Vestibular Dysfunction and Its Therapy

Advances in
Oto-Rhino-Laryngology
Vol. 55
Series Editor W Arnold, Munich
Basel Freiburg Paris London New York

KARGER 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
Basel Freiburg Paris London New York

KARGER 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)
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Index Medlcus.
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However, in view of ongoing research, changes in government regulations, and the constant flow of information
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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 multidisciplin-
ary 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 sum-
mary 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. How-
ever, 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 vestilm-
lar 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 moti-
lity 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 neuropharmaco-
logical 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 Cur-
thoys 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 move-
ment 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 Institute of Anatomy, Ludwig Maximilians University, Munich and
b 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, at-
tempts 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 uevelup-
ment 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 pa-
tients. 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 high-
frequency 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, up-
and 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 connec-
tions 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 immuno-
cytochemlcal techniques for the detection of amino acid transmitters in cell
bodies. Whereas GABA and glycine are thought to occur in high concentra-
tions 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 transmit-
ter populations, e.g. aspartate and glutamate, had di erent ultrastructural and
synaptic features (synaptic vesicle shape, degree of postsynaptic specializa-
tions) , 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 calcium-
binding 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 func-
tional 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 burster-
driving 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].

There are three main e erent projection systems leaving the iC [Kokkoro-
yannis 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 neu-
rons 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 vestibulo-
oculomotor 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 contra-
lesional 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

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 huri-
zontally 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 monosynap-
tically 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.

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 mon-
key 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 repre-
senting 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; Bottner-
Ennever 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 applica-
tion 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 oculo-
motor 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 investiga-
tors: 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 immunocyto-
chemical 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-

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 con-
tain a di erent calcium-binding protein, calretinin, which could serve as a histo-
logical marker for internuclear neurons [De la Cruz et aI., 1998].

The internuclear neurons project to the motaneurons of the medial rectus
muscle in the contralateral oculomotor nucleus, thereby forming the anatom-
ical 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 oculomo-
tor 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 dend-
rites 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 GABA-
ergic 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

The oculomotor nucleus contains the motoneurons innervating the ipsila-
teral inferior rectus (IR), inferior oblique (10) and medial rectus (MR) muscle
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 sub-
groups 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.

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 glycine-
immunoreactive terminals in the oculomotor nucleus contain GABA as well,
whereas only a small fraction of GABA-positive terminals express glycine-

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 nu-
cleus [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 moto-
neurons 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 [Spen-
cer 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 gluta-
mate 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

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
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 oculomo-
tor 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 hypo-
metric 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).

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

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 para-
flocculus 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 pe-
duncle. The superior cerebellar peduncle decussates in the caudal mesence-
phalon 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 (resti-
form 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 re-
viewed 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.
Molecular
layer
Purk;r.rje
cell
fayer
Granular"
fDyer
- -G"kBA,- - - -5"1,' GILU GLUI White

laltJri II DA ' ACH (ASP) matte".
N~ " GABA
:CH
110
t Fl II rl;l 10
I
Inferior (nive I

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 ear-
lier 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, pontino-
cerebellar 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 anti-
motion 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-
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 modu-
lates the parallel fibre-Purkinje cell transmission [Cuenod et aI., 1989].
The fine-beaded, or varicose, fibres form a thick plexus of fibres terminat-
ing in all layers of the cerebellar cortex (fig. 1). They were thought to constitute
the monoaminergic input to the cerebellum carrying either serotonin, nor-
adrenaline or possibly dopamine [Ito, 1984], but Barmack et a1. [1992aJ report
the presence of cholinergic beaded a erents as well. Thin varicose fibres immu-
nopositive 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 Takat-
suji [1998]. There are only two receptors not evenly distributed: one is the dopa-
mine 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

The fastigial nucleus (FN) is the most medial deep cerebellar nucleus.
Through a erent and e erent connections it is intimately related to the vestibu-
lar 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 17

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 move-
ments 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 oscilla-
tions [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 dorso-
medial 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].
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-GABA-
ergic) neurons [De Zeeuw and Berrebi, 1995J. They also project to the (inhibi-
tory) glycinergic interneurons [De Zeeuw and Berrebi, 1995]. The GABA-
induced 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 de-
monstrated 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 cerebel-
lum and brainstem, and it will take many more years of research to understand
their interactions.
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Pettenkoferstrasse 11, D-80336 Munich (Germany)

Blittner U. (ed): Vestibular Dysfunction and Its Therapy.
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 Neurobiologie des Reseaux Sensorimoteurs, CNRS UPRES-A 7060, Paris, France et

b Departement de Physiologie, Centre Medical Universitaire, Geneve, Suisse
Introduction
Oculomotor and postural stabilizing responses result from a complex multi-

sensory integration, which can be defined as the process of matching multiple
internal representations of an external event (head and/or body movement) ob-
tained through di erent sensory modalities (visual, vestibular and propriocept-
ive) , into a unique, intrinsic frame of reference in which appropriate motor
commands can be coded. It is therefore not surprising that such complex sensori-
motor 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 cor-
rect 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 neurophysiolog-
ical 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 re-
views, 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 inte-
grate (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 post-
synaptic 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 ex-
pressed by vestibular neurons. These di erent subclasses can have markedly
di erent distributions, and their activation often induces distinct electrophysio-
logical 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 messen-
ger RNAs leading to the synthesis of receptors, can be used in various behav-
Intrinsic Properties of Central Vestibular Neurons 27

ioral contexts. Therefore, to understand how the emerging properties of the
vestibular network combine with the physiological and pharmacological prop-
erties 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 intracellu-
lar 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 character-
istics 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.
VidaINibertiSerafin/Babaiian/Miihlethaler/de Waele 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 mem-

brane properties of vestibular neurons in two ways: by quantifying the dis-
charge 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 vesti-
bular 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 actu-
ally 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

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 biomechan-
ical 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 con-
stant velocity rotations. They would specifically input the velocity storage
integrator included in the vestibula-ocular network, which improves the com-
pensatory properties of the VOR at low frequency and in response to long-
duration, 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 corre-
sponding 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 afterhyperpol-
arization (AHP). They also exhibit a transient rectification due to the activation
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, calcium-
dependent 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 oscilla-

tory 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 fol-
lowing 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 antago-
nist, 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.

Neuronal oscillations are by no mean restricted to vestibular neurons.
NMDA-induced oscillations were observed in abducens motoneurons [Dur-
and, 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 connectiv-
ity of the brain is preserved, stable intracellular recordings revealing the in-
trinsic 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 post-
synaptic 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 [Shim-
azu 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
2 3 4
A -l,- >~_) tlLUJ 16

B -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

1O ~ type A VNn

CIl
c:
2:::l 8 type B VNn
'"c:
"-'
6
0
.... 4
15
E
:::l 2
c:
0
A
a N.
0
"l. v.
0 0
"'-
0
"'. "".
0 0
<Xl.
0
"'.
0
q -. N. "l. v.
CV
c:
0
":;l
'"
"@
0,8
0,6

.c type A
type B
....>0 type B+LTS

0,4
i:
"C'"
i:B 0,2
'"0
U B
0,0
5 1O 15 20 25
AHP (mV)
CIl
c:
2:::l
15
10
extracell ular
....'"c:
0
....
.0'"
E
:::l
c:
0 e
N
a a a a a
C') V Ll)
"'. "".
0 0
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0 "'.
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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.
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 mono-
synaptic 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 hyperpolar-
ized. 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 rele-

vance 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 re-
views, 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 activa-
tion 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 [Col-
lewijn, 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.

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 vestibulo-
ocular 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 oscilla-
tions 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 mem-
brane 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
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 proper-
ties. 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 summa-
tion of these long-lasting plateau potentials could be one of the neuronal
mechanisms underlying the velocity storage system included in vestibulo-
ocular networks [Raphan et a!., 1979J. This would fit well with the hypothesis
of Angelaki and Perachio [1993] stating that irregular neurons would specifi-
cally 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

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 stabili-
zation of gaze and posture [for reviews, see Vertes, 1979; Peterson, 1984;
Grantyn and Berthoz, 1987]. They are input by visual, vestibular and somato-
sensory 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
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 [Melvill-
Jones 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 neu-

rons 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 metabo-
tropic 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

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 aspar-
tate 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 recep-
tors, 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 recep-
tors 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
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 AMPA NMOA Trans-ACPO

conditions
potential and resistance potential and resistance potential and resistance
discharge discharge discharge
Type A 20 121 13 114 22 124 7 18 17 120 180

neurons (95%) (93%) (92%) (88%) (85%) (56%)
Type B 20 120 8 18 31 135 14 117 26 126 8

Control neurons (100%) (100%) (89%) (82%) (100%) (25%)
Type
10 110 4 14 13 114 4 15 8 18 6
B LTS
(100%) (100%) (93%) (80%) (100%) (19%)
neurons
12 112 31 131 13 113

TTX
(100%) (100%) (100%)
14 /14 250/31 150/18
(100%) (81%) (83%)
Synaptic 20 120 14 /]4 16 116
uncoupling (100%) (100%) (100%)
Experimen tal Kainate Quisqualate Glutamate

conditions
potential and resistance potential and resistance potential and resistance
discharge discharge discharge
Type A 6 16 6 16 4 15
neurons (100%) (100%) (80%)
Type B 8 19 14 115 5 15 12 113 5 16 4 18

Control neurons (89%) (93%) (100%) (92%) (83%) (50%)
Type
3 13 3 13 I II
B LTS
(100%) (100%) (100%)
neurons
Increase; decrease; 0 no e ect.

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 oscillat-
ory 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; Gal-
lagher 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 glu-
tamate and/or aspartate as transmitter [Cochran et aI., 1987; Dieringer, 1995J.
Finally, the excitatory second-order vestibular neurons which input the con-
tralateral 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 be-

tween 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
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 recep-
tors 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, meta-
botropic 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;

(b) they were absolutely essential to maintain a normal resting discharge ofneu-
rons 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 potenti-
ate postsynaptic I\lMDA receptors, and contribute to decrease the Mg 2 block.
The functional relevance of the glycinergic modulation of NMDA recep-
tors 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 op-
posite direction, revealing a hypoactivity of vestibular neurons. These results
demonstrated that, in vivo, the vestibular NMDA receptors could be modu-
lated through their glycinergic site. The extent to which this may be of func-
tional importance remains to be clarified.
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 ques-
tion 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 er-
ented 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 sug-
gested that they could be strongly involved in the recovery of resting dis-
charge 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 con-
tribute 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 recep-
tor synthesis in both vestibular nuclei, which disappeared during compensa-
tion. 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.,

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 caus-
ally 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 vesti-
bulospinal pathways [for reviews, see Kawato and Gomi, 1992; Cohen et aI.,
1992; du Lac et aI., 1995]. Based on extracellular field recordings, the occur-
rence of such long-term synaptic modulations, and the concomitant involve-
ment 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 [Sivil-
otti 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 recep-
tors 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 demon-
strated that vestibular neurons were endowed with GABAA , both pre- and
postsynaptic GABA s receptors [Holstein et aI., 1992], and glycinergic recep-
tors. 30% of MVNn were shown to be GABAergic neurons expressing glutam-
ate decarboxylase (GAD), the specific enzyme for GABA synthesis [de Waele
et a1., 1994; Holstein et a1., 1996]. These cells would correspond to the inhibi-
tory 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, extracellularly-
recorded 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 in-
hibited (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 spontane-
ously active in the slice and often exerted a tonic inhibition on the recorded
neurons; (b) bath application of GABA and muscimol inhibited these interneu-
rons, 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 -contain-
ing solution, which indicated that MVNn display postsynaptic, strychnine-
sensitive 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.

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
Experimental E ects of GABA E ects of muscimol E ects of baclofen Bicuculline
~
5' conditions
"~ potential discharge resis- potential discharge resis- potential discharge resis- potential resis-
CIl
tance tance tance and tance
~ discharge
"'co-
Ol
CT
g. Control
"'-
3:
Type A 11 /23 22 /23 6 /8 22 /36 36 /36 14 /16 30 /34 31 /34 8 /12 8 /9 7 /7
c'
0- neurons (48%) (96%) (75%) (61%) (100%) (88%) (88%) (91%) (67%) (89%) (100%)
"
8Ol- Type B
neurons
5 /25
(20%)
21 /25
(84%)
9 /9
(100%)
17 /38
(45%)
38 /38
(100%)
13 /14
(93%)
23 /25
(92%)
25 /25
(100%)
120/16
(75%)
7 17
(100%)
7 /7
(100%)
"i l Type 1 /6 6 /6 2 /2 4 /17 17 /17 7 17 13 /13 12 /13 40/6 1 /1 1 /1
"
~ B LTS (17%) (100%) (100%) (24%) (100%) (100%) (100%) (92%) (67%) (100%) (100%)
"" neurons
TTX 7 17 3 /3 15 /15 10 /10 8 /8 3 /6 6 /8 3 /5

(100%) (100%) (100%) (100%) (100%) (50%) (75%) (60%)
Synaptic 6 /6 2 /2 23 /24 6 /6 15 /15 8 /10 30/3 30/3

uncoupling (100%) (100%) (96%) (100%) (100%) (80%) (100%) (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.
.,.
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 interneu-
rons (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 habitu-
ation 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, perfu-
sions 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 er-
ent subtypes of both the nicotinic and muscarinic receptors [for reviews, see
Hosey, 1992; Clarke, 1995].

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 vestibu-
lar 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 re-
versibly suppressed by nicotinic or muscarinic antagonists [for reviews, see Dar-
lington 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
VidalNibertiSerafinlBabaiianlMiihlethaler/de Waele 50
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 es-
terase 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 cho-
linergic agonists and disfacilitated by muscarinic antagonists. Finally, the in-
ferior 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 unilaterallabyrinthec-
tomy. The central cholinergic system could accordingly be involved in vestibu-
lar 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 re-
appearance of the postural syndromes in compensated animal (postural de-
compensation). 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-nod-
ulus has been reported to be strongly involved in the triggering of this syn-
drome. 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-

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 neu-
rons 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, de-
pending 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 modula-
tions 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 dis-
orders like schizophrenia or Parkinson's disease are linked to dysfunctions of
the aminergic systems. Therefore, the importance of monoaminergic modula-
tion 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 recep-
tors 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-
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 somno-
lence. 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 essen-
tial 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 phospho-
lipase 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 feed-
back 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 neu-
rons could be modulated by the histaminergic system. The histaminergic neurons
of the posterior hypothalamus have been shown to project onto the entire vesti-
bular complex [Takeda et aI., 1987] with a predominance for the medial and
superior nuclei [Tighilet and Lacour, 1996]. Autoradiographic and in situ hybrid-
ization 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 his-
tamine 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 methylhis-
tamine 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

-methylhistamine or thioperamide, which are respective agonists and antago-
nists 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 dysfunc-
tions 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 antago-
nists 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 thio-
peramide. We think therefore that one could e ciently modulate the sensitivity
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 seroton-
inergic 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 recep-
tors (5-HT zA , 5-HTzB , and 5-HTzcl are positively coupled with phospholipase
C. Their activation increases the intracellular calcium concentration. The 5-
HT 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-select-
ive channel, induce short-lasting depolarization and would be mainly localized
presynaptically. They are believed to facilitate the release of various neuro-
transmitters, 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 demon-
strated 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 record-
ings (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

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 serotoni-
nergic 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 Serotonin -Methyl-5-HT 8-0H-DPAT 2-Methyl-5-HT

conditions
potential resis- potential resis- potential potential
and tance and tance and and
discharge discharge discharge clischarge
Control
Type A 25 /37
neurons (68%) 7 /8 4 /4 1 /1 30/3 40/4
8 /37 (87%) (100%) (100%) (100%) (100%)
(21%)
Type B 48 /54
or (89%) 14 /15 12 /12 2 /2 60/8 50/7
B LTS 6 /54 (93%) (100%) (100%) (75%) (72%)
neurons (11%)
TTX or synaptic uncoupling'

lYpe A 3 /16
neurons (19%)
120/16
(75%)
lYpe B 15 /20
or (75%) 10 /10
B LTS 20/20 (100%)
neurons (10%)
Increase; - decrease; 0 no e ect.

1In 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).
being more sensitive than the type A neurons. Moreover. serotonin directly acti-
vated postsynaptic receptors on type B MVNn, whereas excitation of type A
MVNn was indirect. As previously shown [Johnston et aI., 1993], -methylsero-
tonin (a specific agonist of 5-HTz receptors) reproduced the depolarizing e ects
ofserotonin. which were however only partly blocked by ketanserin (an antago-
nist 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 inac-
tivation of potassium conductances [Bobker, 1994]. Similar depolarizations, ac-
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 dis-
play excitatory responses probably mediated through 5-HT2 receptors, inhibi-
tory 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 neuromodu-
lator 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 dopa-
minergic 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 nigrostria-
tal 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-

fundibular pathway originates from dopaminergic neurons located in the hypo-
thalamus, 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. Dopa-
minergic 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 pre-
and 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 pre-
synaptic 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 con-
ductances [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
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
Experimental Dopamine (1 mAt) Piribedil DA(IOO At) Quinpirole SKF-38393
'"
::+
[f conditions
o potential discharge resis- potential discharge resis- potential potential discharge potential and
....,
n tance tance discharge
'~"
eo. Control
~
5'
Type A 19 /30 13 (68%) 7 /12 13 /16 5 (38%) 6 /9 4 /10 3 /3 3 /3 20/2
E.
neurons (63%) 4 (21%) (59%) (81%) 4 (31%) (67%) (40%) (100%) (100%) (100%)
e; 20(11%) 40(31%)
z Type B 34 /41 24 (71%) 12 /22 23 /30 10 (43%) 17 /20 4 /9 7 /8 5 (72%) 80/8
'"
a or (83%) 8 (24%) (55%) (77%) 9 (39%) (85%) (44%) (87%) 1 (14%) (100%)
iii 20(5%) 40(18%) 10(14%)
B LTS
neurons
-
TTX 7 /13 30/5 6 /8 not
(54%) (60%) (75%) tested
Synaptic 8 /10 3 /3 6 17 not

uncoupling (80%) (100%) (86%) 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">
<D
resistance, and mediated through 'Dz-like' receptors. This result was rather
unusual in the sense that activation of postsynaptic 'Drlike' receptors is gener-
ally 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 hyper-
polarizing e ects as in synaptic uncoupling conditions; (d) similar presynaptic,
inhibitory e ects of dopaminergic agonists on the release of various neuro-
transmitters 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 ejec-
tions 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' dop-
aminergic 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
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 brain-
stem. 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 situ-
ation, 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 trans-
mitter release, the postsynaptic ones activate potassium channels. thus decreas-
ing 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

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 intracellularly-
recorded 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 Noradrenaline Clonidine Isoproterenol L- P henylephrine

conditions
potential resis- potential resis- potential res is- potential resis-
and tance and tance and tance and tance
discharge discharge discharge discharge
Control
Type A 20 /44
neurons (45%) 5 /6 4 17 1 /1 6 /10 1 /1 3 /5 2 /2
9 /44 (83%) (57%) (100%) (60%) (100%) (60%) (100%)
(21%)
Type B 35 /52
or (67%) 11 /14 9 /15 3 /5 15 /24 4 /4 10 /17 3 /4
B LTS 9 /52 (79%) (60%) (60%) (63%) (100%) (59%) (75%)
neurons (17%)
TTX 1 17 8 /20 5 /15

(14%) (40%) (33%)
3 (33%)
4 /4 11 /18 6 /8 5 /8
3 (33%)
(100%) (61%) (75%) (63%)
30(33%)
Synaptic 5 17 4 /20 4 /15
uncoupling (72%) (20%) (27%)
numerous in the lateral and superior subnuclei, 2 receptors are mainly local-
ized 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 be-
tween type A and type B cells. Isoproterenol, (a receptor agonist) depolarized
about 60% of MVNn while decreasing their membrane resistance. L-Phenyl-
ephrine (an I receptor agonist) also depolarized about 60% of MVNn but, in
contrast to isoproterenol, while increasing their membrane resistance. Finally,
clonidine (an 2 receptor agonist) hyperpolarized most MVNn, while decreas-
ing 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 modi-
fied 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 norad-
renergic modulation of vestibular neurons could therefore be essential to regu-
late 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 informa-
tion 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 nor-
adrenaline than type A cells. This makes sense if the type B cells really corre-
spond 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

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. Nor-
adrenaline 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 neuro-
peptide 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 I
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 periventric-
ular 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
vestibular nucleus. In situ hybridization studies have revealed that they corre-
sponded 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 labyrinth-
ectomy, 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 -endor-
phins, respectively. In the brain, opiate receptors generally activate inwardly-
rectifying 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 struc-
tures 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].

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 postsyn-
aptic 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 neu-
rons. The decrease mediated by met-enkephalin was dose-dependent, sug-
gesting that this peptide could be used as a neurotransmitter in the
cerebellovestibular pathways (like somatostatin). On the other hand, the leu-
enkephalin 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 enke-
phalinergic 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 vestibu-
lar nucleus [for reviews, see de Waele et aI., 1995; Vibert et aI., 1996]. These
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 intracellularly-
recorded MVNn are given for type A. type B and type B LTS neurons
Experimental Substance P Agonists E ects of various tachykinin

conditions receptor agonists on
potential resis-
and tance' neurons neurons
discharge depolarized hyperpolarized
by by
Control substance P substance P
Type A 19 /49 8 /12
neurons (39%) (67%) GR-73632 120/14 3 /3
4 /49 2 /2 (86%) (100%)
(8%) (100%)
Type B 46 /67 16 /25 Sar Met-SP 80/8 1 /1
neurons (69%) (64%) (100%) (100%)
6 /67 I /1
(8%) (100%) Pro-substance 20/2 not tested
Type II /18 3 /6 P (100%)
B LTS (61%) (50%)
neurons 2 /18 1 /l Neurokinin 50/5 not tested
(12%) (100%) A (100%)
TTX 16 /23 6 /7
GR-64349 50/5 not tested
(70%) (86%)
(100%)
3 /23 2 /2
(13%) (100%)
Senktide 70/7 not tested
Synaptic 6 /8 (100%)
uncoupling (75%)
2 /8 2 /2 Substance 60/6 2 /2
(25%) (100%) P,-, (100%) (100%)
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) propor-
tion 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

Fig 3. Summary diagram of the neurochemistry of vestibulo-oculomotor and vestibulo-
spinal 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 somatosta-
tin; VCR vestibulocollic reflex; VER VOR vertical vestibulo-ocular reflex; VSR vestibu-
lospinal reflex.
VidalNibertiSerafinlBabalianlMiihlethaler/de Waele 68
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 immuno-
histochemical 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, intrasys-
temic injections of ACTH accelerate the recovery of the postural and oculomo-
tor 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.

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 under-
taken 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 emer-
ging properties of vestibular networks and the individual properties of each
VidalNibertiSerafinlBabaiianlMiihlethaler/de Waele 70
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. Need-
less 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 Founda-
tions, 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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Buttner U. (ed): Vestibular Dysfunction and Its Therapy.
Vestibular Compensation
Ian S. Curthoysa, G. Mjchael Halmagyjb

a Department of Psychology, University of Sydney, N.S.W, and
b 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 signifi-
cance and its potential value as a model for understanding the neural mecha-
nisms 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 identi-
cal 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 well-
compensated 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.
Vestibular Compensation 83
(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 sys-
tems. 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 second-
ary consequences which are additional sensory consequences resulting from
Curthoys/Halmagyi 84
Table 1. Clinical feature as related to physiological mechanisms
Clinical feature Probable physiological mechanism
Spontaneous nystagmus
With head stationary there is a vigorous rhythmic The UL results in loss of semicircular canal input
nystagmus with mainly horizontal components. The to one vestibular nucleus resulting in a large imbal-
quick phases are directed away from the a ected ear. ance in activity between the average neural resting
The nystagmus strength decreases over the following discharge between the two vestibular nuclei. Such a
days. Visual stimuli suppress this spontaneous nys- neural imbalance would occur during a very large
tagmus so Frenzel lenses or equivalent means are angular acceleration in the horizontal plane and
necessary for observing it. horizontal eye movement is the appropriate re-
sponse to such a stimulus.
Asymmetrical horizontal VOR response

Reduced or absent eye movement response to sud- During horizontal head accelerations to the ipsile-
den unpredictable horizontal head movements to- sional side the relatively weak disinhibition relayed
wards the lesioned ear. Slightly reduced response from the intact labyrinth is the only source of ocu-
for head movements towards the intact side. lomotor drive. For rotations to the contralesional
side the usual facilitation takes place. Brief natural
head accelerations reveal this asymmetry - slow un-
natllfal sinusoidal stimuli do not.
Maintained rolJed ocular torsional position

After UL both eyes are rolled around the visual Absence of otolithic and vertical canal input pro-
axis towards the lesioned side. This is large (around duces an imbalance in resting discharge between the
9-10) shortly after the lesion and decreases over two vestibular nuclei, eqUivalent to the imbalance
the first weeks after UL. There is a corresponding during a maintained roll-tilt to the intact side in a
perceptual deviation: short lines in an otherwise healthy person.
darkened room appear to be roll-tilted by the same
amount as the ocular torsion [Curthoys et a1., 19911.
the inadequate motor response to the vestibular stimulus. The following elabo-
rates 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.
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 com-
pensate 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 vestibu-
lar 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 mech-
anisms involving anatomical changes, such as axonal sprouting, later in com-
pensation. 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 compensa-
tion (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 per-
ceptual responses are appropriate for such a natural stimulus.
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 Midposition Horizontal nystagmus Nystagmus Yes

position to the intact side disappears
Torsional eye Upright Both eyes roll to the Eye torsion Yes
position lesioned side decreases
Sensation of felt Upright and stable Sensation of turning Vertigo disappears Yes
body position (vertigo)
Dynamic horizontal Compensates for Inadequate for VOR gain No

VOR head rotation in ipsilesional rotations; asymmetry persists
both directions VOR gain asymmetry
Axis of eye rotation Aligned with axis Eye axis is misaligned Misaligned No
of head rotation
Posture Normal FaIJs to the a ected Posture is normal Yes
side
Gait Normal Ataxic and turns to Gait returns to Yes
the a ected side normal
Figure 1 shows the neural equivalence of UL-induced SN and rotation-

induced nystagmus, based on the known anatomical and physiological connec-
tions 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
Qukll; !thB_
sr~
~ .. 11111: IJ
Fjg 1. The equivalence of horizontal head rotation (A) and unilateral loss (B) in generat-
ing 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 contralat-
eral 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; Mark-
hametal., 1977,19781.
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, prob-
ably 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
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 responsi-
ble for the absence of nystagmus at later times after UL. This seamless inter-
twining of di erent neural processes responsible for the same behavior must
be borne in mind in considering the neural mechanisms of vestibular com-
pensation.
Dynamic Responses
Rotational Tests
Objective measures of purely vestibular dynamic response (Le. eye move-
ments 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
CUfthoys/Halmagyi 90
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 com-
pensated 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 cumpar-
able 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
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 gener-
ate 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 re-
sponse: 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 post-
operative period had abnormal postural control in conditions where the move-
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 pre-
sumed 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 post-
UL 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 chal-
lenge 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
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 compo-
nents 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 inad-
equate 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, low-
frequency 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 neu-
roma removal can show good performance on such low-frequency sinusoidal
rotation tests [Halmagyi and Curthoys, 1987J. With the natural head accelera-
tions 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
A
Fig 2. A In a normal
healthy person during head
rotation, the velocity of eye
rotation is equal and oppo-
site to the head rotation. The
axes of both eye and head
rotation are parallel. B In a
patient after unilateral vesti-
bular 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
B image to be smeared.
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. Experi-
mental 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 asym-
metry. 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 pa-
tients probably rely more on learning other behavioral responses (such as
blinks) than on potentiation of VOR gain, has profoundly important implica-
tions 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
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 vestibu-
lar 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 tran-
quilizers, 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 vestibu-
lar 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
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 re-
duced 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 oculomo-
tor 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: 2-
deuxyglucose 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
CUfthoys/Halmagyi 98
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 con-
tinuously 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 preopera-
tively. 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 semicircu-
lar canal stimulation, these ipsilesional type I VN neurons must be driven
indirectly via the disfacilitation of the contralesional semicircular canal pri-
mary 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
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 demon-
strated 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 anatom-
ical 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].
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 com-
pensation 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 commis-
sural 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 physiologi-
cal 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 cervical-
spinal 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 er-
ent 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

intervals and probably ensure the permanence of the recovery. Of the short-
term 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 com-
plex. 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
new guinea pig isolated whole brain preparation allows even more comprehen-
sive 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 phenom-
enon 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 be-
tween 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

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. Con-
currently 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 per-
ception. 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
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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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 ianc@psychvax.psych.su.oz.au
Buttner U. (ed): Vestibular Dysfunction and Its Therapy.
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) vesti-

bular 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 popu-
lation [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 rota-
tional 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
R
J
I~ Fig 1. Ocular signs, perception (vertigo,
subjective visual vertical, and subjective
straight ahead), and posture in the acute
L
stage of right-sided vestibular neuritis. Spon-
~ Vertigo
taneous vestibular nystagmus is always hori-
zontal-rotatory away from the side of the
lesion (best observed with Frenzel's glasses).
The initial perception of apparent body mo-
tion (vertigo) is also directed away from the
~
Ocular torsion
side of the lesion, whereas measurable desta-
bilization (Romberg fall) is always toward
Subjective visual vertical the side of the lesion. The latter is the com-
Subjective straight ahead pensatory vestibulospinal reaction to the ap-
parent 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].
Strupp/Brandt liZ
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 spontane-
ous nystagmus (contraversive) with oscillopsia, and (4) nausea and vomiting.
Ocular motor evaluation reveals apparent horizontal saccadic pursuit, gaze-
evoked 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, hypo-
or 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 oppos-
ite to the fast phases [9]. Subjective straight-ahead and tilts of perceived
Vestibular Neuritis 113

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.
Strupp/Brandt 114
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 clus-
tered 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 stimu-
lation 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

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 compo-
nent (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
Strupp/Brandt IIG
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 30C 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 vesti-
bular 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 menin-
gitis. 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-fre-

quency defect of the VOR in patients whose semicircular canal function is
not restored. Ewald's second law [21], which states that horizontal canal func-
tion has a directional asymmetry, predicts this: ampullopetal stimulation (cup-
ula deflection toward the utricle) during ipsiversive head rotation is more

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 Tl-
weighted 2-D FLASH sequence with gadoliniwn-
c DTPA: 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 en-
hancement 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 ar-
row) is seen; the cochlear nerve is indicated by the
short arrow [from 82].
Strupp/Brandt 118
h~a'lthy con1ml I onoU
FUGHT lab)! nih
_ HEAD IilOrAiItON
21
I ~ L
~l
a 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 ut-
ricle) during contraversive head rotation. Electrophysiological studies of pri-
mary 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 rota-
tion 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.

This indicates a unilateral high-frequency deficiency of VOR, produced by
functional asymmetry of the remaining labyrinth. Furthermore, the well-
known 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 high-
velocity 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 syn-
drome 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 diag-
nosis 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 posi-
tional nystagmus) which were detected by careful neuro-ophthalmological
examination. A central cause was always suspected prior to MRI. The two
Strupp/Brandt 120
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 semicir-
cular 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-

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 pa-
tients 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 nystag-
mus, 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 depo-
larization). 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
Strupp/Brandt 122
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 oppo-
site direction to head acceleration and transduce the sensation of head motion.
Sensorimotor transformation proceeds via canal planes to planes of eye move-
ments 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 pos-
tural 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 indi-
vidual, 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

Fig 7. VN. a partial labyrinthine
lesion with horizontal semicircular ca-
nill piln~sis: Vilsflllilr or virill p.tiology?
Vasculature
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 spar-
ing the inferior division. the func-
tioning of which is necessary for the
simultaneous occurrence of VN and
benign paroxysmal positioning nystag-
mus on the same side. AC Anterior
Innervation 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 investi-
gations by these authors found degeneration of the nerve fibers leading to the
Strupp/Brandt 124
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 com-
bined 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 laby-
rinthine 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] distingu-
ished between acute viral labyrinthitis (cochlear and/or vestibular). acute viral
neuritis, and delayed endolymphatic hydrops as the sequel to labyrinthitis. Sim-
ilarly, viral cochleitis is a convincing explanation for sudden idiopathic sensorin-
eural 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 vesti-
bular 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

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 blood-
brain barrier or local immunoglobulin production (rising antibody titers) or
to demyelination of the vestibular nerve [53]. Increases in various seI'Um anti-
body 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 autop-
sied human vestibular ganglia by using polymerase chain reaction [24] (fig. 9).
Strupp/Brandt 126
14 Fjg 9. Polymerase chain reaction show-
. ().2 ing HSY-I DNA in a human vestibular gan-
~ glion. 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 obser-
vation 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 sup-
port of viral etiology must be critically weighed against each other, particularly
with respect to the therapeutic consequences.

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 move-
ments, 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 cen-
trally compensated lesion regains function. 'Erholungsnystagmus' then reflects
a tone imbalance secondary to compensation. Bechterew's phenomenon, a re-
versal 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 ofsponta-
neous 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 compensa-
tion' [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 symp-
toms 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).
Strupp/Brandt 128
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 sub-
stances 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 accord-
ing to current knowledge of vestibular physiology (table 1), also called vestibu-
lar rehabilitation [33]. Vestibular exercises consist mainly of eye, head, and
body movements designed to provoke a sensory mismatch; they enhance com-
pensatiun 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].

en
0"
0)
30
:s
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0)
25
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..:3
'0; 20 control
,---- !
.9-
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o vestibular exercises
..... 15
0
'~i:::::~!
"
.2
El
e
0
10
,.,
-0
U
5
0 10 15 20 25 30
time (day after symptom onset)
lOA
Ol)
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'";;
.;; 10
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.:: control
t3
B ";; vestibular exercises
~
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~

.~
.~
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0
0 10 15 20 25 30
lime (day after symptom onsel)
lOB
Fjg 10. A Time course of the changes of cyclorotation (compare with figure 3) of the
eye ipsilateral to the peripheral vestibular lesion in the control and physiotherapy groups:
there is no di erence between the two groups, i.e., vestibular exercises have no e ect on
vestibulo-ocular functions. There was always an ocular torsion ipsiversive to the peripheral
vestibular lesion (part of the incomplete ocular tilt reaction), which normalized over time.
The dotted line indicates the normal range (mean 2 SD: -I to 11.5). B Time course of
the deviations of the subjective visual vertical in the control and physiotherapy groups:
there is no di erence between the two groups, i.e., vestibular exercises have no influence on
perceptional functions. Patients with VN always exhibited a deviation toward the side of the
lesion, which normalized over time. The dotted line indicates the normal range
(mean 2SD 2.5).
Strupp/Brandt 130
45
40
35
---. control
t::
30
' o vestibular exercises
1
'i-I--"r,"
25
-5 20
'";>-.
0.
15
'"~
(/)
10
5
------------,.-~'-"-'-2n~20
0
0 10 15 20 25 30
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 compensa-
tion. 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
total SP - (calculated as ( ( x 2 y2 )). There was a significant di erence (ANOVA,
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 pro-
mote 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 peri-
pheral 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

Table 1. Physical therapy for acute, unilateral labyrinthine lesions
Clinical stage Physical exercise Strategy
1. Approximately days 1-3

Nausea No exercise; bed rest Prevent falls
Spontaneous nystagmus with Head immobilization Avoid active head accelerations
fixation leading to 'cross-coupled' e ects
Eyes closed Avoid visual-vestibular mismatch
II. Approximately days 3-5
No spontaneous nausea Exercise in bed (supine and sitting)
with rapid mobilization
Incomplete suppression of I) Fixation straight ahead; Visual control of stabilization of
spontaneous nystagmus by voluntary saccades and eccentric gaze in space by suppressing
fixation straight ahead gaze-holding (l0, 20, and 40 spontaneous nystagmus through
horizontaVvertical) ; voluntary fixation impulse
reading exercise (retinal slip)
Smooth pursuit (finger movements Visually guided control of
or pendulum 20-40; 20-60 0 /s) target fixation
Active head oscillations with Provoke vestibular stimuli for
fixation of a stationary target at recalibration of VOR under
1 m distance (0.5-2 Hz; 20-30; visual control of retinal slip of
yaw pitch roll) the viewed target
2) First balance exercise-free Circulatory training, prophylaxis
sitting and stance and gUided gait of thrombosis
(eyes open, eyes closed)
III. Approximately days 5-7
Suppression of spontaneous 1) Static stabilization: Recalibrate visuovestibulo-
nystagmus with fixation Four point stance. Stance on spinal reflexes for postural
gaze nystagmus in the one knee and one foot control and eye-head
straight ahead, but continued Upright stance (eyes open/eyes coordination during free body
direction of fast phase, and closed; head upright/head extension) movements
spontaneous nystagmus with 2) Dynamic stabilization: Smooth
Frenzel's glasses 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)
IV Approximately weeks 2-3
No spontaneous vertigo Complex balance exercise, successive Expose the subjectively
Weak spontaneous nystagmus increase in di culty, above the 'recovered patient' increasingly to
with Frenzel's glasses demands for postural control under unstable body positions in order
everyday conditions to facilitate rearrangement and
recruitment of control capacities
Strupp/Brandt 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 peri-
pheral vestibular lesions is both dynamic and fragile [86]. Alcohol, phenobar-
bital, 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 decompensa-
tion. 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) advocat-
ing 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.
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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 mstrupp@nefo.med.uni-muenchen.de
Strupp/Brandt 136
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. There-
fore, 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 AAO-
HNS (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 compart-
ments of the cochlea developed in completely di erent regions (fig. 1).
Hamann!Arnold 138
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 homeo-
stasis of the endolymph (fig. 2).
Merrie'res Disease 139

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 im-
paired 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 peri-
lymphatic 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. Schu-
knecht [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.
Hamann!Arnold 140
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 ac-
cording 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 sup-
ported 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
Meniere's Disease 141

of patients not su ering from Meniere's disease, in the form of delayed endo-
lymphatic hydrops [68J.
Fundamental far the possible development of the mechanism in Meniere's
disease is the assumption that endolymphatic hydrops is caused by an imbal-
ance of endolymph production in the stria vascularis and endolymph reabsorp-
tion in the endolymphatic sac, in other words either by overproduction or a
reduced absorption of the endolymph. The di erent hypotheses must be mea-
sured 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 Men-
iere'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 somatopsycholog-
ical 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 compres-
sion 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].
Hamann!Arnold 142
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 (in-
flammatory) 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 immuno-
suppressives. 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 endo-
lymph sac presents as a site of immunological defense was made by Rask-
Anderson 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

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 responsi-
ble, 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 reac-
tions. This determines the decisive defense mechanism in the inner ear. Al-
though 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 subepithel-
ial 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 hy-
drops 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 obser-
vations 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
Hamann!Arnold 144
Exogenous agent (e.g. virus)
~ Via coch ear windows or bloodstream

Cochlear immmunoreaction
~ Via endolymphatic flow

Inflammation of the saccus endolymphatlcus (SE)
~ Chroniflcatlon
Rbrous tissue and ossification In the (SE)
~
:~::~::~:ti:n K:f the endolymph
nce
DiSlur
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 inter-
preted as immunological, autoaggressive, and tissue-damaging reaction. There-
fore, 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 endo-
lymph 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-

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.
Hamann!Arnold 146
1. Normal 2. Endolymphatic hydrops
Membranous
labyrinth adherent _.-------------
~/ Perilymph to bony wall
Membranous labyrinth~~ \
~ Endolymph
Endolymphatic duct
'I? p-
. }
00 0
S
ense organ
~~~~=c,.,..JjU ' I' Internal auditory canal

Cerebrospinal fluid Decreased resorptive
(subarachnoid space) function of the
endolymphatic sac
3. Rupture of membranous labyrinth 4. Healed membranous labyrinth

and recurring hydrops
Partial collapse Endolymph
of membranous reaccumulating
~
Iabyrlnth
Rupture
Healed rupture
"8~~'" Potassium
K" .... contamination of
perylymph with Permanent
paralysis of sensory alterations
and neural tissues 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

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 Men-
iere'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 intoxica-
tion 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 provoca-
tion 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 bal-
anced reaction on rotational stimuli or a directional preponderance corre-
sponding 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 dis-
ease. 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.
Hamann!Arnold 148
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 recruit-
ment' which was proven in the Fowler test (positive in 73-100% according to

125 250 500 1,000 2,000 4,000 8,000 Hz
-10
til
E-O
0
z
10
A 20
30
B 40
50
60
C 70
80
90
100
110
120
1,500 3,000 6,000 12,000
Hg 6. Typical form of pure tone audiograms in patients with Menihe's disease.

A 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 ophthalmo-
logy, 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
Hamann!Arnold 150
2 ms
f----------1
Fjg 7. Electrocochleographic potential of a patient with endolymphatic hydrops: patho-

logic 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 poten-
tial 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] intro-
duced 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

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 manage-
ment 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 explana-
tion 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.
Hamann!Arnold 152
Special Forms
Lermoyez Syndrome
In 1919, M. Lermoyez [57] described a recidiving of vertigo attacks accom-
panied 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 pseudo-
movement in a vertical direction. 'Drop attacks' occur without warning, with-
out 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 character-
istics, 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 neu-
rectomy.

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 radi-
ography, 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. Interes-
tingly, 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.
Hamann!Arnold 154
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 vestibu-
lar portion of the eighth cranial nerve in the internal auditory canal. The

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 compart-
ments, 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 diagno-
sis 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 symp-
toms 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-
Hamann!Arnold 156
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 thera-
peutic 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.

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 1. Dizziness has no e ect on activities at all.
following formula: 2. Dizziness does not necessitate changes in
XlY numerical value (rounded to plans or activities.
the nearest whole number) where X is the 3. Dizziness necessitates some changes in
average number of definitive spells per plans.
month for the 6-month period 18-24 4. Patient is able to engage in essential activi-
months after therapy and Y is the average ties but constant adjustments are required.
number of definitive spells per month for 5. Patient is unable to work, drive, take care
the 6 months before surgery. The resulting of a family member, or do most active
value is used to classifY the patient as fol- things. Even essential activities are limited.
lows: 6. Patient has been disabled for 1 year or
longer and receives compensation.
Class Numerical value
A 0
B 1-40
C 41-80
D 81-120
E 120
F 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 accom-
panied by severe attacks of vertigo, agents with sedative and antiemetic proper-
ties 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, espe-
cially 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
Hamann!Arnold 158
Table 4. Drug management of Meni~re's disease
Acute stage
Symptomatic Dimenhydrinate 150 mg supp. or
Dimenhydrinate 62 mg Lv.
'Etiologic'
1st day 1.000 mg prednisolone Lv. 2 150 mg ranltidine
2nd day 1,000 mg prednisolone Lv. 2 150 mg ranitidine
3rd day 1,000 mg prednisolone Lv. 2 150 mg ranitidine
or
100 mg prednisolone orally 150 mg ranitidine for 2 days
IO mg prednisolone orally 150 mg ranitidine for 2 days
2.5 mg prednisolone orally 150 mg ranitidine for 2 days
Chronic stage
betahistine 3 12 mg/day 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 diur-
etics 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.

In recent years, glucocorticoids have been frequently used in the treatment
of Meniere's disease as a direct consequence of the possible immunopatho-
genesis of endolymphatic hydrops [108] (table 4). However, controlled long-
term 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 corti-
costeroids 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. Ini-
tially, 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 ther-
apy 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 de-
stroyed 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,
Hamann!Arnold 160
in some cases, observed as a result of an earlier intratympanical application
of streptomycin. A reduction of endolymph production leads to a decom-
pression 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 strepto-
mycin has been shown in animal experiments to be more destructive to vestibu-
lar 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 at-
tempted 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-

lymphatical space. Based on these findings he developed the 'cochleosacculo-
tomy', 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 in-
creased rate of hearing deterioration. Therefore this technique is mainly re-
commended 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 devel-
opment 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 mastoidec-
tomy. Based on these data they could not find a significant therapeutic di er-
ence 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 mastoi-
dectomy 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
Hamann!Arnold 162
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 menin-
gitis 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

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.
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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
Hamann!Arnold 168
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 nystag-
mus 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 poster-
ior 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 accelera-
tion. 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 (diminu-
tion 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, disper-
sion 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. Combina-
tions are possible, and transitions from p-BPPV to h-BPPV occur, if the clot
moves from one to the other semicircular canal. Transitions from canalolithi-
asis 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, verte-
brobasilar 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.).
Patients with typical BPPV report attacks of rotatory vertigo, postural

imbalance, and sometimes nausea preCipitated by the following maneuvers:
l3randt 170
(a) sitting up from a supine position (particularly after awaking in the morn-
ing); (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
Benign Paroxysmal Positioning Vertigo 171

Fig 1. Precipitating positioning maneuvers for typical posterior semicircular canal
BPPV: lateral head-trunk tilt toward the a ected ear.
Brandt 172
latency of seconds, rotatory vertigo and positioning nystagmus occur in a
crescendo/descrescendo mode. The horizontal rotatory nystagmus beats to-
ward 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 ever-
lessening 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 canaloli-
thiasis 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 nystag-
mus without concomitant subjective vertigo, although some lesions around
the fourth ventricle may also induce very violent vertigo and nausea. Central

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 Wald-
enstrOm'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 long-
continuing 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 [Schu-
knecht, 1962, 1969; Schuknecht and Ruby, 1973], who postulated a mechanical
pathogenesis, which they termed cupulolithiasis'. They found basophilic de-
posits 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, gravi-
tate 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 centrifu-
ging 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
Brandt 174
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 [Ga-
cek, 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

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 correspond-
ence 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 poster-
ior 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 laby-
rinthitis, 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 posi-
tioning 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.
Brandt 176
A B C
Fig 3. 'Canalolithiasis'; schematic representation of a free-floating' heavy clot' of oto-

conial 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 vesti-
bular habituation e ects [Steenerson and Cronin, 1996; Smouha, 1997], canalo-
lithiasis 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 back-
ward 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

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.
l3randt 178
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 intract-
able 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 instanta-
neously 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 Kash-
garian, 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

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 sex-
adjusted 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 retrospec-
tive 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 stimu-
lation of the posterior semicircular canal; to remain in the position until the
l3randt 180
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 se-
quence, 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 (poste-
rior 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

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
Brandt 182
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 (ampullofu-
gal), 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 at-
tempts 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-

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 184
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 nystag-
mus 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 Brandt-
Daro 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 p-
BPPV (horizontal canal: 3, anterior canal: 2) after they had undergone liber-
atory maneuvers [Herdman and Tusa, 1996]. 'Canalithjam' is another specula-
tive 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.'

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 pro-
longed 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, how-
ever, 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 com-
plied with before the possibilities of physical therapy are completely exhausted.
This view is shared by Epley [1995], who has invented his own e ective liber-
atory procedure. He believes that the disability ensuing from multiple, unpre-
dictable 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 sensorineu-
ral 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 El-
Naggar, 1994J. Possible complications are surgical labyrinthitis with reversible
Brandt 18G
ataxia and sensorineural hearing loss, which also mostly recovers, or inadver-
tent 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, Pag-
nini 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 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

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' [Ba-
loh 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.
l3randt 188
AY~~~~........J"".I""""""'-'---: 40"
B
I~
}to"
C ~
lW I
,,
.~~I4oP
L
1-
5S .
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 pathogno-
monic sign of central vestibular disturbance. However, it can indicate occa-
sional 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

in about 20%, or the result of physical liberatory maneuvers for treating p-
BPPV (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 h-
BPPV 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 clin-
ical 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 semicircu-
lar 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 config-
uration 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 transi-
ent 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
0
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 repeti-
l3randt 190
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 main-
tained 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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Klinikum crosshadern, Marchioninistrasse 15, 0-81377 Munchen (Germany)
Tel. 49 89 70 95 25 70/1, Fax 49 89 70 95 88 83
13randt 194
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 optoki-
netic nystagmus (OKN) , This nystagmus helps to stabilize the visual environ-
ment, However, in pathological nystagmus with both the head and visual
surround stationary, the eye movements cause movements to the visual sur-
round on the retina, called oscillopsia, which are the most frequent of com-
plaints 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 down-
beat 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 percep-
tion 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 nys-
tagmus, 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 ves-
tibular 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 prae-
positus 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 gaze-
evoked nystagmus and characteristically the slow phase decays exponentially.
The null-position does not have to coincide with the midposition of the eye,
BiittnerlFuhry 196
i.e. gaze straight ahead. It has indeed been shown experimentally that the null-
and 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 com-
pletely 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
Drug Therapy of Nystagmus and Saccadic Intrusions 197

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, -amino-
butyric 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 norad-
renaline, 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
BllttnerlFuhry 198
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 ( -amino-
3-hydroxy-5-methyl-4-isoxalone-propionic acid) subtypes and metabotropic
receptors. In neurons, which act on NMDA receptors, glutamate can be co-
localized 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-
Drug Therapy of Nystagmus and Saccadic [ntrusions 199

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 musci-
mol 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-antago-
nist 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. Barbitu-
rates 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 (meta-
butrupic) receptors. Buth classes uf receptors have beell detected ill all vesti-
bular 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,
BllttnerlFuhry 200
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 distri-
bution 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 behav-
ioral 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 (acetyl-
choline-esterase inhibitor) might be beneficial in some central vestibular dis-
orders (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 clin-
ically 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,

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 semicir-
cular 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 compensa-
tory downward beating quick eye movements [1 OOJ. Accordingly, experimental
ablation of the flocculus and paraflocculus invariably produces downbeat nys-
tagmus [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 nystag-
mus 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 down-
beat nystagmus. the influence of anticholinergic drugs seems to be potentially
beneficial. In a double-blind. randomized study [IIJ the centrally acting scopol-
amine and benztropine were tested in comparison to the peripheral acting
BiittnerlFuhry 202
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) I
Upbeat: Dieterich et aI., 1991 (2/2)
PAN: Halmagyi et aI., 1980 (2/3); Carlow, 1986 (2/2); Isago et aI., 1985 (l/q
SSN: Carlow, 1986 (1/1)
CN: Yee et aI., 1982 (417)
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: Gay et aI., 1969 (oral 60 mg/day) (111)
MSWJ; 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)

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: Fowler. 1976 (2 mg/kg/24 h) (2/2 infants)
SOM: 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 macro-

square wave jerks; OM ocular myoclonus; PAN periodic alternating nystagmus;
SSN seesaw nystagmus; SWJ square wave jerks.
BiittnerlFuhry 204
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 demon-
strated 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 inves-
tigation, 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 GABA-
ergic 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. Conver-
gence can increase and decrease upbeat nystagmus or convert it to downbeat

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 nystag-
mus. 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 me-
dulla 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 imbal-
ance 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 ven-
tral 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 musci-
mol 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.
BiittnerlFuhry 206
Besides intramuscular or retrobulbar injection of botulinum toxin A [see
chapter by LeighJ there are no other systematic studies showing an improve-
ment 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 implica-
tions were derived using both cholinergic or anticholinergic acting drugs [138].
Drugs causing upbeat nystagmus: Upbeat nystagmus with tobacco con-
sumption (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 neuromyo-
tonia. 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.

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 mi-
graine is often combined with nystagmus and ataxia. There is evidence that
attacks in episodic ataxia are linked with abnormally high intracellular cerebel-
lar 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,

161, 164]. Prolonged treatment can lead to long-lasting improvement. Side
e ects such as hyperhydrosis, paraesthesia, muscle sti ening and easy fatig-
ability 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 phenobar-
bital 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 consid-
ered as a special form of congenital nystagmus [100].

PAN is closely associated with the 'velocity storage' mechanism of the
vestibular system. 'Velocity storage' normally extends the postrotatory vestibu-
lar 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].
BllttnerlFuhry 208
Patient Studies
In 2 patients the acquired PAN was eliminated with baclofen in midposi-
tion and patients were relieved of oscillopsia [70). Carlow [33) and Nuti et al.
[112J (1 patient with aperiodic alternating nystagmus) also reported improve-
ment 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 improve-
ment [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 disap-
peared 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 malforma-
tion 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.

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 posi-
tion and conjugate torsion [157J. However, unilateral muscimol injection into
the iC in the monkey only led to downbeat and upbeat nystagmus in combination

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 otolith-
ocular VOR have been proposed to cause jerk-waveform SSN by tonic imbal-
ance. Lesions to the MLF can disrupt the connections between the vertical semi-
circular canals and the vertical-torsional eye muscles. The combination ofjerk-
waveform 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] de-
scribed 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 de-
creased 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.
BllttnerlFuhry 210
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].

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 ampli-
tude [163].
None ective drugs: Not known.
Drugs causing eN: Not known.

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 re-
sulting 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 leukodys-
trophies.

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 signifi-
cantly 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].
BiittnerlFuhry 212
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 peripher-
ally, 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 im-
prove 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].

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 nonocu-
lar 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.

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 rhyth-
mic spontaneous activity which is caused by damage to inhibitory dentato-
olivary 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 un-
changed [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-
BiittnerlFuhry 214
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 direc-
tion, 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

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.

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. How-
ever, 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 opso-
clonus. Two-thirds of the children also respond to corticosteroids. Either
ACTH or prednisone are used with doses similar to immunosuppressive ther-
apy [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 recur-
rences have been reported for paraneoplastic opsoclonus.
BiittnerlFuhry 216
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, lisur-
ide, 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

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

SWJ are seen in 20-40% of normal people. They have also been associated
with a number of diseases, including progressive supranuclear palsy, multisys-
tem 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.
BllttnerlFuhry 218
Drugs causing saccadic intrusions: L- Tyrosine, the precursor for dopamine
biosynthesis, increased the frequency of saccadic intrusions in all 8 schizo-
phrenic patients tested [49]. Depletion of catecholamines by metyrosine in-
creased 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].

Electromyographical examination in SOM showed polyphasic action po-
tentials 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

showed a temporarily beneficial e ect. In 6 out of 7 patients treated with
carbamazepine, a prompt cessation in ocular symptoms was noted [121]. Dur-
ing 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 ad-
ministered in 1 patient without noticeable e ect [83]. The same patient also
did not improve after intravenous edrophonium injection. Baclofen adminis-
tered in a patient by Staudenmaier [135] showed no influence on SOM.
Drugs causjng SOM: Not known.
Comment
Despite our detailed knowledge about the neurophysiology, neuroanat-

omy, 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 compar-
able 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.
BllttnerlFuhry 220
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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

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 high-
speed 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
2
0;1
<ll
~
Z 0
o
E
(/)
-1
~ -2
LU
1U -3
-4
0.0 0.2 0.4 0.6 08 1.0

TIME (sec)
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 perturba-
tions that occur during locomotion. Patients who have 'lost their balancing
mechanism' complain of blurred vision and oscillopsia only when they walk or
Nonpharmacological Treatment of Nystagmus 229

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
Leigh 230
VIEWING NEAR
1.0
'Oil 0.5
3"
"
.9
.~ 0.0
0
~
"
0>-
>Il
-0.5
-1.0
0.0 0.2 0.4 0.6 0.8 1.0

Time (sec)
VIEWING FAR
1.0
'Oil 0.5
3"
c
:~ 0.0
0
~
"
0>-
>Il
-0.5
-1.0
0.0 0.2 0.4 0.6 0.8 1.0

Time (sec)
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 com-
ponent 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

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 polymethylmethac-
rylate 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 infrared-
reflectance 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
Leigh 232
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 com-
pared before and after injection. Repka et a1. [1994J also described improve-
ment 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 hypermet-
ric (fig. 4A) and the vestibulo-ocular reflex, evaluated during rotation in dark-
ness, 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 nystag-
mus emanated eitller fwm une uf the eye movement systems that had under-
gone 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-

LEFT EYE RIGHT EYE
0.5 0.5
~ .,
00
~ ~
vi
13
c..
0
c..
...J 0.0 ...J 0.0

u

u
i= i=
'"
LLl
> -0.5
'"
LLl
> ..(l.S
A B
..(l.S 0.0 0.5 ..(l.s 0.0 0.5
HORIZONTAL POS. (deg) HORIZONTAL POS. (deg)
0.5 0.5
00 00
~ ~
vi
13
c..
0
c..
...J 0.0 ...J 0.0

..:
u
i=
u
i= J
'"
LLl
> '">
LLl
..(l.s ..(l.s
C D
..(l.s 0.0 0.5 -0.5 0.0 0.5
HORIZONTAL POS. (deg) HORIZONTAL POS. (deg)
Fig 3. E ects of botulinum toxin on acquired pendular nystagmus in a 27-year old

woman with multiple sclerosis. A Oeft eye) and B (right eye) display representative I-second
records of her nystagmus as 'scan paths' prior to injection with botulinum toxin. C and D
display characteristics of her nystagmus, I week after injection of the right medial rectus
and 2 weeks after injection of the right lateral rectus muscle. The horizontal component of
nystagmus in the right eye was almost abolished, and visual acuity increased from 20/40 '
to 20/25 3 in this eye. The amplitude of the horizontal component of nystagmus in the left,
noninjected eye has increased, however, and visual acuity declined from 20/70 to 20/100.
Positive values correspond to rightward or upward eye rotations. [See Leigh et aI., 1992, for
details.]
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 kera-
titis, perhaps due to denervation of the ciliary ganglion, that has persisted for
several years. No patient that we treated with retrobulbar botulinum toxin
Leigh 234
40
LEFT EYE RIGHT EYE
40
00 20 00
... 20 TARGET
~ ~
Z Z
9 0
E-
Vi
O E 0
0
0..
'"2
UJ UJ
>-
UJ
-20 >-
UJ
-20
A -40 B -40
0 2 4 6 0 6
TIME (sec) TIME (se<')
20 20
00
... 00
~
Z
10
:3 10
Z
0 0
f= 0 i= 0
Vi Vi
2 0
0..
UJ -10 UJ 10
>-
UJ >-
UJ
EYE
-20 -20
EYE
C D
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
TIME (se<') TIME (se<')
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.

Two surgical procedures may be e ective as treatment for selected patients
with congenital nystagmus. One is the Anderson-Kestenbaum operation [And-
erson, 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 improve-
ment of visual acuity is reported, but no reliable measurements of eye move-
ments 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 quanti-
tatively 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 Arnold-
Chiari 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 treat-
ments, 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
2,-----.-------,------,------,----,-----,,---.,---,-----,------,
g> o
~
z
o
t=
iii
oc.
w
10 -1
VIBRATION ON NECK
-2
-3 '--_--'-_----'--_ _'--_--'-_-----'-_ _'--_---'-_-----'-_ _-'----------J

o 2 3 4 5 6 7 8 9 10
TIME (sec)
Fig 5. E ects of applying a vibratory stimulus to the neck of a patient with congenital
nystagmus. The peak-to-peak amplitude of the nystagmus was reduced by over 60%, and
gaze was stable enough for the image of the object of regard to remain within a 'foveation
window' of 0.5. [See Sheth et a!., 1995, for details.]
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 vibra-
tion 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

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 inher-

ently 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 move-
ments 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 treat-
ment 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.
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R. John Leigh, MD, Department of Neurology, University Hospitals, 11100 Euclid Avenue,
Cleveland, 01-1, 44106-5000 (USA)
Tel. 1 2168443190, Fax 1 2168443160
Leigh 240
Subject Index
Abducens nucleus (VI) Baclofen, nystagmus treatment 202, 203,

a erent and e erent connections 10 205, 206, 209, 212, 220
structure and function 9, 10 Benign paroxysmal positioning vertigo
transmitters 10 canalolithiasis in etiology 168, 169,
Acetazolamide, episodic ataxia treatment 176-178
204, 207, 208 clinical presentation 170, 171
Acoustic neuroma, di erential diagnosis cupulolithiasis in etiology 174-176
ISS, 156 diagnosis 171, 173
Acquired pendular nystagmus di erential diagnosis ISS, 173, 174
clinical aspects 212 horizontal benign paroxysmal positioning
drugs vertigo
causes of nystagmus 213 atypical disease with ageotropic
therapy 212, 213 positional nystagmus 188, 189
pathophysiology and experimental studies clinical presentation 187, 188
221 conversion from posterior disease 187
Acupuncture, nystagmus suppression 238 etiology and pathomechanism
Acute hearing loss, di erential diagnosis 155 189, 190
Acyclovir, vestibular neuritis management incidence 170, 187
129, 133 management 190, 191
Adenosine triphosphate, sensitivity of incidence and age dependence 169, 180
central vestibular neurons 70 natural course 173
Adrenaline, modulation of central vestibular nystagmus 173
neurons 52 physical therapy 170
Adrenocorticotropin, modulation of central Brandt-Daro exercise 180, 181,
vestibular neurons 69 185, 186
Aminoglycosides, Meniere's disease Epley maneuver 183, 186
management 160, 161 recurrence following therapy 183, 185
Amobarbital, nystagmus treatment 203,214 Semont maneuver 181, 183, 186
AMPA receptors surgical management
medial vestibular nucleus neurons 40 guidelines 186
principles of drug therapy 199 neurectomy, posterior ampuJlary nerve
Apoplexia labyrinthi, di erential diagnosis 155 186
241
Benign paroxysmal positioning vertigo, Dopamine, modulation of central vestibular
surgical management (continued) neurons
plugging of posterior semicircular canal agonists in therapy 60
186, 187 central pathways 52, 57, 58
unilateral versus bilateral disease 180 electro physiological studies 58, 60
Benztropine, nystagmus treatment receptors 58, 60
204, 205 Downbeat nystagmus
Botulinum toxin, nystagmus treatment clinical aspects 201
207, 233-235 drugs
Brandt-Daro exercise, benign paroxysmal causes of nystagmus 205
positioning vertigo milnilgement 180,181, thempy 202, 205
185, 186 pathophysiology and lesion studies
201, 202
Canalolithiasis, see Benign paroxysmal Dramamine, vestibular neuritis management
positioning vertigo 129
Carbamazepine, superior oblique myokymia
treatment 203, 219, 220 Electrocochleography, Meniere's disease
Cerebellum 151, 152
a erent and e erent connections 13, 14 Endolymphatic hydrops, see Meniere's
structure and function 12, 13 disease
transmitters Episodic ataxia
climbing fibers 16 clinical aspects 207
in terneu rons 16 drug therapy 207, 208
mossy fibers 16 pathophysiology and lesion studies 207
Purkinje cells 14, 16 Epley maneuver benign paroxysmal
varicose fibers 17 positioning vertigo management
Clonazepam, nystagmus treatment 202,203, 183, 186
205, 212, 218 Eye movement generation
Cochleosacculotomy, Meniere's disease abducens nucleus 9, 10
management 161, 162 cerebellum 12-14, 16, 17
Congenital nystagmus fastigial nucleus 17-19
clinical aspects 210,211 interstitial nucleus of Cajal 4-6
drug therapy 211 oculomotor nucleus 10-12
pathophysiology and experimental studies paramedian pontine reticular formation
211 6-8
Contact lenses, nystagmus suppression paramedian tract neurons 8, 9
237, 238 rostral interstitial nucleus of the medial
Corticosteroids longitudinal fascicle 1-3
opsoclonus management 216,217
vestibular neuritis management 129 Fastigial nucleus
Cupulolithiasis, see Benign paroxysmal a erent and e erent connections 18
positioning vertigo lesion studies of eye movement 12, 13
structure and function 17, 18
Dimenhydrinate, Meniere's disease transmitters 19
management 158, 159
Diphenylhydantoin, nystagmus treatment Gabapentin, nystagmus treatment 203, 210,
203, 209 215,220
Subject Index 242

GABA receptors therapy 218
medial vestibular nucleus neurons pathophysiology and experimental
anatomical studies 46, 47 studies 218
electrophysiological studies 47 Macro-square wave jerks
functional roles 49 clinical aspects 217, 218
principles of drug therapy 198-200 drugs
Gigantocellular reticular nucleus neurons, causes of jerks 219
membrane properties and gaze control therapy 218
38, 39 pathophysiology and experimental
Glycine receptors studies 218
mediul vestibulur nucleus neurons Mugnetic resomllce imuging
anatomical studies 46, 47 Meniere's disease diagnosis 154
electrophysiological studies 47 vestibular neuritis cliagnosis
functional roles 49 117, 120, 121
principles of drug therapy 198, 200 Medial vestibular nucleus neurons
Glycopyrrolate, nystagmus treatment 204 intrinsic membrane properties and
functional speculations 36-38
Herpesviruses in vivo recorclings 29, 30
Meniere's disease 143 modulation of central vestibular
vestibular neuritis 126, 127 neurons
Histamine, modulation of central vestibular adrenaline 52
neurons dopamine
binding sites 53 agonisL~ in therapy 60
central pathways 52, 53 central pathways 52, 57, 58
electrophysiological studies 53, 54 electrophysiological stuclies 58, 60
receptor antagonists 54, 55 receptors 58, 60
-Histamine, Meniere's disease histamine
management 159 binding sites 53
Horizontal benign paroxysmal positioning central pathways 52, 53
vertigo, see Benign paroxysmal electrophysiological stuclies 53, 54
positioning vertigo receptor antagonists in therapy 54, 55
noradrenaline
Interstitial nucleus of Cajal central pathways 52, 61
a erent and e erent connections 4, 5 electrophysiological stuclies 62, 63
structure and f,mction 4 receptors 61, 62
transmitters 5, 6 serotonin
Isoniazid, nystagmus treatment 203 central pathways 55
electrophysiological studies 55-57
Labyrinthectomy, Meniere's disease receptors 55
management 163 neuropeptides in central vestibular
Lermoyez syndrome, see Meniere's disease network regulation
Long-term depression, cerebeUar regulation 17 adrenocorticotropin 69
nerve growth factor 69
Macrosaccadic osciUations neurokinins 66, 69
clinical aspects 217, 218 opioid peptides 65, 66
drugs somatostatin 64, 65
causes of oscillations 219 substance P 66, 67, 69
Subject Index 243

Medial vestibular nucleus neurons apoplexia labyrinthi 155
(continued) benign paroxysmal positioning vertigo
neurotransmitters 155
AMPA receptors 40 overview 137
classification 39 perilymph fistula 156
GABA and glycine receptors pharmacological side e ects 156, 157
anatomical studies 46, 47 vertebrobasilar insu ciency 156
electro physiological studies 47 vestibular neuritis 154
functional roles 49 magnetic resonance imaging 154
isolation of electrophysiological e ects endolymphatic hydrops
39,40 pathophysiological model 145, 146
metabotropic glutamate receptors 40 epidemiology 141
muscarinic and nicotinic receptors etiology of endolymphatic hydrops
anatomical studies 50 autoimmunity 143-145
behavioral studies 51, 52 genetics 142
electrophysiological studies 50, 51 overview 141, 142
NMDA receptors psychological factors 142
functional plasticity role 46 vascular compression 142
functional roles and correlation with viral factors 143
in vivo data 43 history of research 138-140
postlesional plasticity role 45, 46 Lermoyez syndrome 153
subunits 40 signs and symptoms
pharmamlogical analysis of excitatory aural filllness 152
amino acid transmission 42, 43 cochlear function 149-152
specificity for neuron types 64 oculomotor symptoms 148
operation relationship to behavior 27, 28 subjective complaints 147, 148
oscillatory behavior and functional tinnitus 152
speculations 35, 36 vestibular-spinal signs 149
plasticity 26 treatment
purine receptors and ATP sensitivity 70 aminoglycoside therapy 160, 161
response to horizontal angular decompression surgery
accelerations 98-100 cochleosacculotomy 161, 162
slice recordings saccotomy 162, 163
classification of neuron types 30, 31 transtympanic ventilation tubes 161
rhythmic activity in type B neurons 31,32 drug therapy 158-160
whole-brain recordings, in vitro 32, 33, 35 guidelines 158
Memantine, nystagmus treatment labyrinthectomy 163
204, 213, 220 neurectomy of vestibular nerve 163,164
Meniere's disease symptom relief 157
clinical course 140, 141 Tumarkin otolith crisis 153
definition 137 Metabotropic glutamate receptors
diagnosis medial vestibular nucleus neurons 40
audiological testing 149, 150 principles of drug therapy 199
diagnostic scale 137, 138 Methylphenidate, nystagmus treatment 204
di erential diagnosis Muscarinic receptors
acoustic neuroma 155, 156 medial vestibular nucleus neurons
acute hearing loss 155 anatomical studies 50
Subject Index 244

behavioral studies 51, 52 optical methods for negating visual
electrophysiological studies 50, 51 consequences 230-233
principles of drug therapy 200, 201 surgery 236
vibratory stimuli 237
Nerve growth factor, modulation of central velocity reduction and oscillopsia
vestibu lar neurons 69 elimination 195, 228, 229
Neurectomy visual consequences 228-230
posterior ampullary nerve 186
vestibular nerve in Meniere's disease Ocular flutter
management 163, 164 clinical aspects 215, 216
Neurokinins, moduliltion of centml drugs
vestibular neurons 66, 69 causes of flutter 217
Nicotinic receptors therapy 216,217
medial vestibular nucleus neurons pathophysiology and experimental
anatomical studies 50 studies 216
behavioral studies 51, 52 Ocular myoclonus
electrophysiological studies 50, 51 clinical aspects 214
principles of drug therapy 200, 201 drugs
NMDA receptors, medial vestibular nucleus causes of myoclonus 215
neurons therapy 214, 215
functional plasticity role 46 pathophysiology and experimental
functional roles and correlation with in studies 214
vivo data 43 Ocu lomotor nucleus
postlesional plasticity role 45, 46 a erent and e erent connections 11
subunits 40 structure and function 10, 11
Noradrenaline, modulation of central transmitters 11, 12
vestibular neurons Opioid peptides, modulation of central
central pathways 52, 61 vestibular neurons 65, 66
electrophysiological studies 62, 63 Opsoclonus
receptors 61, 62 clinical aspects 215, 216
Nystagmus drugs
see also Acquired pendular nystagmus, causes of opsoclonus 217
Congenital nystagmus, Downbeat therapy 216,217
nystagmus, Episodic ataxia, Periodic pathophysiology and experimental
alternating nystagmus, Seesaw studies 216
nystagmus, Spontaneous nystagmus, Oscillopsia
Upbeat nystagmus causes 196
benign paroxysmal positioning vertigo elimination by nystagmus velocity
173, 188, 189 reduction 195, 228, 229
decaying of slow phase 196, 197 treatment 197, 198
phases 195-197
treatment Paramedian pontine reticular formation
acupuncture 238 a erent and e erent connections
base-in prisms 230 7,8
botulinum toxin 207, 233-235 saccade generation 197
contact lenses 237, 238 structure and function 6, 7
drugs, see specific diseases and drugs transmitters 8
Subject Index 245

'-"'-1 ............ '-' ........ '-' JV' .~ .....
185. 186 clinical aspects 217. 218

Epley maneuver 183. 186 drugs
recurrence after therapy 183. 185 causes of jerks 219
Semont maneuver 181, 183, 186 therapy 218
vestibular neuritis management pathophysiology and experimental
129, 130, 132 studies 218
Positional vertigo. see Benign paroxysmal Substance P. modulation of central
positioning vertigo vestibular neurons 66. 67. 69
Prednisolone. Meniere's disease Superior oblique myokymia
management 159. 160 clinical aspects 219
Prepositus hypoglossi nucleus neurons. drug therapy 219. 220
membrane properties and gaze control pathophysiology and experimental
38. 39 studies 219
Propranolol. nystagmus treatment 204
Transtympanic ventilation tubes,
Rostral interstitial nucleus of the medial Meniere's disease management 161
longitudinal fascicle Tridihexethyl, nystagmus treatment
a erent and e erent connections 2 204,210,213
saccade generation 197 Tumarkin otolith crisis. see Meniere's
structure and flJnction 1. 2 disease
transmitters 2. 3
Unilateral vestibular loss
Saccotomy. Meniere's disease management see also Vestibular neuritis
162. 163 clinical features and mechanism
Scopolamine asymmetrical horizontal vestibulo-
nystagmus treatment 204 ocular response 85
vestibular neuritis management 129 maintained rolled ocular torsional
Seesaw nystagmus position 85
clinical aspects 209 spontaneous nystagmus 85
drug therapy 210 consequences. direct versus indirect 84-86
Subject Index 246

Vestibular Dysfunction and Its Therapy

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Vestibular Dysfunction and Its Therapy

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Advances in

Series Editor W Arnold, Munich

Basel Freiburg Paris London New York

Volume Editor U Battner, Munich

28 figures. 3 in color and 10 tables. 1999

Basel Freiburg Paris London New York

Library of Congress Cataloging-In-Publicatlon Data

Copyright 1999 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland)

C!::: Brainstem and Cerebellar Structures for Eye Movement Generation

[26 Intrinsic Physiological and Pharmacological Properties of Central

82] Vestibular Compensation

[1371 Meniere's Disease

11691 Benign Paroxysmal Positioning Vertigo

1195' Drug Therapy of Nystagmus and Saccadic Intrusions

[228 Nonpharmacological Treatment of Nystagmus

1241J Subject Index

Brainstem and Cerebellar Structures for

AKE. Horn a , U Battner b, JA Battner-Ennever a

Rostral Interstitial Nucleus of the Medial Longitudinal Fascicle

Structure and Function I

Supported by the Deutsche Forschungsgemeinschaft (SFB 462).

A erent and E erent Connections

Brainstem and Cerebellar Structures for Eye Movement Generation 3

Structure and Function

A erent and E erent Connections

Brainstem and Cerebellar Structures for Eye Movement Generation

Paramedian Pontine Reticular Formation

Structure and Function

A erent and E erent Connections

Brainstem and CerebelJar Structures for Eye Movement Generation 7

Paramedian Tract Neurons

Structure i:lIJ(.l FunctiuIJ

A erent and E erent ConnecUons

Structure am} FUIlcUun

Brainstem and Cerebellar Structures for Eye Movement Generation 9

A erent and E erent Connections

Oculomotor and Trochlear Nucleus

Structure and Function

A erent and E erent Connections

Brainstem and Cerebellar Structures for Eye Movement Generation 11

Structure and Function

A erent and E erent Connections

Brainstem and Cerebellar Structures for Eye Movement Generation 13

- -G"kBA,- - - -5"1,' GILU GLUI White

Brainstem and Cerebellar Structures for Eye Movement Generation 15

Structure and Function

Brainstem and CerebelJar Structures for Eye Movement Generation 17

A erent and E erent ConnecUons

The growing knowledge about the histochemistry and transmitters of the

Brainstem and Cerebellar Structures for Eye Movement Generation 19

Brainstem and Cerebellar Structures for Eye Movement Generation 21

Brainstem and Cerebellar Structures for Eye Movement Generation 23

AK.E. Horn, Institute of Anatomy, Ludwig Maximilians University,

Brainstem and Cerebellar Structures for Eye Movement Generation 25

Intrinsic Physiological and

Pjerre-Paul VMaJ", Njcolas Vjber(", Mauro Serafin b, Alexander BabaJjan a,

a Neurobiologie des Reseaux Sensorimoteurs, CNRS UPRES-A 7060, Paris, France et

Oculomotor and postural stabilizing responses result from a complex multi-

Intrinsic Properties of Central Vestibular Neurons 27

Physiological Properties of Central Vestibular Neurons

Most studies have focused on medial vestibular nucleus neurons (MVNn).

MVN Neurons Physiological Properties: In vivo Recordings

We tried to investigate the functional significance of the intrinsic mem-

Intrinsic Properties of Central Vestibular Neurons 29