemic occurrence in certain periods of the year. and there is a high frequency of preceding or concurrent upper respiratory tract

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Fig 8. Histopathology of a patient with a right VN who died 12 years after symptom onset. A Right ear. This view shows degeneration of the ampullary branch of the superior division of the vestibular nerve as well as the lateral canal crista, including the sensory epithelium. 39. B Left ear. The ampullary nerve and lateral canal crista, including the sensory epithelium, appear normal. 39. [From 67, with permission.]

infections (about 30% in adults [71, 74]); however, a critical appraisal of the significance of these epidemiological arguments seems called for [84]. (2) Vestibular nerve histopathology in cases of VN [69] is similar to that seen in single cases of herpes zoster oticus, when temporal bone histopathology was available. (3) Cerebral spinal fluid (CSF) examinations show an increase in protein (not in cells) beginning about 2 weeks after onset of VN. This could be due to increased entry of plasma proteins caused by either a disruption of the bloodbrain barrier or local immunoglobulin production (rising antibody titers) or to demyelination of the vestibular nerve [53]. Increases in various seI'Um antibody titers have been found in about one-half of patients with VN [35, 72]. but no increase in IgG or viral antibody titers in the CSF [54]. (4) Herpes simplex virus (HSV) DNA was repeatedly detected in autopsied human vestibular ganglia by using polymerase chain reaction [24] (fig. 9).

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14 . ().2

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Fjg 9. Polymerase chain reaction showing HSY-I DNA in a human vestibular ganglion. The vestibular ganglion was from a patient who died of a heart attack. According to the patient's history there was no evidence of a vestibular disorder [unpublished observation of V. Arbusow, P. Schulz, M. Strupp and Th. Brandt].

Tills indicates that vestibular ganglia are latently infected by HSY-l; however, the latency-associated transcript was found to be negative. (5) An animal model of VN was developed by inoculating HSY-l into the auricle of mice [36J. Postural deviation was observed in 5% of the mice 6-8 days after the inoculation. Degeneration of Scarpa's ganglion and HSY-l antigens were found only in symptomatic animals. Vestibular symptomatology can be induced by intraperitoneal, intracerebral, intralabyrinthine, or intracutaneous inoculation of various viral agents [16, 17, 36J. The sum of all these arguments fails to establish a common etiology and pathomechanism for YN, and does not identify a single or typical causative virus. If herpes simplex is the most likely candidate, it can be assumed to reside in a latent state in the vestibular ganglia, e.g., in the ganglionic nuclei as has been reported in other cranial nerves [58]. As a result of intercurrent factors, it suddenly replicates and induces an autoimmune reaction, leading to inflammation and edema, and subsequent demyelination of the nerve [84], which increases protein in the CSF, indicating a deficient barrier between bluml amI CSF [54]. Increases iII serum antibudy titers, huwever, were fuund not only for herpes simplex, but also for Epstein-Barr, rubella, adenovirus, influenza, and cytomegaloviruses. Both convergent and divergent data in support of viral etiology must be critically weighed against each other, particularly with respect to the therapeutic consequences.

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Natural Course

There is usually a sudden onset of the disease (sometimes preceded by a short vertigo attack hours or days earlier) with rotatory vertigo, oscillopsia, impaired fixation, postural imbalance, nausea, and often vomiting. Patients feel severely ill and prefer to stay immobilized in bed. They avoid head movements, which exaggerate symptoms, until the vertigo, postural imbalance, and nausea subside, usually after 1-3 days. After 3-5 days spontaneous nystagmus is largely suppressed by fixation in the primary position, although - depending on the severity of the canal palsy - it is still present for 2-3 weeks with Frenzel's glasses and on lateral gaze directed away from the lesion. After recovery of peripheral vestibular function, in some patients spontaneous nystagmus transiently reverses its direction ('Erholungsnystagmus'), i.e., when the centrally compensated lesion regains function. 'Erholungsnystagmus' then reflects a tone imbalance secondary to compensation. Bechterew's phenomenon, a reversal of post-unilateral labyrinthectomy spontaneous nystagmus occurring after contralateral labyrinthectomy in animals or humans [47, 87], is produced by a similar mechanism. Stage assessment ofVN is possible by means ofspontaneous and head-shaking nystagmus findings [55J. In the first stage spontaneous nystagmus of the paralytic type can be observed after 4 weeks; subsequently head-shaking nystagmus directed toward the una ected ear indicates central compensation. Head-shaking nystagmus can disappear transiently during the process of labyrinthine recovery or be directed toward the a ected ear, as seen during recovery of peripheral vestibular function in the compensated state. After 1-6 weeks most of the patients feel symptom-free, also during slow body movements, but actual recovery depends on whether and how quickly functional restitution of the vestibular nerve occurs during 'central compensation' [IIJ and possibly on how much physical exercise the patient has done. Rapid head movements, however, may still cause slight oscillopsia of the visual scene and impaired balance for a second in those who do not regain normal labyrinthine function (see following paragraph). This explains why only 34 (57%) of 60 patients with VN reported complete relief from subjective symptoms at long-term follow-up [62], roughly corresponding to the 50-70% complete recovery rate of labyrinthine function assessed by caloric irrigation [56, 61, 62]. The prognosis for rare VN in children seems better than in adults, since persistent canal paresis was found in only 14% of 17 cases on re-examinatiun [83J. FUI'thermure, in predispused subjects the experience uf severe rotatory vertigo and imbalance in the acute stage of VN may initiate anxious introspection and balance control, which can escalate to panic attacks and promote development of a phobic postural vertigo [7J (for management of phobic postural vertigo, see below).

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Management

Management of VN involves: (1) drug treatment (antivertiginous agents (dimenhydrinate, scopolamine), corticosteroids, and/or virostatics) and (2) physical therapy (vestibular exercises). During the first 1-3 days, when nausea is pronounced, vestibular sedatives such as antihistamine dimenhydrinate (Dramamine) 50-100 mg every 6 h or the 'anticholinergic' scopolamine (Transdermscop) 0.6 mg every 6-12 h, can be administered parenterally for symptomatic relief. The major side e ect is general sedation. The most probable sites of primary action are the synapses of the vestibular nuclei, which exhibit a reduced discharge and diminished neuronal reaction to body rotation. These drugs should not be given after nausea disappears, because they prolong the time required to achieve central compensation [86]. To date, two studies have reported a beneficial e ect of corticosteroids on the course ofVN. The study by Ariyasu et a1. [31 included 20 randomly selected patients and was double-blind, prospective, placebo-controlled, and crossover; however, uncertainties about the precise diagnosis remained ('acute vestibular vertigo'). Patients took a single 32-mg dose of methylprednisolone oraJly on the first day and divided doses of 16 mg twice a day for 3 days; then the dosage was tapered to zero after 8 days. While the second study by Ohbayashi et a1. [61 Jhadl no clearly prospective design, it also reported that corticosteroids facilitated early recovery from vertigo and nystagmus. The recovery rate of caloric re-' sponses at follow-up was significant for moderate horizontal semicircular canaJl paresis but not for marked paresis. The administration ofsteroids included infu-I sian of hydrocortisone (initial dosage of 500 mg was decreased gradually b~ 100 mg/2 days for 10 days) or oral prednisolone starting with 30-40 mg/day. Antiviral substances, such as acyclovir, or the combination of antiviral substances with steroids have not yet been systematically studied. However, a recent study showed that the combination of both drugs significantly improves the outcome of Bell's palsy [1], which most probably has the same pathogenesis. Another mode of treatment (which should complement drug therapy) is physicaJ therapy with the Cawthorne-Cooksey [13J exercises, modified according to current knowledge of vestibular physiology (table 1), also called vestibular rehabilitation [33]. Vestibular exercises consist mainly of eye, head, and body movements designed to provoke a sensory mismatch; they enhance compensatiun by facilitating central recalibratiun, althuugh the symptums are initially uncomfortable. Therapy for vestibular imbalance should be designed to expose the patient increasingly to unstable body positions in order to facilitate rearrangement and recruitment of control capacities [10]. Elderly patients seem to take longer to recover [43, 75].

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time (day after symptom onset) JOC Fig JOe. Time course of the changes in total sway path values (SP) for the control and physiotherapy groups: vestibular exercises improved central vestibulospinal compensation. For postural control [39J we measured the SP values (mlmin, mean SD) of patients with eyes closed and standing on a compliant foam-padded posturography platform. The total SP is the length of the path described by the center of force during a given time (20 s), which is generated by the inherent instability of a subject standing on a recording platform. SP is approximated by the sum of the distances between two consecutive sampling points in the anteroposterior (sagittal x) plane, i.e., sagittal sway (calculated as x ), mediolateral (frontal y) plane, i.e., frontal sway (calculated as ( y ), or for two dimensions as - the y2 )). There was a significant di erence (ANOVA, total SP - (calculated as ( ( x 2 p 0.00l) between the two groups at the statistical end point (day 30 after symptom onset). The dotted line indicates the normal range. a During the first days after symptom onset not all patients could stand long enough ( 20 s) on the platform to permit accurate quantitative measurement of the SP values [from 78[.

Animal experiments have shown that visual and physical exercises promote central compensation of spontaneous nystagmus [14] as well as postural reflexes in locomotion [42, 49J. A recent prospective clinical study has also shown that vestibular exercises (table 1) improve central vestibulospinal compensation in humans (fig. 10). Central compensation of unilateral peripheral vestibular lesions involves multiple processes occurring in distributed networks at ui erent lucatiuns (spinal coru, vestibular nuclei, commissural brainstem connections between vestibular nuclei) and with di erent time courses. For example, after hemilabyrinthectomy in the frog, 50% of the postural recovery is accomplished within the first 2 weeks. At that time the commissural vestibular changes have reached only 5% of maximum, which

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Table 1. Physical therapy for acute, unilateral labyrinthine lesions Clinical stage

Physical exercise

Strategy

No exercise; bed rest Head immobilization

Prevent falls Avoid active head accelerations leading to 'cross-coupled' e ects Avoid visual-vestibular mismatch

1. Approximately days 1-3

Nausea Spontaneous nystagmus with fixation

Eyes closed II. Approximately days 3-5

No spontaneous nausea Incomplete suppression of spontaneous nystagmus by fixation straight ahead

III. Approximately days 5-7 Suppression of spontaneous nystagmus with fixation gaze nystagmus in the straight ahead, but continued direction of fast phase, and spontaneous nystagmus with Frenzel's glasses

IV Approximately weeks 2-3 No spontaneous vertigo Weak spontaneous nystagmus with Frenzel's glasses

Strupp/Brandt

Exercise in bed (supine and sitting) with rapid mobilization I) Fixation straight ahead; voluntary saccades and eccentric gaze-holding (l0, 20, and 40° horizontaVvertical) ; reading exercise Smooth pursuit (finger movements or pendulum 20-40°; 20-60 0 /s) Active head oscillations with fixation of a stationary target at 1 m distance (0.5-2 Hz; 20-30°; yaw pitch roll) 2) First balance exercise-free sitting and stance and gUided gait (eyes open, eyes closed)

Visual control of stabilization of gaze in space by suppressing spontaneous nystagmus through voluntary fixation impulse (retinal slip) Visually guided control of target fixation Provoke vestibular stimuli for recalibration of VOR under visual control of retinal slip of the viewed target Circulatory training, prophylaxis of thrombosis

1) Static stabilization: Four point stance. Stance on one knee and one foot Upright stance (eyes open/eyes closed; head upright/head extension) 2) Dynamic stabilization: Smooth pursuit and head oscillation exercises during free stance as described in preceding section. Exercises with rope, ball, and club with fixation (eye and head) of the object (sitting/standing/ walking)

Recalibrate visuovestibulospinal reflexes for postural control and eye-head coordination during free body movements

Complex balance exercise, successive increase in di culty, above the demands for postural control under everyday conditions

Expose the subjectively 'recovered patient' increasingly to unstable body positions in order to facilitate rearrangement and recruitment of control capacities

132

is reached for postural recovery as well as commissural changes about 60 days after hemilabyrinthectomy [48 ,77J. Pharmacological and metabolic studies in animals suggest that the state of central compensation for peripheral vestibular lesions is both dynamic and fragile [86]. Alcohol, phenobarbital, chlorpromazine, diazepam, Ca 2 channel antagonists [15], and ACTH antagonists [25J may retard compensation; ca eine, amphetamines, and ACTH accelerate compensation; cholinomimetics, cholinesterase inhibitors, adrenergic agents, GAB A agonists, and alcohol can (re)produce decompensation. It still remains to be proven if the use of drugs accelerates compensation in patients [76]. As mentioned above, many patients develop phobic postural vertigo [7], secondary VN, even if peripheral vestibular function has completely recovered. Our therapeutic regimen for phobic postural vertigo consists mainly of: (a) relieving the patients of their fear of a severe organic disease; (b) providing them with a detailed explanation of the causative mechanism and the factors that provoke phobic postural vertigo attacks; (c) initiating self-controlled 'desensitization' - within the context of behavioral therapy - by repeated exposure to situations that evoke the vertigo, and (d) advocating regular but not overly strenuous physical activity to improve the sense of diminished fitness. In summary: (1) Antiemetlcs and sedatives should be given only during the period of 1-3 days after symptom onset, because they prolong the time required to achieve central compensation; (2) on the basis of the probable viral etiology of vestibular neuritis, steroids in combination with antiviral substances (acyclovir) may improve the outcome, although this has not yet been systematically studied, and (3) vestibular exercises improve vestibulospinal compensation and should be begun as early as possible after symptom onset.

References Adour KK, Ruboyianes JM. Von Doersten PC, Byl FM. Trent CS, Quesenberry CP Jr. Hitchcock T: Bell's palsy treatment with acyclovir and prednisone compared with prednisone alone: A doubleblind, randomized, controlled trial. Ann Otol Rhinol Laryngol 1996;105:371-378.

2

Arbusow V, Dieterich M, Strupp M. Dreher V, Jager L, Brandt T: Herpes zoster neuritis involving superior and inferior parts of the vestibular nerve cause ocular tilt reaction. Neuro-ophthalmology

3

Ariyasu L, Byl FM, Sprague MS, Adour KK: The beneficial e ect of methylprednisolone in acute vestibular vertigo. Arch Otolaryngol Head Neck Surg 1990; 116:700-703. Bergstrom B: Morphology of the vestibular nerve. II. The number of myelinated vestibular nerve fibers in man at various ages. Acta Otolaryngol (Stockh) 1973;76:173-179. Bohmer A, Rickenmann]: The subjective visual vertical as a clinical parameter ofvestibular function in peripheral vestibular diseases. J Vestib Res 1995;5:35-45. Brandt T: Vertigo: Its Sensorimotor Syndromes, ed 2. London, Springer. 1999.

1998;19:17-22.

4 5 6

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7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

27 28 29 30

31 32 33 34

Brandt T: Phobic postural vertigo. Neurology 1996;46: 1515-1519. Brandt T. Allum JH, Dichgans J: Computer analysis of optokinetic nystagmus in patients with spontaneous nystagmus of peripheral vestibular origin. Acta Otolaryngol (Stockh) 1978;86:115-122. Brandt T. Daro RB: The multisensory physiological and pathological vertigo syndromes. Ann Neurol 1980;7: 195-203. Brandt T, Krafczyk S, Malsbenden I: Postural imbalance with head extension: Improvement by training as a model for ataxia therapy. Ann J\.ry Acad Sci 1981;374:636-649. Brandt T, Strupp M, Arbusow V, Dieringer N: Plasticity of the vestibular system: Central compensation and sensory substitution for vestibular deficits. Adv Neurol 1997;73:297-309. Buchele W, Brandt T: Vestibular neuritis - A horizontal semicircular canal paresis? Adv Otorhinolaryngol 1988;42:157-161. Cawthorne T: The physiological basis for head exercises. J Chart Soc Physiother 1944;106-107. Courjon JH, Jeannerod M, Ossuzio I, Schmid R: The role of vision in compensation of vestibuloocular reflex after hemilabyrinthectomy in the cat. Exp Brain Res 1977;28:235-248. Darlington CL, Smith PF: Pre-treatment with a Ca' channel antagonist facilitates vestibular compensation. Neuroreport 1992;3: 143-145. Davis LE: Viruses and vestibular neuritis: Review of human and animal studies. Acta Otolaryngol Suppl (Stockh) 1993;503:70-73. Davis LE, Johnson RT: Experimental viral infections of the inner ear. 1. Acute infections of the newborn hamster labyrinth. Lab Invest 1976;34:349-356. Depondt M: Vestibular neuronitis. Vestibular paralysis with special characteristics. Acta Otorhinolaryngol Belg 1973;27:323-359. Dieterich M. Buchele W: MR1 findings in lesions at the entry zone of the eighth nerve. Acta Otolaryngol Suppl (Stockh) 1989:468:385-389. Dix MR, Hallpike CS: The pathology. symptomatology, and diagnosis of certain common disorders of the vestibular system. Ann Otol 1952;61:987-991. Ewald R. Physiologische Untersuchungen nber das Endorgan des Nervus octavus. Wiesbaden, Bergmann. 1892. Fetter M, Dichgans J: Vestibular neuritis spares the inferior division of the vestibular nerve. Brain 1996;119:755-763. Francis DA. Bronstein AM. Rudge p. Du Bou]ay EP: The site of brainstern lesions causing semicircular canal paresis: An MRI study. J Neurol Neurosurg Psychiatry 1992;55:446-449. Furuta Y. Takasu T, Fukuda S, Inuyama Y, Sato KC. Nagashima K. Latent herpes simplex virus type 1 in human vestibular ganglia. Acta Otolaryngo] Supp] (Stockh) 1993;503:85-89. Gilchrist DP, Smith PF, Darlington CL: ACTH(4-1O) accelerates ocular motor recovery in the guinea pig following vestibular dea erentation. Neurosci Lett 1990;118:14-16. Goldberg JM. Fernandez C: PhysIology of peripheral neurons innervating semicircular canals of the squirrel monkey.!. Resting discharge and response to constant angular accelerations. J Neurophysial 1971;34:635-660. Hain TC, Fetter M, Zee DS: Head-shaking nystagmus in patients with unilateral peripheral vestibular lesions. Am J Otolaryngo] 1987;8:36-47. Ilallpike CS: The pathology and di erential diagnosis of aural vertigo. Proc 4th Int Congress Oto]aryngo], London. Br Med Assoc 1949;2:514 Ha]magyi GM, Curthoys IS: A clinical sign of canal paresis. Arch Neuro] 1988;45:737-739. Ha]magyi GM, Curthoys IS, Cremer PD, Henderson Cj, Todd Ivl], Staples MJ, D'Cruz DM: The human horizontal vestibula-ocular reflex in response to high-acceleration stimulation before and after unilateral vestibular neurectomy. Exp Brain Res 1990;81:479-490. Hasuike K, Sekitani T, Imate Y: Enhanced MRI in patients with vestibular neuronitis. Acta Otolaryngo] Suppl (Stock h) 1995;519:272-274. I-lelmchen C, Jager L, Buttner U, Reiser M, Brandt T: Cogan's syndrome: High-resolution MRI as an Indicator of activity. J Vestib Res 1998;8:155-167. Herdman SJ: Vestibular Rehabilitation. Philadelphia, Davis. 1994. HUding DA, Kanda T, House WF: Vestibular neuronitis and small acoustic neuroma: Electron microscopic observations. Oto] Clin North Am 1968;112:305-318.

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56 57 58 59 60 61

62

Hirata T, Sekitani T, Okinaka Y, Matsuda Y: Serovirological study of vestibular neuronitis. Acta Otolaryngol Suppl (Stock h) 1989;468:371-373. Hirata Y, Gyo K, Yanagihara N: Herpetic vestibular neuritis: An experimental study. Acta Otolaryngal Suppl (Stock h) 1995;519:93-96. Honrubia V: Quantitative vestibular function tests and the clinical examination; in Herdman SJ (ed): Vestibular Rehabilitation. Philadelphia, Davis, 1994, pp 113-164. Hopf HC: Vertigo and masseter paresis. A new local brainstem syndrome probably of vascular origin. J Neurol 1987;235:42-45. Hufschmidt A, Dichgans J, Mauritz KH, Hufschmidt M: Some methods and parameters of body sway quantification and their neurological applications. Arch Psychiatr Nervenkr 1980;228; 135-150. Huppert D, Brandt T, Dieterich M, Strupp M: Phobic vertigo. The second most common diagnosis in specialized ambulatory care for vertigo. Nervenarzt 1994;65:421-423. Hyden D, Odkvist LM, Kylen P: Vestibular symptoms in mumps deafness. Acta Otolaryngol Suppl (Stockh) 1979;360: 182-183. Igarashi M, Levy JK, 0 Uchi T, Reschke MF: Further study of physical exercise and locomotor balance compensation after unilateral labyrinthectomy in squirrel monkeys. Acta Otolaryngol (Stockh) 1981;92;101-105. Ishikawa K, Edo M, Togawa K: Clinical observation of 32 cases of vestibular neuronitis. Acta Otolaryngol Suppl (Stockh) 1993;503:13-15. Ishizaki H, Pyykko I, Nozue M: Neuroborreliosis in the etiology of vestibular neuronitis. Acta Otolaryngol Suppl (Stock h) 1993;503:67-69. Jager L, Strupp M, Brandt T, Reiser M: Imaging of the labyrinth and vestibular nerve: Clinical relevance for di erential diagnosis of vestibular disorders. Nervenarzt 1997;68:443-458. Kamei T: The two-phase occurrenceofhead-shaking nystagmus. Arch OtorhinolaryngoI1975;209:59--£7. Katsarkas A, Galiana HL: Bechterew's phenomenon in humans. A new explanation. Acta Otolaryngal Suppl (Stock h) 1984;406:95-100. Kunkel AW, Dieringer N: Morphological and electrophysiological consequences of unilateral preversus postganglionic vestibular lesions in the frog. J Camp Physiol A 1994; 174 :621-632. Lacour M, Roll JP, Appaix M: Modifications and development of spinal reflexes in the alert baboon (Papio papio) following a unilateral vestibular neurectomy. Brain Res 1976; 133;255-269. Lindsay JR, Hemenway WG: Postural vertigo due to unilateral sudden partial loss of vestibular function. Arch Otolaryngol 1956;65:692-706. Langridge NS: Recurrent vestibulopathy: Support for a viral etiology. J Otolaryngol 1989;18:99-100. Lorente de No R: Vestibula-ocular reflex arc. Arch Neurol Psychiatry 1933;30:245-291. Matsuo T: Vestibular neuronitis - Serum and CSF virus antibody titer. Auris Nasus Larynx 1986; 13:11-34. Matsuo T, Sekitani T, Honjo S, Imate Y, Inokuma T: Vestibular neuronitis. Pathogenesis in the view of virological study of CSF. Acta Otolaryngol Suppl (Stockh) 1989;468:365-369. Matsuzaki M, Kamei T: Stage assessment of the progress of continuous vertigo of peripheral origin by means of spontaneous and head-shaking nystagmus findings. Acta Otolaryngol Suppl (Stockh) 1995;519: 188-190. Meran A, Pfaltz CR: The acute vestibular paralysis. Arch Otorhinolaryngol 1975;209:229-244. Nadal JB Jr: Vestibular neuritis. Otolaryngol Head Neck Surg 1995;112:162-172. Nahmias N, Roizman B: Infection with herpes simplex viruses I and 2. II. N Engl J Med 1973; 289:719-725. Nylen CO: Some cases of ocular nystagmus due to certain positions of the head. Acta Otolaryngol (Stockh) 1924;6:106-137. Ogata Y, Sekitani T, Shimogori H, Ikeda T: Bilateral vestibular neuronitis. Acta Otolaryngol Suppl (Stock h) 1993;503:57-60. Ohbayashi S, Oda M, Yamamoto M, Urano M, Harada K, (-lorikoshi I-I, Orihara H, Kitsuda C: Recovery of the vestibular function after vestibular neuronItis. Acta Otolaryngol Suppl (Stockh) 1993;503:31-34. Okinaka Y, Sekitani T, Okazaki H, Miura M, Tahara T: Progress of caloric response of vestibular neuronItis. Acta Otolaryngol Suppl (Stockh) 1993;503:18-22.

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Proctor L. Perlman H, Lindsay J, Matz C: Acute vestibular paralysis in herpes zoster oticus. Ann Otol Rhinal Laryngol 1979;88:303-310. Ruttin B: Zur Di erentialdiagnose der Labyrinth- und Hornerverkrankungen. Z Ohrenheilkunde 1909;57:327-333. SafranAB, Vibert 0, Issoua 0, Hausler R: Skew deviation after vestibular neuritis. Am J Ophthalmol 1994; 118:238-245. Sando I, Black FO, Hemenway WC: Spatial distribution of vestibular nerve in internal auditory canal. Ann Otol 1972;81:305-319. Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea & Febinger, 1993. Schuknecht HF, Donovan ED: The pathology of idiopathic sudden sensorineural hearing loss, Arch Otorhinolaryngol 1986;243; 1-15. Schuknecht HF, Kitamura K: Vestibular neuritis. Ann Otol 1981;90(suppI78);1-19. Schuknecht HF, Witt RL: Acute bilateral sequential vestibular neuritis. Am J Otolaryngol 1985;6: 255-257. Sekitani T, Imate Y. Noguchi T, Inokuma T: Vestibular neuronitis: Epidemiological survey by questionnaire in Japan. Acta Otolaryngol Suppl (Stockh) 1993;503:9-12. Shimizu T, Sekitani T, Hirata T, Hara H: Serum viral antibody titer in vestibular neuronitis. Acta Otolaryngol Suppl (Stock h) 1993;503:74-78. Shirabe S: Vestibular neuronitis in childhood. Acta Otolaryngol Suppl (Stockh) 1988;458:120-122. Silvoniemi P: Vestibular neuronitis. An otoneurological evaluation. Acta Otolaryngol Suppl (Stockh) 1988;453:1-72. Sloane PO, Baloh RW. Honrubia V: The vestibular system in the elderly: Clinical implications, Am J Otolaryngol 1989; 10:422-429, Smith PF, Darlington CL: Can vestibular compensation be enhanced by drug treatment? J Vestib Res 1994;4:169-179. Straka H, Dieringer N: Spinal plasticity after hemilabyrinthectomy and its relation to postural recovery in the frog. J Neurophysiol 1995;73:1617-1631. Strupp M, Arbusow V. Brandt T: Vestibular exercises improve central vestibula-spinal compensation after an acute unilateral peripheral vestibular lesion: A prospective clinical study. Neurology 1998. in press, Strupp M, Arbusow V, Dieterich M, Sautier W. Brandt T: Perceptual and oculomotor e ects of neck muscle vibration in vestibular neuritis; Ipsilateral somatosensory substitution of vestibular function. Brain 1998; 121:677-685. Strupp M, Brandt T: Vestibulo-okularer Reflex; in Huber A, Kampf 0 (eds): Klinische Neuroophthalmologie. Stuttgart, Thieme, 1997, pp 78-85. Strupp M, Brandt T, Steddin S: Horizontal canal benign paroxysmal positioning vertigo: Reversible ipsilateral caloric hypoexcitability caused by canalolithiasis? Neurology 1995;45:2072-2076, Strupp M, Jager L. Moller-Lisse U. Arbusow V, Reiser M, Brandt T; High resolution MRI in 60 patients with vestibular neuritis: No contrast enhancement of the labyrinth or vestibular nerve. J Vestib Res 1998;8:1-7. Tahara T, Sekitani T. Imate Y, Kanesada K. Okami M: Vestibular neuronitis in children. Acta Otoiaryngol Suppl (Stock h) 1993;503:49-52. Tran Ba Huy P: Physiopathology of peripheral non-Meniere's vestibular disorders. Acta Otolaryngol Suppl (Stockh) 1994;513:5-10. Vibert 0, Hausler R, Safran AB, Koerner F: Diplopia from skew deviation in LUlilateral peripheral vestibular lesions. Acta Otolaryngol (Stockh) 1996; 116: 170-176. Zee OS: Perspectives on the pharmacotherapy of vertigo. Arch Otolaryngol 1985;111:609-612. Zee OS, Preziosi TJ, Proctor LR: Bechterew's phenomenon in a human patient (letter). Ann Neurol 1982; 12;~95-~96.

Dr. Michael Strupp, MD, Department of Neurology, University of Munich, KJinikum Crosshadern, Marchioninistrasse 15, 0-81377 Munich (Cermany) Tel. 49 89 7095 2571, Fax 49 89 7095 8883, E-Mail [email protected]

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Meniere's Disease K. -F Hamann, W Arnold Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum rechts der Isar, Technical University of Munich, Germany

Definition

Meniere's disease can be defined as an inner ear disorder of unknown cause [92J. Clinically it is characterized by fluctuating hearing loss, vertigo attacks, tinnitus and a sensation of aural fullness in which its pathological anatomical correlate is endolymphatic hydrops (fig. 1). This definition makes it clear that the term Meniere's disease does not fulfil the criteria of a nosologic entity since the etiology is not fully known. However, it is more than just a syndrome, it is a state of illness. Although there are restrictions to the term Meniere's disease, it will be used in the following chapter as it is used worldwide. In addition, other diseases of the cochlea-vestibular system or central nervous system (e.g, acoustic neuroma) tend to mimic the disease by presenting with similar clinical symptoms. Therefore, di erential diagnosis of Meniere's disease is challenging. Even for an experienced clinician it is not simple to recognize and diagnose Meniere's disease until the complete picture of the classical triad exists, and in addition a retrocochlear cause has been excluded. Even though the International Meniere Society has attempted to classify an 'inner ear profile' for the symptoms of the definite diagnosis, the AAOHNS (American Academy of Otolaryngology, Head and Neck Surgery) has published specific guidelines to define Meniere's disease and the development of endolymphatic hydrops [23J. Classification of Meniere's disease depends on the severity uf tile symptums, vertigu, hearing luss and tinnitus (table 1). These recommendations should serve the purpose of comparing diagnosis and clinical studies with di erent neum-otological centers and clinics. Similar gUidelines have been presented by the AAO-HNS [1) in order to compare the di erent types of treatment (see below).

Table 1. Diagnostic scale for Meniere's disease of the AAO-HNS 1 [1]

Certain Meniere's disease Definite Meniere's disease, plus histopathological confirmation Definite Meniere's disease Two or more episodes of vertigo of at least 20 min Audiometrically documented hearing loss on at least one occasion Tinnitus or aural fullness Probable Meniere's disease One definite episode of vertigo Audiometrically documented hearing loss on at least one occasion Tinnitus or aural fuJJness Possible Meniere's disease Episodic vertigo without documented hearing loss Sensorineural hearing loss, fluctuating or fixed, with dysequilibrium, but without definite episodes I In all scales, other causes must be excluded using any technical method (e.g. imaging, laboratory, etc,),

The Development of Research in Meniere's Disease

Following Hard's [45] first description of the combination of symptoms of vertigo, hearing loss and tinnitus in 1821, it was the merit of Prosper Meniere [62], who in 1861 presented in Paris the clinical a ictions of the inner ear disorder thereby crediting him with the recognition of the syndrome as more than a sign of 'apoplectic cerebral congestion'. P. Meniere was influenced by the findings of the physiology of the inner ear by Flourens [31J well known to him. Thereby he correctly classified the symptoms to the inner ear. A few years later the syndrome of fluctuating hearing loss accompanied by vertigo and tinnitus was named by Duplay [27J as Meniere's disease. In 1921, G. Portmann [78] performed an investigation on Selacian fish and determined endolymphatic hydrops as a possible cause for Meniere's disease, the proof however was not given until 1938 by Hallpike and Cairns [39] in London and at the same time independently, by Yamakawa [117] in Osaka. This finding not only made for a better understanding of Meniere's disease, but was alsu an impurtant landmark in experimental research. Schuknecht and Igarashi [91J demonstrated in a series of temporal bone examinations of Meniere patients that endolymphatic hydrops always involved the sacculus and utriculus although hydrops in the endolymphatic compartments of the cochlea developed in completely di erent regions (fig. 1).

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2

Fig. 1. Left cochlea from a 67-year-old patient suffering from Menie'res disease on both sides. The endolymphatic space (El is enlarged and Reissners membrane (RMl is not in its normal anatomic position. The folding of the lateral part of RM indicates a collapse of this area. PPerilymphatic space: S = spiral ganglion. Fig. 2. Guinea pig cochlea 6 weeks following destruction ofthe endolymphatic sac. The endolymphatic spaces (El of the scala media are enlarged indicating endolymphatic hydrops.

Based on the experimental results in animals from Guild [36] in which he demonstrated that by infusing dye into the cochlear endolymph it reappears in concentrated form in the endolymphatic sac, in 1959, Naito [69] was able to produce endolymphatic hydrops in the guinea pig by surgically destroying the endolymphatic duct and sac thereby producing hydrops. This method was then improved by Kimura and Schuknecht [48J in 1965 and is currently the most common model for experimental studies on endolymphatic hydrops. It was also proven that the endolymphatic sac is a decisive factor for the homeostasis of the endolymph (fig. 2).

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In order to better understand the relationships between endolymphatic hydrops and the appearance of characteristic symptoms, Tasaki and Fernandez [100] in 1952 made the important finding that a reversible reduction of cochlear microphonic potentials and action potentials takes place - equivalent to impaired hearing - when the perilymphatic space of the cochlea is injected with Ringer solutions containing 0.25% potassium chloride. Two years later, Tasaki et al. [101] could show that this phenomenon only appears when the electrode into the scala tympani is inserted, however not when it is located in the scala vestibuli. In the mid-1950s it was proven that the endolymph only contains a limited amount of sodium concentration (3-5 mval), however an abundant amount of potassium (130-145 mval); the opposite is true for the perilymph [94J. Finally, Lawrence and McCabe [56J postulated that ruptures of the endolymph membranes extended by the hydrops, followed by a mixing of potassium-rich endolymph and sodium-rich perilymph, are the cause of the symptoms of the attacks. This hypothesis was confirmed when they succeeded in simulating Meniere attacks in animals by injecting potassium-rich solution into the perilymphatic space until the concentration was comparable to that of endolymph [25J. As a result, the concept for potassium intoxication of the demyelinated nerve fibers within the sensory epithelia of the cochlear vestibular organ was accepted as the basis of the fundamental mechanism for attacks and the cause of a lesion nystagmus in monkeys [25]. Current research supports the hypothesis that Meniere's disease is caused by a malabsorption of the endolymph in the endolymphatic sac. Therefore, special interest is focused on this structure and its pathological changes. Schuknecht [92] demonstrated on temporal bones of Meniere patients that not only are endolymphatic hydrops present in this area but also a fibrosis or an osseous obliteration of the endolymphatic duct and sac. Immunological investigations on the human endolymphatic sac have proven that this organ has additional immunological functions [3, 7, 8] which will be discussed below.

Clinical Course and Epidemiology

Meniere's disease is characterized by a clinical triad which consists of attacks of vertigo, fluctuating hearing loss, tinnitus and a sensation of fullness uf the ear. Huwever, the disease dues nut always lJegin with a complete picture of the above-mentioned symptoms and often develops monosymptomatically, yet acute vertigo or an acute loss of hearing has been observed in the same frequency. In 90% of the patients the complete symptom picture does not become clear until 1 year after the first symptoms have been experienced [77J.

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The course of the disease is also not homogeneous. Frequency and length of vertigo attacks, the most disturbing symptom, are variable so that the e ect of di erent therapies is di cult to evaluate. The spontaneous remission rate is remarkable, but di cult to determine since intervals between attacks can last days, months or sometimes even years. Nevertheless, many patients' symptoms normally subside within 8-10 years because the disease is 'burnt out'. Loss of hearing may worsen during the course of the disease which can result in deafness. Tinnitus may remain or disappear, vertigo attacks may yield slightly to a constant unsteadiness [74]. Wide variation exists in the published incidence of Meniere's disease. Incidence varies from 4/100,000 persons in Japan [109] to 160/100,000 persons in Great Britain [20] and 15/100,000 in the USA [116J. It is unclear whether these di erences can be deduced back to genetic or environmental factors or whether it is more the di erences of diagnostic criteria. Contrary to a genetic disposition is a study by Kitahara et al. [51] which demonstrated no di erences in occurrence of Meniere's disease in di erent ethnic groups in America. A sexual preponderance of the disease is not clearly defined although some reports show a slight predominance in women. The disease can appear at any age, however a peak has been noted between the 3rd and 4th decade [74]. Remarkable is the frequent appearance of occurrence of bilateral Meniere's disease which continually increases within the period of observation and according to Paparella's data can increase up to 50%. These figures allow for the assumption that Meniere's disease has a systematic cause, e.g. an underlying immunological mechanism a ecting both sides of the inner ear.

Etiology

Today, more than a hundred years after Meniere's first publication, the disease is still classified as 'a disorder of unknown or multiple causes' [92J. Many di erent etiologies have been discussed in the last decades, each supported by numerous arguments although convincing evidence for one of these hypotheses is still outstanding. In the following the most important hypotheses of the past will be presented, due to its actuality and high plausibility the immunological hypothesis will be discussed in more detail. Since it is generally accepted that the pathological anatomical correlate of Meniere's disease is endolymphatic hydrops (see below), the etiological question is, which factors lead to the development of endolymphatic hydrops. It must certainly be taken into consideration that endolymphatic hydrops is not only present in Meniere's disease, but has also been found in inner ears

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of patients not su ering from Meniere's disease, in the form of delayed endolymphatic hydrops [68J. Fundamental far the possible development of the mechanism in Meniere's disease is the assumption that endolymphatic hydrops is caused by an imbalance of endolymph production in the stria vascularis and endolymph reabsorption in the endolymphatic sac, in other words either by overproduction or a reduced absorption of the endolymph. The di erent hypotheses must be measured with respect to these basic assumptions.

Genetic Hypothesis Several authors have inferred genetic connections although they have not been confirmed by others [15]. The e arts of Bernstein et al. [14], in which the role of the MHC gene (major histocompatibility complex) with particular antigens is connected to Meniere patients, have not been convincing. Psychogenk Factors The hypothesis that psychological factors play an important role in Meniere's disease has been suggested numerous times. Fowler and Zeckel [32] favored this opinion since they relied on the observation of their own patients. Other authors dismiss this point of view and suggest a more somatopsychological e ect [113J. The main argument against this hypothesis is however the fact that there are not direct connections between inner ear structures and higher cerebral structures such as in the limbic system; a vegetative innervation is also not known. Vascular Hypothesis A more historical aspect is the hypothesis [88] that a circulatory insu ciency may cause Meniere's disease. This hypothesis must however be dismissed in that there is no valid evidence. The fluctuating characteristics of Meniere's disease led to the assumption that a vascular compression can cause the symptoms. This presumption leaves out the fact that the development of endolymphatic hydrops is the fundamental morphological basis in Meniere's disease. Supporters of the vascular compression hypothesis consider hydrops only as an epiphenomenon. They support their viewpoint with electron microscopic investigations [22] in which lesions to the central parts of the vestibular nerve were found in Meniere patients. Therefore, they cuncluded the cause uf these changes stems frum a vascular compression. Moreover, other authors argue that lesions in the central parts of the vestibular nerve must be interpreted as a degenerative change following years of Meniere attacks [95].

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Viral Hypothesis In analogy to the modern view of the cause of facial palsy, a viral etiology of Meniere's disease [115] is postulated. Bergstrom et a1. [13] found viral antibodies in the serum of 20 of 21 Meniere patients against the herpes simplex virus in comparison to 18 of 21 controls. However, the increased antibody reactivity indicates individual HSV1 proteins in Meniere's patients in which a viral reactivation took place. In 1996, Kumagami demonstrated in healthy human endolymphatic sacs a homing of herpes simplex type I micro-organisms. Perilymph samples from Meniere patients demonstrated in contrast to those of otosclerosis patients or cochlear implant patients a significant increase of specific anti-HSV IgG titer, which is also remarkably higher than in the sera of the a ected patients [9]. These results can also be interpreted as a sign of viral reactivation of the endolymphatic sac virus which finally induced the development of endolymphatic hydrops and results as an immunological (inflammatory) reaction to the endolymphatic sac (see below). Immunological Hypothesis In the 1920s, Duke [26J first suspected a relationship between Meniere's disease and allergies. He observed in several patients who su ered from this disease, an increase in frequency of vertigo attacks related to food intolerance. This paint of view was rejected for decades since the inner ear was thought of as an organ which was privileged against immunological reactions. Based on experimental results of the last 20 years, a fundamental re-examination of these viewpoints is necessary. In 1979, McCabe [59] postulated that specific inner ear disorders can be caused by autoimmune phenomena. He reached this conclusion due to several etiologically unclear inner ear diseases which reacted positively to immunosuppressives. In his first reports he explicitly distinguished Meniere's disease to that of an autoimmune disease. Although these viewpoints were later revised, this working hypothesis triggered systematic examinations. Special interest was focused on the endolymphatic sac where endolymph reabsorption occurs and a disorder in this area could explain the development of endolymph hydrops. The first indications for the evidence that the endolymph sac presents as a site of immunological defense was made by RaskAnderson and Stahle [83]. They found in the guinea pig in the epithelia of the endolymphatic sac lymphocytes and in the lumen macrophages. Arnold et a1. [7] succeeded in 1984 to show irIlInunoglolJin G and A as well as secretory components in the human endolymphatic sac. These findings proved that the immunocompetence of the cochlea to the endolymphatic sac exists. Yet the question arises which immunological mechanisms can lead to these conceivable morphological changes found in Meniere patients. A first step in clarifying

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this was given by the animal experiments of Harris [42] in which he could demonstrate that local immune reactions in the inner ear could be produced by applying exogen antigen stimulants thereby causing specific antibodies to appear. Gloddek and Harris [34] showed that a transfer of antigens injected in the cochlea to the endolymphatic sac exists. For the local immunological response the endolymphatic sac is responsible, with a high degree of probability [7, 83]. These observations were supported by findings made with the same experimental approach, where destruction of the endolymphatic sac leads to a reduction in the immune reaction [67]. However, lymphocytes can also enter the cochlea through the bloodstream. This takes place through the modiolar vessel and the posterior modiolar spiral veins [43]. Therefore, the inner ear is also connected to the control system of the systematic immune apparatus. The endolymphatic sac can also react to di erent antigens coming either through the bloodstream to the inner ear or through the membranes of the cochlear windows of the middle ear, in other words the endolymph sac responds immunologically by inflammatory reactions. This determines the decisive defense mechanism in the inner ear. Although these seem to be biologically reasonable processes, they can however have negative consequences if the reocurrence of the inflammations of the endolymphatic sac leads to morphological persisting changes of the subepithelial inner surface of the saccus. A disorder of the reabsorption function of the endolymphatic sac is therefore assumed which leads to a predominant change in the homeostasis between continuing endolymph secretion and endolymph reabsorption in the endolymph's favor. As a consequence, endolymphatic hydrops develops, as has been determined histologically in patients with Meniere's disease [8]. An important step in investigation of the causes of Meniere's disease was the development of a method in which endolymphatic hydrops could be produced experimentally. Kimura and Schuknecht [48] perfected this method by producing endolymphatic hydrops in the guinea pig by obliterating the endolymphatic sac. It must however be mentioned here that although this model leads to endolymphatic hydrops in the guinea pig, this could not be reproduced in higher species such as monkeys. The question therefore remains as to whether the results of animal experiments along with their consequences can be transferred directly to humans if the recurrent inflammations of the endolymphatic sac lead to morphological persisting changes. In spite of these restrictiuns, the must convincing puint uf view in tile develupment ufMeniere's disease remains the current immunological hypothesis gained by clinical observations and animal models. A very important support for this hypothesis came from Rask-Andersen et al. [84], who removed the endolymphatic sac of a patient su ering from

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Exogenous agent (e.g. virus)

~

Via coch ear windows or bloodstream

Cochlear immmunoreaction

~

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Inflammation of the saccus endolymphatlcus (SE)

~

Chroniflcatlon

Rbrous tissue and ossification In the (SE)

~ DiSlur

nce

:~::~::~:ti:n K:f the endolymph

Endolymphatic hypdrops

Fjg 3. Etiologic cascade of the development of endolymphatic hydrops.

active Meniere's disease for therapeutical reasons. The electron microscopic examination showed granular lymphocytes adhering to the disturbed and degenerating epithelial cells in combination with further signs of immunologic - finally cytotoxic - interactions on epithelial cells. These changes were interpreted as immunological, autoaggressive, and tissue-damaging reaction. Therefore, they named it 'saccitis' which could explain the disturbance of endolymph reabsorption followed by the development of an endolymph hydrops leading to the symptoms of Meniere's disease (fig. 3).

Pathophysiology of Meniere Attacks

The knowledge that the pathological anatomical equivalent to Meniere's disease consists of endolymphatic hydrops, provoked by an imbalance of endolymph production and endolymph reabsorption, led to the development of a pathophysiological model in explaining Meniere attacks. The basis of this model was developed by Lawrence and McCabe [56], elaborated by Schuknecht and Igarashi [91J and modified by Jahnke [46]. It is highly probable that the disturbed reabsUI'ption of the endolymph in the endolymphatic sac results in an increase in potassium while steady endolymph secretion continues. This gives rise to an increase of the osmotic pressure in the endolymphatic area whereby water from the surrounding areas, especially from the scala vestibuli, pours in. By this mechanism the semiperme-

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sv

RM

....

Fig. 4. Chronic Menie'res disease. There is a large connection between the scala media (SM) and scala vestibuli (SV) caused by rupture of Reissners membrane (RM).

able Reissner membrane distends and then bulges out. The Reissner membrane or the sacculus and utricular membranes, the locus minoris resistentiae in this system, are initially distended until finally they rupture (fig. 4, 5). Because the natural diaphragm between endo- and perilymph is lost. a mixture of both lymphs which originally each have different ion concentrations results [100]. The inflow of higher potassium levels from the endolymph causes at the level of the sensory cells, which are normally surrounded by the perilymph, such an intense depolarization that abnormal stimulation of the affected sensory cells results. This stage is comparable to that of an attack and clinically implies hearing loss and vertigo seizures. As a result of this decompression, leaks which developed during the rupture can close again. Since new ion gradients are reproduced, the acute symptoms of the attack disappear. Simultaneously however, conditions are created for hydrops to form again, leading to yet another rupture thereby causing a new attack. The appearance of irreversible cochlear and vestibular losses in the course of Menie'res disease can be explained by the repeated bulging of the endolymph space causing persisting damage [92]. This model concept explains Menie're attacks with all symptoms (fig. 4). It is however unclear why some patients experience attacks of shorter intervals yet may recur within days, whereas others can remain symptom-free for months or even years.

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1. Normal

2. Endolymphatic hydrops

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Membranous labyrinth adherent _.------------to bony wall

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Internal auditory canal Cerebrospinal fluid (subarachnoid space)

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~

Decreased resorptive function of the endolymphatic sac

4. Healed membranous labyrinth and recurring hydrops

Partial collapse of membranous Iabyrlnth Rupture

Potassium K" .... contamination of perylymph with paralysis of sensory and neural tissues

Endolymph reaccumulating

Healed rupture Permanent alterations in sense organs

Fjg 5. Schematic drawing of di erent steps of development of seizures in Meniere's disease; from Schuknecht [92J.

Symptomatology - Disorders of the Vestibular System

Subjective Complaints The most common complaints of Meniere's disease are the disturbing attacks of vertigo in which the patient finally seeks the advice of a doctor. Hence, the necessity of a well-taken history, mainly the typical pattern of vertigo complaints, plays a vital role for the diagnosis of Meniere's disease. The most frequent type of vertigo in Meniere's disease is the sudden attack of torsional vertigo. Sensation of linear movements or 'drop attacks', which are usually typical for Tumarkin's otolithic crisis, are rare. The frequency and intensity of the attacks are irregular and unpredictable. Some patients report uf singular attacks during the course uf years whereas uther su er more intense vertigo attacks on several days in the course of a week. Especially characteristic, almost pathognomonic, for Meniere's disease is the time course of a vertigo seizure, the duration as well as its presentation of the attack. The duration of a typical Meniere vertigo seizure lasts minutes

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to hours, however never seconds or several days. An exception is only the first seizure which can last longer than 24 h and then often conceal the cochlear symptoms (see below). In advanced Meniere's disease acute torsional vertigo attacks change to a constant feeling of unsteadiness.

Oculomotor Symptoms Examination of oculomotor functions must take into account that Meniere's disease is characterized by an exchange of acute exacerbation and more or less silent periods so that objective signs of a vestibular disorder are to vary considerably. During the acute phase of a seizure, spontaneous nystagmus has been noted to beat towards the a ected ear (so-called potassium intoxication nystagmus or paralytic nystagmus) [19, 60J; however, shortly after the acute phase, spontaneous nystagmus beats toward the intact ear. This phenomenon reflects the change between the irritative stage and the destructive stage during the acute seizure. The same can be demonstrated with caloric testing in that hyperexcitability is present during the very acute stage of the a ected side, however in the symptom-free interval hypoexcitability or balanced excitability is present. Therefore vestibular testing as a diagnostic criteria for Meniere's disease is not suitable and does not lead to a final diagnosis. In the early stages of the disease no pathological signs of vestibular disorders in between attacks can be noted, neither spontaneous nor provocation nystagmus; caloric testing shows no side di erence in excitability. Only in the later stages of the disease is a persisting hypofunction of the a ected ear seen [110J. Rotatory testing shows corresponding findings, a directional preponderance of the nystagmus of the nona ected side. In the symptom-free (or symptom-poor) interval, depending on the activity of the disease, a balanced reaction on rotational stimuli or a directional preponderance corresponding to the side of hypofunction is determined. Oculomotor testing such as the 'eye tracking test' or triggering of an optokinetic nystagmus have not shown any specific changes in Meniere's disease. Test results are generally normal. That the otolith system is also a ected by the course of the disease can be deduced from the barbecue rotations in patients with Meniere's disease [49J. Torsional eye movements were seen in some patients as asymmetric, regardless if caloric testing showed side di erences in excitability or not. It should be mentioned again that even if nystagmus reaction was observed in the acute stage uf Menihe's disease, it dues nut pwvide adequate evidence of the a ected side although this is more so the case in the later stages of the disease.

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Vestibular-Spinal Signs Reports on posture disorders due to Meniere's disease are rare. GeneraUy a patient's posture, with the exception during acute attacks, remains stable in the Romberg test if visual or proprioceptive information is available. Under sharpened conditions such as visual stabilization ('visual conflict stimulation') or destabilization by suddenly tilting the platform, pathological signs appear corresponding to the marked momentary vestibular lesion [71].

Symptomatology - Disorders of the Cochlear System

The fluctuating hearing loss of the a ected ear which increases during an attack in Meniere's disease is one of the most common symptoms of the disease. In the early stages it may be the only symptom resulting in an initial false diagnosis of sudden hearing loss. Often diplacusis is reported in addition to hearing loss, giving the patients the impression that their hearing is distorted. Although it is certain to say that hearing loss in Meniere's disease develops at the level of Corti's organ, it is di cult to find a plausible explanation. It can only be partly explained by the hydrostatical tension of the basilar membrane, because the outer hair cells should function normally, which is rarely the case [76J, as it is proven by recording of otoacoustic emlssions. Whether this is caused as a result of hydrostatical pressure of the tectorial membrane on the stereocilia of the outer hair cells, is only speculation. Hearing loss is generally recovered after the first attacks. Also after further attacks it may appear a 'restitutio ad integrum'. A remaining loss of cochlear function is only seen in later stages of the disease. Studies of large numbers of patients have shown that low-frequency hearing loss is most frequently seen in the early stages of the disease, however other forms have also been reported. During the course of the disease, high-frequency hearing is also incorporated and finally almost aJl hearing frequencies are a ected (fig. 6). The above cited findings describe why there is no uniform audiometric as well as reliable model for tone decay in the hydrops ear. Speech audiometry has not always shown, especially in long-lasting cases of Meniere's disease, typical findings of cochlear damage, more often a higher degree of speech discrimination loss is found than seen in pure tone audiometry. The reason can be found in the increasing deterioration of the spiral ganglia cell as a result of a retrograde nerve degeneration, which was proven by histological examinations [95J. Measurement of the stapedius reflex confirms the diagnosis of a cochlear disorder identified by the Metz recruitment. For many years evidence of recruitment' which was proven in the Fowler test (positive in 73-100% according to

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125 til

250

500

1,000

2,000

4,000

8,000 Hz

-10

E-O

0

z

10

A

20

30 B

40 50 60

C

70 80 90 100 110 120 1,500

A

3,000

6,000

12,000

Hg 6. Typical form of pure tone audiograms in patients with Menihe's disease. Early stage; B progressive stage; C end stage.

Hallpike) as well as in the Luscher or SISI test was accepted as a decisive clinical finding in Meniere's disease. These tests however lost their importance due to their limited validity. In recent years, objective methods for measuring the function of the outer hair cells such as the transitorial otoacoustic emissions (TEOAE) and the distortion products otoacoustic emissions (DPOAE) were developed in order to topographically classify hearing loss. In Meniere's disease they have not yet been useful in determining the final diagnosis. Only in rare cases can OAE be recorded as proof of intact outer hair cells, otherwise they cannot be recorded or only in a reduced form [76]. The main interest of audiological tests was directed to prove the evidence of endolymphatic hydrops. Two tests were favored: the glycerol test [52J and electrucuchleugraphy [29, 30]. In the Klockho test [52], adapted from the glaucoma test in ophthalmology, the intake of glycerol, a powerful osmotic agent, should temporarily induce dehydration of the endolymphatic hydrops. If this succeeds, a temporary increase of function of the hair cells as well as the hearing threshold curve is

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2 ms

f----------1 Fjg 7. Electrocochleographic potential of a patient with endolymphatic hydrops: pathologic relationship between summating potential (SP) and NAP (nerve action potential) 35%.

to be expected. If this e ect occurs, it is considered proof for endolymphatic hydrops. However, a negative result does not indicate that Meniere's disease does not exist. On the other hand, a positive result of this test. in which hearing loss improves within a short period of time, indicates that the cause is related to the mechanical processes of the inner ear thereby leading to a functional disorder. Electrocochleography is among the 'evoked response audiometry' methods which comprises very early potentials (up to 2 ms). The source is usually seen in the cochlea itself and at the beginning of the n. cochlearis. The electrocochleographical potential consists of three components in which microphonic potentials are eliminated by the change in stimulation polarity, in which the summating potential (SP) represents a DC component, which reflects the distension of the basilar membrane and in which the action potential of the nerve has its source at the beginning of the n. cochlearis [29, 30]. The SP is significantly higher in Meniere's patients than in normals [3D]. The augmented SP is considered as the correlate of a basilar membrane distension to the scala tympani, which is caused by endolymphatic hydrops. Since potential amplitudes vary between individuals, Eggermont [29] introduced a practical method for evaluating electrocochleographic potentials by determining the ratiu uf the amplitudes uf the SP tu the actiun putential thereby identifying the existence of endolymphatic hydrops [30] (fig. 7). If the SP/AP ratio is 0.35, endolymphatic hydrops can be assumed. At the actual stage of knowledge, electrocochleography is currently the best objective method in determining endolymphatic hydrops. However. the rule also applies here, that

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only a positive test result indicates the existence of endolymphatic hydrops. A negative test result however, does not indicate that Meniere's disease does not exist since drainage of the hydrops could have occurred shortly prior to testing.

Tinnitus

Tinnitus a ects up to 90% of Meniere patients [74J and thereby ranks to the classical Meniere triad. Tinnitus is otherwise only present in approximately 5% of the population. Tinnitus may remain as an uncomfortable symptom long after vertigo attacks and hearing loss have stabilized. In Meniere's disease, tinnitus presents as a constant low-pitched rumbling or roaring with fluctuating intensity. Many times this tinnitus is masked by noises from the surrounding environment. Tinnitus in Meniere's disease can be compressed with a Politzer balloon, it disappears as long as the air column is compressed in the auditory canal. This phenomenon points to a peripheral, therefore cochlear origin of tinnitus [IOJ. The pathophysiological substrate for tinnitus is not known. The Tonndorf model [103J can be used to determine its origin by uncoupling the tectorial membrane from the stereocilia of the outer hair cells. This could also be an explanation for the positive result of the compression test. Interestingly, tinnitus as well as vertigo often disappear when a small hole in the stapedial foot plate is made and a small amount of perilymph is drained. Since the exact etiology of Meniere's disease is not known, the management of tinnitus can only be symptomatic. Although there is no valid general concept for treatment, an overview of the di erent types of therapies was given at the last tinnitus seminars [80, 81J.

Sensation of Pressure and Fullness of the Ear (Aural Fullness) Pressure or fullness of the ear do not belong to the classical Meniere triad, although many patients describe these sensations in the sense of aura before the onset of an attack (74%) [74]. This sensation of pressure can last in a milder form during as well as after the attack. Because pressure receptors have not yet been proven, an anatomical basis for inner ear complaints as an explanation does not exist [47]. Another explanation focuses on the sensory innervation of the dura mater which surrounds the emlulymphatic sac. This hyputhesis has a certain amuunt uf probability since it is known in the course of the disease that inflammatory reactions occur within the endolymphatic sac leading to morphologically persisting changes [83J. However, a satisfying general explanation for this frequently reported symptom is still unknown.

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Special Forms

Lermoyez Syndrome In 1919, M. Lermoyez [57] described a recidiving of vertigo attacks accompanied by improved hearing of the a ected ear: 'Ie vertige, qui fait entendre' (Lermoyez syndrome). Because all signs of Meniere's disease were apparent, these complaints were seen as a special form. It is however rarely seen and its frequency is estimated as only 1% in Meniere patients [92]. Lermoyez himself postulated the cause as a spasm of the labyrinth vessels, resulting in long-lasting hearing loss and tinnitus. The sudden release of the spasm during the attack should lead to both a reduction in hearing loss and vertigo attacks. A clear pathophysiological explanation for Lermoyez syndrome actually does not exist. It is possible that in this unusual form of endolymphatic hydrops, ruptures solely of the sacculus or utricular area are present so that during a vertigo attack a decompression without ruptures in the cochlear areas results in a functional recovery of cochlear hair cells. Results of pathological-anatomical examinations from patients who su ered from Lermoyez syndrome are currently not known. Tumarkin Otolithic Crisis In 1936 the British otologist A. Tumarkin [105] reported on 3 patients who su ered from so-called 'drop attacks'. These are sudden falls in which the patient collapses. They are accompanied by a strong sense of pseudomovement in a vertical direction. 'Drop attacks' occur without warning, without loss of consciousness or relation to movement, yet often lead to injury. Tumarkin crises are typicalJy short, lasting only up to a minute. Complaints of other existing types of vertigo are rare, these appear only towards the final stages of this disease. The other symptoms fulfil the criteria for Meniere's disease. The exact incidence of Tumarkin crisis is not known; Schuknecht [92J estimated it at 10%. Tumarkin [105J himself postulated a vestibular origin for 'drop attacks'. Today it is assumed that due to its typical symptom characteristics, endolymphatic hydrops are localized in the otolith apparatus and not in the semicircular canals. Therefore it is called an otolithic crisis. In a case study of 11 patients with Tumarkin crisis, Owen Black et a1. [72] demonstrated that only with conservative treatment complete recovery was not pOSSible. All patients were finally surgically treated either with labyrinthectomy or neurectomy.

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Imaging Techniques

The value of imaging techniques as a diagnostic tool in Meniere's disease was, until recently, underestimated. Due to its small size, structural changes in the temporal bone could not be detected with conventional methods so that reliable evidence of the disease could not be produced. Only in the past few years have there been attempts by using new high-resolution imaging techniques in detecting the structural changes in the area of the endolymphatic sac typically seen in Meniere's disease. During the 1970s and 1980s a perisaccular reduction of pneumatization was described [114J. With the aid ofa lateral polytomography, a computer-assisted radiography, a hypoplastic endolymphatic duct could be proven in Meniere's patients. The 3-DFT-CISS-MR technique allows the presentation of soft tissue of the endolymphatic sacs in the human temporal bone. The results of a study on 20 patients, in which 23 ears were a ected by Meniere's disease, were compared to 50 healthy normals [2). In 74% of the diseased ears an altered or not visualized endolymphatic duct and sac could be determined. Interestingly, the same pathological findings existed in 79% of nondiseased ears [2J. It is di cult to decide, based on these findings, whether these positive cases concern ears which may later be a ected by Meniere's disease. At the moment, imaging techniques as a diagnostic tool in Meniere's disease are of minor contribution, unless it is used to exclude other diseases (for example acoustic neuroma).

Differential Diagnosis

Vestibular Neuritis Vestibular neuritis presents as an acute reduction in unilateral function of the peripheral vestibular apparatus or of the vestibular nerve, clinically seen as severe systematic vertigo. The etiology is unclear although it has been suggested that an acute circulation disorder at the level of the vestibular apparatus may be a cause. However, since 1981 [89J a viral infection of the vestibular nerve was made probable by pathological examinations. Gradual recovery of vertigo takes place within days as a result of the spontaneous course of compensation mechanisms, however a full recovery is not always seen. Long-term prognosis is good in that the compensation mechanisms are supported by active rehabilitation management [40J. Meniere's disease is usually easy to define from that of vestibular neuritis in that in the latter cochlear symptoms are not present and in the former vertigo complaints have a longer duration.

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Acute Hearing Loss Acute hearing loss is defined, in the closer sense, as a unilateral sudden deafness of the inner ear of unknown cause. The clinical picture presents as a cochlear counterpart to vestibular neuritis. Spontaneous recovery of sudden deafness is shown in 70% of cases [Ill]. Since it cannot be determined at the onset of the disease whether patients will experience a spontaneous remission or not, it must be treated as an urgent case. Treatment is usually polypragmatical among which corticosteriods are used due to the assumed inflammatory pathogenesis of sudden hearing loss and circulatory-promoting agents providing oxygen for the recovery of cochlear hair cells. The acute hearing loss is generally simple to diagnose in that the typical vertiginous symptoms of Meniere's disease are not apparent. Cases which are di cult to determine are those presenting as the onset of Meniere's disease with an acute hearing loss, but can only retrospectively be diagnosed. Loss of Labyrinthine Function (Apoplexia labyrinthi) The acute loss of labyrinthine function, cochlear and vestibular, presenting with vertigo, tinnitus and hearing loss can mimic Meniere's disease initially. The final diagnosis is determined by the varying time course of the symptoms. In contrast to an acute Meniere attack lasting minutes to hours, loss of labyrinthine function can last up to days. The etiology in this syndrome is also unknown and therapy is polypragmatical and symptomatic (see above). Suggested treatment corresponds to that of vestibular neuritis and of acute hearing loss. Benign Paroxysmal Positioning Vertigo (BPPY) BPPV is characterized with brief (seconds) attacks of vertigo without cochlear symptoms, typically evoked by head movements [24). In recent years, findings have suggested that BPPV can be attributed to a canalolithiasis [18, 112). Its pathogenesis, namely the pathological stimulation of sensory cells in the semicircular canal by free-floating otolith particles, explains the course of vertigo. Although BPPV is rotational as in Meniere's disease, its typical varying time characteristics prevent it from being confused with Meniere's disease particularly since cochlear symptoms are never present. Acuustic NeuIUIIla

Acoustic neuromas have the tendency to mimic Meniere's disease due to the various constellation of symptoms. Acoustic neuroma is defined as a schwannoma stemming from the vestibular portion of the eighth cranial nerve in the internal auditory canal. The

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primary damage is therefore done to the vestibular nerve yet rarely leads to vertigo, since the slow progressing lesion is almost synchronously compensated in the vestibular nuclei. Progressive hearing loss or occasional sudden deafness may be a result of an acoustic neuroma in which a lesion of the tumor to the cochlear nerve or compression to the labyrinth artery has been produced. Hearing loss in these cases can recover so that their seizure-like attacks lead to diagnosis of Meniere's disease. A careful neuro-otological examination including caloric test, brainstem evoked response audiometry (BERA) and, if necessary, MRI can determine if an acoustic neuroma exists. Perilymph Fistulas Perilymph fistulas are caused by overpressure to the inner ear compartments, e.g. that experienced when diving or strenuous physical exertion or without any recognizable cause [35, 98]. Apart from the acute sensorineural hearing loss, vertigo and tinnitus may also present making a di erential diagnosis of Meniere's disease often di cult. The temporary characteristics also point to correct diagnosis. Although a pronounced reduction of symptomatology in the initial stages of Meniere's disease can be seen, this is not the case with perilymph fistulas. Final diagnosis can be made with a tympanotomy and control of the windows to the inner ear. In these cases the fistula can be surgically closed. VertebrobasiJar lnsu ciency (VBI) VBI, with short ischemias of the vertebral and basilar arteries, is seen in a sense as a TIA (transient ischemic attacks) or a PRIND (prolonged reversible ischemic neurologic deficit). Vertigo is indeed one of the most frequent symptoms of VBI, however it is never the sale symptom [16J. Based on the vascular supply of the brainstem, in case of an impairment of circulation, symptoms apart from the cochlea-vestibular symptoms must appear. Reduced visual acuity or oscillopsia are the typical ophthalmological symptoms. The risk of mistaking VBI for Meniere's disease is due to its having the same time characteristics. Di erential diagnosis to Meniere's disease can only be made by a thorough neurological examination since there is no current imaging technique available to determine VBI except for complete infarction. Pharmacological Side E ects Numerous medications have side e eets which can either damage the peripheral cochlea-vestibular system or its central part. Of relevance are the ototoxic antibiotics which cause damage to the peripheral sensory epithelium [l1J. Drugs which contain typical agents with central e ects to the vestibular system are nonsteroidal anti-inflammatories as well as anti-epileptics and sed-

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Table 2. Treatment of Menieres disease [data from 1]

Drug therapy Conservative (e.g. betahistine) Destructive (e.g. gentamicin) Surgical therapy Nondestructive Ventilation tube Cochleosacculotomy Saccotomy Destructive Labyrinthectomy Neurectomy of vestibular nerve

atives [17]. In these cases a close chronological relationship exists between intake and onset of symptoms. On the other hand, these unwanted side e ects often last longer than the typical symptoms of a Meniere attack. A complete drug anamnesis would bring prompt clarification.

Treatment

General Remarks Treating Meniere's disease has per se two special problems: on the one hand, an etiologic therapy is excluded due to unknown cause, and on the other, because of its cycliC course with frequent spontaneous remissions, it is di cult to evaluate the e ect of each treatment. Until recently, most of the treatment regimens aimed at influencing endolymphatic hydrops, since it is the only pathological substrate presenting in Meniere's disease, or they were directed at relieving the symptoms, especially vertigo. Recently published studies [e.g. 108] have also brought about new therapeutic perspectives, which now attempt to focus on the suppression of the immunological reactions in the endolymphatic sac. Management can be divided into two large groups: medical and surgical. most being destructive techniques (table 2). Because evaluation of the therapy's e ect is often di cult, guidelines have been developed by the AAO-HNS [1], in order to compare di erent types of therapy for Meniere's disease. They emphasize that a lung uuservatiun periud is needed iII order tu determine the e ects of therapy, since a long symptom - free interval can either be due to the success of treatment or a spontaneous remission (table 3). A general rule for treating Meniere's disease is that prior to a destructive and irreversible surgical procedure, other medical regimens should be tried.

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Table 3. AAO-HNS guidelines for the evaluation of therapy in Meniere's disease

Frequency of vertigo

Functional level scale

Treatment e cacy is assessed using the following formula: XlY numerical value (rounded to the nearest whole number) where X is the average number of definitive spells per month for the 6-month period 18-24 months after therapy and Y is the average number of definitive spells per month for the 6 months before surgery. The resulting value is used to classifY the patient as follows:

1. Dizziness has no e ect on activities at all. 2. Dizziness does not necessitate changes in plans or activities. 3. Dizziness necessitates some changes in plans. 4. Patient is able to engage in essential activities but constant adjustments are required. 5. Patient is unable to work, drive, take care of a family member, or do most active things. Even essential activities are limited. 6. Patient has been disabled for 1 year or longer and receives compensation.

Class Numerical value A B C D E F

0 1-40 41-80 81-120 120

Secondary treatment initiated because of disability from vertigo

The advantage is a gain of time which brings the patient closer to spontaneous remission. Drug Therapy

Numerous studies on medical therapy for Meniere's disease have been published, however none has been able to describe an e ective treatment regimen unanimously accepted so that the discussion can be closed. It has been noticed in meta-analyses that e cacy for vertigo is almost always between 60 and 80% [21, 104J. For this reason a placebo e ect cannot be ruled out. In the acute stage normally lasting no longer than 3 days, however accompanied by severe attacks of vertigo, agents with sedative and antiemetic properties have been empluyed tu diminish the sensatiun uf vertigu, Amung these are antihistamines such as dimenhydrinate, meclizine and diphenhydramine (table 4). Neuroleptics have been successfully used as an acute therapy, especially in cases of severe attacks because they can be applied in parenteral form. Diazepam, a minor tranquilizer, can also be taken in the active stage of a

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Table 4. Drug management of Acute stage Symptomatic

Meni~re's

disease

Dimenhydrinate Dimenhydrinate

150 mg supp. or 62 mg Lv.

'Etiologic' 1st day 2nd day 3rd day

1.000 mg prednisolone 1,000 mg prednisolone 1,000 mg prednisolone

Lv. Lv.

or 100 mg prednisolone 80 mg prednisolone 60 mg prednisolone 40 mg prednisolone 20 mg prednisolone IO mg prednisolone 5 mg prednisolone 2.5 mg prednisolone

orally orally orally orally orally orally orally orally

Chronic stage betahistine

3

12 mg/day

Lv.

2 2 2 150 150 150 150 150 150 150 150

150 mg ranltidine 150 mg ranitidine 150 mg ranitidine mg mg mg mg mg mg mg mg

ranitidine ranitidine ranitidine ranitidine ranitidine ranitidine ranitidine ranitidine

for for for for for for for for

2 2 2 2 2 2 2 2

days days days days days days days days

for months

Meniere attack. These agents however are not suitable for long-term treatment in that they are counteractive to the vestibular compensation processes [41, 85J, and can lead to side e ects in the extrapyramidal motor system. Placebo-controlled double-blind studies only for betahistine and diuretics have been proven e ective long-term treatments [21, 86J. However, these studies - explainable at the time of their publication - have not yet met the criteria of the AAO-HNS gUidelines (table 3). The relatively short observation period of these studies allows for a more critical judgement of the results. Studies have shown the higher e cacy of betahistine to placebo or other substances [63J. However it must be critically noted that the observation period lasted no longer than 3 months and e cacy did not exceed 80% [86] (table 4). Diuretics have been proven to have a dehydrating e ect on endolymphatic hydrops, which is diagnostically applied in the Klockho test [52]. Although placebo-controlled double-blind studies have shown diuretics as an e ective lung-term treatment [53], its use has been limited because uf the accumpanying e ects of changes in electrolyte levels which must be corrected. Convincing evidence for the frequently recommended 'vasoactive agents' does not exist. In addition, it has not been proven that the development of endolymphatic hydrops is of vascular origin.

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In recent years, glucocorticoids have been frequently used in the treatment of Meniere's disease as a direct consequence of the possible immunopathogenesis of endolymphatic hydrops [108] (table 4). However, controlled longterm studies are needed to prove the clinical e ects of this well-established concept. Drug therapy used in treating Meniere's disease has been described as being relatively e ective in reducing the symptoms of vertigo, however hearing loss improvement has only been reported in the early stages. Only for corticosteroids a direct influence on the course of disease can be expected (table 4), although it has not yet been proven. Currently there is no evidence for all other drugs used. Table 4 shows the management actually used in our hospital. Aminoglycoside Therapy Based on the fact that aminoglycosides are ototoxic, Schuknecht [87] introduced this pharmacological principle for therapeutic purposes in the form of a parenteral application. The intention was to destroy the vestibular hair cells so that they could not be irritated by endolymph flow disorders. When it was made clear that the sensory cells of the a ected ear reacted more sensitively to aminoglycoside than those of the healthy cells, a systematic application through intramuscular injection was attempted. This method was ultimately not accepted since the unwanted bilateral e ects as well as damage to the cochlear hair cells could not be avoided. Lange [12, 55] introduced locally applied aminoglycoside treatment. Initially, gentamicin was applied via a small plastic tube by tympanotomy, later via an ear tube which was placed into the middle ear as close as possible to the windows. In individually varying periods, gentamicin di used through the cochlear windows into the inner ear leading to a local toxic e ect. Although di erent types of dosage regimens exists, a common factor in all is that the prescribed dosage is generally dependent on and determined by objective symptoms of functional loss. Prior to each new application, audiograms are performed for early detection of cochlear damage thereby discontinuing therapy and for spontaneous nystagmus indicating functional loss of the end organ. In 90%, satisfactory reduction in vertigo has been published by several authors, cochlear complications have been shown in 15% [65]. In order to classify local toxic e ects of arninoglycoside, histological investigations have shown that vestibular hair cells are not essentially destroyed as previously assumed. Instead the so-called 'dark cells' presenting the secretory epithielium [75] are damaged. Consequently, the result of this therapy is a decrease in endolymph production thereby positively influencing endolymphatic hydrops. In this manner improved hearing can be explained,

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in some cases, observed as a result of an earlier intratympanical application of streptomycin. A reduction of endolymph production leads to a decompression of endolymphatic hydrops resulting in a recovery of cochlear hair cells. The question as to whether streptomycin or gentamicin is more destructive to vestibular hair cells has undoubtedly not been answered. Although streptomycin has been shown in animal experiments to be more destructive to vestibular than cochlear hair cells, the reverse seems to be true in favor of gentamicin in humans [11, 70J. In order to instill ototoxic agents more e ectively into the inner ear, the 'chemical labyrinthectomy' by means of alcohol injection was modified [64], in which streptomycin was locally injected into the perilymphatic space of the lateral semicircular canal [28J. However, a relative high amount of hearing loss is noticeable. Therefore it is doubtful if this method can be expanded. The e cacy of locally applied gentamicin is so high that it reaches the figures of successful surgical destruction [12J. However, since cochlear damage cannot be excluded with certainty, intratympanical application of gentamicin should be performed primarily on patients experiencing severe hearing loss [28J.

Nondestructive Surgery

Transtympanic Ventilation Tubes Since some patients with Meniere's disease reported the disappearance of vertigo with changes in atmospheric pressure, Tumarkin [106] in 1966 attempted to equalize middle ear pressure by inserting a transtympanal tube. His encouraging results were confirmed by a group of British otologists [54] in which they proved in 77% a reduction or temporary relief of vertigo. Contradictory evidence was presented by Hall and Brackmann [38]. Findings in a long-term study by Montandon et al. [66] showed an improvement in vertigo in 82% (23/28), however no e ect on hearing or tinnitus. Independent of this, this observation explains the reduction of vertigo following a simple mastoidectomy [102J since pressure equalization is also gained between middle ear and mastoid. Cochleosacculotomy In 1982, Schuknecht [901 detected in a histopathological study in humans and animals in the later stage of Meniere's disease, following the disappearance of vertigo, persisting fistulas between the endolymphatical space and the peri-

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lymphatical space. Based on these findings he developed the 'cochleosacculotomy', a surgical procedure in which a permanent fistula between the round window and the sacculus is produced. The advantage of this relatively simple procedure is a remarkable reduction in vertigo, the disadvantage is the increased rate of hearing deterioration. Therefore this technique is mainly recommended for older patients in which the more extensive destructive procedure is not an option and in patients with a pre-existing advanced hearing loss [50J. Saccotomy In 1921, G. Portmann [78J performed experiments which led him to the conviction that overpressure in the endolymphatic sac is involved in the development of Meniere's disease. Consequently, in 1927 [79J he performed the first decompression operation of the endolymphatic sac, the saccotomy. Many studies have reported on good results [5, 82], the e cacy being at 80% in reducing vertigo. Nevertheless, this method is not without risk to hearing, the complication rate for hearing loss is assessed at 15%. For many years, surgery of the endolymphatic sac was the method of choice when all other conservative techniques failed in treating the intolerable symptoms of vertigo in Meniere's disease. The success rate however was seen in another light when Thomsen and Bretlau [102J published a 'double-blind study', a controlled study in which they compared the results of a saccotomy with the results of a single mastoidectomy. Based on these data they could not find a significant therapeutic di erence between either surgical techniques so that they classified the saccotomy as a 'sham operation'. This critical opinion led to lively discussions. Arenberg et a1. [5J dismissed the interpretation of a mastoidectomy not having a specific e ect. By recording early evoked potentials during a mastoidectomy which precedes a saccotomy, changes are registered in the electrocochleographic potentials so that a mastoidectomy was seen as active surgery and not as an unspecific procedure. That is not to say that the observations by Bretlau and co-workers are refuted. The positive e ect, which can be achieved only with a mastoidectomy, can be explained as such, that during a mastoidectomy the middle ear and the mastoid are decompressed, leading to the same phenomenon when a transtympanical ventilation tube is used (see above). These simple sac decompression techniques were refined by inserting a small silicun slice keeping the sac upenlunger, and in order tu prevent adhesiuns by valves which only open with higher pressure [4]. Despite the studies by Thomsen and Bretlau, saccotomies continue to be performed and their positive results to be published [82J. It must be critically noted that most of these studies do not have control groups so that the

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benefit of endolymphatic sac surgery cannot be viewed as an approved method. Opposing opinions for a saccotomy in patients with Meniere's disease have been given by honest surgeons who state that locating the sac can be di cult due to a heavy fibrosis to the area (see above). Even if the endolymphatic sac is identified, the lumen is frequently not found and surgery is not applicable.

Destructive Procedures

To free patients from the intolerable symptoms of vertigo, a unilateral dea erentation of the vestibular apparatus either with a labyrinthectomy or a vestibular neurectomy is e ective as a last resort. Labyrinthectomy The purpose of labyrinthectomy is to achieve a unilateral dea erentation of the peripheral receptors by destroying the vestibular sensory apparatus allowing for a central compensation. Labyrinthectomy is primarily performed on patients with existing deafness or severe cochlea dysfunction because of the inevitable loss of cochlear function. The procedure is usually performed by a transtympal approach, is of little discomfort to the patient, requires only a short stationary stay and is cost-e cient [33]. Almost a 100% resolution of vertigo has been reported in the literature [see outlines in 44, 61]. Despite these excellent results, the procedure can be applied only to a limited patient group, due to its related consequence of deafness which must be considered especially in bilateral Meniere's disease. Neurectomy of the Vestibular Nerve The goal of a vestibular neurectomy is also to dea erentate the a ected peripheral vestibular apparatus. This is gained by a selective vestibular nerve section in the inner auditory canal. Both of these mainly used approaches, the suboccipital ( retrosigmoidal [58]) and the transtemporal [37]. have the advantage of maintaining not only the cochlea nerve, but cochlear function as well. The cost and risk of complications is higher, stationary stay longer than with a labyrinthectomy [33], yet all of these can be justified if hearing is preserved. Approximately 90% resolution of vertigo has been reported [see outlines iII 37,58,61,93]. Complications such as cerebral spinal fluid fistulas, facial palsy and meningitis are rarely seen. On the other hand its e cacy is not substantially higher than that of transtympanlcal gentamicin treatment. Therefore neurectomy of the vestibular nerve should only be used when all other therapies have proven

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unsuccessful. A surgeon's ambition should not be a reason for not choosing a so-called simpler method with similar e cacy such as the application of a drainage tube or locally applied gentamicin treatment. References

2

3

6

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

23

AAO-HNS Guidelines for the evaluation of therapy in Meniere's disease. Otolaryngol Head Neck Surg 1995;113:181-185. Albers FWJ, Casselman JW: 3-DFT-magnetic resonance imaging of the inner ear in Meniere's disease; in Filipo R, Barbara M (eds): Proc 3rd Int Symp Men Dis. Amsterdam. Kugler. 1994, pp 43-46. Altermatt HJ, Gebbers JO, Muller C, Arnold W, Laissue JA: Human endolymphatic sac: Evidence fur a role in inner ear immune defence. ORL 1990;82:143-148. Arenberg IK, Stahle J: Unidirectional ear valve implants: A nondestructive alternative to labyrinthectomy in Meniere's disease. Am J Otol 1981;3:9-10. Arenberg IK, Serkowsky M, Mihalco L, Wu CM, Moorhead JF: Danish sham surgery revisited: Intraoperative electrocochleographic evidence that mastoidectomy/drilling actively changes hydrops; in Filipo R, Barbara M (eds): Proc 3rd Int Symp Men Dis. Amsterdam, Kugler, 1994, pp 533-536. Arenberg IK Lemke C, Shambough GE Jr: Viral theory for Meniere's disease and endolymphatic hydrops: Overview and new therapeutic option for viral labyrinthitis. Ann NY Acad Sci 1997;830: 306-312. Arnold W, Altermatt HJ, GebbersJO: Qualitativer Nachweis von Immunglobulinen immenschlichen Saccus endolymphaticus, Laryng Rhinol Otol 1984:63:464-467, Arnold W, Altermatt HJ: The significance of the endolymphatic sac and its possible role in Meniere's disease. 1\ct" Otol"ryngol (Stockh) 1995(suppl 519):36-42. Arnold W, Niedermeyer HP: Herpes simplex virus antibodies in the perilymph of patients with Meniere's disease. Arch Otolarnygol Head Neck Surg 1997;123:53-56. Arnold W: Personal communication. Bagger-Sjoback 0: E ect of streptomycin and gentamicin on the inner ear. Ann NY Acad Sci 1997;830:120-129. Beck C, Schmidt CL: Ten years of experience with intratympanically applied streptomycin (gentamicin) in the therapy of morbus Meniere. Arch OtolaryngoI1978;21:149-152. Bergstrom T, Edstrom S, Tjellstrom A, Vahlne A: Meniere's disease and antibody reactivity to herpes simplex virus type 1 polypeptides. Am J Otolaryngol 1992;13:259-300. Bernstein JM, Shanahasu TC, Scha er FM: The genetics of hearing loss in Meniere's disease and otosclerosis. Acta Otolaryngol (Stockh) 1996;116:666-671. Birgerson L, Gustavson KH, Stahle J: Familiar Meniere's disease: A genetic investigation. Am J Otolaryngol 1987;8:323-326. Brandt T: Vascular vertigo: in Brandt T (ed): Vertigo. Berlin, Springer, 1991. pp 171-188. Brandt T: Drug and vertigo; in Brandt T (ed): Vertigo. Berlin, Springer, 1991, pp 213-228. Brandt T, Stedclin S, Daro RB: Therapy for benign paroxysmal positioning vertigo revisited. Neurology 1994;44:796-800. Brown DH, McClure JA, Down-Zapolski Z: The membrane rupture theory of Meniere's disease: Is it valid? Laryngoscope 1988;98:599-60 I. Cawthorne T, Hewlett AB: Meniere's disease. Proc R Soc Med 1954;47:663-670. Claes J, van de Heyning PH: Medical treatment of Meniere's disease: A review of literature. Acta Otolaryngol (Stockh) 1997(suppI526):37-42. Coletti V, Carner M, Fiorino FG, Sharbati A: Electron microscopic evaluation of the vestibular nerve in patients su ering from Meniere's disease and vascular cross-compression syndrome; in Filipo R, Barbara M (eds): Proc 3rd Int Symp Men Dis. Amsterdam, Kugler, 1994, pp 221-225. Committee on Hearing and Equilibrium: Guidelines for the diagnosis and evaluation of therapy in Meniere's disease. Otolaryngol Head Neck Surg 1995;113:181-185.

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K.-F. Hamann, Department of Otorhinolaryngology, Head and Neck Surgery, Technical University of Munich, Ismaningerstrasse 22, D-S 1675 MLmich (Germany) Tel. 49 89 4140-2370, Fax 49 89 4140-4853

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Buttner U. (cd): Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger. 1999, vol 55, pp 169-194

Benign Paroxysmal Positioning Vertigo Thomas Brandt Department of Neurology, Ludwig-Maximilians University, Munich, Germany

Benign paroxysmal positioning vertigo (BPPV; also known as positional vertigo) was initially defined by Barany in 1921. The term itself was coined by Dix and Hallpike [1952]. Lanska and Remler [1997] 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 which 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 (h-BPPV) or the anterior semicircular canal (a-BPPV). Schuknecht [1969] and Schuknecht and Ruby [1973J 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, however, that the debris float freely within the endolymph of the canal ('canalolithiasis') [Parnes and McClure, 1991; Epley, 1992; Brandt and Steddin, 1992]. The debris - possibly 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 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. Canalolithlasis 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 e cacy of physical therapy [Brandt and Steddin, 1993; Baloh et al., 1993; Brandt et a\., 1994]. In 1980, Brandt and Daro proposed the first e ective 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 a\. introduced a single liberatory maneuver, and Epley promoted a variation in 1992, which Herdman et al. [1993] later modified. If performed properly, all three forms of therapy (Brandt-Daro exercises and Semont and Epley's liberatory maneuvers) are e ective in BPPV patients [Herdman, 1990; Herdman et aI., 1993]. The e cacy of physical therapy makes selective surgical destructions such as transection of the posterior nerve [Gacek, 1978] or nonampullary plugging of the posterior semicircular canal [Pace-Balzan and Rutka, 19911 largely unnecessary. About 5-10% of BPPV patients su er from horizontal canalolithiasis (h-BPPV) [McClure, 1985]. 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 [Steddin and Brandt, 19961. 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. 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 (p. 188) who exhibit positional nystagmus beating toward the uppermost ear for several minutes. Di erential diagnosis includes di erent forms of central vestibular vertigo or nystagmus, vestibular paroxysmia, perilymph fistula, drug or alcohol intoxication, vertebrobasilar ischemia, Meniere's disease, and psychogenic vertigo. The following is largely adopted from a more detailed presentation in the book 'Vertigo: Its Multisensory Syndromes' by Th. Brandt (2nd ed.).

The Clinical Syndrome

Patients with typical BPPV report attacks of rotatory vertigo, postural imbalance, and sometimes nausea preCipitated by the following maneuvers:

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(a) sitting up from a supine position (particularly after awaking in the morning); (b) when first lying down in bed; (c) turning over in bed from one side to the other; (d) extending the neck (head) to look up or get something from above, and (e) flexing the neck (head) when bending over. The occurrence of BPPV in the supine position is very disturbing and makes patients afraid of falling backward, an almost unique complaint. In the upright position, vertigo attacks produced by changes in head position are incapacitating and can be dangerous, for example when a su erer is looking up at the ceiling while standing on a ladder. In such a situation, BPPV can cause a catastrophic fall. Sometimes the 'probable' diagnosis of BPPV is simply based on the typical patient history, because the condition has spontaneously resolved by the time of examination in accordance with its usually benign course. However, there is no absolute reliability of a diagnosis based on history, and some patients may describe their vertigo in a rather atypical way [None, 1995]. Most patients are aware that tilting or rotating of the head toward the right, the left, or in both directions will induce the attacks. Since as a rule the first positioning maneuver triggers the strongest attack of vertigo and the most obvious positioning nystagmus, the first examination of a patient with a history of BPPV should always be a positioning maneuver toward the side of the posterior semicircular canal thought to be a ected. This initial step is all the more important as repeated positioning maneuvers cause fatigue of the induced vertigo and nystagmus, thus making diagnostic evaluations more di cult and uncertain. The following rules have proven sound for examining patients with BPPY: (1) Positioning testing should be done first during the physical examination, and the initial positioning maneuver should be directed toward the ear assumed to be a ected, because vertigo and nystagmus will fatigue during repeated maneuvers. (2) Frenzel's lenses should be used whenever possible, to avoid partial suppression of the positioning nystagmus by fixation. (3) Patients should be instructed before the positioning maneuver to ensure better cooperation. They should also be asked not to shut their eyes when vertigo begins. (4) Vertigo and nystagmus are maximal if the patient is positioned rapidly and the head is abruptly halted at its final position. We usually perform the lateral head-trunk tilt with the patient in a sitting position on a couch (fig. 1). Others prefer the so-called Dix-Hallpike maneuver [Dix-Hallpike, 1952], during which the patient is tilted backward until the head is both turned and hanging (fig. 1). To confirm a suspected canalolithiasis of the posterior semicircular canal of the right labyrinth, the head of the sitting patient is rotated 45° to the left. Then the observer tilts the passive patient quickly to the right side. After a

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Fig 1. Precipitating positioning maneuvers for typical posterior semicircular canal BPPV: lateral head-trunk tilt toward the a ected ear.

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latency of seconds, rotatory vertigo and positioning nystagmus occur in a crescendo/descrescendo mode. The horizontal rotatory nystagmus beats toward the undermost ear. After vertigo and nystagmus cease, the patient is again quickly returned to the initial upright position. In most cases this will result in a less violent and shorter vertigo and nystagmus toward the opposite direction. To confirm a suspected canalolithiasis of the posterior semicircular canal of the left labyrinth, the head of the sitting patient is turned 45° to the right and the tilting maneuver is performed to the left for the first time. Thereafter, one should always check for canalolithiasis of the horizontal semicircular canal (p. 187), since combinations of both conditions may manifest simultaneously in the same patient. Finally, one should check for rare anterior canal BPPV. Observation of the positioning nystagmus provides the definite diagnostic criteria for typical p-BPPV. They include: (1) Latency: vertigo and nystagmus begin 1 s or more after the head is tilted toward the a ected ear and increase in severity to a maximum. (2) Duration less than 40 s: nystagmus gradually reduces after 10-40 s and ultimately abates even when the precipitating head position is maintained. (3) Linear-rotatory nystagmus: the nystagmus is best seen with Frenzel's glasses (for example, lenses 16 dpt), which prevents suppression by fixation. The nystagmus is linear-rotatory, with the fast phase beating toward the undermost ear or upward when gaze is directed to the uppermost ear. (4) Reversal: when the patient returns to the seated position, the vertigo and nystagmus may recur less violently in the opposite direction. (5) FatiguabjJjty: constant repetition of this maneuver will result in everlessening symptoms. These five criteria are crucial for further discussion of the confusing literature on the mechanism of BPPV. They provide the major arguments to prove or disprove any hypothetical explanation of cupulolithiasis or canalolithiasis as the causative factor.

Natural Course The natural history of BPPV is considered benign because it resolves spontaneously within weeks or months in most patients. However, in about 20-30% of the patients the condition persists when untreated, and it recurs in another 30% after variable periods for years. Di erential Diagnosis The most important di erential diagnosis is that of central vestibular positional nystagmus. It should be suspected in all cases of positional nystagmus without concomitant subjective vertigo, although some lesions around the fourth ventricle may also induce very violent vertigo and nausea. Central

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positional nystagmus does not subside with maintenance of the head in the precipitating position, it may not exhibit fatigability with repetitive stimulation, it may change its direction when di erent head positions are assumed, or it may occur as downbeat nystagmus only in the head-hanging position. Frequently, additional neurological (in particular oculomotor) signs point toward a central cause of the symptoms. BPPV must also be di erentiated from positional nystagmus in Meniere's disease, perilymph fistulas, drug andJor alcohol intoxication, neurovascular cross-compression (vestibular paroxysmia), and rare conditions such as WaldenstrOm's macroglobulinemia.

Pathomechanism

Typical posterior canal BPPV is caused by canalolithiasis, a free-floating clot within the endolymph of the posterior canal. There was, however, a longcontinuing controversy in the quite extensive literature, which arose over the questions: Is cupulolithiasis compatible with the clinical features of BPPV? Is canalolithiasis compatible with the clinical features of BPPV?

The Traditional View of Cupulolithiasis The early assumption by Barany [Barany, 1921; Dix and Hallpike, 19521 that the underlying lesion must be situated in the vestibular end-organ and must involve the otolith was later supported by Schuknecht and Ruby [Schuknecht, 1962, 1969; Schuknecht and Ruby, 1973], who postulated a mechanical pathogenesis, which they termed ·cupulolithiasis'. They found basophilic deposits on the cupula of the causative posterior semicircular canal in individual patients who manifested unilateral BPPV prior to death from unrelated disease. These deposits exceeded the size of those found in more than 30% of temporal bones in a control population. They argued that inorganic particles, detached from the otoconiallayer by spontaneous degeneration or head trauma, gravitate to and settle on the cupula of the posterior semicircular canal, which is situated directly inferior to the utricle when the head is upright. The posterior semicircular canal thus serves as a receptacle for the detached sediment. In fact, otoconia are easily dislodged by linear accelerations or centrifuging in animals [Hasegawa, 1933; Igarashi and Nagaba, 1968J. Otoconial debris become displaced in old age [Johnson and Hawkins, 1972] and lodge either in the posterior semicircular canals [Vyslonzil, 1963] or in the cochlea in cochleosaccuJar degeneration [Gussen, 1980J. Moriarty et al. [1992] identified basophilic granular deposits on 22% of the cupulae of 1,038 canals of 566 examined individual postmortem temporal bones. They determined a higher

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B

Fjg 2. A, B Cupulolithiasis: schematic drawing of the cupula in the ampulla of the posterior semicircular canal carrying otoconia! debris. If this were the pathology causing BPPV, then the static lateral head position (B) rather than the positioning maneuver should be the precipitating factor, irrespective of which side the debris lodge on. Clinically, however, typical BPPV is a positioning vertigo, and cupulolithiasis of this type cannot explain aU clinical features. [From Brandt and Steddin, 1993.J

incidence for the posterior than for the horizontal or anterior semicircular canals. Naganuma et al. [1996J found an even higher percentage of basophilic deposits (horizontal canal: 41 %, posterior canal: 37%, anterior canal: 26%), which increased with increasing age. The cupula normally has the same specific gravity as the endolymph and is a transducer of angular acceleration only. When heavily loaded, it should theoretically become sensitive to changes in head position relative to the gravitational vector (buoyancy hypothesis). The buoyancy mechanism is used to explain some forms of positional vertigo/nystagmus which arise after the ingestion of compounds with di ering specific gravities, such as alcohol [Money et a\., 1974], glycerol [Rietz et a\., 1987], or 'heavy water' [Money and Myles, 1974]. The common view was that BPPV simply reflects transformation of the a ected cupula from a transducer of angular acceleration to one of linear acceleration and (abnormal) angular acceleration, secondary to the acquired specific gravity di erential between the cupula and endolymph [Gacek, 1984; Schuknecht, 1969; Rietz et aI., 1987J. Therefore, in cupulolithiasis it should be irrelevant on which side of the cupula the heavy debris become attached (fig. 2). The traditional view of cupulolithiasis and the buoyancy mechanism must be incorrect for several reasons. BPPV is a positioning rather than a positional

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vertigo/nystagmus, because it is induced only by rapid changes in head position, with the paroxysmal nystagmus being compatible with the cupulogram of an ampullofugal stimulation of the posterior semicircular canal. If cupulolithlasis were valid, then an ongoing positional vertigo/nystagmus would be expected, as occurs in positional alcohol nystagmus [Money et aI., 1974]. The mechanism of cupulolithiasis may account for the subtle static (persistent) positional nystagmus, which Baloh et al. [1987] observed in 41 % of their patients with BPPV There was, however, no consistent relation between the side of the lesion and the static positional nystagmus. This lack of directional correspondence makes interpretation di cult. Arguments for CanaJolithiasis There is histological proof that inorganic 'heavy particles' detached from the otoconiallayer (by degeneration or head trauma) gravitate into the posterior semicircular canal. This is moreover supported by large series of patients in whom the common clinical finding indicates that the following conditions figure in the etiology of BPPV: head (labyrinthine) trauma, viral neural labyrinthitis, vertebrobasilar ischemia, postsurgery (ear and general), prolonged bedrest due to unrelated diseases [Gyo, 1988], and aging [Baloh et aI., 1987; Katsarkas and Kirkham, 1978]. A clot formed by specific heavy material floating in the ampullofugal branch of the posterior canal would be compatible with all five clinical criteria mentioned above. The diameter of the semicircular canal (0.32 mm in humans; Curthoys and Oman [1987]) is about one-fifth to one-seventh of the ampulla. A clot approximately this size in diameter would act as a plunger on the endolymph and the cupula, if the slightly turned head is positioned from an upright to a precipitating lateral position (fig. 3) as soon as the angle between the canal's plane and the gravity vector altered. The clot produces pressure or suction in the canal, thereby deflecting the cupula and eliciting a BPPV attack. This mechanism would be compatible [Brandt and Steddin, 1993] with (1) a latency of a few seconds (time needed for the clot-induced flow mechanism to develop by gravitational force); (2) the ine ectiveness of a very slow positioning maneuver (then the clot would slowly gravitate along the undermost wall of the canal without a ecting the cupula); (3) the limited duration of the positioning vertigo/nystagmus (cupula deflection due to elastic restoring force ends when the heavy clot reaches its lowest position in the canal with respect to the earth surface); (4) the fatigability with repetitive provocation (explained by dispersion of single particles from the clot, which decreases the plunger e ect); (5) the reactivation of the vertigo after prolonged bedrest (the result of a new clot being formed by the particles, and (6) the direction of the nystagmus during the positioning maneuvers as explained below.

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A

B

C

Fig 3. 'Canalolithiasis'; schematic representation of a free-floating' heavy clot' of otoconial debris acting like a plunger on endolymph and cupula of the posterior semicircular canal, the proposed mechanism for BPPV. In the normal upright position (A) the debris rest at the base of the cupula without any noticeable e ect. If the head is turned and rapidly positioned to the side in the plane of the posterior semicircular canal. the clot. thanks to its greater specific weight, gravitates downward (B) and, together with endolymph flow, deflects the cupula in an ampullofugal direction. When the clot has gravitated to the lowest curvature of the posterior canal. vertigo and nystagmus subside because the cupula assumes its normal resting position (C). If the patient returns to the seated position, a similar e ect could explain the reversed direction of nystagmus and vertigo (for explanation of fatiguability due to repeated provocation and physical therapy, p. 176). [From Brandt and Steddin 1993.]

Attempts were made earlier to attribute BPPV to floating particles in the semicircular canal [Hall et aI., 1979; Epley, 1980; Pagnini et al., 1989; McClure, 1988]. We believe there are now convincing arguments that canalolithiasis and a clot-induced endolymph flow mechanism are the significant causative factors [Brandt and Steddin, 1993]. Despite ongoing discussions about possible vestibular habituation e ects [Steenerson and Cronin, 1996; Smouha, 1997], canalolithiasis is the only mechanism that explains the success of the highly e ective physical therapy by positioning maneuvers, as proposed by Brandt and Daro [1980], Semont et a1. [1988], Epley [1992], or Lempert et a1. [1996], who demonstrated the e cacy of canal-clearing maneuvers by performing backward rotation of the posterior canal during the use of a flight simulator. As figure 4 shows, we believe that the floating clot of particles can be sluiced down by both of the described positioning maneuvers via the upper ampullofugal branch of the posterior canal into other labyrinthine recesses where they are no longer causative. The mechanism demonstrated in figure 4 coincides with the hitherto unexplained observation [Pace-Balzan and Rutka, 1991; Semont et al., 1988; Hausler and Pampurik, 1989J that after a positioning

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c Fjg 4. Schematic drawing of the clot of otoconial debris dispersed and sluiced by positioning maneuvers from the normal (A) to the challenging (B) position and to the opposite side (C). Depending on the change of the head position relative to the gravitational vector, the clot settles to the lowermost part of the canal, and after transition from position B to C, leaves the canal in order to enter other labyrinthine recesses where it no longer causes vertigo attacks. This scheme demonstrates why physical therapy with positioning maneuvers is e ective when the clot or the debris leave the a ected semicircular canal. The direction of induced nystagmus in C indirectly proves that canalolithiasis rather than cupulolithiasis is the significant mechanism. Only with a free-floating clot is the direction of positioning nystagmus in C the same as in B. [From Brandt and Steddin, 1993.1

maneuver from the position B (with the a ected ear undermost) to C (with the a ected ear uppermost), the induced nystagmus still rotates toward the uppermost ear. Cupulolithiasis predicts an ampullopetal deflection of the cupula, which results in nystagmus toward the undermost ear. The unexpected direction, however, can be easily explained by the clot-induced endolymph flow mechanism, which acts in the same direction in the two di erent positioning maneuvers in figures 4B and C. We interpret the direction of the nystagmus thus induced by the positioning maneuver as indirect proof that canalolithiasis is valid. Free-floating endolymphatic particles were first found intraoperatively during posterior semicircular canal occlusion by Parnes and McClure [1992J.

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In a prospective study on 26 patients undergoing the posterior canal occlusion procedure and 73 patients undergoing labyrinthine surgery for vestibular Schwannoma or labyrinthectomy, particulate matter was observed in 8 of 26 patients with BPPV; no particles were observed in any of the 73 patients [Welling et al., 1997J. The possibility of a combination of canalolithiasis with cupulolithiasis has been demonstrated for h-BPPV [Steddin and Brandt, 1996]. There are positions of the head in which the free-floating clot should settle on the cupula, and subsequently after initial canalolithiasis, cupulolithiasis should occur, according to the buoyancy mechanism. Do some of the patients with intractable BPPV have precipitate settled on the cupula? If this is the case, the nystagmus pattern should be di erent from that in treatable cases. On the basis of our observations and the assumption of a free-floating heavy clot (leading to canalolithiasis and cupulolithiasis), head-positioning maneuvers were described in which unilateral BPPV mimics bilateral BPPV [Steddin and Brandt, 1994J. Suzuki et a!. [1996J described a functional animal model of BPPV using an isolated frog semicircular canal. When otoconia were placed on the cupular surface to mimic cupulolithiasis, ampullary nerve action potential instantaneously responded; when otoconia were dropped into the canal to mimic canalolithiasis, action potentials responded with the otoconial flow after a latent period. Etiology Particles have been frequently found in the membranous labyrinth of symptomatic and asymptomatic patients. These particles seem to be identical to otoconia or otoconial (calcite) fragments [Cussen, 1974; Kveton and Kashgarian, 1994J. The particular matter from within the membranous posterior semicircular canal from a patient at the time of canal occlusion for intractable BPPV was examined by scanning electron microscopy. It appeared to be morphologically consistent with degenerated otoconia [Welling et a!., 1997]. However, there is still some uncertainty about the origin of these deposits, and it seems likely that more than one possible explanation is needed to account for their existence [Moriarty et a!., 1992J. Large series of patients [Katsarkas and Kirkham, 1978; Baloh et a!., 1987] provided support for the common clinical finding that the following playa role in the etiology of BPPY: head (labyrinthine) trauma, vestibular neuritis, vertebrobasilar ischemia, postsurgery (ear and general), prolonged bedrest due to unrelated diseases, and most often 'idiopathic' conditions (e.g., aging). Single case descriptions include postoperative bedrest [Cyo, 1988] or neurosurgical removal of an osteoma using hammer and chisel [Andaz et aI., 1993J. In the

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early stages, BPPV is usually experienced on awaking in the morning rather than on first lying down. In the series of 240 patients described by Baloh et al. [1987J, the origin was idiopathic in about half of the cases. In the remainder the most commonly identified causes were head trauma (17%) and vestibular neuritis (15%). When patients present with post-traumatic BPPV [Gordon, 1954; Barber, 1964]. it is sometimes di cult to determine retrospectively whether the trauma caused the vertigo or vice versa. In less than 10% of patients, BPPV is bilateral (mostly asymmetrical); this is particularly more frequent in posttraumatic cases [Longridge and Barber, 1978J. We found that 12% of a total of 104 patients with unilateral BPPV had su ered from vestibular neuritis days or years previously [Bochele and Brandt, 1988]. The relatively frequent occurrence of BPPV following vestibular neuritis was first attributed to ischemia of the anterior vestibular artery [Lindsay and Hemenway, 1956]. but it is more likely to be due to viral inflammation at the site of the vestibular nerve (see Vestibular Neuritis, p. 111). Vestibular neuritis is a partial rather than complete unilateral vestibular paresis [Bochele and Brandt, 1988]. since the resulting BPPV requires that the function of the posterior canal be preserved. In a retrospective population-based study in Minnesota, the age- and sexadjusted incidence of BPPV was 64/100,000 population per year [Froehling et aI., 1991J. Incidence increased by 38% with each decade of life. From epidemiological surveys, the incidence of BPPV in Japan was estimated to be between 11 and 17/100,000 population [Mizukoshi et aI., 19881. In a retrospective study of 806 patients 70 years of age or older who complained of dizziness, 41 % had a history strongly suggestive of BPPV [Bloom and Katsarkas, 1989J. The age of onset of BPPV ranges from adolescence to old age, and in the idiopathic group exhibits a peak incidence in the sixth and seventh decades, but onset tends to be earlier on the average in symptomatic forms of BPPV. In the idiopathic group, females exceed males by 2: 1 [Katsarkas and Kirkham, 1978; Baloh et aI., 1987]. whereas the sexes are about equally distributed in the post-traumatic and postvestibular neuritis forms.

Management Positional Exercises and Liberatory Maneuvers The positional exercises proposed by Brandt and Daro in 1980 were the first e ective physical therapy (fig. 5). The exercises were a sequence of rapid lateral head/trunk tilts, repeated serially to promote dispersion of the debris toward the utricular cavity. We instructed the patients to sit; to then move rapidly into the challenging position to induce the correct plane-specific stimulation of the posterior semicircular canal; to remain in the position until the

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Fig 5. Positional exercises for e ective physical therapy for BPPV as proposed by Brandt and Daro in 1980. Patients are instructed to sit and then to move rapidly into the challenging position, to remain in the position for at least 30 s, and then to sit up for 30 s before assuming the opposite head-down position for 30 s. These exercises are repeated serially 5-10 times a day.

evoked vertigo subsided, or for at least 30 s, and then to sit up for 30 s before assuming the opposite head-down position for an additional 30 s. Troost and Patton [1992] reviewed and diagrammed this exercise protocol. The Semont and Epley liberatory maneuvers require only a single sequence, making them preferable to the multiple repetitions over many days required by the Brandt-Daro exercises. With canalolithiasis as the established mechanism of BPPV, we can now explain the e cacy of the therapies according to anatomic and physical principles. Figure 6 illustrates the Semont maneuver in a patient with typical (posterior canal) left-sided BPPV The clot causes no deflection of the cupula in the upright position. When the patient is quickly tilted toward the a ected left

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Fig 6. 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 resul ting 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 45° to the una ected ear. The clot, which is heavier than endolymph, settles at the base of the left posterior semicircular canal. 2The patient is tilted approximately 105 0 toward the left (a ected) 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 3 min. 3The patient is turned approximately 195 0 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 3 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; UT utricular cavity; RE right eye, and LE left eye. [From Brandt et aI., 1994.1

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ear with a 45° head rotation to the right (moving the left posterior canal to a plane corresponding to the plane of the head tilt), the clot gravitates toward the lower part of the canal, causing the cupula to deflect downward (ampullofugal), and triggering a typical BPPV attack. These events explain the latency of a few seconds (the time needed for the clot-induced endolymph flow to develop by gravitational force), the ine ectiveness of a very slow positioning movement (the clot would then slowly gravitate along the undermost wall of the canal without plugging the canal and deflecting the cupula) , and the short duration of the positional vertigo/nystagmus (the cupula deflection ends when the clot reaches its lowest position in the canal) [Brandt and Steddin, 1993]. If the patient is swung toward the opposite right side with the nose down, the clot will gravitate downward, causing stimulation of the posterior canal of the a ected left ear (now uppermost). If no vertigo and nystagmus are elicited, we gently shake the patient's head in this position; this sometimes seems to facilitate settlement of the clot. The patient is then slowly moved to the upright position; the clot will gravitate downward through the common crus of the posterior and anterior canals and enter the utricular cavity, where it becomes harmless. We share the experience of others [Serafini et a!., 1996J that complete recovery after a single maneuver is achieved in about 50-70% of cases. Semont et a!. [1988] recommended having the patient maintain the upright position for 48 h following the liberation, but we have not found this to be necessary. Figure 7 illustrates the Epley maneuver [Epley, 1992J as modified by Herdman et a!. [1993J and Harvey et a!. [1994J in a patient with typical (posterior canal) left-sided BPPV The clot causes no deflection of the cupula in the upright position with the head turned horizontally 45° to the a ected ear. When the patient is qUickly tilted backward into a slight head-hanging position, the clot gravitates downward in the posterior canal, deflecting the cupula downward and inducing a BPPV attack. Rotation of the head and trunk toward the una ected right ear causes further movement of the clot downward (ampullofugal) toward the exit of the canal, resulting in positioning vertigo and nystagmus toward the a ected (now uppermost) ear. The final uprighting of the patient causes the clot to enter the utricular cavity, and it becomes harmless. Li [1995J found that the success rate improved if the procedure is combined with mastoid vibration; this corresponds to our attempts to promote 'canal-clearing' by additional head shaking. In our opinion, the frequently used term 'canalith repositioning maneuver' [Epley, 1992] is incorrect, since it is unlikely that the clot is 'repositioned' to its original location. Following e ective physical liberation, approximately 50% of patients [BaJoh et a!., 1987J will experience a recurrence of attacks; 10-20% occur in the first 2 weeks [Herdman et a!., 1993J. The recurrences may be due to re-

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5 RE

LE

FIg 7. Schematic drawing of modified Epley liberatory maneuver. Patient characteristics and abbreviations as in figure 6 (Cup cupula). I In the sitting position, the head is turned horizontaUy 45° to the a ected (left) ear. 2The patient is tilted approximately 105° backward into a slight head-hanging position, causing the clot to move in the canal, deflecting the cupula downward, and inducing the BPPV attack. The patient remains in this position for 3 min. 3a The head is turned 90° to the una ected ear, now undermost, and 3b the head and trunk continue turning another 90° to the right, causing the clot to move toward the exit of the canal. The patient remains in this position for 3 min. The positioning nystagmus beating toward the a ected (uppermost) ear in positions 3a and 3b indicates e ective therapy. 5 The patient is moved to the sitting position. [From Brandt et aI., 1994.1 Brandt

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entry of the debris into the posterior canal from the utricular cavity and should be treated with the same maneuver that induced resolution of the initial episode. The process illustrated in figures 6 and 7 explains the seemingly paradoxic observation [Brandt and Steddin, 1993; Semont et a\., 1988; Pace-Balzan and Rutka, 1991; Hausler and Pampurik 1989J that the finalliberatory positioning with the a ected ear uppermost (fig. 6, panel 3; fig. 7, panel 3b) induces nystagmus that beats toward that ear. As described above, cupulolithiasis predicts an ampullopetal deflection of the cupula that would cause nystagmus to beat toward the undermost ear, whereas in canalolithiasis, the clot-induced endolymphatic flow causes ampullafugal deflection of the cupula and nystagmus beating to the uppermost ear. Moreover, the upward direction of the nystagmus induced by the final positionings is a clinically relevant observation in that it provides reasonable certainty that the clot has exited the canal (or will so exit in the modified Epley maneuver) and the patient will be free of symptoms ('liberated') . If the nystagmus does not beat upward toward the a ected ear, the clot is probably still inside the canal; if the nystagmus beats downward toward the una ected ear, the clot must have moved toward the cupula, causing an ampullopetal deflection. In either situation, the procedure should be repeated. If the nystagmus fails to beat upward following the second procedure and the BPPV persists, we schedule a return visit for the same maneuver. If the second session fails, we try a di erent Iiberatory maneuver (Le., modified Epley, if we first used Semont, or vice versa). If both Iiberatory maneuvers fail, we prescribe BrandtDaro exercises. A possible complication of liberatory maneuvers is that the clot leaves the posterior canal but instead of staying in the utricular cavity enters the anterior (via common crus) or the horizontal canal. Thus, p-BPPV may convert to h- or a-BPPV This occurred in 5 of 85 patients originally with typical pBPPV (horizontal canal: 3, anterior canal: 2) after they had undergone liberatory maneuvers [Herdman and Tusa, 1996]. 'Canalithjam' is another speculative description of hitherto unexplained transient phenomena that rarely occur during physical treatment [Epley, 1995]: 'An interesting phenomenon that I have occasionally observed while undertaking the canalith repositioning procedure is a sudden conversion of transient nystagmus to a rapid form that persists irrespective of head position. Simultaneously the patient usually complains of intense vertigo. I believe the mechanism to be a jamming of the canaliths when migrating from a wider to a narrower segment (Le., from ampulla to canal or at the bifurcation of the common crus). For treatment the crus is repositioned (inverted) and vibration is applied. Gravity backs dense debris out of the jam.'

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In conclusion, there are three highly e ective therapies for the common posterior canal BPPV The Semont and modified Epley liberatory maneuvers are easily performed by a physician or trained therapist, and the instructions for home use of the Brandt-Daro exercises are simple. With both liberatory maneuvers, nystagmus beating toward the uppermost a ected ear confidently predicts therapeutic success. Surgjcal Procedures In those rare patients who do not respond even to appropriate and prolonged physical therapy (1) surgical plugging of the posterior semicircular canal via a transmastoid approach or (2) surgical transection of the posterior ampullary nerve via a middle ear approach can be considered. In our experience with more than 1,000 patients with typical BPPV, however, only a few individual patients did not respond to physical therapy, and they ultimately required selective surgical transection or canal plugging. We believe that an indication for surgical intervention is still too frequently complied with before the possibilities of physical therapy are completely exhausted. This view is shared by Epley [1995], who has invented his own e ective liberatory procedure. He believes that the disability ensuing from multiple, unpredictable recurrences is over the long term a more common indication for surgery.

Singular Neurectomy Transection of the posterior ampullary nerve provides relief of vertigo; it is, however, not easy to locate surgically the relevant semicircular canal [Leuwer and Westhoven, 1996], and sensorineural hearing loss is a possible complication among several others [Gacek, 1978, 1984; Epley, 1980]. In his series of 137 patients, Gacek [1995J found complete relief of vertigo in 94% with sensorineural hearing loss in 3%.

Plugging of the Posterior Semicircular Canal Parnes and McClure [1990, 1991] first described transmastoid posterior semicircular canal occlusion with complete relief ofBPPV and preserved lateral semicircular canal function as a simpler and safer alternative to singular neurectomy. Others have confirmed the success of fenestration and occlusion of the posterior canal [Pace-Balzan and Rutka, 1991; Hawthorne and ElNaggar, 1994J. Possible complications are surgical labyrinthitis with reversible

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ataxia and sensorineural hearing loss, which also mostly recovers, or inadvertent plugging of neighboring (e.g., horizontal) semicircular canals. Arai et al. [1989J observed direction-changing positional nystagmus that continued for several months after vertical canal plugging in monkeys. Modifications of the procedure using laser techniques have also been reported [Anthony, 1991, 1993; Kartusch and Sargent, 1995; Nomura et aI., 1995], but convincing proof of their superiority is lacking. It should be noted here that in 1950, Vogel was the first not only to speculate that endolymph flow could be the cause of BPPV attacks, but also to propose the plugging of semicircular canals as a possible treatment.

Horizontal Semicircular Canal BPPV (h-BPPV)

The first cases of h-BPPV were described by McClure [1985J. Later, Pagnini et ai. [1989) and Baloh et al. [1993J presented more detailed clinical descriptions of this condition. Now h-BPPV accounts for about 10-20% of all patients presenting with BPPV It may be combined with p-BPPV of the same or the contralateral ear. Transitions between h-BPPV and p-BPPV are also possible, particularly as a result of therapeutic positioning maneuvers. Whereas typical h-BPPV is caused by canalolithiasis, atypical h-BPPV may occur with ageotropic positioning nystagmus caused by cupulolithiasis. The etiological factors are the same as in p-BPPV Patients do not report experiencing episodic vertigo when getting in or out of bed, but when rolling the head from side to side while supine. Consequently, positioning testing of BPPV patients should include the sitting-to-lateral head positioning maneuver for p-BPPV and the supine-to-lateral head rotation maneuver for h-BPPV (fig. 8). The most e ective physical therapy seems to be a forced prolonged bedrest, during which the a ected ear remains uppermost. Relapses of h-BPPV seem to occur more frequently than relapses of p-BPPV The Clinical Syndrome The clinical characteristics of the horizontal semicircular canal variant ofBPPV are easy to distinguish from those of posterior canal BPPV [McClure, 1985; Pagnini et aI., 1989; Baloh et aI., 1993). The diagnosis of h-BPPV is based on the following features [Strupp et aI., 1995J: (1) The patient has a history of brief episodes of vertigo, usually induced by rolling the head from side to side while supine. (2) Positioning testing reveals a linear horizontal nystagmus toward the undermost ear (geotropic) when the head of the supine patient is rapidly turned from side to side around the longitudinal z-axis (barrel roll). (3) Horizontal positioning nystagmus with the head turned to either side

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Fjg 8. Precipitating positioning maneuvers for horizontal sernicircular canal SPPV: the head of the supine patient is rapidly turned from side to side around the longitudinal z-axis (barrel roll).

beats stronger toward the a ected ear (fig. 9); when tills position is maintained, nystagmus often reverses its direction. (4) Positioning nystagmus in h-BPPV exhibits short latencies ( 5 s) and lasts longer (20-60 s) than in p-BPPY. (5) h-BPPV rarely fatigues with repetitive positioning maneuvers. (6) About one-third of the patients show moderate, horizontal semicircular paresis during caloric irrigation of the a ected ear. (7) Positioning vertigo attacks are often more severe than in p-BPPV and more frequently associated with nausea. As distinct from p-BPPV, attacks are not elicited by the patient getting in or out of bed. bending over, or extending the neck. However, some patients report brief episodes of vertigo when turning their head while erect [Baloh et aI., 1993J.

Atypical h-BPPV with Apogeotropic Positional Nystagmus Atypical cases of h-BPPV have been described in which the positional rather than positioning nystagmus beats toward the uppermost ear [Agus et aI., 1995; Baloh et al., 1995; Nuti et aI., 1996J. They have been identified as horizontal canal 'cupulolithiasis' as distinct from typical 'canalolithiasis' [Baloh et a1.. 1995; Steddin and Brandt. 1996]. In these exceptional patients. episodic vertigo and nystagmus can be termed positional, since they depend on the head position relative to gravity rather than on the positioning maneuver.

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Fig 9. h-BPPV of the right ear. Schematic drawing of the right horizontal canal membranous duct illustrating the mechanism of canalolithiasis in di erent head positions while supine. Rotation of the head of the patient around the longitudinal z-axis from (A) the supine (nose up) to the right lateral, (B) right lateral to left lateraL and (C) left lateral to right lateral positions while recumbent. Lower part shows the induced horizontal eye movements, which were most intense with ampullopetal stimuli (B versus C) and with maximal rotation angles of the head (A versus C). The maximum slow-phase velocity (mean SO of n number of positioning maneuvers) was 54.6 13.6°/s (n 3) in A, 17.4 1O.4°/s (n 7) in B, and 176.2 13.00 /s (n 9) in C. [From Strupp et aI., 1995.[

Vertigo and nystagmus may be more or less severe than in canalolithiasis. The following are the typical di erential diagnostic criteria [Baloh et aI., 1995; Steddin and Brandt, 1996J: (1) the direction of positional nystagmus is toward the uppermost ear (apogeotropic); (2) nystagmus may last for minutes when the precipitating position is maintained, and (3) nystagmus depends only on the assumed head position rather than the net angle of head rotation. Thus, positional nystagmus beating toward the uppermost ear is not a pathognomonic sign of central vestibular disturbance. However, it can indicate occasional cupulolithiasis of the horizontal semicircular canal. EUoJogy and Pathomechanism

The etiology of h-BPPV is the same as that of p-BPPV [Baloh et aI., 1993; De la Meilleure et al., 1996J. ltis 'idiopathic' in most cases, posttraumatic

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in about 20%, or the result of physical liberatory maneuvers for treating pBPPV (transition from p-BPPV to h-BPPV), general or temporal bone surgery, or prolonged bedrest. In an attempt to explain the clinical features of h-BPPV, McClure [1985] proposed canalolithiasis as the underlying mechanism, a theory that was backed by Baloh et ai. [1993J. This concept is strongly supported by the intensity of the positioning nystagmus: it is maximal when a patient with hBPPV of the right horizontal semicircular canal turns his head about the longitudinal z-axis from the left lateral to the right lateral position while supine, and it is much slower when he turns his head to the right lateral position while in a supine position (nose up) (fig. 9) [Strupp et aI., 1995J. The fact that this di erence in intensity of nystagmus depends on the initial head position and direction of head rotation indirectly proves that the clot moves freely (to and fro) within the segment of the horizontal semicircular canal diametrically opposite the ampulla. Canalolithiasis is compatible with all clinical features of typical h-BPPY.

Management Several features of h-BPPV remain unclear and are still a subject of speculation. For instance, why does canalolithiasis of the horizontal semicircular canal occur despite the fact that debris leave the canal on a simple head or body tilt from one side to the other, as is often performed while lying in bed? We suspect that the following two conditions must be fulfilled for the debris to remain in the canal [Steddin and Brandt. 1996]: (1) The diameter of the congealed debris must be greater than that of the bottleneck-like narrowing of the distal branch of the canal [Curthoys and Oman, 1987J. (2) The configuration of the debris, which congeal in the canal, must be so stable that the clot does not break into pieces small enough to pass the bottleneck. If the fatigability of symptoms on repetitive testing is explained by transient dissolving of the debris, then nonfatigability, which is frequently seen in h-BPPV, may prove the above assumption. Consequently, as long as there is no fatigue of vertigo and nystagmus in h-BPPV, maneuvers intended to sluice the debris out of the canal should have minor success. In fact, the liberatory maneuvers that Lempert [Lempert. 1994; Lempert and Tiel-Wilck, 1996] and Baloh [1994] proposed were each based on only 2 patients. Lempert [1994] described a single 270 0 'barbecue rotation' toward the una ected side, which was performed in rapid steps of 90 at 30-s intervals. Baloh [1994J suggested a 360 0 rotation around the yaw axis in four quick steps of 90 0 with the initial motion toward the healthy side; each position was held for about 1 min. Vannucchi et ai. [1997] compared the therapeutic results obtained by maintaining a prolonged position on the healthy side (35 patients) with repeti0

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tive head shaking in a supine position (24 patients) and no therapy (15 patients). More than 90% of the patients treated with prolonged position recovered within 3 days, although 6 of 35 patients subsequently developed p-BPPV (which responded successfully to repositioning maneuvers). The rationale was obviously that the 'heavy particles' in the nonampullary arm of the horizontal canal gradually moved out when the patient maintained a prolonged position on the side of the nona ected ear. This maneuver was not e ective if performed only for a duration of 10-20 min; it was intended to be maintained for up to 12 h. In those who failed to respond, the Brandt-Daro exercises [Brandt and Daro ,1980) were performed and within a matter of days led to full recovery. This agrees with the report of Baloh et a1. [1993) and our own experience with such patients. Thus, for the time being, we propose that prolonged bedrest with the head turned toward the una ected ear [Vannucchi et aI., 1997] be maintained for up to 12 h. If this is still unsuccessful after 2 days, we advise the patients to perform the Brandt-Daro exercises (fig. 5). Both physical therapies can be performed at home and do not require the presence of a physical therapist.

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Kartusch JM, Sargent EvV: Posterior semicircular canal occulusion for benign paroxysmal positional vertigo-C0 2 laser-assisted technique: Preliminary results. Laryngoscope 1995; 105:268-273. Katsarkas A, Kirkham Th: Paroxysmal positional vertigo as a complication of postoperative bedrest. Laryngoscope 1978;98:332-333. Kveton JF, Kashgarian M: Particulate matter within the membranous labyrinth: Pathologic or normal? Am J OtoI1994;15:173-176. Lanska OJ. Remler B: Benign paroxysmal positioning vertigo: Classic descriptions, origins of the provocative positioning technique, and conceptual developments. Neurology 1997;48: 1167-1177. Lempert T: Horizontal benign positional vertigo (letter). Neurology 1994;44:2213-2214. Lempert T, Tiel-Wilck K: A positional maneuver for treatment of horizontal-canal benign positional vertigo. Laryngoscope 1996; 106:476-478. Lempert T, Wolsley C, Davies R, Gresty MA, Bronstein AM: Curing benign positional vertigo in a 3D night simulator. Lancet 1996;347:1192. Leuwer RM, Westhofen M: Surgical anatomy of the singular nerve, Acta Otolaryngol (Stockh) 1996; 116:576-580. Li JC: Mastoid oscillation: A critical factor for success in the canalith repositioning procedure. Otolaryngol Head Neck Surg 1995; 112:670-675. Lindsay JR, Hemenway vVG: Postural vertigo due to unilateral sudden partial loss of vestibular function. Ann Otol Rhinal Laryngol 1956;65:692-708. Langridge NS, Barber HO: Bilateral paroxysmal positioning nystagmus. Can J Otol 1978;7:395-400. McClure JA: Horizontal canal BPPY. J Otolaryngol 1985;14:30-35. McClure JA: Functional basis fOr horizontal canal BPPV; in Barber HO, Sharpe JA (eds): Vestibular Disorders. Chicago, Year Book Medical. 1988, pp 233-238. tVlizukoshi K, Watanabe Y, Shojaku H, Okubo J, Watanabe l: Epidemiological studies on benign paroxysmal positional vertigo in Japan. Acta Otolaryngol Suppl (Stockh) 1988;447:67-72. Money KE, Myles WS: Heavy water nystagmus and e ects of alcohol. Nature 1974;247:404-405. Money KE, Myles WS, Ho ert BM: The mechanism of positional alcohol nystagmus. Can J Otolaryngol 1974;3:302-313. Moriarty B, Rutka J, Hawke M: The incidence and distribution of cupular deposits in the labyrinth. Laryngoscope 1992;102:56-59. Naganuma H, Kohut RI, Tokumasu K, Okamoto M, Fujino A, Arai M: Basophilic deposits on the cupula: Preliminary findings describing the problems involved in studies regarding the incidence of basophilic deposits in the cupula, Acta Otolaryngol Suppl (Stockh) 1996;524:9-15, Nomura Y, Ooki S, Kukita N, Young YH: Laser labyrinthectomy, Acta Otolaryngol (Stockh) 1995;115: 158-161. Norn~ ME: Reliability of examination data in the diagnosis of benign paroxysmal positional vertigo. Am J OtoI1995;16:806-81O. Nuti 0, Vannucchi P, Pagnini P: Benign paroxysmal positional vertigo of the horizontal canal: A form of canalolithiasis with variable clinical features. J Vestib Res 1996;6:173-184. Pace-Balzan A, Rutka JA: Non-ampullary plugging of the posterior semicircular canal for benign paroxysmal positional vertigo, J Laryngol Olol 1991; 105:901-906, Pagnini P, Nuti D, Vannucchi P: Benign paroxysmal vertigo of the horizontal canal. ORL 1989;51: 161-170. Parnes LS, McClure JA: Posterior semicircular canal occlusion for intractable benign paroxysmal positional vertigo. Ann Otol Rhinal Laryngol 1990;99:330-334. Parnes LS, McClure JA: Posterior semicircular canal occlusion in the normal hearing ear. Otolaryngol Head Neck Surg 1991;104:52-57. Parnes LS, McClure JA: Free-floating endolymph particles. Laryngoscope 1992;102:988-992. Rietz R, Troia BW, Yonkers AJ, Norris TW: Glycerol-induced positional nystagmus in human beings. Otolaryngol Head Neck Surg 1987;97:282-287. Schuknecht HF: Positional vertigo. Clinical and experimental observations. Trans Am Acad Ophthal Otolaryngol 1962;66:319-331. Schuknecht J-lF: Cupulolithiasis. Arch Otolaryngol 1969;90:765-778.

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Smouha EE: Time course of recovery after Epley maneuvers for benign paroxysmal positional vertigo. Laryngoscope 1997;107:187-191. Steddin S, Brandt Th: Unilateral mimicking biJateral benign paroxysmal positioning vertigo. Arch Otolaryngol Head Neck Surg 1994; 120: 1339-1341. Steddin S, Brandt T: Horizontal canal benign paroxysmal positioning vertigo (h-BPPV): Transition of canalolithiasis to cupulolithiasis, Ann Neurol 1996;40:918-922, Steenerson RL, Cronin CW: Comparison of the canalith repositioning procedure and vestibular habituation training in forty patients with benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 1996;114:61-64. Strupp M, Brandt Th, Steddin S: Horizontal canal benign paroxysmal positioning vertigo: Reversible ipsilateral caloric hypoexcitability caused by canalolithiasis? Neurology 1995;45:2072-2076. Suzuki M, Kadir A Hayashi N, Takamoto M: Functional model of benign paroxysmal positional vertigo using an isolated frog semicircular canaL J Vest Res 1996;6: 121-125. Troost BT, Patton JM: Exercise therapy for positional vertigo. Neurology 1992;42:1441-1444. Vannucchi P, ciaonnoni B, Pagnini P: Treatment of horizontal semicircular canal benign paroxysmal positional vertigo. J Vestib Res 1997;7:1-6. Vogel K: Zur Entstehung des peripheren Lagenystagmus. Arch OhrenheiJkd 1950; 157:89-98. VyslonziJ E: Ober eine umschriebene Ansammlung von Otokonien in hinteren hautigen Bogengangen, Monatschr Ohrenheilkd 1963;97:63. Welling DB, Parnes LS, O'Brien B, Bakaletz LO, Brackman DE, Hinojosa R: Particulate matter in the posterior semicircular canaL Laryngoscope 1997;107:90-94.

Prof Dr. med. Thomas Brandt, Direktor der Neurologischen Universitats-Klinik, Klinikum crosshadern, Marchioninistrasse 15, 0-81377 Munchen (Germany) Tel. 49 89 70 95 25 70/1, Fax 49 89 70 95 88 83

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Btittner U. (ed): Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger, 1999, vol 55, pp 195-227

Drug Therapy of Nystagmus and Saccadic Intrusions U Battner, L. Fuhry Neurologische Klinik, Klinikum Grosshadern der Ludwig-Maximilians-Universitat, MOnchen, Deutschland

Nystagmus, consisting of a slow compensatory and a fast resetting phase, is the normal oculomotor response to extended head movements during the vestibulo-ocular reflex (VOR) and to large moving visual fields during optokinetic nystagmus (OKN) , This nystagmus helps to stabilize the visual environment, However, in pathological nystagmus with both the head and visual surround stationary, the eye movements cause movements to the visual surround on the retina, called oscillopsia, which are the most frequent of complaints from the a ected patient. In addition, these movements also decrease visual acuity, which is the other reason for treating these pathological eye movements [95J, Fortunately, the movements of the visual surround on the retina during pathological nystagmus are not as strongly perceived as predicted by the nystagmus velocity. Motion perception during long-lasting visual stimuli or continuous nystagmus is considerably lower than the actual velocity of the visual stimuli or the nystagmus, which can both be demonstrated during physiological and pathological conditions [19J, With congenital [52J or downbeat nystagmus the threshold for visual motion detection is Significantly higher than in normal subjects, Also patients with high velocity congenital nystagmus only seldom complain about oscillopsia [50]. This reduction of motion perception has been attributed to a central adaptation mechanism [19], aimed at suppressing unwanted visual motion. Thus, the central nervous system can partly suppress the e ects of self-generated visual motion. However, this e ect is only su cient up to a certain level. If nystagmus velocity can be reduced below SOls, then oscillopsia is eliminated and vision is improved [98J. With higher velocities the e ects can still be very disturbing.

There are several disorders which can lead to oscillopsia. They usually occur with a peripheral vestibular disorder, where nystagmus and oscillopsia are combined with vertigo. In contrast to oscillopsia, vertigo also persists with the eyes closed. [Peripheral Vestibular Disorders and Their Management, see chapter by Strupp and Brandt]. Central causes of oscillopsia are jerk nystagmus as in downbeat, upbeat, torsional, horizontal and periodic alternating nystagmus. Other forms of nystagmus, such as congenital and acquired pendular, also lead to oscillopsia. In general, not only nystagmus, but all pathological, frequently occurring eye movements lead to oscillopsia. This includes ocular flutter and opsoclonus, ocular myoclonus and superior oblique myokymia. The latter eye movements have no relation to a vestibular disorder, i.e. opsoclonus and ocular flutter are considered as a saccadic disorder [26]. Thus, the symptoms (oscillopsia, reduced visual acuity) to be cured are very similar in all conditions, although the causes are very di erent. This does not only apply to the di erences between a saccadic disorder and jerk nystagmus. Even jerk nystagmus can have di erent causes, which often are not related to a central vestibular disorder. For spontaneous nystagmus, which is nystagmus while looking straight ahead, several di erent pathomechanisms can be distinguished [24]. Usually spontaneous nystagmus is attributed to a peripheral or central vestibular imbalance. With head movements under normal conditions the vestibular nerve activity increases on one side and decreases on the other side (vestibular imbalance). Accordingly, lesions of peripheral or central vestibular structures also lead to nystagmus. The main feature of this type of nystagmus is a constant velocity slow phase [32, 139]. In contrast, nystagmus due to a neural integrator deficit is characterized by an exponential decay ofthe slow phase velocity After each saccade, neuronal (and muscle) activity is required in order to maintain the eye in its new position. Since premotor structures for eye movements including those for saccades encode eye velocity, this signal has to be integrated (in the mathematical sense) to obtain eye position. Such a neural integrator for horizontal eye movements has been localized in the region of the medial vestibular nucleus/nucleus praepositus hypoglossi complex in the lower pons [32] and for the vertical and torsional system in the interstitial nucleus of Cajal (iC) in the mesencephalon [73]. The cerebellum, particularly the floccular region, supports the neural integrator, i.e. gaze-hulding. With a neural integrator deficit the eye drifts back after each saccade to a null-position and a new saccade has to be made in an attempt to maintain the desired eye position. This manifests as gazeevoked nystagmus and characteristically the slow phase decays exponentially. The null-position does not have to coincide with the midposition of the eye,

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i.e. gaze straight ahead. It has indeed been shown experimentally that the nulland midposition can di er up to 35° [139J. In these instances a spontaneous nystagmus is evident, which characteristically has an exponentially decayjng slow phase. There are also reports which consider some instances of spontaneous nystagmus as a consequence of a smooth pursuH jmbalance. This has been attributed mainly to vertical disorders, particularly downbeat nystagmus, but also to horizontal nystagmus. Finally, it has recently been shown that a saccade generator deficHcan lead to spontaneous nystagmus. The saccade generator for the horizontal system is located in the paramedian pontine reticular formation (PPRF) and for torsional and vertical saccades in the rostral interstitial nucleus of the medial longitudinal fasciculus (rostral iMLF). Lesions of the PPRF lead to a horizontal ipsilateral gaze palsy and lesions of the rostral iMLF to a loss of torsional saccades to the ipsilateral side [142]. In addition to the loss of saccades in a specific direction after a unilateral saccade generator lesion, spontaneous nystagmus to the contralateral side with a PPRF lesion [75] and contratorsional nystagmus with a rostral iMLF lesion have been found [73J. Thus, a similar phenomenon (spontaneous nystagmus) can have completely di erent causes, which of course has to be considered when a drug therapy based on neurophysiological and neuropharmacological mechanisms is conceived. Furthermore, lesions in di erent locations in the bralnstem and/ or the cerebellum can lead to nystagmus of the same appearance [24]. Since the vestibular nuclei are a major site of central vestibular control, it should be stressed that not only are vestibular functions relayed in these nuclei, but that they also play (among others) an important role for smooth pursuit generation and the oculomotor neural integration. There are several means to reduce oscillopsia caused by involuntary eye movements. Often the patients develop strategies themselves. It is a common experience that patients with congenital nystagmus turn their head in order to bring their gaze direction close to the null-position, i.e. the eye position with minimal or no nystagmus velocity. As mentioned above, this null-position often does not coincide with the midposition of the eye, i.e. gaze straight ahead. Individual patients with periodic alternating nystagmus (PAN) can also reduce nystagmus by appropriate VOR interaction. First they can figure out in which direction their nystagmus is currently beating by looking to the side. If they look to the right and the nystagmus intensity (velocity) increases, they have right nystagmus (Alexander's law). With this infUI'matiun and their experience that their vestibular responses are functioning [60], they can induce postrotatory nystagmus by a sudden stop after rotating several times around their body axis. Tills postrotatory nystagmus counteracts the PAN for a willIe and reduces the disturbing oscillopsia. Unfortunately, this method is rather

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elaborate and mistakes in the turning direction lead to a worsening of the symptoms. For therapy several approaches are used [95; also see chapter by Leigh]. They consist of surgery, injection of botulinum toxin into selected extraocular muscles, optical treatments and drug therapy. Eye muscle surgery is most often applied in patients with congenital nystagmus. The aim here is to move the null-position to the midposition of the eye (Anderson-Kestenbaum procedure). Injection of botulinum toxin into selected extraocular muscles or into the retrobulbar space reduces muscle strength and can thereby reduce unwanted eye movements. For optical treatments, prisms and lenses are used. Depending on the method used they move the null-position, alter the vergence angle (which a ects some forms of acquired nystagmus) or stabilize images on the retina [see chapter by LeighJ. In the following only drug therapy will be considered. Often di erent approaches are used to treat the same disorder. Rarely are di erent approaches combined to treat one disorder. Hardly any treatment is successful in all instances.

Principles of Drug Therapy

Drugs to reduce involuntary eye movements aim at neurotransmitter receptor sites in the central nervous system. In the following a few points important for the understanding of drug therapy will be reviewed [46; also see chapter by Vidal et a1.J. Neurotransmitters can be divided into fast- and slow-acting substances. With regard to the system under consideration, fast-acting neurotransmitters are excitatory and inhibitory amino acids, which include glutamate, -aminobutyric acid (GABA) and glycine. About 30-40% of synaptic connections in the central nervous system use GABA as their transmitter, and another 15-20% use glutamate. They act mainly on postsynaptic, ionotropic receptors. In contrast. the slower acting substances mostly activate metabotropic (second messenger-linked) receptors. The monoaminergic substances noradrenaline, dopamine, serotonin and histamine belong to this group, together with acetylcholine (muscarinic receptors). All these substances are universal in the central nervous system or at least have been found in many areas, so they are by no means specific to vestibular structures. In experimental animal studies these substances ur related drugs can be specifically delivered by microinjections into circumscribed central nervous structures and the resulting oculomotor changes can be observed [46, 139]. This, however, is not yet possible for treating patients. Drugs have to be given systemically, which often cause intolerable side e ects, since the drug is

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not only acting on central vestibular structures. Furthermore, with systemic application the blood-brain barrier has to be taken into account, which often decreases the e ciency of the proposed drug on the site of action [11]. Several drugs have been shown to be e ective by intravenous application [11]. which however rarely provides a long-lasting e ect. It has also been shown that the chronic use of anticholinergic drugs (muscarine antagonists) increase the receptor density in many brain areas, which is not seen after single applications [12]. and reduces the e ect of long-term therapy. Glutamate is an excitatory amino acid. In central structures at least two di erent classes of glutamatergic receptors have been distinguished: Ionotropic receptors including NMDA (N-methyl-D-aspartate) and AMPA ( -amino3-hydroxy-5-methyl-4-isoxalone-propionic acid) subtypes and metabotropic receptors. In neurons, which act on NMDA receptors, glutamate can be colocalized with glycine [119]. The co-release of glutamate and glycine thus then potentiates the postsynaptic excitatory e ect on NMDA receptors. Otherwise glycine is an inhibitory transmitter acting on strychnine-sensitive ionotropic receptors (see below). Apart from the vestibular nerve, a erents from other structures to the vestibular nuclei might also use glutamate as a transmitter [46]. Glutamate is also the excitatory transmitter for some of the mossy fibers [130] and the granule cells in the cerebellum. It also acts as the excitatory transmltter for vestibula-ocular pathways on AMPA receptors on abducens motaneurons [I36J. Memantine, a glutamate antagonist, has been successfully applied in the treatment of patients with acqUired pendular nystagmus (APN) [I34J. This drug is considered to block the NMDA receptor channel and to modulate the AMPA receptor. In addition it also has some dopaminergic action. The site of action for memantine within the brain is not yet clear, except for APN the vestibular nuclei seem to be an unlikely location. One possible site would be the excitatory input to the motoneurons, particularly since in APN both eyes can be a ected di erentially. GABA is the main inhibitory substance in the central nervous system. An ionotropic GABA A and a metabotropic GABA B receptor can be distinguished. All vestibular nuclei contain dense innervation by GABA-ergic a erent fibers. They include Purkinje cell axons, which use GABA as their main transmitter. A GABA-ergic projection originating from the contralateral inferior olive has also ueen suggested. Vestiuular nuclei neurons contain GABA A and pre- and postsynaptic GABA B receptors. A high percentage of vestibular nuclei neurons also use GABA as their transmitter. These neurons would correspond to inhibitory interneurons within the vestibular nuclei and to inhibitory neurons projecting to motoneurons mediating the verticalVOR. In contrast, the inhibi-

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tory neurons for motoneurons of the horizontal VOR utilize glycine as a transmitter [131]. GABA is also a putative neurotransmitter for mossy fibers in the cerebellum [72]. Behavioral e ects of GAB A have been shown in a number of experimental studies. In the monkey unilateral microinjections of the GABA A agonist muscimol in the vestibular nuclei lead to failure of the common neural integrator for horizontal eye movements [139]. For torsional/vertical eye movements muscimol yields such an e ect after injection in the iC [73]. A failure of the neural integrator leads to a severe gaze-holding deficit with gaze-evoked nystagmus. In contrast to muscimol, injections of the GABA A receptor-antagonist bicuculline in the vestibular nuclei lead to a vestibular imbalance with constant velocity slow phases of nystagmus [139J. Systemic application of baclofen (GABA B agonist) strongly impairs the velocity storage mechanisms in normal and nodulus/uvula lesioned monkeys [38, 155]. The inhibitory action of systemically applied baclofen is probably not due to a direct e ect on GABA-ergic synapses, since it has been shown that in usual oral doses baclofen is not a GABA-mimetic agent [57J and that one e ect is the presynaptic inhibition of glutamate release [106, 115]. In addition, baclofen also increases the glycine turnover (at least in the spinal cord) suggesting that bac10fen might also a ect inhibitory glycinergic interneurons [115]. Benzodiazepines (clonazepam, diazepam) are thought to modify GABA actions acutely and chronically [144] by acting on GABA A receptors. Barbiturates are also intimately related to the ionotropic GABA receptor complex [113J. Gabapentin, which has recently been shown to be successful in the treatment of APN in a double-blind controlled study [7], also e ects GABA metabolism and release [81J. However, although structurally similar to GABA it shows no direct e ect on GABA A or GABA B receptors [148J. Besides GABA, glycine is the main inhibitory transmitter in the central nervous system. Glycine receptors are ionotropic. Vestibular nuclei neurons express postsynaptic, strychnine-sensitive glycinergic receptors, which proves the hyperpolarizing e ect of these receptors. Glycine is used (beside GABA) as an inhibitory transmitter for commissural interneurons in the vestibular nuclei and for the inhibition of motoneurons during the horizontalVOR [131J. It is also the transmitter of the pause neurons, which inhibit saccadic burst neurons in the paramedian pontine reticular formation [82]. Cholinergic substances act on nicotinic (ionotropic) and muscarinic (metabutrupic) receptors. Buth classes uf receptors have beell detected ill all vestibular nuclei [46J. The origin for many of the neurons acting on these vestibular nuclei neurons has yet to be determined. They could be localized within the vestibular nuclei (intrinsic neurons) or originate in the contralateral inferior olive. Cholinergic neurons from the vestibular nuclei project to the flocculus,

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nodulus [10], dorsal cap of the inferior olive and the spinal cord. The visual climbing fiber input to the cerebellum also has a high cholinergic activity [123]. At least 5 subtypes of muscarinic receptors (M I-M5) with di erent distribution in the central nervous system can be distinguished. Whereas granule cells in the cerebellum primarly express M2 and M3 receptors [1], neurons in the pons and medulla almost exclusively express M2 [116]. Cholinergic substances have also been shown to be e ective on a behavioral level. In intact animals unilateral microinjections into the vestibular nuclei lead to a postural deficit. Injections of carbachol (cholinergic agonist) or betanechol (muscarinic agonist) into the rabbit flocculus increase the gain of sinusoidal OKN [145-147]. Interestingly, in patients, physostigmine (acetylcholine-esterase inhibitor) might be beneficial in some central vestibular disorders (hyperactive horizontal VOR, disturbed fixation suppression of caloric nystagmus) [149. 151], but deteriorating in others (downbeat nystagmus) [51].

Downbeat Nystagmus

Clinical Aspects Downbeat nystagmus is usually present during gaze straight ahead and increases on lateral gaze, downward gaze and during convergence. According to Alexander's law. downbeat nystagmus decreases on upward gaze. Fixation usually does not eliminate the nystagmus. There are also many exceptions to these rules [24J. In the head-hanging position. slow phase velocity of the downbeat nystagmus is often enhanced [100J. Downbeat nystagmus is probably the most common form of acquired jerk nystagmus of central origin. There are a variety of clinical conditions resulting in downbeat nystagmus. In most cases it is seen with cerebellar lesions (Arnold-Chiari malformation. cerebellar degeneration). It has rarely been clinically related to defined brainstem lesions [15J. Other common causes are drugs and nutritional deficiencies. In about 40% of cases with downbeat nystagmus, the cause remains unclear [42]. Although downbeat nystagmus can resolve, particularly when due to drugs or nutritional deficiencies, it can often last for many years. Pathuphysiulugy and Expeljmental Studies Downbeat nystagmus is always of central origin. As one possible cause an imbalance of the central vertical vestibular tone has been assumed. The vertical VOR is driven by signals deriving from the posterior and anterior semicircular canals. Posterior semicircular canal a erences mediate downward,

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signals from the anterior semicircular canals mediate upward eye movements. The vertical VOR is di erentially controlled for up and down. Imbalance can therefore be either achieved by a relative decrease of the signals originating in the posterior semicircular canals or a relative increase of the anterior semicircular canal a erences. Lesions to the posterior cerebellar midline structures can evoke downbeat nystagmus as well. Anatomically, these structures only have an inhibitory influence on the VOR elicited by the anterior semicircular canals. In contrast, a erent information from the posterior semicircular canals is not a ected by means of this pathway [851. Due to this asymmetry, loss of Purkinje cells in the midline structures of the posterior cerebellum could lead to a disinhibition of anterior canal input resulting in both upward drift ofthe eyes and compensatory downward beating quick eye movements [1 OOJ. Accordingly, experimental ablation of the flocculus and paraflocculus invariably produces downbeat nystagmus [165]. Thus, downbeat nystagmus is one of the few disorders which can be elicited experimentally. However, it has not yet been pharmacologically attempted to treat this type of nystagmus in experimental animals. Brainstem lesions causing downbeat nystagmus are rare. In the monkey a midsagittal section in the dorsal tegmentum at the pontomedullary border causes downbeat nystagmus [44J. This lesion site. however. has not yet been established in patients [24J.

Patient Studies As a result of the anatomical. physiological and neuropharmacological data. most studies investigating the e ects of drug therapy on downbeat nystagmus concentrated on agents interfering with the GABA-ergic or cholinergic system (table 1). In an open study, baclofen reduced the slow phase velocity resulting in a long-lasting improvement [51J. However. in a recent double-blind controlled study ofbaclofen vs. gabapentin. neither ofthese two drugs showed a significant improvement of downbeat nystagmus in 6 patients when administered for 2 weeks [7J. There was also no response to baclofen seen in another patient [33]. Downbeat nystagmus improved with clonazepam in all 8 patients in an open study [42]. With single doses of 1-2 mg. the sedative side e ects were tolerable. In addition, there are casuistic reports of the beneficial e ect of clonazepam [34, 105]. but unsuccessful treatments are also reported [33, 162]. The usefulness uf drugs acting un the chulinergic transmissiun was tested in several studies. While cholinergic agents had a deteriorating e ect on downbeat nystagmus. the influence of anticholinergic drugs seems to be potentially beneficial. In a double-blind. randomized study [IIJ the centrally acting scopolamine and benztropine were tested in comparison to the peripheral acting

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Table 1. Drugs used for the treatment of nystagmus and saccadic intrusions: after each reference the total number of investigated patients (second value) and the responding patients (first value) is shown; studies in which no patient responded are not listed Baclofen (15-60 mg/day) Downbeat: Dieterich et aI., 1991 (2/3) Upbeat: Dieterich et aI., 1991 (2/2) PAN: Halmagyi et aI., 1980 (2/3); Carlow, 1986 (2/2); Isago et aI., 1985 SSN: Carlow, 1986 (1/1) CN: Yee et aI., 1982 (417)

I

(l/q

Clonazepam (1-6 mg/day) Downbeat: Currie and Matsuo, 1986 (8/8); Chambers et aI., 1983 (111); McConnell et aI., 1990 (1/1); Yee, 1989 (2/4) SSN: Cochin et a!., 1995 (111); Currie and Matsuo. 1986 (111) APN: Currie and Matsuo. 1986 (2/2) Opsoclonus: Leigh and Zee. 1983 (111); Carlow. 1986 (1/1); Anderson et a!., 1988 (2/4) MSWJ; Fukazawa et a!.. 1986 (Ill) Gabapentin (900 mg/day) APN: Averbuch-Heller et a!.. 1997 (10/15 including 2 OM and 3 SSN); Stahl et a!.. 1996 (2/2) OM: Stahl et a!., 1996 (Ill). Averbuch-Heller et a!., 1997 (2/2) Isoniazid (400-600 mg/day) APN: Traccis et al.. 1990 (2/3) Phenobarbital CN: MSWJ;

Gay et aI., 1969 (oral 60 mg/day) (111) Fukazawa et al.. 1986 (single dose 150 mg Lm.) (Ill)

Amobarbital (single dose 50-300 mg Lv.) CN: Bender. 1946 (7) APN: Nathanson et al.. 1953 (717) OM: Bender et aI., 1952 (3/3); Lawrence and Lightfoote. 1975 (111) Carbamazepine (200-1,200 mg/day) SOM: Susac et a!.. 1973 (4/5); Herzau et al.. 1978 (2/4): Morrow et a!.. 1980 (112): Rosenberg and Glaser. 1983 (617): Brazis et al.. 1994 (117) Diphenylhydantoin (200-300 mg/day) PAN: Davis and Smith, 1971 (111) Valproic acid (750-2.000 mg/day) OM: Lefkowitz and Harpold. 1985 (111)

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Table 1 (continued)

Scopolamine (single dose 0.4 mg Lv.) Downbeat: Barton et al.. 1994 (2/2) APN: Barton et al.. 1994 (SiS); Starck et aI.. 1997 (TIS: 0.5 mg172 h) (2/8); Gresty et aI.. 1982 (SIS) Benztropine (single dose 2 mg Lv.) Downbeat: Barton et aI.. 1994 (2/2) APN: Barton et al., 1994 (SiS) Trihexyphenidyl (15-40 mg/day) Downbeat: Leigh et aI.. 1991 (111) APN: Herishanu and Louzoun. 1986 (III); Jabbari et al.. 1987 (414) OM: Herishanu and Zigoulinski. 1991 (111) Tridihexethyl (100 mg/day) APN: Leigh et al., 1991 (2/4) SSN: Leigh et al.. 1991 (Ill) Glycopyrrolate (single dose 0.2 mg Lv.) APN: Barton et at.. 1994 (3/5) Memantine (15-60 mg/day) APN: Starck et al., 1997 (11111 Propranolol Opsoclonus: SOM:

Fowler. 1976 (2 mg/kg/24 h) (2/2 infants) Tyler and Ruiz. 1990 (10 mg/day) (Ill); Brazis et al..1994 (dosage?) (1/3)

Methylphenidate (single dose 20 mg oral) SWJ: Currie et al.. 1986 (?) Acetazolamide (60-750 mg/day) Episodic ataxia: Wolf. 1980 (3/3); Zasorin et al.. 1983 (III); Griggs et al.. 1978 (3/3); Brunt and van Weerden, 1990 (8/12) Sulthiame (50-300 mg/day) Episodic ataxia: Brunt and van Weerden, 1990 (9/12); Wolf, 1980 (3/3) ACTH. corticosteroids Opsoclonus: PranzatelJi, 1992 Immunoglobulin Opsoclonus:

Petruzzi and de Alarcon. 1995 (1 child); Sugie et at.. 1992 (1 child)

Plasma exchange Opsoclonus:

Cher et at.. 1995 (3/6)

APN Acquired pendular nystagmus; CN congenital nystagmus; MSWJ macrosquare wave jerks; OM ocular myoclonus; PAN periodic alternating nystagmus; SSN seesaw nystagmus; SWJ square wave jerks.

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glycopyrrolate. All results were derived from single dose intravenous injections. Scopolamine led to a marked improvement in both patients tested, in one the nystagmus was eliminated completely. Benztropine was less e ective and glycopyrrolate deteriorated the nystagmus [IIJ. Thus, the authors demonstrated that only central acting anticholinergic drugs may be beneficial in the treatment of downbeat nystagmus. The di erential e ect of scopolamine and benztropine might be caused by the diverse profile of action on di erent muscarinic receptor subtypes (see above). Another double-blind study showed slight improvement with the centrally acting trihexyphenidyl[96]. In this investigation, medication was administered orally over a period of 1 month. Thus, at present, GABA-ergic drugs (baclofen, clonazepam) are the drugs of choice for the treatment of downbeat nystagmus with tolerable side e ects. However, it is quite clear that the drugs are not e ective in all instances and that an e ect could not be demonstrated in the only available controlled double-blind study [7J. Anticholinergic drugs might help, but so far an e ect has only been shown with intravenous administration which limits the use of long-term therapy. Side e ects are also more disturbing. For both GABAergic and anticholinergic drugs, long-term e ects are not known. Casuistic reports described single patients with improvement of their downbeat nystagmus after treatment with magnesium. This was particularly the case when magnesium depletion was diagnosed as the reason for the nystagmus [125]. Substitution of thiamine may also occasionally improve downbeat nystagmus [125J. None ective drugs: Gabapentin (up to 900 mg/day) had no e ect in 6 patients in a double-blind controlled study [7J. Drugs causing downbeat nystagmus: Cholinergic agents like physostigmine had a deteriorating e ect on the downbeat nystagmus in all 5 patients after administration of 1 mg intravenously [51J. Lithium intoxication can cause downbeat nystagmus [40, 160J. Anticonvulsant medication with phenytoin [2J or carbamazepine [158] is a common cause of downbeat nystagmus.

Upbeat Nystagmus

Clinical Aspects Like downbeat nystagmus, upbeat nystagmus usually does not disappear with fixatiun. Fulluwing Alexander's law, sluw phase velucity is greatest in upward gaze, though upbeat nystagmus can be transformed to downbeat nystagmus on upward gaze in some patients [1001. Oi erent from downbeat nystagmus, lateral gaze often does not enhance slow phase velocity. Convergence can increase and decrease upbeat nystagmus or convert it to downbeat

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nystagmus. The head-hanging position also increases upbeat nystagmus in some cases [100J. In contrast to downbeat nystagmus, which often lasts many years, upbeat nystagmus frequently subsides within weeks, requiring no specific treatment [138J. Upbeat nystagmus is less common than downbeat nystagmus. Lesions of the anterior cerebellar vermis and metabolic or toxic changes (drugs, tobacco, see below) as a cause have been described [100]. In contrast to downbeat nystagmus, lesions of the brainstem are frequent in patients with upbeat nystagmus. A critical structure for upbeat nystagmus is located at the midline in the lower medulla, but more rostal lesions have also been encountered [24J.

Pathophysiology and Experimental Studies Several clinical reports on upbeat nystagmus showing lesions of the medulla prompted to hypothesize similar to downbeat nystagmus an imbalance of central vertical vestibular tone to be the cause of upbeat nystagmus [20, 100]. As has been described for downbeat nystagmus, a erences from the posterior semicircular canals conveying vestibular signals which mediate downward eye movements follow pathways di erent from those deriving from the anterior semicircular canals mediating upward movements. In principle, tonic imbalance leading to upbeat nystagmus can be due to a relative decrease of anterior semicircular canal a erences or due to a relative increase of the signals from the posterior semicircular canals. Besides vertical vestibular tone imbalance a gaze-holding deficit with a shift of the null-position has also been considered as a cause [24]. Excitatory a erences originating in the anterior semicircular canals project via di erent pathways: after being relayed in the vestibular nuclei, signals are either transferred to the contralateral oculomotor complex through the brachium conjunctivum, the medial longitudinal fasciculus (MLF) or the ventral tegmentum. Lesions in both the brachium conjunctivum and the ventral tegmentum have been found in patients with upbeat nystagmus. A critical structure for upbeat nystagmus may be the paramedian tract in the lower medulla [24], which is located at the midline ventrally to the nucleus prepositus hypoglossi and possibly involved in vertical gaze-holding [29J. Bilateral muscimol injections into the iC can occasionally lead to upbeat nystagmus in the monkey which often has a torsional component [74J. Ketanest (a narcotic glutamate antagonist) elicited transient upbeat nystagmus in the monkey [51]. Patient Studies Dieterich et a1. [51J showed in an open study a long-lasting improvement with a reduction of the slow phase velocity after administration of baclofen for 2-4 weeks.

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Besides intramuscular or retrobulbar injection of botulinum toxin A [see chapter by LeighJ there are no other systematic studies showing an improvement of upbeat nystagmus. It is remarkable that thus far there is only one study on drug therapy for upbeat nystagmus. One reason may be that upbeat nystagmus in contrast to downbeat nystagmus usually reverses within a few weeks by itself. None ective drugs: Although tobacco. which has a cholinergic e ect. is known to produce upbeat nystagmus in healthy subjects, no therapeutical implications were derived using both cholinergic or anticholinergic acting drugs [138]. Drugs causing upbeat nystagmus: Upbeat nystagmus with tobacco consumption (cholinergic e ect) lasts for 10-20 min [128J.

Episodic Ataxia

Clinical Aspects Two groups of episodic ataxia can be distinguished. In type I episodic ataxia. paroxysms of ataxia are short (seconds to minutes) and deficits between paroxysms consist of general motor activity with myokymia and neuromyotonia. In type II the paroxysms of ataxia last longer (hours to days) usually combined with vertigo and between paroxysms pathological nystagmus is present. The nystagmus for type II consists of upbeat, downbeat and horizontal nystagmus during gaze straight ahead. Type I usually starts between the ages of 5-7. For type II the onset varies from early childhood to late in adult life. Spontaneous improvement or occasional remission but also progressive ataxia have been described for type II [21J. Pathophysiology and Experimental Studies Both type I and II episodic ataxia are autosomal-dominant disorders. Both types are ion channel disorders. type I a potassium channelopathy and type II a calcium channelopathy. Type II has been localized on chromosome 19p, I.e. the same region to which familial hemiplegic migraine and CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukencephalopathy) is linked [68]. Interestingly, also familial hemiplegic migraine is often combined with nystagmus and ataxia. There is evidence that attacks in episodic ataxia are linked with abnormally high intracellular cerebellar pH values (which reduces putassium cumJuctance uf the cell membrane). Patient Studies Acetazolamide (a carbonic anhydrase inhibitor) reduces the pH and is e ective in more than 75% of the patients. who tolerate the side e ects [23. 67,

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161, 164]. Prolonged treatment can lead to long-lasting improvement. Side e ects such as hyperhydrosis, paraesthesia, muscle sti ening and easy fatigability can be reduced by potassium chloride supplement [23]. Sulthiame, another carbonic anhydrase inhibitor, has also been a successful treatment. With less side e ects than acetazolamide and equal e ectiveness it is often the drug of choice [23J. A child was also successfully treated with the calcium entry blocker flunarizine (10 mg/day) [18]. None ectivedrugs: Phenobarbital, phenytoin, carbamazepine, betahistine, cinnarizine, clomipramine, clonazepam [23J. Worsening ofsymptoms has been reported under phenytoin and phenobarbital for a type II patient [67J.

Periodic Alternating Nystagmus

Clinical Aspects PAN is a well-defined and uniform oculomotor disorder. It consists of horizontal nystagmus with alternating directions while looking straight ahead. Reversal of nystagmus occurs every 70-150 s, Le. within a period of 2-3 min. One distinguishes between an acquired and a congenital form. The acquired form is mostly due to a lesion of the nodulus/uvula region of the cerebellar vermis as seen in posterior-fossa malformation. Loss of vision due to a vitreous hemorrhage or cataract, can also lead to PAN. The congenital form is considered as a special form of congenital nystagmus [100]. Pathophysiology and Experimental Studies PAN is closely associated with the 'velocity storage' mechanism of the vestibular system. 'Velocity storage' normally extends the postrotatory vestibular time constant and is under inhibitory control of the nodulus/uvula region. Lesions here have shown in experimental animals to induce slow nystagmus oscillations in the dark with reversing directions [155J. Vision normally has an inhibitory e ect on velocity storage, which would explain the occurrence of PAN in patients with eye disease (cataract, etc.) [97]. The inhibitory e ect of the nodulus/uvula region is directly transmitted to the vestibular nuclei via Purkinje cells (Pcs) , which use GABA as an inhibitory transmitter. In experimental studies orally administered baclofen [38J and picmtuxin [61J had an inhibitury e ect un the velucity sturage mechanism in normal monkeys. Diazepam mildly enhanced velocity storage [16J. This is remarkable, considering that baclofen (GABA B) and diazepam (GABA A ) are agonists and picrotoxin is a GABA A receptor antagonist. Baclofen eliminated the alternating nystagmus in monkeys with nodulus/uvula lesions [155].

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Patient Studies In 2 patients the acquired PAN was eliminated with baclofen in midposition and patients were relieved of oscillopsia [70). Carlow [33) and Nuti et al. [112J (1 patient with aperiodic alternating nystagmus) also reported improvement after baclofen. An e ect of baclofen can be seen within a few days [33). However, Furman et a1. [60) reported on 2 patients treated with 30 mg baclofen/ day, who did not improve. One patient had impaired vision and cerebellar vermis atrophy and the other a cerebellar atrophy. Congenital PAN, which might have a di erent cause, has been reported to improve [33, 84J or remain unchanged [65, 70) after baclofen therapy. Hydantoin can decrease the duration of the nystagmus cycle with a slight slowing of the oscillations [43J. Intravenous chlorpromazine or barbiturates only transiently eliminated the nystagmus [17J. There are no systematic studies on long-term e ects, which however have been reported in individual cases [33). One patient took baclofen successfully for 3 months, before the drug was discontinued due to indigestion [70). None ective drugs: Trials of meclizine or carbamazepine showed no improvement [43J. Atropine had no significant e ect in a patient with congenital PAN [9J. Drugs causing PAN: PAN has been observed after phenytoin [31) and after primidone/phenobarbital intoxication [127) (l patient each), which disappeared after toxic levels were discontinued.

Seesaw Nystagmus

Clinical Aspects Seesaw nystagmus (SSN) is a combination of a conjugate torsional and dissociated vertical nystagmus. While one eye is elevated and intorted, the other eye is synchronously depressed and extorted. In the second half of a full cycle the vertical and torsional movements reverse. SSN often has a pendular waveform and has been identified in mesodiencephalic lesions due to parasellar masses, head trauma, brainstem stroke, Arnold-Chiari malformation or septo-optic dysplasia [69J. SSN due to parasellar masses or head trauma is often associated with bitemporal hemianopia. It can also be congenital [118J. In unilateral mesencephalic lesions, jerk-waveform SSN has been observed [69J. Pathophysiology and Experimental Studies Olle critical structure ill patiellts withjerk-wavefurm SSN might ue the iC [69J. Electrical unilateral stimulation of the iC and its vicinity in the monkey resulted in a sustained ocular tilt reaction including a vertical divergent eye position and conjugate torsion [157J. However, unilateral muscimol injection into the iC in the monkey only led to downbeat and upbeat nystagmus in combination

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with ipsilesionally beating torsional nystagmus, but not to SSN [74]. Thus, the precise role of the mesencephalon for SSN has yet to be determined. Alternatively, lesions to the central vertical-torsional VOR and the otolithocular VOR have been proposed to cause jerk-waveform SSN by tonic imbalance. Lesions to the MLF can disrupt the connections between the vertical semicircular canals and the vertical-torsional eye muscles. The combination ofjerkwaveform SSN and internuclear ophthalmoplegia seen in patients, supports this hypothesis [54]. SSN in animal experiments has not yet been elicited.

Patient Studies SSN is a rare syndrome. Therefore most therapeutical data evolved from casuistic reports, which concentrated on GABA-ergic drugs. Carlow [33] described a patient with marked improvement after administration of baclofen. Other studies, however, could not demonstrate the beneficial e ect of baclofen (1 patient [37], 3 out of 3 patients [7]). Cochin et al. [37] demonstrated a benefit in 1 patient with clonazepam. SSN disappeared and did not return after withdrawal. A beneficial e ect of clonazepam was also reported by Currie and Matsuo [42] and Carlow [33]. Gabapentin (900 mg/day) also reduced median eye speed by more than 25% in 2 of the 3 patients [7]. There are two case reports on e cacy of ethanol in SSN [58, 10 1]. The benefit, however, only lasted for 1 h and the patient was noticeably inebriated at an ethanol intake of 1.2 g/kg body weight [58]. The dampening e ect of diazepam on SSN for a few minutes after intravenous administration [126] also supports the hypothesis that GABA-ergic transmission is important in SSN. There is a report on anticholinergic drugs in 1 patient with SSN [96], which showed marked decrement of nystagmus after administration of the peripherally acting tridihexethyl. The centrally acting trihexyphenidyl decreased slow phase velocity at gaze straight ahead but increased it in other directions. The results are limited due to the concomitant medication in this patient (carbamazepine, baclofen and protryptiline) which potentially could interact with the nystagmus. None ective drugs: Not known. Drugs causing SSN: Not known.

Congenital Nystagmus

Clinical Aspects Congenital nystagmus (CN) usually manifests itself in the first few months of life and only seldom becomes evident during adult life. The nystagmus has variable waveforms ranging from jerk to pendular nystagmus.

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It is almost always conjugate and horizontal. Vertical or torsional forms are rare exceptions. Usually there is an eye position in the orbit where the eye is quieter, i.e. the null-position, which often does not coincide with the midposition of the eye in the orbit. Another characteristic feature of CN is inverted OKN or inverted smooth pursuit eye movements. These findings supposedly result from interaction of CN and a dynamic shift of the null-position. with the smooth pursuit mechanisms being basically intact [90J. Although retinal image velocities in CN can exceed 100 0 /s. patients seldom complain about oscillopsia [50]. It is thought that in CN visual perception takes place mainly during short foveation periods (lasting about 50 ms). i.e. episodes during each nystagmus cycle in which the eye is not moving. To improve vision it is common that patients turn their head to bring the null-position of the eyes and gaze direction together. Patients might also benefit from convergence. Some patients show intermittent head-shaking, when attending to visual tasks. This stimulation of the VOR might improve vision in a few cases [95].

Pathophysiology and Experimental Studies The cause of CN is unknown. It may be familial. The well-known association with albinism is of interest. since these patients present evidence for wrongly directed visual pathways. This has also been proven in albino rabbits. which can exhibit inverted optokinetic nystagmus and nystagmus slow phases with increasing velocity as well. Visual depriviation in monkeys can cause ocular oscillations which resemble CN. Miswiring of the neural integrator leading to unstable gaze-holding has also been suggested as a cause of CN. Patient Studies Most patients do not require a specific therapy. If required it mostly consists of nondrug approaches such as surgery or biofeedback [see chapter by Leigh]. Bender [13J reported in 1946 that small doses of barbiturates given intravenously improved vision and decreased nystagmus in patients with CN. This was also seen in 1 patient with CN receiving phenobarbital [62J. The approach has not been routinely pursued due to the side e ects of barbiturates. Other drug trials include 5-hydroxytryptophan (antidepressant drug) [91J and uaclofen. which moderately improved vision and decreased nystagmus amplitude [163]. None ective drugs: Not known. Drugs causing eN: Not known.

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Acquired Pendular Nystagmus

Clinical Aspects APN is a spontaneous sinusoidal nystagmus of 3-7 Hz (amplitude 1-4°) which cannot be divided into fast and slow phases and is typically enhanced during fixation. The direction of APN is not restricted to the horizontal plane like in most patients with congenital forms of pendular nystagmus. Depending on the phase/amplitude relationship between di erent components, the resulting eye movements in APN are horizontal, vertical, oblique or circular/ elliptical. APN never occurs without additional brainstem or cerebellar signs. In contrast to CN, APN does not show inversion of the OKN. There is often a dissociation between the nystagmus found in both eyes and it can also be monocular. Di erent than CN, patients with APN almost always su er from osci1lopsia. APN is most commonly caused by demyelination, in adults as a consequence of multiple sclerosis or toluene abuse, in children by leukodystrophies. Pathophysiology and Experimental Studies Three lesion sites have been suggested leading to APN. Cerebellar midline structures are frequently lesioned in patients su ering from APN caused by multiple sclerosis. This is supported by the fact that electrical stimulation of cerebellar nuclei in man can evoke pendular nystagmus. On the other hand, disconjugacy of both eyes in APN has led to the hypothesis that structures in the vicinity of the oculomotor nuclei must be damaged in this disease. A third possible cause could be the dysfunction of the reciprocal feedback circuits between cerebellum and brainstem nuclei [8]. To date, there is no animal model simulating APN. Therefore, from both clinical and experimental data, it is still unclear what the critical structure for the occurrence of APN is. Patient Studies GABA-ergic, anticholinergic or antiglutaminergic medication has been tested. The e ect of the GABA-ergic system was tested in a double-blind controlled study (n 15) of baclofen vs. gabapentin [7]. Gabapentin significantly reduced median eye speed and enhanced visual acuity, whereas baclofen did nut shuw a beneficial e ect [7]. In anuther upen study, gabapentin was also e ective [133J. Clonazepamimproved APN in an open study [42], although no benefit was observed in 2 patients [66, 133J. Treatment with barbiturate [110J or ethanol consumption [108J can also diminish pendular nystagmus. Isoniazid eliminated APN in 2 out of 3 patients [152].

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Di erent anticholinergic agents were tested in six studies. In 1 patient with APN, after massive brainstem hemorrhage due to eclampsia, chronic trihexyphenidyl treatment markedly improved the pendular nystagmus [77]. The same therapeutic agent with higher dosages (up to 40 mg/day) also showed significant beneficial e ects in all 4 patients [86]. In a double-blind study, however, trihexyphenidyl failed to demonstrate an improvement in any of the 4 patients [96]. Tridihexethyl chloride, which does not cross the blood-brain barrier, improved visual acuity and reduced eye speed moderately in 2 out of 4 patients. It was proposed that anticholinergic agents suppress nystagmus by peripheral rather than central mechanisms [96J. In contrast, single-dose application of the centrally acting scopolamine (hyoscine) eliminated APN in all 5 patients in a double-blind controlled study [11]. This is in accordance with an earlier open study [66]. In an open study of scopolamine (TIS applied as a plaster for 3 days) APN was only reduced in 2 out of 8 patients [134J. Response failures to scopolamine have also been reported [133]. Benztropine, which crosses the blood-brain barrier and glycopyrrolate, which acts peripherally, had only a mild e ect [IIJ. As has been discussed above, the diverse profile of action on di erent muscarinic receptor subtypes might be responsible for the di erential e ect of scopolamine and benztropine [11]. In conclusion, there are controversial results for the e ect of anticholinergic agents on APN. One reason for the di erence between the results from the studies mentioned above might be the type of administration of the therapeutical agents. While single-dose intravenous application eliminates APN, long-term usage of related drugs is less beneficial. This might be due to a dose-dependent increase of receptor density after chronic exposure of muscarinic antagonists [12, 53]. Further double-blind studies have to be conducted in order to solve this discrepancy. In a recent open study the glutamate antagonist memantine eliminated APN in 11 patients after oral administration for 1 week [134J. A positive e ect of memantine was followed up for 3 years in 6 of the patients. None ective drugs: Two patients responding to gabapentin did not improve with valproic acid and baclofen [133J. The ine ectiveness of baclofen also agrees with other studies (14 patients) [7, 66J. The Na-channel blocker mexiletine did not show any significant e ect on APN in 4 patients [134J. Without supplying any detailed information, Gresty et al. [66] stated that there is no improvement of APN from L-DOPA, prochlorperazine, carbamazepine and tetraoenazine. Drugs causing acquired pendular nystagmus: Toluene abuse in sni ers can cause APN by di usely damaging the white matter [102, 122].

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Ocular Myoclonus

Clinical Aspects Ocular myoclonus (OM) consists of binocular, usually regular pendular eye movements of 1-3 Hz. It is always combined with rhythmic movements of nonocular muscles. Most often the soft palate is involved. In these instances, OM is also called oculopalatal myoclonus. The nystagmus frequently has a vertical direction and is not a ected by fixation. The movements of the nonocular muscles are often sychronized with the nystagmus. OM is caused by lesions ofthe inferior olivary nucleus (io) orits connections. Most frequently these lesions are due to bleedings and tumors as weU as due to strokes, trauma or inflammation. Characteristically, OM develops within months after the primary damage. OM seldom disappears spontaneously. Pathophysiology and Experimental Studies As described above, OM (like pure palatal myoclonus) can be found after destruction of the inferior olivary nucleus or its connections. Within months, hypertrophy of io can be found on MRI scans [132]. Vacuolated neurons causing the pseudohypertrophy are seen with postmortem histological workup. Increased levels of acetylcholinesterase reaction products have been found in these neurons [88J. Such neurons show cholinergic hyperexcitability and rhythmic spontaneous activity which is caused by damage to inhibitory dentatoolivary tracts [104J. 10 neurons are known to project to the cerebel1ar flocculus mediating adaptive properties of the VOR. Ocular oscillations in OM may be caused by an instability of this adaptive mechanism [109J. Electrical stimulation of io and its vicinity in the monkey led to palatal myoclonus, sometimes involving the eyeballs [156]. Patient Studies There are a variety of studies describing the e ect of medication on palatal myoclonus. As there is a di erential benefit on palatal myoclonus and concurrent OM (see below), results from studies on palatal myoclonus cannot simply be used to estimate e cacy of these drugs in OM [14, 92]. Cholinergic hyperexcitability of io has been shown to be a main factor in the evolution of OM. Therefore the use of anticholinergic agents should be the logical consequence. However, only one study in OM reported the successful administration of the anticholinergic drug trihexyphenidyl [78]. Treatment had to be discontinued due to psychomotor irritability. Amobarbital ceased nystagmus, but nonocular movements remained unchanged [14, 92J. Valproic acid was reported to strikingly decrease OM in 1 patient [94]. In a patient with palatal myoclonus it had no e ect [55]. Gaba-

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pentin decreased the mean slow phase velocity of OM by more than 25% in 2 patients in a double-blind, controlled study [7J. Another patient also improved after single oral doses of 600 mg gabapentin [133]. Unfortunately, all patients reported side e ects (feeling drunk, worsening of ataxia). There are a number of reports concerning treatment in palatal myoclonus without ocular oscillations. It has been supposed that both disorders, palatal and ocular myoclonus, have the same etiology. Although it has been shown that both deficits can respond di erently, some of the substances used for palatal myoclonus, which have not been tried for OM, will be mentioned. Combination of 5-hydroxytryptophan and carbidopa resulted in cessation of myoclonus in 2 patients [103, 159]. Carbamazepine had a beneficial e ect in 1 patient with palatal myoclonus [124], but worsened the clinical symptoms in another [55]. None ective drugs: Trifluoperazine (1 patient [36]), clonazepam (3 patients [33]), baclofen (3 patients [33], 2 patients [7]), diazepam (1 patient [124]) and diphenylhydantoin (1 patient [92]). Drugs causjng ocular myoclonus: Not known.

Opsoclonus and Ocular Flutter

Clinjcal Aspects Ocular flutter is defined as a series of involuntary back-to-back saccades in the horizontal plane without intersaccadic interval. For opsoclonus these pathological, involuntary eye movements do not only occur in the horizontal, but also in the vertical plane [26, 1OOJ. Originally the term opsoclonus referred to irregular, chaotic, conjugate and partly continuous eye movements. A bout of ocular flutter consists of 3-5 saccadic eye movements and lasts usually less than 1 s. Rarely more than 4 salves occur within a 10-s interval. As a rule, ocular flutter is only seen in adults. It usuaJly subsides spontaneously (without therapy) either within weeks or up to 5 months. In general. it presents as a uniform oculomotor pattern. In contrast, the eye movement patterns of opsoclonus are much more variable. In many instances the clinical picture (as well as the etiology, see below) is very similar to that of ocular flutter, except that the eye movements also have a vertical and/or an oblique component. In these instances, eye muvements between buuts are normal. This is in cuntrast tu patients with continuous opsoclonus. If cooperative, these patients can alter their gaze direction, otherwise there is little evidence for normal eye movements. Often patients with continuous opsoclonus are in severe clinical conditions. However, also alert and cooperative patients are not uncommon. Opsoclonus is seen more

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often in children than in adults. The course of opsoclonus is related to its etiology. For children as well as adults, paraneoplastic as well as viral infections are the most common cause for opsoclonus (and ocular flutter). In adults a toxic-metabolic disorder is also often present [26J. In parainfection cases, opsoclonus generally subsides within a week to a few months. Opsoclonus will disappear when the toxic substances are removed.

Pathophysiology and Experimental Studies Opsoclonus as well as ocular flutter are not elicited by a circumscribed brain lesion. Based on the frequent association with peripheral tumors and viral diseases, an autoimmune mediated oculomotor dyskinesia is discussed [117]. It is not known which neurons and transmitters in the brainstem and/ or cerebellum are involved. Earlier it was assumed that the lack of saccadic omnipause neurons in the brainstem would lead to saccadic oscillations. However, a more recent model supported by experimental evidence [87], showed that lesions to the omnipause area in the brainstem [30J actually only led to a slowing of saccades. Furthermore, with light microscopy the omnipause region appeared normal in the neuropathological examination of patients with opsoclonus [120J. Patient Studies In children, a neuroblastoma is the most common tumor associated with opsoc1onus. The detection of the neuroblastoma is often di cult and delays for years have been reported. When detected, removal is the therapy of choice and leads in approximately 50% of all cases to a complete remission of opsoclonus. Two-thirds of the children also respond to corticosteroids. Either ACTH or prednisone are used with doses similar to immunosuppressive therapy [117]. Hammer et al. [71J reported an improvement in children with ACTH but not with prednisone. Even if the eye movements improve under prednisone or ACTH, relapses during withdrawl or after discontinuation are common, prompting an increase or restart of therapy. Even with therapy, symptoms can last for several years. Parainfectious or idiopathic opsoclonus in children may also respond to ACTH [117J. In a few children treated so far. symptoms also improved after the application of immunoglobulin [114, 140J. In 2 infants unresponsive to corticosteroid treatment, propranolol (2 mg/kg/24 h) markedly improved all abnormal movements [56]. In genera!' ucular flutter is self-limiting and dues nut require a specific treatment. This also applies to opsoclonus of parainfectious origin. Adult patients with paraneoplastic opsoclonus usually die within months with the opsoclonus being present all the time. Also spontaneous remissions and recurrences have been reported for paraneoplastic opsoclonus.

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There is no established drug therapy for adult patients with paraneoplastic opsoclonus. In 3 patients an immunoadsorption therapy (plasma exchange) has been recently shown to be e ective in treating opsoclonus [35]. In analogy to children, corticosteriods have been applied successfully [76J. Drug trials were performed with clonazepam [3, 33, 99J. Clonazepam might help in cases which did not respond to corticosteroids or propranolol [33J. However, it might also be ine ective (1 patient [143]). Propranolol has shown to be e ective [56J as well as ine ective in 2 patients [33,143]. One patient with paraneoplastic opsoclonus improved with thiamine [111], which often has no e ect [3J. None ective drugs: Carbamazepine, primidone, baclofen, valproate, lisuride, methysergide, bromocriptine, cinnarizine and neuroleptic drugs [3J. Drugs causing ocular flutter or opsoc1onus: An overdose of amitriptyline [4], the combination of diazepam/phenytoin [48J and lithium/haloperidol [39] have been reported to cause opsoclonus. Gizzi et al. [64] reported ocular flutter after vidarabine.

Square Wave Jerks, Macro-Square Wave Jerks and Macrosaccadic Oscillations

Clinical Aspects All three disorders consist of saccades occurring at a high rate, which can lead to blurred vision. Patients do not complain of oscillopsia. Especially patients with square wave jerks (SWj) are often unaware of their involuntary eye movements. SWj consist of small saccades (0.5-5°) bringing the eyes away from fixation and after an intersaccadic interval of normal duration (about 200 ms) back to the starting point. SWj are found in normal subjects, slightly more common in the elderly. Frequencies over 25/min during fixation are considered pathological, which can be as high as 240/min. The amplitude should almost be the same for each saccade within a burst. For macro-square wave jerks (MSWj) the saccade amplitudes are larger (20-50°) and the intersaccadic intervals are shorter than 100 ms. MSWj occur in bursts with the amplitUde not varying within a single burst. They can also be continual with frequencies up to 120-180/min. MSWj are not seen in healthy subjects. Macro-saccadic oscillations (MSO) also have large amplitudes (20-60°) seen in bursts lasting several secunds. Huwever, in cuntrast tu MSWJ, the saccadic interval is longer (150-200 ms), the amplitude for MSO within a burst first increases and then decreases and the MSO take place around the point of fixation, whereas MSWj are to-and-fro saccades with regard to the point of fixation. All three of these forms of saccadic intrusions are mostly

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restricted to the horizontal plane and are rarely seen with vertical or torsional directions [lOOJ.

Pathophysiology and Experimental Studies SWJ are seen in 20-40% of normal people. They have also been associated with a number of diseases, including progressive supranuclear palsy, multisystem degeneration, Parkinson's disease, Huntington's chorea, spinocerebellar degeneration or cortical cerebel1ar atrophia, schizophrenia and in connection with cerebral lesions [100]. Originally SWJ were considered as a cerebellar sign. However, since it has been shown that SWJ also occur with lesions outside the cerebellum and that cerebellar oculomotor deficits show no correlation with SWJ, this concept is no longer valid. In contrast to this, MSO and MSWJ can usually be related to disorders of the brainstem and cerebellum. MSO has been related to lesions of the midline cerebellum and the underlying deep cerebellar nuclei. They have been considered as a consequence of an increased gain in relation to visually guided saccades. But clearly severe saccadic hypermetria after bilateral deep cerebellar nuclei lesions can also occur without MSO [25, 27J. MSO has also been seen after a pontine lesion [5J. Recent experimental evidence has provided a model for SWJ related to the basal ganglia and the superior colliculus. The caudate nucleus projects to the nondopaminergic portion of the substantia nigra pars reticulata, which in turn has a tonic GABA-ergic inhibitory influence on the superior colliculus. Accordingly, injection of bicuculline into the superior colliculus leads to an increase of saccadic intrusions [80]. Patient Studies People with SWJ are usually not aware of their saccadic intrusions. If the frequency is not too high, leading to impaired vision, no specific treament is required. Dyslexic patients with SWJ have been successfully treated with methylphenidate [41]. There are no systematic studies about the long-term course of SWJ. In a patient who had both MSO and MSWJ, these eye movements were almost completely eliminated by clonazepam and phenobarbital [59]. In 1 patient with MSO the amplitude was reduced after a single dose of 600 mg gabapentin as well as the frequency by a single dose of 250 mg cycloserine, an antiuiotic that is a partial glycine agonist [6J. It has to ue considered however in these studies, that MSO and MSWJ are the consequence of an acute disease, mostly of the cerebellum, which usually disappears spontaneously. None ective drugs: Haloperidol and hydroxyzine pamoate had no e ect on MSO and MSWJ [59J.

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Drugs causing saccadic intrusions: L- Tyrosine, the precursor for dopamine biosynthesis, increased the frequency of saccadic intrusions in all 8 schizophrenic patients tested [49]. Depletion of catecholamines by metyrosine increased amplitude and frequency of saccadic intrusions in 3 normal subjects [153]. Tabacco smoking leads to saccadic intrusions during smooth pursuit eye movements [129].

Superior Oblique Myokymia

Clinical Aspects Superior oblique myokymia (SOM) is a recurrent episodical condition with short phasic contractions of the superior oblique muscle in one eye. This leads to small- and high-frequency monocular eye movements and as a consequence to vertical and torsional diplopia and oscillopsia. SOM is not a saccadic eye movement since there is no fixed relationship between amplitude and peak velocity of the movement (main sequence). SOM is most commonly found in otherwise normal patients. Occasionally SOM has been described in patients after su ering from superior oblique palsy. Lesions to the trochlear nucleus also seem to be a possible cause ofSOM in patients with posterior fossa tumors and subsequent tectal compression [47]. Pathophysiology and Experimental Studies Electromyographical examination in SOM showed polyphasic action potentials of high amplitude suggesting neurogenic disease. Neuronal activity in the antagonistic inferior oblique muscle was not reduced during SOM [89J. Therefore, SOM is unlikely to be caused by supranuclear lesions. As SOM followed su perior oblique palsy at intervals of months or years in some patients, misdirection-regeneration might be the cause of SOM in these patients [93]. As stated above, lesions to the trochlear nucleus itself can also lead to SOM [47]. Another cause could be a pathological contact between the trochlear nerve and a vessel, similar to hemifacial spasm [137]. Patient Studies The natural history of SOM typically shows a relapsing and remitting course for months to years. As a consequence, beneficial e ects of any treatment in SOM have tu be carefully interpreted. Anticonvulsant medication has been used most frequently in the medical treatment of SOM. There are a number of reports from patients responding to carbamazepine [22, 79, 107, 121, 141]. Unfortunately, if followed up for more than a year, most patients initially responding to carbamazepine only

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showed a temporarily beneficial e ect. In 6 out of 7 patients treated with carbamazepine, a prompt cessation in ocular symptoms was noted [121]. During the follow-up period of an average 31/ 2 years however, all patients su ered from at least one subsequent relapse [121J. Brazis et al. [22] reported that only 1 patient experienced a lasting benefit (more than 4 years) with carbamazepine. No improvement with carbamazepine was reported in all 3 patients of de Sa et al. [45] as well as in single patients [63, 135, 150, 154]. Propranolol (10 mg/ day) stopped SOM in a patient after carbamazepine did not show any benefit [154J. Transient improvement was also observed by Brazis et al. [22]. In conclusion, carbamazepine is the drug most often used. It is e ective for many patients, however relapses within 1-3 years are common. None ective drugs: Phenobarbital and chlordiazepoxide were orally administered in 1 patient without noticeable e ect [83]. The same patient also did not improve after intravenous edrophonium injection. Baclofen administered in a patient by Staudenmaier [135] showed no influence on SOM. Drugs causjng SOM: Not known.

Comment

Despite our detailed knowledge about the neurophysiology, neuroanatomy, neurochemistry and clinical aspects of central vestibular and oculomotor disorders [28, 46, 100], the drug therapy for nystagmus of central origin and saccadic intrusions still is only emerging and certainly many more studies are needed. Most reports are uncontrolled and based on single cases. Only a few double-blind controlled studies are available [7, 11, 96]. Since many of the described disorders are not very common, future studies have to be performed in international multicenter studies. There is certainly also the need for new and more e cient drugs. Single dose injections of anticholinergic drugs are e ective for APN [11], however comparable anticholinergic drugs for oral use needed for long-term therapy are still lacking [96]. Duwnbeat nystagmus has been shuwn tu respunu tu baclufen [51], yet many patients do not [7, 33]. When all studies are taken together a response has only been observed in 20% (2 out of 10) of the patients. That new drugs can provide promising results has recently been shown by using gabapentin [7] and the glutamate antagonist memantine [134] for treating APN.

Acknowledgments We would like to thank B. Pfreundner and 1. Wend I for preparing the manuscript and M. Seiche for editing it.

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Prof. Dr. med. U. Buttner, Dr. L. Fuhry, Neurologische Klinik, Klinikum Grosshadern der Ludwig-Maximilians-Universitat, Marchioninistrasse 15, 0-81366 Munchen (Germany) Tel. 49 897095 2561, Fax 4989 7095 8883

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Btittner U. (ed): Vestibular Dysfunction and Its Therapy. Adv Otorhinolaryngol. Basel, Karger, 1999, vol 55, pp 228-240

Nonpharmacological Treatment of Nystagmus R. John Leigh Departments of Neurology, Neuroscience, Otolaryngology, and Biomedical Engineering, Department of Veterans A airs Medical Center, and Case Western Reserve University, Cleveland, Ohio, USA

Introduction: Visual Consequences of Abnormal Eye Movements

Before reviewing measures available to null the visual consequences of nystagmus, it is worthwhile considering the normal relationship between eye movements and vision [Carpenter, 1991]. Clear vision of an object requires that its image be held fairly steadily on the foveal region of the retina. Visual acuity declines steeply from the fovea to the retinal periphery and so the image of the object of regard should, in general, be within 0.5° of the center of the fovea. In health, our eyes are in constant motion due to drifts and saccades [Ott et aI., 1992], and so also are retinal images of stationary objects. The visual system tolerates - even needs - some retinal image slip but, if the speed of images increases, visual acuity may decline. The threshold above which vision su ers depends upon what we look at but, for objects with higher spatial frequencies - such as Snellen optotypes - retinal image motion above about 5°/s impairs visual acuity [Burr and Ross, 1982]. During fixation, saccadic eye movements also occur; these produce highspeed movement of images upon the retina - too high for clear vision and, through a combination of 'masking' and suppression of visual inputs, the brain finds it relatively easy to ignore the smeared retinal signal due to the saccade [Campbell and Wurtz, 1978; Burr et aI., 1994], Patients in whom inappropriate saccades repeatedly misdirect the fuvea uften cumplain uf di culty with reading, Excessive image drift not only impairs vision but also causes oscillopsia - the illusory movement of the environment [Bender, 1965]. Whereas the relationship between retinal image velocity and visual acuity is a fairly direct

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Fig 1. A pendular type of congenital nystagmus waveform with superimposed quick phases. Note that following each quick phase, 'foveation periods' (indicated by arrows) occur, at which time the eye is close to desired fixation point (00) and eye velocity is low (i.e. the image is on the fovea and image slip is low). This patient experienced no oscillopsia. Positive values correspond to rightward eye rotations.

one, the correlation between retinal image velocity and the development of oscillopsia is less consistent, and varies among patients. The magnitude of oscillopsia is usually less than the magnitude of nystagmus. For example, patients with downbeat nystagmus report that their oscillopsia is about one third of the amplitude of the nystagmus IBuchele et aI., 1983J. A 'special case' seems to be patients with congenital nystagmus, who may intermittently have images moving across the retina with speeds exceeding 100 0 /s but seldom complain of oscillopsia [Dickinson and Abadi, 1985; Dell'Osso and Leigh, 1992]. It seems that this is partially due to 'foveation periods' - a brief epoch during each cycle of the nystagmus when the fovea is pointing at the object of interest and the eye is temporarily still (fig. 1). Thus, patients with congenital nystagmus appear to view the world during brief, stationary 'snapshots', and somehow suppress the visual perception that accompanies the high-speed portions of the waveform, when images are smeared across the retina. If the head is still, eye movements are not required but if subjects are in motion, eye movements must be generated to compensate for head perturbations amI huld the line uf sight steady un the ubject uf interest. Eye muvements that compensate for head movements are largely due to the vestibula-ocular reflex, which acts at short latency and so can cope with the high-frequency perturbations that occur during locomotion. Patients who have 'lost their balancing mechanism' complain of blurred vision and oscillopsia only when they walk or

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run [lC, 1952; Leigh and Brandt, 1993]. This point is relevant to treatments for nystagmus that seek to prevent or negate eye movements, since they also disable the vestibula-ocular reflex and so will impair vision while the subject is in motion [Yaniglos and Leigh, 1992]. Thus, although methods to stop the eyes oscillating seem attractive, they may also disable normal eye movements, and this is a major disadvantage compared with drug therapies aimed at suppressing the oscillatory mechanism itself (see chapter Bottner, Fuhry). In this chapter, four basic nonpharmacological strategies for treating nystagmus will be considered: (1) methods that attempt to place the eye in a versional or vergence position in which nystagmus is minimized; (2) methods for negating the visual consequences of the nystagmus; (3) procedures for weakening the extraocular muscJes, and (4) application of somatosensory or auditory stimuli to suppress nystagmus.

Methods That Place the Eye in a Position in Which Nystagmus Is Minimized

One optical approach that often benefits patients whose nystagmus damps while viewing a near target is convergence prisms. An arrangement that is often e ective is 7.00 dpt base-out prisms with 1.00 dpt spheres added to compensate for accommodation [Dell' Ossa, 1973]. The spherical correction may not be needed in presbyopic individuals. Especially in some patients with congenital nystagmus, the improvement of vision due to nystagmus suppression when wearing base-out prisms may be su cient for them to qualify for a driving license. Some patients with acquired nystagmus also benefit [Lavin et aI., 1983]. Occasionally, in patients whose nystagmus is worse during near viewing (fig. 2), base-in prisms help. Theoretically, it should be possible to use prisms to help patients whose nystagmus is quieter when the eyes are moved into a particular position in the orbit - the 'null region'. For patients with congenital nystagmus, there is usually some horizontal eye position in which nystagmus is minimized, and, in patients with downbeat nystagmus, the eyes may be quieter in upgaze. In practice, patients use head-turns to bring their eyes to the quietest position, and only rarely are prisms that produce a conjugate shift helpful.

Optical Methods for Negating the Visual Consequences of Nystagmus

A di erent approach has been to use an optical system that stabilizes images upon the retina [Rushton and Cox, 1987]. This system consists of a

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Fig 2. Suppression of nystagmus by changing the angle of vergence. The patient was a 41-year-old woman with multiple sclerosis. Representative records of the horizontal component of her acquired pendular nystagmus are shown as she viewed a target at far (top) or near (bottom). Note that her high-frequency nystagmus increased in amplitude at near. leading to complaints of blurred vision, especially during reading. Her near vision was improved by applying a 5-dpt base-in paste-on prism over her right spectacle lens (to induce divergence). Positive values correspond to rightward eye rotations.

high-plus spectacle lens wum in cumuinatiun with a high-minus cuntact lens. The system rests on the principle that stabilization of images on the retina could be achieved if the power of the spectacle lens focused the primary image close to the center of rotation of the eye. However, such images are defocussed, and a contact lens is required to extend back the focus onto the retina. Since

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the contact lens moves with the eye, it does not negate the e ect of retinal image stabilization produced by the spectacle lens. With such a system it is possible to achieve up to about 90% stabilization of images upon the retina. There are several limitations to the system, however. One is that it disables all eye movements (including the vestibulo-ocular reflex and vergence), so that it is only useful while the patient is stationary and views monocularly. Another is that with the highest power components (contact lens of 58.00 dpt and spectacle lens of 32 dpt), the field of view is limited. Some patients with ataxia or tremor (such as those with multiple sclerosis) have di culty inserting the contact lens. However, initial problems posed by rigid polymethylmethacrylate contact lenses [Leigh et aI., 1988J have been overcome by development of gas- permeable [Yaniglos and Leigh, 1992J or even soft contact lenses. Most patients do not need the highest power components for oscillopsia to be abolished and vision to be useful. We have found that, in selected patients, the device may prove useful for limited periods of time, for example, if the patient wishes to watch a television program. Another technique that has been used experimentally to negate the visual consequences of nystagmus is to record the ocular oscillation and use this signal to move the visual stimulus in synchrony with the eyes. Thus, we have measured nystagmus with the magnetic search coil technique and used the electrical signal from the system's amplifiers to drive a mirror galvanometer that controlled the position of a visual stimulus (an optotype) projected onto a tangent screen [Leigh et a1., 1988J. We found that when we carried out this technique in the plane of maximum nystagmus oscillation, visual acuity improved - presumably because image slip was substantially reduced. However, to be of therapeutic value, a contactless, reliable method for recording eye movements would need to be employed and visual images also controlled in both horizontal and vertical directions. New infraredreflectance and video-based eye movement recording devices allow reliable measurement of both horizontal and vertical eye movements [DiScenna et aI., 1995J and might eventually be used to control the position of a visual signal on a video monitor. Such a system would have to allow for head movements (or the patient's head would have to be fixed), and there would also be need to be able to easily null any 0 set of the image from the fovea (which otherwise leads to a series of saccades as the eyes 'chase' the stabilized image). The issue of fading of images is, in practice, not a practical problem because electronically based systems are nut precise enuugh tu produce the high degrees of stabilization reqUired. Thus, as these technologies advance, a practical system for canceling out the visual e ects of nystagmus may become possible. However, such a system would also negate normal eye movements - like the optical device described above - unless a filter could

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be developed to di erentiate them from the abnormal oscillations. This ability also seems likely to become possible in the near future, perhaps using a 'neural network' approach.

Procedures for Weakening the Extraocular Muscles

One method to treat nystagmus that has gained popularity, has been injection of botulinum toxin either into the extraocular muscles or retrobulbar space [Crone et aI., 1984; Helveston and Pogrebniak, 1988]. Using both of these techniques, Ruben et a1. [1994] reported improvement of vision in most of their 12 patients with a variety of diagnoses; the major side e ect was ptosis. However, eye movements were not systematically measured and compared before and after injection. Repka et a1. [1994J also described improvement of vision following retrobulbar injection of botulinum toxin in 6 patients, and documented the e ects on eye movements. Their main reservation was the temporary nature of the treatment. We measured binocular eye rotations in three planes prior to and following monocular injection of botulinum toxin into the horizontal recti in 2 patients with acquired pendular nystagmus due to multiple sclerosis [Leigh et aI., 1992]. In both patients, the amplitude of the horizontal components was abolished (fig. 3), and visual acuity was slightly improved. However, the persisting vertical oscillations were more annoying. Furthermore, diplopia and ptosis were more annoying to the patients than visual symptoms due to the nystagmus. Finally, 1 patient reported a complication that illustrates the limitations of methods that aim to mechanically reduce ocular oscillations: the nystagmus got worse in the non-injected eye (compare fig. 3A and C). Since her better vision was in the injected eye, she preferred to use this to view her environment. The botulinum toxin had weakened all horizontal eye movements - not just those due to her nystagmus. This caused plastic-adaptive changes to take place, and the increased innervation caused saccades made by her left eye to be hypermetric (fig. 4A) and the vestibulo-ocular reflex, evaluated during rotation in darkness, to have increased gain for the left eye (fig. 4C). One other aspect of this result deserves further study: How were these plastic-adaptive changes related to an increase in the amplitude of the horizontal component of her nystagmus in the noninjected eye? This finding suggests that her acquired pendular nystagmus emanated eitller fwm une uf the eye movement systems that had undergone plastic-adaptive changes or, that the oscillations somehow arose from the adaptive mechanism itself. We also treated acquired nystagmus in 3 patients by injecting botulinum toxin into the retrobulbar space [Tomsak et aI., 1995]. Nystagmus was abol-

Nonpharmacological Treatment of Nystagmus

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ished ur reduced ill the treated eye fur a!.Juut 2-3 mUIlths, !.Jut ptusis alld diplopia were even more troublesome than when botulinum was injected into the extraocular muscles. Furthermore, 1 patient developed filamentary keratitis, perhaps due to denervation of the ciliary ganglion, that has persisted for several years. No patient that we treated with retrobulbar botulinum toxin

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Fig 4. Horizontal eye movements of the patient shown in figure 3, 2 weeks after the second injection of botulinum into the right horizontal recti. Positive deflections correspond to rightward movements. A, B Saccades made to targets located 15° from the midline (dashed lines) are shown. When the patient viewed with her right eye (B), saccades were generally hypometric, with dynamic overshoots. Following saccades to the eccentric target, the eye drifted back, requiring a corrective saccade. When she viewed with her left eye (A), there was pronounced saccadic hypermetria. C. D Compensatory eye movements during active horizontal head rotations in darkness are shown. The same time segment of head position (HEAD) is shown in both. It is evident that the compensatory movements (EYE) of the left eye (C) exceeded those of the right eye (D) by more than 50%. [See Leigh et at.. 1992, for details.]

elected to repeat the procedure, Thus, in summary, botulinum toxin may abolish nystagmus and improve vision in some patients, but its relatively short period of action (about 2-3 months) and side e ects may limit its therapeutic value. In particular, diplopia due to botulinum toxin may be more distressing to some patients than the visual consequences of the nystagmus.

Nonpharmacological Treatment of Nystagmus

235

Two surgical procedures may be e ective as treatment for selected patients with congenital nystagmus. One is the Anderson-Kestenbaum operation [Anderson, 1953; Kestenbaum, 1953]. This aims to move the attachments of the extraocular muscles so that the null angle corresponds with the eyes' new central position. It is best planned after measuring eye movement and with a knowledge ofthe particular surgeon's 'calibration factor' as to the necessary amount of surgery for the required shift in the position of the null [Dell'Osso and Flynn, 1979; D'Esposito et aI., 1989; Flynn and Dell'Osso, 1981; Zubkov et a!., 1993J. The Anderson-Kestenbaum procedure not only shifts and broadens the null, but also results in decreased nystagmus outside the null region. It is of unproven value in the treatment of acquired forms of nystagmus. The second procedure is an artificial divergence operation [Cuppers, 1971; Sendler et a!., 1990]; it may be helpful in patients with congenital nystagmus that suppresses at near, and who have stereopsis. Studies comparing these two methods indicate that the artificial divergence procedure and combined operations give better vision improvement than the Anderson-Kestenbaum procedure alone [Zubkov et aI., 1993; Kaufmann and Kolling, 1981; Sendler et a!., 1990J. Another operation that has been proposed as treatment for congenital nystagmus is large recessions of the horizontal rectus muscles. Modest improvement of visual acuity is reported, but no reliable measurements of eye movements were made [Helveston et a!., 1991; von Noorden and Sprunger, 1991]. In this situation also, it might be predicted that plastic-adaptive changes would be stimulated by weakening the horizontal rectus muscles and that, as these occurred, the oscillations would increase again. Thus, there is a need to quantitatively evaluate the e ect of such surgery. Finally, it has been suggested that simply detaching and then reattaching the muscles may lead to suppression of congenital nystagmus [Dell'Osso, 1998J. The role of any surgical procedure in the treatment of acquired nystagmus is much less established. However, there is a consensus that neurosurgery does have a clear role in the therapy of the nystagmus associated with the ArnoldChiari syndrome; suboccipital decompression has been reported to improve downbeat nystagmus and to prevent progression of other neurological deficits [pederson et a!., 1980; Spooner and Baloh, 1981]. In cases of superior oblique myokymia that are refractory to drugs treatments, superior oblique tenectomy in combination with an ipsilateral inferior ublique weakening [Huyt amI Keane, 1970; Susac et a!', 1973; Kummer-ell ano Schaubele, 1980] or a Harada-Ito procedure [Kosmorsky et a!., 1995J may prove e ective.

Leigh

236

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Application of Somatosensory or AUditory Stimuli to Suppress Nystagmus

Contact lenses alone sometimes suppress congenital nystagmus; this e ect is not due to the mass of the lenses but is probably mediated via trigeminal a erents [Dell 'Ossu et aI., 1988). A variety uf utiler treatments have been reported, principally for congenital nystagmus. Electrical stimulation or vibration over the forehead or neck may suppress congenital nystagmus [Sheth et aI., 1995); an example is shown in fig. 5. It is postulated that this e ect, as well as wearing contact lenses [Dell'Osso et al., 1988), may be exerted

Nonpharmacological Treatment of Nystagmus

237

via the trigeminal system, which receive extraocular proprioception. Not all patients gain benefit from this procedure and, in some, nystagmus is made worse. Acupuncture administered to the neck muscles may suppress congenital nystagmus in some patients, perhaps due to a similar mechanism [Ishikawa et aI., 1987]. Biofeedback has also been reported to help some patients with congenital nystagmus [Abadi et aI., 1980; Ciu reda et aI., 1982]. However, the role of any of these treatments outside the laboratory - during natural activities - have yet to be demonstrated.

Conclusions

Although the strategy of weakening the extraocular muscles is an inherently appealing approach for treating nystagmus, it often induces diplopia and provokes adaptive changes that may actually counteract the treatment. Optical devices that partially stabilize images on the retina despite eye movements provide a monocular, limited view of the world. Both of these approaches abolish the capacity to make eye movements that compensate for head movements and so make vision wor.se while patients are in motion. If nystagmus can be suppressed with convergence, then this may provide substantial benefit so that, for example, driving is possible. Methods that use somatosensory or auditory stimuli to suppress nystagmus are unreliable, especially during natural activities. Thus, all these methods are potentially inferior to pharmacological suppression of the ocular oscillations. Because e ective pharmacological treatment for some forms of nystagmus is not yet available, these alternative methods still require consideration and, with careful evaluations, may be found to appreciably help selected patients.

Acknowledgments Supported by USPHS grant EY067J7, the Department of Veterans A airs, and the Evenor Armington Fund.

References Abadi RV, Carden D, Simpson J: A new treatment for congenital nystagmus. Br J Ophthalmol 1980;64: 2-6. Anderson JR: Causes and treatment of congenital eccentric nystagmus. Br J OphthalmoI1953;37:267-281. Bender MB: Oscillopsia. Arch Neurol 1965; 13:204-213. Buchele W, Brandt T, Degner D: Ataxia and oscUlopsia in downbeat-nystagmus vertigo syndrome; in Pfaltz CR (ed): Neurophysiological and Clinical Aspects of Vestibular Disorders. Adv Otorhinolaryngo!. Basel, Karger, 1983, vol 30, pp 291-297.

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Burr DC. Morrone MC, Ross]: Selective suppression of the magnocellular visual pathway during saccadic eye movements. Nature 1994;371:511-513. Burr DC, Ross]: Contrast sensitivity at high velocities. Vision Res 1982;22:479-484. Carpenter RHS. The visual origins of ocular motility; in Cronly-Dillon JR (ed): Vision and Visual Function, vol 8: Eye Movements. London, Macmillan Press. 1991, pp 1-10. Campbell FW, Wurtz RH: Saccadic omission: \Nhy we do not see a grey out during a saccadic eye movement. Vision Res 1978;18:1297-1303. Ciu reda KJ, Goldrich SG, Neary C: Use of eye movement auditory biofeedback in the control of nystagmus. Am J Optom Physiol Optics 1982;59:396-409. Crone RA, de Jong PTVM, Notermans G: Behandlung des Nystagmus durch Injektion von Botulinustoxin in die Augenmuskeln. Klin Monatsbl Augenheilkd 1984;184:216-217. COppers C: Probleme der operativen Therapie des okularen Nystagmus. Klin Monatsbl Augenheilkd 1971; 159: 145-157. Dell'Osso LF: Improving visual acuity in congenital nystagmus; in Smith JL, Glaser JS (ed): Neuroophthalmology. St Louis, Mosby, 1973, vol 7, pp 98-106. Dell'Osso LF: Extraocular muscle tenotomy, dissection, and suture: A hypothetical therapy for congenital nystagmus, J Pediatr Ophthalmol Strabismus 1998. in press. Dell'Osso LF. Flynn JT: Congenital nystagmus surgery. A quantitative evaluation of the e ects. Arch Ophthalmol 1979;97:462-469. Dell'Osso LF, Leigh RJ; Ocular motor stability of foveation periods. Required conditions for suppression of oscillopsia. Neuroophthalmology 1992; 12:303-326. Dell'Osso LF, Traccis S, Abel LA, Erzurum SI: Contact lenses and congenital nystagmus. Clin Vis Sci 1988;3:229-232. D'Esposito M, Reccia R. Roberti G, Russo P: Amount of surgery in congenital nystagmus. Ophthalmologica 1989;198:145-151. Dickinson CM, Abadi RV: The influence of nystagmoid oscillation on contrast sensitivity in normal observors. Vision Res 1985;25:1080-1096. DiScenna AO, Das VE, Zivotofsky AZ, Seidman SH, Leigh RJ; Evaluation of a video tracking device for measurement of horizontal and vertical eye rotations during locomotion. J Neurosci Methods 1995;58;89-94, Flynn JT, Dell'Osso LF: Surgery of congenital nystagmus, Trans Ophthalmol Soc UK 1981;101:431-433, Helveston EM. Ellis FD. Plager DA: Large recession of the horizontal recti for treatment of nystagmus. Ophthalmology 1991;98:1302-1305. Helveston EM, Pogrebniak AE: Treatment of acquired nystagmus with botulinum A toxin. Am J Ophthalmol 1988; 106:584-586. Hoyt WF. Keane JR: Superior oblique myokymia: Report and discussion on five cases of benign intermittent uniocular microtremor, Arch OphthalmoI1970;84;461-467. JC: LiVing without a balancing mechanism, N Engl J Med 1952;246:458-460, Ishikawa S, Ozawa H, Fujiyama Y: Treatment of nystagmus by acupunture; in Highlights in Neuroophthalmology. Proceedings of the Sixth Meeting of the International Neuro-Ophthalmology Society (INOS). Amsterdam, Aeolus Press, 1987, pp 227-232. Kaufmann I I, Kolling G: Operative Therapie bei Nystagmuspatienten mit I3inokularfLmktionen mit und ohne Kopfzwangshaltung. Ber Dtsch Ophthalmol Ges 1981;78:815-819. Kestenbaum A: Nouvelle operation de nystagmus. Bull Soc Ophthalmol Fr 1953;6:599-602. Kommerell G, Schaubele G: Superior oblique myokymia: An electro-myographical analysis. Trans Ophthalmol Soc UK 1980; 100:504-506. Kosmorsky GS, Ellis BD, Fogt N, Leigh RJ: The treatment of superior oblique myokymia utilizing the Harada-Ito procedure. J Neuroophthalmol 1995; 15: 142-146. Lavin PJM, Traccis S, Dell'Osso LF, Abel LA, Ellenberger C Jr: Downbeat nystagmus with a pseudocycloid waveform: Improvement with base-out prisms. Ann Neurol 1983;13:621-624. Leigh RJ, Brandt Th; A re-evaluation of the vestibulo-ocular reflex; New ideas of its purpose, properties. neural substrate. and disorders. Neurology 1993;43:1288-1295. Leigh RJ. Rushton ON, Thurston SE, Hertie RW. Yaniglos SY: E ects of retinal image stabilization on acquired nystagmus due to neurological disease. Neurology 1988;38:122-127.

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Leigh Rj, Tomsak RL, Grant MP, Remler BF, Yaniglos SS, Lystad L, DelrOsso LF: E ectiveness of botulinum toxin administered to abolish acquired nystagmus. Ann Neurol 1992;32:633-642. Leigh Rj, Tomsak RL, Seidman SH, DelrOsso LF: Superior oblique myokymia. Quantitative characteristics of the eye movements in three patients. Arch Ophthalmol 1991;109:1710-1713. Ott 0, Seidman SH, Leigh Rj: The stability of human eye orientation during visual fixation. Neurosci Lett 1992; 142: 183-186. Pedersen RA, Troost BT, Abel LA, Zorub, 0: Intermittent downbeat nystagmus and oscillopsia reversed by suboccipital craniectomy. Neurology 1980;30:1239-1242. Repka MX, Savino PJ, Reinecke RD: Treatment of acquired nystagmus with botulinum neurotoxin A. Arch Ophthalmol 1994;112:1320-1324. Ruben ST, Lee JP, O'Neil 0, Dunlop I, Elston JS: The use of botulinum toxin for treatment of acquired nystagmus and oscillopsia. Ophthalmology 1994;101:783-787. Rushton 0, Cox N: A new optical treatment for oscillopsia. J Neurol Neurosurg Psychiatry 1987;50: 411-415. Sendler S, Shallo-Ho mann J, MOhlendyck H: Die Artifizielle-Divergenz-Operation beim kongenitalen Nystagmus. Fortschr Ophthalmol 1990;87:85-89. Sheth NV, Delrosso LF, Leigh Rj, Van Doren CL, Peckham HP: The e ects of a erent stimulation on congenital nystagmus foveation periods. Vision Res 1995;35:2371-2382. Spooner JW, Baloh RVV: Arnold-Chiari malformation. Improvement in eye movements after surgical treatment. Brain 1981; 104 :51-60. Susac JO, Smith JL, Schatz NJ; Superior oblique myokymia. Arch Neurol 1973;29:432-434. Tomsak RL, Remler BF, Averbuch-Heller L, Chandran M, Leigh Rj: Unsatisfactory treatment of acquired nystagmus with retrobulbar botulinum toxin. Am J Ophthalmol 1995;119:489-496. von Noorden GK, Sprunger DT: Large rectus muscle recession for the treatment of congenital nystagmus. Arch OphthalmoI1991;109:221-224. Yaniglos SS, Leigh Rj: Refinement of an optical device that stabilizes vision in patients with nystagmus. Optom Vis Sci 1992;69:447-450. Zubkov AA, Stark N, Weber A, Wizov SS, Reinecke RD: Improvement of visual acuity after surgery for nystagmus. Opht ha lmology 1993;100: 14 88-1497.

R. John Leigh, MD, Department of Neurology, University Hospitals, 11100 Euclid Avenue, Cleveland, 01-1, 44106-5000 (USA) Tel. 1 2168443190, Fax 1 2168443160

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240

Subject Index

Abducens nucleus (VI) a erent and e erent connections 10 structure and function 9, 10 transmitters 10 Acetazolamide, episodic ataxia treatment 204, 207, 208 Acoustic neuroma, di erential diagnosis ISS, 156 Acquired pendular nystagmus clinical aspects 212 drugs causes of nystagmus 213 therapy 212, 213 pathophysiology and experimental studies 221 Acupuncture, nystagmus suppression 238 Acute hearing loss, di erential diagnosis 155 Acyclovir, vestibular neuritis management 129, 133 Adenosine triphosphate, sensitivity of central vestibular neurons 70 Adrenaline, modulation of central vestibular neurons 52 Adrenocorticotropin, modulation of central vestibular neurons 69 Aminoglycosides, Meniere's disease management 160, 161 Amobarbital, nystagmus treatment 203,214 AMPA receptors medial vestibular nucleus neurons 40 principles of drug therapy 199 Apoplexia labyrinthi, di erential diagnosis 155

Baclofen, nystagmus treatment 202, 203, 205, 206, 209, 212, 220 Benign paroxysmal positioning vertigo canalolithiasis in etiology 168, 169, 176-178 clinical presentation 170, 171 cupulolithiasis in etiology 174-176 diagnosis 171, 173 di erential diagnosis ISS, 173, 174 horizontal benign paroxysmal positioning vertigo atypical disease with ageotropic positional nystagmus 188, 189 clinical presentation 187, 188 conversion from posterior disease 187 etiology and pathomechanism 189, 190 incidence 170, 187 management 190, 191 incidence and age dependence 169, 180 natural course 173 nystagmus 173 physical therapy 170 Brandt-Daro exercise 180, 181, 185, 186 Epley maneuver 183, 186 recurrence following therapy 183, 185 Semont maneuver 181, 183, 186 surgical management guidelines 186 neurectomy, posterior ampuJlary nerve 186

241

Benign paroxysmal positioning vertigo, surgical management (continued) plugging of posterior semicircular canal 186, 187 unilateral versus bilateral disease 180 Benztropine, nystagmus treatment 204, 205 Botulinum toxin, nystagmus treatment 207, 233-235 Brandt-Daro exercise, benign paroxysmal positioning vertigo milnilgement 180,181, 185, 186 Canalolithiasis, see Benign paroxysmal positioning vertigo Carbamazepine, superior oblique myokymia treatment 203, 219, 220 Cerebellum a erent and e erent connections 13, 14 structure and function 12, 13 transmitters climbing fibers 16 in terneu rons 16 mossy fibers 16 Purkinje cells 14, 16 varicose fibers 17 Clonazepam, nystagmus treatment 202,203, 205, 212, 218 Cochleosacculotomy, Meniere's disease management 161, 162 Congenital nystagmus clinical aspects 210,211 drug therapy 211 pathophysiology and experimental studies 211 Contact lenses, nystagmus suppression 237, 238 Corticosteroids opsoclonus management 216,217 vestibular neuritis management 129 Cupulolithiasis, see Benign paroxysmal positioning vertigo Dimenhydrinate, Meniere's disease management 158, 159 Diphenylhydantoin, nystagmus treatment 203, 209

Subject Index

Dopamine, modulation of central vestibular neurons agonists in therapy 60 central pathways 52, 57, 58 electro physiological studies 58, 60 receptors 58, 60 Downbeat nystagmus clinical aspects 201 drugs causes of nystagmus 205 thempy 202, 205 pathophysiology and lesion studies 201, 202 Dramamine, vestibular neuritis management 129 Electrocochleography, Meniere's disease 151, 152 Endolymphatic hydrops, see Meniere's disease Episodic ataxia clinical aspects 207 drug therapy 207, 208 pathophysiology and lesion studies 207 Epley maneuver benign paroxysmal positioning vertigo management 183, 186 Eye movement generation abducens nucleus 9, 10 cerebellum 12-14, 16, 17 fastigial nucleus 17-19 interstitial nucleus of Cajal 4-6 oculomotor nucleus 10-12 paramedian pontine reticular formation 6-8 paramedian tract neurons 8, 9 rostral interstitial nucleus of the medial longitudinal fascicle 1-3 Fastigial nucleus a erent and e erent connections 18 lesion studies of eye movement 12, 13 structure and function 17, 18 transmitters 19 Gabapentin, nystagmus treatment 203, 210, 215,220

242

GABA receptors medial vestibular nucleus neurons anatomical studies 46, 47 electrophysiological studies 47 functional roles 49 principles of drug therapy 198-200 Gigantocellular reticular nucleus neurons, membrane properties and gaze control 38, 39 Glycine receptors mediul vestibulur nucleus neurons anatomical studies 46, 47 electrophysiological studies 47 functional roles 49 principles of drug therapy 198, 200 Glycopyrrolate, nystagmus treatment 204 Herpesviruses Meniere's disease 143 vestibular neuritis 126, 127 Histamine, modulation of central vestibular neurons binding sites 53 central pathways 52, 53 electrophysiological studies 53, 54 receptor antagonists 54, 55 -Histamine, Meniere's disease management 159 Horizontal benign paroxysmal positioning vertigo, see Benign paroxysmal positioning vertigo Interstitial nucleus of Cajal a erent and e erent connections 4, 5 structure and f,mction 4 transmitters 5, 6 Isoniazid, nystagmus treatment 203 Labyrinthectomy, Meniere's disease management 163 Lermoyez syndrome, see Meniere's disease Long-term depression, cerebeUar regulation 17 Macrosaccadic osciUations clinical aspects 217, 218 drugs causes of oscillations 219

Subject Index

therapy 218 pathophysiology and experimental studies 218 Macro-square wave jerks clinical aspects 217, 218 drugs causes of jerks 219 therapy 218 pathophysiology and experimental studies 218 Mugnetic resomllce imuging Meniere's disease diagnosis 154 vestibular neuritis cliagnosis 117, 120, 121 Medial vestibular nucleus neurons intrinsic membrane properties and functional speculations 36-38 in vivo recorclings 29, 30 modulation of central vestibular neurons adrenaline 52 dopamine agonisL~ in therapy 60 central pathways 52, 57, 58 electrophysiological stuclies 58, 60 receptors 58, 60 histamine binding sites 53 central pathways 52, 53 electrophysiological stuclies 53, 54 receptor antagonists in therapy 54, 55 noradrenaline central pathways 52, 61 electrophysiological stuclies 62, 63 receptors 61, 62 serotonin central pathways 55 electrophysiological studies 55-57 receptors 55 neuropeptides in central vestibular network regulation adrenocorticotropin 69 nerve growth factor 69 neurokinins 66, 69 opioid peptides 65, 66 somatostatin 64, 65 substance P 66, 67, 69

243

Medial vestibular nucleus neurons (continued) neurotransmitters AMPA receptors 40 classification 39 GABA and glycine receptors anatomical studies 46, 47 electro physiological studies 47 functional roles 49 isolation of electrophysiological e ects 39,40 metabotropic glutamate receptors 40 muscarinic and nicotinic receptors anatomical studies 50 behavioral studies 51, 52 electrophysiological studies 50, 51 NMDA receptors functional plasticity role 46 functional roles and correlation with in vivo data 43 postlesional plasticity role 45, 46 subunits 40 pharmamlogical analysis of excitatory amino acid transmission 42, 43 specificity for neuron types 64 operation relationship to behavior 27, 28 oscillatory behavior and functional speculations 35, 36 plasticity 26 purine receptors and ATP sensitivity 70 response to horizontal angular accelerations 98-100 slice recordings classification of neuron types 30, 31 rhythmic activity in type B neurons 31,32 whole-brain recordings, in vitro 32, 33, 35 Memantine, nystagmus treatment 204, 213, 220 Meniere's disease clinical course 140, 141 definition 137 diagnosis audiological testing 149, 150 diagnostic scale 137, 138 di erential diagnosis acoustic neuroma 155, 156 acute hearing loss 155

Subject Index

apoplexia labyrinthi 155 benign paroxysmal positioning vertigo 155 overview 137 perilymph fistula 156 pharmacological side e ects 156, 157 vertebrobasilar insu ciency 156 vestibular neuritis 154 magnetic resonance imaging 154 endolymphatic hydrops pathophysiological model 145, 146 epidemiology 141 etiology of endolymphatic hydrops autoimmunity 143-145 genetics 142 overview 141, 142 psychological factors 142 vascular compression 142 viral factors 143 history of research 138-140 Lermoyez syndrome 153 signs and symptoms aural filllness 152 cochlear function 149-152 oculomotor symptoms 148 subjective complaints 147, 148 tinnitus 152 vestibular-spinal signs 149 treatment aminoglycoside therapy 160, 161 decompression surgery cochleosacculotomy 161, 162 saccotomy 162, 163 transtympanic ventilation tubes 161 drug therapy 158-160 guidelines 158 labyrinthectomy 163 neurectomy of vestibular nerve 163,164 symptom relief 157 Tumarkin otolith crisis 153 Metabotropic glutamate receptors medial vestibular nucleus neurons 40 principles of drug therapy 199 Methylphenidate, nystagmus treatment 204 Muscarinic receptors medial vestibular nucleus neurons anatomical studies 50

244

behavioral studies 51, 52 electrophysiological studies 50, 51 principles of drug therapy 200, 201 Nerve growth factor, modulation of central vestibu lar neurons 69 Neurectomy posterior ampullary nerve 186 vestibular nerve in Meniere's disease management 163, 164 Neurokinins, moduliltion of centml vestibular neurons 66, 69 Nicotinic receptors medial vestibular nucleus neurons anatomical studies 50 behavioral studies 51, 52 electrophysiological studies 50, 51 principles of drug therapy 200, 201 NMDA receptors, medial vestibular nucleus neurons functional plasticity role 46 functional roles and correlation with in vivo data 43 postlesional plasticity role 45, 46 subunits 40 Noradrenaline, modulation of central vestibular neurons central pathways 52, 61 electrophysiological studies 62, 63 receptors 61, 62 Nystagmus see also Acquired pendular nystagmus, Congenital nystagmus, Downbeat nystagmus, Episodic ataxia, Periodic alternating nystagmus, Seesaw nystagmus, Spontaneous nystagmus, Upbeat nystagmus benign paroxysmal positioning vertigo 173, 188, 189 decaying of slow phase 196, 197 phases 195-197 treatment acupuncture 238 base-in prisms 230 botulinum toxin 207, 233-235 contact lenses 237, 238 drugs, see specific diseases and drugs

Subject Index

optical methods for negating visual consequences 230-233 surgery 236 vibratory stimuli 237 velocity reduction and oscillopsia elimination 195, 228, 229 visual consequences 228-230 Ocular flutter clinical aspects 215, 216 drugs causes of flutter 217 therapy 216,217 pathophysiology and experimental studies 216 Ocular myoclonus clinical aspects 214 drugs causes of myoclonus 215 therapy 214, 215 pathophysiology and experimental studies 214 Ocu lomotor nucleus a erent and e erent connections 11 structure and function 10, 11 transmitters 11, 12 Opioid peptides, modulation of central vestibular neurons 65, 66 Opsoclonus clinical aspects 215, 216 drugs causes of opsoclonus 217 therapy 216,217 pathophysiology and experimental studies 216 Oscillopsia causes 196 elimination by nystagmus velocity reduction 195, 228, 229 treatment 197, 198 Paramedian pontine reticular formation a erent and e erent connections 7,8 saccade generation 197 structure and function 6, 7 transmitters 8

245

'-"'-1 ............ '-' ........ '-' JV'

185. 186

Epley maneuver 183. 186 recurrence after therapy 183. 185 Semont maneuver 181, 183, 186 vestibular neuritis management 129, 130, 132

Positional vertigo. see Benign paroxysmal positioning vertigo Prednisolone. Meniere's disease management 159. 160 Prepositus hypoglossi nucleus neurons. membrane properties and gaze control 38. 39

.~

.....

clinical aspects 217. 218 drugs causes of jerks 219 therapy 218 pathophysiology and experimental studies 218 Substance P. modulation of central vestibular neurons 66. 67. 69 Superior oblique myokymia clinical aspects 219 drug therapy 219. 220 pathophysiology and experimental studies 219

Propranolol. nystagmus treatment 204 Rostral interstitial nucleus of the medial longitudinal fascicle a erent and e erent connections 2 saccade generation 197 structure and flJnction 1. 2 transmitters 2. 3 Saccotomy. Meniere's disease management 162. 163

Scopolamine nystagmus treatment 204 vestibular neuritis management 129 Seesaw nystagmus clinical aspects 209 drug therapy 210

Subject Index

Transtympanic ventilation tubes, Meniere's disease management 161 Tridihexethyl, nystagmus treatment 204,210,213

Tumarkin otolith crisis. see Meniere's disease Unilateral vestibular loss see also Vestibular neuritis clinical features and mechanism asymmetrical horizontal vestibuloocular response 85 maintained rolled ocular torsional position 85 spontaneous nystagmus 85 consequences. direct versus indirect 84-86

246