Medical treatment of vestibular disorders

Review

10.1517/14656560902976879 © 2009 Informa UK Ltd ISSN 1465-6566 1537All rights reserved: reproduction in whole or in part not permitted

MedicaltreatmentofvestibulardisordersThomas Brandt†, Andreas Zwergal & Michael StruppLudwig-Maximilians-University, Department of Neurology, Munich, Germany

Background: The lifelong prevalence of rotatory vertigo is 30%. Despite this high figure, patients with vertigo generally receive either inappropriate or inadequate treatment. However, the majority of vestibular disorders have a benign cause, take a favorable natural course, and respond positively to therapy. Objective: This review puts special emphasis on the medical rather than the physical, operative, or psychotherapeutic treatments available. Methods: A selected review of recent reports and studies on the medical treatment of peripheral and central vestibular disorders. Results/conclusions: In vestibular neuritis, recovery of the peripheral vestibular function can be improved by oral corticosteroids; in Menière’s disease, there is first evidence that high-dose, long-term administration of betahistine reduces attack frequency; carbamazepine or oxcarbamazepine is the treatment of first choice in vestibular paroxysmia, a disorder mainly caused by neurovascular cross-compression; the potassium channel blocker aminopyridine provides a new therapeutic principle for treatment of downbeat nystagmus, upbeat nystagmus, and episodic ataxia type 2.

Keywords: aminopyridine, betahistine, carbamazepine, corticosteroids, downbeat nystagmus, episodic ataxia type 2, Menière’s disease, upbeat nystagmus, vertigo, vestibular neuritis, vestibular paroxysmia

Expert Opin. Pharmacother. (2009) 10(10):1537-1548

1. Introduction

Vertigo and dizziness are among the most common key symptoms in medicine (lifelong prevalence of rotatory vertigo 30%) [1]. It is the authors’ opinion that despite this high figure, patients with vertigo generally receive no appropriate treatment. Consequently these patients consult one specialist after the other from various disciplines (neurology, otolaryngology, internal medicine, orthopedics, psychiatry) and undergo unnecessary diagnostic tests, only to receive the wrong diagnosis and ineffective treatment. Long phases of disablement, with substantial psychosocial and economic consequences, are the result.

The current unsatisfactory management of dizzy patients results from the following deficits of academic medicine, medical training, and clinical research:

a narrow view of single aspects of the disorders due to the existing borders separating •the clinical specializationsnon-uniform guidelines for diagnosis and therapy that are specific for each •specializationinsufficient interdisciplinary cooperation between basic and clinical scientists•difficulty to recruit patients for clinical research because of the partitioning of •clinical care by specialization and sitedeficiencies in the treatment and research of chronic vertigo/dizziness and gait disor-•ders in the different stages of life, from childhood to old age (e.g., falls in the elderly).These deficits are further amplified by the structural weaknesses of

academic medicine.

1. Introduction

2. Vestibular neuritis

3. Menière’s disease

4. Vestibular paroxysmia

5. Downbeat nystagmus

6. Upbeat nystagmus

7. Episodic ataxia type 2

8. Conclusion

9. Expert opinion

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.

Medicaltreatmentofvestibulardisorders

1538 ExpertOpin.Pharmacother.(2009) 10(10)

The combination of administrative, clinical, and teaching duties results in multiple responsibilities that overtax the clinical scientist. Moreover, there are too few attractive career options available for interdisciplinary specialists.

However, most syndromes of vertigo can as a rule be cor-rectly diagnosed by specialists with interdisciplinary training on the basis of a careful medical history and a physical exami-nation of the patient. Not only does this obviate excessive diagnostic measures, it also ensures adequate treatment. In the following we will discuss effective pharmacological treatment of selected peripheral and central vestibular disorders such as vestibular neuritis, Menière’s disease, vestibular paroxysmia due to neurovascular cross-compression, downbeat nystagmus, upbeat nystagmus, and episodic ataxia type 2.

2. Vestibularneuritis

Vestibular neuritis is the third most common cause of peripheral vestibular vertigo (the first being benign paroxys-mal positioning vertigo; the second, Menière’s disease) [2]. It accounts for 7% of the patients who present at outpatient clinics specializing in the treatment of dizziness [2] and has an incidence of 3.5 per 100,000 population [3]. The key signs and symptoms of vestibular neuritis are the acute onset of sustained rotatory vertigo, horizontal spontaneous nystag-mus toward the unaffected ear with a rotational component, postural imbalance with falls, with the eyes closed, toward the affected ear, and nausea. Caloric testing invariably shows ipsilateral hyporesponsiveness or nonresponsiveness. In the past, either inflammation of the vestibular nerve or labyrin-thine ischemia was proposed to cause vestibular neuritis. Currently a viral cause is favored. The evidence, however, remains circumstantial. Herpes simplex virus type 1 (HSV-1) DNA has been detected on autopsy with the use of poly-merase chain reaction in about two of three human vestibular ganglia [4-8]. This, as well as the expression of CD8+ T-lymphocytes, cytokines, and chemokines, indicates that the vestibular ganglia are latently infected with HSV-1 [9].

A prospective randomized, double-blind, two-by-two fac-torial trial was performed, in which patients with acute ves-tibular neuritis were randomly assigned to treatment with placebo, methylprednisolone (100 mg/day, doses tapered by 20 mg every third day), valacyclovir (1 g t.i.d. for 7 days), or methylprednisolone plus valacyclovir [10]. Vestibular func-tion was determined by caloric irrigation, with the use of the vestibular paresis formula (to measure the extent of uni-lateral caloric paresis), within 3 days after the onset of symp-toms and 12 months afterwards. A total of 141 patients underwent randomization. The mean improvement in peripheral vestibular function at 12-month follow-up was 39.6 percentage points in the placebo group, 62.4 percent-age points in the methylprednisolone group, 36.0 percentage points in the valacyclovir group, and 59.2 percentage points in the methylprednisolone plus valacyclovir group (Figure 1). Analysis of variance showed that methylprednisolone had a

significant effect, but valacyclovir did not. The antiviral drug did not improve the outcome in patients with vesti-bular neuritis, despite the assumed viral cause. It is conceiv-able that replication of HSV-1 in the vestibular ganglia may already have occurred at the time the antiviral drug was initiated – that is, within 3 days after the onset of symp-toms. Therefore, this study showed that methylprednisolone alone significantly improves the recovery of peripheral ves-tibular function in patients with vestibular neuritis, whereas valacyclovir is not required [10].

Symptom outcome at 12 months was not addressed for two reasons. First, animal experiments show that steroids improve central vestibular compensation. Thus, parameters other than vestibular paresis, such as postural imbalance or ‘vertigo and dizziness’, would not help differentiate between the effects of steroids on the recovery of peripheral vestibu-lar function and on central vestibular compensation. Sec-ond, there are no validated scales for measuring vertigo and dizziness. In a recent study prednisone therapy enhanced earlier recovery, but did not improve the long-term progno-sis of vestibular neuritis [11]. All in all, this cheap and well-tolerated therapy can be recommended as the pharmaceutical treatment of choice for vestibular neuritis. Short-term high-dose treatment with methylprednisolone may be as effective as the long-term treatment and have fewer side effects. Treat-ment should be as early as possible, i.e., within the first days after onset of the condition, certainly not after 1 week.

3. Menière’sdisease

Menière’s disease is clinically characterized by recurrent spontaneous attacks of vertigo, fluctuating hearing loss, tin-nitus, and aural fullness. A recently reported prevalence of Menière’s disease of 0.51% is much higher than previous estimates [12,13]. Its incidence is 7.5 – 160 per 100,000 per-sons (for references, see [14]). Endolymph hydrops is assumed to be the pathological basis of Menière’s disease, either due to too high a production or too low an absorption of the endolymph. The increased endolymphatic pressure may cause periodic rupturing or leakage (possibly by the opening of non-selective, stretch-activated ion channels [15]) of the membrane separating the endolymph from the perilymph space. Therefore, pathophysiologically it makes sense to reduce the production and increase the absorption of endo-lymph. The clinical aims of treatment of Menière’s disease are to stop vertigo, reduce or abolish tinnitus, and preserve hearing loss. Most studies focus on the severest symptom of Menière’s disease: recurrent attacks of vertigo.

There is a plethora of treatment strategies for Menière’s disease. Destructive procedures involving the lateral semicir-cular canal and vestibule have been proposed since 1904. The first endolymphatic sac decompression was performed in 1926. This method is still used in some settings, despite its evident ineffectiveness. Restricting salt and fluid intake and diuretics were first proposed in 1934. Salt restriction

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.

Brandt,Zwergal&Strupp

ExpertOpin.Pharmacother.(2009) 10(10) 1539

Vestibular paresis (%)

100 90 80 70 60 50 40 30 20 10 0

Ons

etF

ollo

w-u

p

Val

acyc

lovi

rM

ethy

lpre

dnis

olon

e pl

us v

alac

yclo

vir

Vestibular paresis (%)10

010

0 90 80 70 60 50 40 30 20 10 0O

nset

Fol

low

-up


100 90 80 70 60 50 40 30 20 10 0

Ons

etF

ollo

w-u

p

100 90 80 70 60 50 40 30 20 10 0

Ons

etF

ollo

w-u

p

90 80 70 60 50 40 30 20 10 0O

nset

Fol

low

-up

100 90 80 70 60 50 40 30 20 10 0

Ons

etF

ollo

w-u

p


100 90 80 70 60 50 40 30 20 10 0

Ons

etF

ollo

w-u

p

100 90 80 70 60 50 40 30 20 10 0

Ons

etF

ollo

w-u

p

Con

trol

Met

hylp

redn

isol

one

Fig

ure

1.U

nila

tera

lves

tib

ula

rfa

ilure

wit

hin

3d

ays

afte

rsy

mp

tom

on

set

and

aft

er1

2m

on

ths.

Ves

tibul

ar f

unct

ion

was

det

erm

ined

by

calo

ric ir

rigat

ion,

usi

ng t

he ‘v

estib

ular

pa

resi

s fo

rmul

a’ (w

hich

allo

ws

a di

rect

com

paris

on o

f th

e fu

nctio

n of

bot

h la

byrin

ths)

for

eac

h pa

tient

in t

he p

lace

bo (u

pper

left

), m

ethy

lpre

dnis

olon

e (u

pper

rig

ht),

vala

cycl

ovir

(low

er

right

), an

d m

ethy

lpre

dnis

olon

e pl

us v

alac

yclo

vir

(low

er l

eft)

gro

up.

Als

o sh

own

are

box

plot

cha

rts

for

each

gro

up w

ith t

he m

ean

()

± st

anda

rd d

evia

tion

(SD

), an

d 25

and

75%

pe

rcen

tile

(box

plo

t), a

s w

ell a

s th

e 1

and

99%

ran

ge ( *

). A

clin

ical

ly r

elev

ant

vest

ibul

ar p

ares

is w

as d

efine

d as

> 2

5% a

sym

met

ry b

etw

een

the

right

-sid

ed a

nd t

he le

ft-s

ided

res

pons

es

[87]

. Fol

low

-up

exam

inat

ion

show

ed t

hat

vest

ibul

ar f

unct

ion

impr

oved

in a

ll fo

ur g

roup

s: in

the

pla

cebo

gro

up f

rom

78.

9 ±

24.0

(mea

n ±

SD) t

o 39

.0 ±

19.

9, in

the

met

hylp

redn

isol

one

grou

p fr

om 7

8.7

± 15

.8 t

o 15

.4 ±

16.

2, in

the

val

acyc

lovi

r gr

oup

from

78.

4 ±

20.0

to

42.7

± 3

2.3,

and

in t

he m

ethy

lpre

dnis

olon

e pl

us v

alac

yclo

vir

grou

p fr

om 7

8.6

± 21

.1 t

o 20

.4 ±

28

.4.

Ana

lysi

s of

var

ianc

e re

veal

ed t

hat

met

hylp

redn

isol

one

and

met

hylp

redn

isol

one

plus

val

acyc

lovi

r ca

used

sig

nific

antly

mor

e im

prov

emen

t th

an p

lace

bo o

r va

lacy

clov

ir al

one.

The

co

mbi

natio

n of

bot

h w

as n

ot s

uper

ior

to s

tero

id m

onot

hera

py (f

rom

[10]

).

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



and diuretics are still recommended, although in one double-blind study diuretics did not show any effect [16]. Vestibulotoxic drugs have been in use since 1948; local intratympanic delivery has been performed since 1956 (for references, see [17]). It is remarkable that despite the high incidence of Menière’s disease and the large number of studies published on its treatment over the last decades, there are still only very few state-of-the art prospective, placebo-controlled, double-blind trials. Moreover, there are significant differences in the treatment regimen of Menière’s disease between Europe and the United States. In the United States, low-salt diet, diuretics, and intratympanic injection of gentamicin and corticosteroids are preferred. In Europe, betahistine is more often used – in the United States, rarely. A national survey among UK otolaryngolo-gists on the treatment of Menière’s disease revealed that 94% used betahistine, 63% diuretics, 71% salt restric-tion, 52% sac decompression, and approximately 50% insertion of a grommet [17]. Local gentamicin instillation has become increasingly popular since its introduction in the UK 10 years ago: approximately two-thirds of the otolaryngologists use this method.

3.1 IntratympanicinjectionsofgentamicinSeveral studies have been published on intratympanic gen-tamicin application for the treatment of Menière’s disease. Initially, multiple intratympanic injections of gentamicin were given until patients developed vestibular hypofunc-tion. This led to a good control of attacks of vertigo, which, however, was accompanied by a high rate of sen-sorineural hearing loss (approximately 50%). Especially after the demonstration of a delayed onset of ototoxic effects [18], the regimen was changed in two ways: i) single instillations at fixed interims of several days or weeks or ii) single-shot injections and follow-up. Following the latter regimen, a prospective, uncontrolled study with a follow-up time of 2 – 4 years on 57 patients showed that vertigo attacks could be controlled in 95% [19]. Of these patients, 53% needed only one injection of 12 mg gentamicin, 32% two or three injections. A recent meta-analysis of 15 trials with 627 patients on gentamicin injections showed that complete vertigo control was achieved in about 75% of the patients and complete or substantial control in about 93%. The success rate was not affected by the gentamicin treat-ment regimen (i.e., fixed vs titration) [20]. Hearing level and word recognition were not adversely affected, regard-less of treatment regimen. The authors, however, pointed out that the level of evidence reflected in the relevant articles is insufficient, especially because of relatively poor study designs: none of the trials was double-blind or had a blinded, prospective control. Meanwhile there is good evidence that the beneficial effect of gentamicin is due to its damage to the hair cells. A complete ablation of function, however, does not seem necessary in order to control vertigo [21].

3.2 IntratympanicinjectionsofcorticosteroidsIn a retrospective chart review, Barrs [22] evaluated the effects of intratympanic injections of dexamethasone in 34 patients. After a single course of weekly injections of 10 mg/ml dex-amethasone for 1 month, only 24% of the patients reported vertigo control. Another 24% responded to the repeat series of injections. All in all, approximately half of the patients with Menière’s disease achieved control of vertigo with one or more courses of intratympanic injections of corticoster-oids. In another retrospective study of 129 patients with Menière’s disease, intratympanic dexamethasone injection therapy was found to provide vertigo control that was satis-factory [23]. The safety of intratympanic dexamethasone injections was evaluated by transient evoked otoacoustic emission: no change was found in 26 patients after five injections of 4 mg dexamethasone [24].

3.3 BetahistineIn Europe, betahistine is more often used, mainly on the basis of a study by Meyer in 1985 [25] and more recent meta-analyses [26,27]. Betahistine is an H1 agonist and H3 antagonist. It improves the microcirculation by acting on the precapillary sphincters of the stria vascularis [28]. There is evidence that it reduces the production and increases the absorption of endolymph. In an open trial on 112 patients with Menière’s disease, it was shown that a higher dosage of betahistine dihydrochloride (48 mg t.i.d.) and a long-term treatment (12 months) seem to be more effective than a low dosage (16 – 24 mg t.i.d.) and short-term treatment [29]. The high dosage was very well tolerated, even though it was given right from the beginning. This is in agreement with recent safety data [30]. The only relevant side effects were gastrointestinal complaints such as fullness of the stomach, diarrhea, nausea, light-headedness, headache, and mild vege-tative symptoms. These side effects did not require a reduc-tion in dosage or a cessation of treatment. These data are the basis for a recently begun prospective, randomized, double-blind, dose-finding study comparing placebo with 16 and 48 mg t.i.d. betahistine dihydrochloride.

It must, however, be pointed out that up to now no state-of-the-art studies have been conducted in this field despite the large number of trials. A Cochrane database review in 2001 came to the conclusion that so far there is insufficient evidence to say whether betahistine has any effect on Menière’s disease [31].

4. Vestibularparoxysmia

Episodic spells of vertigo, which were assumed to be caused by neurovascular cross-compression (NVCC) on the analogy of trigeminal neuralgia and hemifacial spasm, were first described in 1975 by Jannetta [32], who termed the syn-drome ‘disabling positional vertigo’ [32,33]. Demyelination and subsequent ephaptic spreading of action potentials were thought to be the most likely pathomechanisms. Not all

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



short attacks of rotational to-and-fro vertigo lasting seconds •to minutesattacks frequently dependent on particular head positions•hypacusis or tinnitus permanently or during the attack•auditory or vestibular deficits measurable by neurophysio-•logic methodsefficacy of carbamazepine.•

VP accounts for 4% of all patients with dizziness in our dizziness unit, and it has become an integral part of the diag-nostic repertoire of most major dizziness units despite the aforementioned limitations (Bronstein A, Halmagyi M, Leigh RJ, Zee D, pers. commun.). A recent study evaluated the clinical parameters, neurophysiologic and neuro-ophthalmologic test results, MRI, and the effect of medical treatment on attack frequency, duration, and intensity in 32 patients with probable or definite VP [42]. This follow-up proved the usefulness of the diagnostic criteria (see Table 1 for updated criteria), especially constructive interference in steady-state magnetic resonance imaging to show neurovascular cross-compression and the therapeutic efficacy of medical treatment. Carbamazepine led to a significant reduction in the attack frequency to 10% of baseline, in attack intensity to 15%, and a reduction in attack duration to 11% [42]. In the latter study the mean maximal dose of carbamazepine was 600 mg/d and for oxcarbamazepine, 900 mg/d. There is an ongoing randomized, placebo-con-trolled, double-blind trial on the treatment of vestibular paroxysmia with oxcarbamazepine.

Although strongly motivated by the clinical relevance of this disabling but treatable syndrome, we are fully aware of the methodologic limitations of such an approach, because there is still no gold standard for the proof of VP.

5. Downbeatnystagmus

Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus [43]. It is characterized by slow upward drifts and fast downward phases. Slow-phase velocity increases on lateral and downward gaze and conver-gence, although there may be atypical presentations with enhancement of the DBN on upward gaze or suppression on convergence [44-47]. From a clinical point of view, it is important to look for DBN in lateral gaze, because it might otherwise be overlooked (Table 2).

The most common presenting symptoms are unsteadiness of gait and to-and-fro vertigo [43]. On further inquiry, the patients frequently report blurred vision or oscillopsia that increases on lateral gaze. DBN is often associated with other ocular motor, cerebellar, and vestibular disorders, predomi-nantly smooth pursuit deficits and impairment of the opto-kinetic reflex and visual fixation suppression of the vestibulo-ocular reflex (VOR) [44,47-51].

The etiology of DBN is diverse. Craniocervical malforma-tions, cerebellar degeneration, vascular pathology, inflamma-tory disease, and intoxication with lithium or antiepileptic

Table1.Diagnosticcriteriaforthediagnosisofvestibularparoxysmia[36].

Definitevestibularparoxysmia

AlleastfiveattacksandthepatientfulfillsthefollowingcriteriaA–E

A Vertigo spells lasting seconds to minutes. The individual attack subsides without specific therapeutic intervention

B One or several of the following provoking factors of the attacks

RestCertain head/body positions (not BPPV-specific positioning maneuvers)Changes in head/body position (not BPPV-specific positioning maneuvers)

C One or several of the following characteristics during the attacks

No accompanying symptomsDisturbance of stanceDisturbance of gaitUnilateral tinnitusUnilateral pressure/numbness in or around the ear.Unilaterally reduced hearing

D One or several of the following additional diagnostic criteria

Neurovascular cross-compression demonstrated on MRI (CISS sequence)Hyperventilation-induced nystagmus as measured by oculographyIncrease of vestibular deficit at follow-up investigations as measured by oculographyTreatment response to antiepileptics (not applicable at first consultation)

E The symptoms cannot be explained by another disease

Probablevestibularparoxysmia

AtleastfiveattacksandthepatientfulfillscriterionA,andatleastthreeofthecriteriaB–E

BPPV: Benign paroxysmal positional vertigo.

cases of vestibular paroxysmia are necessarily due to neuro-vascular cross-compression. The clinical diagnosis of this disor-der was made mainly by exclusion: the diagnosis was made when patients did not fulfill the criteria of established vestibu-lar disorders such as Menière’s disease, benign paroxysmal posi-tional vertigo (BPPV), or vestibular neuritis. The limitation of this approach is obvious because it neglects other causes of episodic vertigo, such as vestibular migraine, anterior canal dehiscence syndrome, or somatoform phobic postural vertigo. Surgical decompression as the treatment of first choice was reported to be successful [34-36]. However, this treatment did not gain overall acceptance, although the pathophysiology of NVCC was widely acknowledged [33,37-41]

In 1994, an attempt was made to define positive diagnos-tic criteria for the diagnosis of eighth nerve NVCC, now termed vestibular paroxysmia (VP). The following diagnostic criteria were proposed [37]:

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



drugs have – among others – been implicated [44,47-52]. In a recent study, 117 patients were reviewed to establish whether analysis of a large collective and improved diagnostic means would reduce the number of cases with ‘idiopathic DBN’ and thus change the etiological spectrum [43]. In 62% (n = 72), the etiology was identified (‘secondary DBN’), the most frequent ones being cerebellar degeneration (n = 23) and cerebellar ischemia (n = 10). In 38% (n = 45), no cause was found (‘idiopathic DBN’). A major finding was a high comorbidity of both idiopathic and secondary DBN with bilateral vestibulopathy (36%) and an association with poly-neuropathy and cerebellar ataxia, even without cerebellar pathology on MRI. From this study, one can conclude that ‘idiopathic DBN’ remains common despite improved diag-nostic techniques. These data allow the classification of ‘idiopathic DBN’ into three subgroups: ‘pure’ DBN (n = 17); ‘cerebellar’ DBN (i.e., DBN plus other cerebellar signs in the absence of cerebellar pathology on MRI [n = 6]); and a ‘syndromatic’ form of DBN associated with at least two of the following: bilateral vestibulopathy, cere-bellar signs, and peripheral neuropathy (n = 16). The latter may be caused by multisystem neurodegeneration.

Animal studies in monkeys have shown that bilateral abla-tion of the cerebellar flocculus and paraflocculus results in DBN and an integrator deficit [53], lasting deficits in pursuit eye movements, impaired horizontal VOR adaptation [54,55], and visual suppression of caloric nystagmus. The upward drift of DBN consists of a gaze-evoked drift, which is hypoth-esized to be due to an impaired neural integrator function, and a spontaneous upward drift during gaze straight ahead [48,49]. Three different pathomechanisms are thought to cause the spontaneous upward drift: first, a tone imbalance of the central vestibular pathways of the vertical eye move-ments [45,47,56,57], including otolith pathways, as suggested by the finding that DBN is gravity-dependent [58,59]; second, an imbalance of the vertical smooth pursuit tone in which the

imbalance of upward visual velocity commands results in spontaneous upward drift [60]; and third, a mismatch in the three-dimensional neural coordinate system for vertical saccade generation due to a defect of the neural velocity- to-position integrator for gaze holding [49].

Marti and colleagues [61] have proposed a mechanism by which floccular deficiency causes DBN. They suggest that the distribution of the on-directions of vertical gaze-velocity Purkinje cells (PCs) is inherently asymmetrical. These cells are predominantly activated with ipsiversive and downward gaze velocity, but only around 10% of them show on-direc-tions for upward-gaze velocity [62]. With functional magnetic resonance imaging (fMRI) and F-fluorodeoxyglucose-posi-tron emission tomography (PET), it was recently shown that patients with DBN have diminished activation/metabo-lism of both floccular lobes [63,64]. This supports the view that a functional deficiency of the flocculi causes not only a defect in downward pursuit, but also DBN [61]. More recent studies using voxel-based morphometry demonstrated an atrophy in certain areas of the cerebellum that are mainly related to ocular motor function (Figure 2) [63,65].

Since the inhibitory influence of GABAergic Purkinje cells is assumed to be impaired in DBN, several agents that act on this receptor have been investigated. The GABAA agonist, clonazepam, improved DBN (dosage 0.5 mg t.i.d. to 1 mg b.i.d.), but these studies were not controlled [66,67]. The GABAB agonist, baclofen, is assumed to reduce DBN [68]; but in a double-blind crossover trial in a few patients, only one out of six responded to baclofen [69]. Fur-ther, the alpha-2-delta calcium channel antagonist gabapentin was assumed to have a positive effect on DBN, but again only one out of six patients responded positively [69].

On the basis of the assumed pathomechanism of DBN, the effects of aminopyridines were evaluated in a randomized, controlled, crossover trial involving 17 patients with DBN due to cerebellar atrophy, infarction, Arnold–Chiari

Table2.Summaryoftheclinicalfeatures,pathophysiology,etiology,siteoflesion,andcurrenttreatmentoptionsofdownbeatandupbeatnystagmus.

Directionofthenystagmus(quickphase)

Waveform(slowphase)

Specialfeatures

Sitesoflesion

Etiology Treatment

Downbeat nystagmus

Downward, may be diagonal at lateral gaze

Jerk, linear, increasing or decreasing velocity of the slow phase

Increase in intensity during lateral and downward gaze

Cerebellum (bilateral floccular hypofunction); lower brain-stem

Degenerative cerebellar disorders, ischemia, idiopathic; often associated with bilateral vestibulopathy

4-amino-pyridine,3,4-diaminopyridine, baclofen, clonazepam

Upbeat nystagmus

Upward Jerk, linear, increasing or decreasing velocity of the slow phase

Increase in intensity during upward gaze

Medulla, ponto-mesencephalic and cerebellum

Ischemia, bleeding, Wernicke’s encephalopathy

Since often transient, treatment not necessary; baclofen, 4- aminopyridine

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



malformation, or unknown etiology [70]. Mean peak slow-phase velocity of DBN was measured before and 30 min after ran-domized ingestion of 20 mg of 3,4-DAP or oral placebo. 3,4-DAP reduced peak slow-phase velocity of DBN from 7.2 deg/s mean before treatment to 3.1 deg/s 30 min after inges-tion (p < 0.001). The mean peak slow-phase velocity decreased in 10 of 17 patients by more than 50%. Three patients expe-rienced transient perioral or digital paresthesia and one reported nausea and headache, but no other side effects were observed. The authors demonstrated that the single dose of 3,4-DAP significantly improved DBN and visual acuity, and also reduced distressing oscillopsia. From a clinical point of view, it must be kept in mind that only 50% of all patients with DBN respond to this treatment, mainly those without structural lesions of the cerebellum or brainstem. The assumed underlying mechanism is that aminopyridines increase the activity and excitability of the Purkinje cells (as was found in animal experiments [71]), thus augmenting the physiological inhibitory influence of the vestibular cerebellum on the vestibular nuclei. Meanwhile the effect of aminopyridines on

the gravity dependence of DBN has also been evaluated [72], and an improvement of postural imbalance in DBN was demonstrated [73].

The underlying mechanism of action of 4-AP in DBN was also investigated in two studies using the magnetic search-coil technique [74,75]. The major findings of these studies were as follows: first, 4-AP improved not only DBN, but also smooth pursuit and the gain of the verti-cal vestibulo-ocular reflex [74]. Second, 4-AP improved fixation by restoring gaze-holding ability and neural inte-grator function; further, as regards its etiology-dependent efficacy in DBN, 4-AP may work best when DBN is associated with cerebellar atrophy [75]. 4-DAP penetrates the blood–brain barrier better than 3,4-DAP, which makes it possible to reduce the dose to 3 × 5 mg/d. In our study only transient minor perioral or digital par-esthesia was reported by a few patients. A single patient reported transient nausea and headache. Additional side effects have been described in the literature on patients treated for multiple sclerosis and Lambert-Eaton myasthenic

MST

MT

Cortex

FEF

Eye

Pons

DLPN PMT

3

2

1III

SVN/Y

FL/PFL

Cerebellum

FN

OMN

NRTP

DV

II I

Figure2.SchematicrepresentationofaputativemodelofthepathomechanismofDBN. We propose that all patients with DBN share a final common pathway (disinhibition of the SVN and neurons of the Y group). The ocular motor circuitries involved are the two smooth pursuit eye movement pathways (I, II) and the vertical gaze-holding pathway (III). The different lesion sites that can lead to DBN are shown in red (1 - 3). See Discussion for details (from [65]).Reprinted with permission from Hufner K et al, Structural and functional MRIs disclose cerebellar pathologies in idiopathic downbeat nystagmus. Neurology

2007;69:1128-35.

DLPN: Dorsolateral pontine nuclei; DV: Dorsal, ocular motor vermis; FEF: Frontal eye field; FN: Fastigial nucleus; MST: Medial superior temporal area; MT: Middle

temporal area; NRTP: Nucleus reticularis tegmenti pontis; OMN: Ocular motor nuclei; PMT: Nucleus of the paramedian tract; SVN: Superior vestibular nucleus;

Y: Neurons of the Y group. Reprinted with permission from Hufner K etal, Structural and functional MRIs disclose cerebellar pathologies in idiopathic downbeat

nystagmus. Neurology 2007; 69: 1128 -35.

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



syndrome, as well as a case of epileptic seizure, on high dosages of 3-4-DAP. If DBN is caused by a structural lesion, then 4-AP does not improve the condition in most cases.

A PET study showed that 4-AP – in parallel to improving DBN – increases the metabolic activity of the flocculus [64]. All these studies give additional support both to the above hypothesis about the pathophysiology of DBN and the way that aminopyridines act.

6. Upbeatnystagmus

Upbeat nystagmus (UBN) – that is, UBN with gaze straight ahead – is an ocular motor disorder that manifests with oscillopsia due to retinal slip of the visual scene and postural instability. It is the second most common cause of acquired nystagmus. UBN usually increases with upgaze. Analogously to DBN, it is associated with impaired upward pursuit. UBN can be caused by lesions in different brain-stem and cerebellar regions such as the pontomesenceph-alic junction, medulla, or cerebellar vermis. Lesions in the pathways mediating upward eye movements – in particu-lar, from the vestibular nuclei through the brachium con-junctivum to the ocular motor nuclei – might result in slow downward drift of the eyes, which is corrected by fast upward movements (see [44]). Other hypotheses are that UBN is caused by an imbalance of vertical vestibulo-ocular reflex tone or a mismatch in the neural coordinate systems of saccade generation and neural velocity-to-position integration.

The symptoms persist as a rule for several weeks, but are not permanent in most patients. Because the eye movements generally have larger amplitudes, oscillopsia in upbeat nystagmus is very distressing and impairs vision. Upbeat nystagmus due to damage to the pon-tomesencephalic brainstem is frequently combined with a unilateral or bilateral internuclear ophthalmoplegia, indicating that the medial longitudinal fascicle is affected. The main etiologies are bilateral lesions in multiple scle-rosis, brainstem ischemia or tumor, Wernicke’s encephal-opathy, cerebellar degeneration, and dysfunction of the cerebellum due to intoxication.

GABAergic substances like baclofen have been used to treat UBN and DBN, but they have had only moderate success. One study demonstrated a beneficial effect of baclofen (5 – 10 mg t.i.d.), but this trial was not con-trolled [68]. In a single patient with UBN it was shown that 4-aminopyridine (4-AP) reduces the peak slow-phase velocity in the light from 8.6 to 2.0 deg/s [76]. 4-AP did not affect UBN in darkness, but it obviously activated pathways carrying visual information, which could then be used for UBN suppression in the light. Therefore, it was concluded that 4-AP reduces the downward drift in UBN by augmenting smooth pursuit commands. We

propose that 4-AP helps to activate parallel pathways that can assume the function of the lesioned struc-tures [77]. 4-AP may strengthen these parallel pathways by increasing the excitability of cerebellar PCs [71]. It may also evoke complex spikes in PCs similar to those elicited by climbing fiber stimulation [78].

7. Episodicataxiatype2

Episodic ataxia type 2 (EA2) is clinically characterized by recurrent attacks of ataxia, provoked by stress or exercise, which last for several hours to days [79-81]. Associated find-ings during the non-attack interval include central ocular motor and vestibular dysfunction, mainly DBN. Patients with EA2 can often be successfully treated with acetazol-amide [82]. Genetically, EA2 is an autosomal dominant hereditary disorder caused by mutations of the calcium channel gene CACNA1A [83], which encodes the CaV21 subunit of the PQ-calcium channel expressed mainly in the Purkinje cells. On the basis of the functional changes of the PQ-channel mutation, which leads to a reduced calcium current, it can be assumed that the inhibitory effect of Purkinje cells is reduced in EA2 [84]. This causes disinhibi-tion of the deep cerebellar nuclei, and thus ataxia and DBN. Since aminopyridines (as potassium channel block-ers) were shown to improve DBN (see below), most likely by increasing the inhibitory influence of the Purkinje cells, and this hypothesis was supported by animal experi-ments [71], we evaluated its effects on the occurrence of attacks with EA2 [85]. In three patients with EA2 (two with proven mutations of the CACNA1A gene), attacks could be prevented with the potassium channel blocker 4-aminopyri-dine (5 mg t.i.d.). Attacks recurred after treatment was stopped; subsequent treatment alleviated the symptoms (mean follow-up time > 12 months). These effects might be due to an improvement of the impaired functioning of Purkinje cells. It must be pointed out that these three patients no longer responded to the standard treatment with acetylzolamide. Again on the basis of this open trial, a placebo-controlled study is currently in progress. The clini-cal findings were supported by an animal study on the calcium channel mutant tottering mouse. Aminopyridines blocked the attacks characteristic of the tottering mouse via cerebellar potassium channels by increasing the threshold for attack initiation without mitigating the character of the attack [86].

8. Conclusion

Current pharmacological treatment options of vestibular and ocular motor disorders are reviewed for four drugs: corticos-teroids, the H1-agonist and H3-antagonist betahistine, the anticonvulsant carbamazepine, and the potassium channel blocker aminopyridine. Oral treatment with methylpredniso-lone alone significantly improved the long-term outcome of

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



peripheral vestibular function among patients with vestibular neuritis, whereas oral treatment with the antiviral agent vala-cyclovir did not improve the outcome. In two retrospective studies, intratympanic injections of dexamethasone were ben-eficial to provide satisfactorily vertigo control. In an open, non-masked trial in Menière’s disease, the number of attacks after 12 months was significantly lower in the high-dosage (48 mg t.i.d.) betahistine group than in the low-dosage (16 or 24 mg t.i.d.) betahistine group. In vestibular paroxysmia due to neurovascular cross-compression, carbamazepine led to a significant reduction in attack frequency, intensity and duration. Aminopyridines increase the activity and excitabil-ity of cerebellar Purkinje cells. By thus augmenting the inhibitory output of the vestibular cerebellum, they provide a new effective therapeutic principle for central vestibular and ocular motor disorders such as DBN, UBN, and EA2.

9. Expertopinion

The various forms of vertigo can be treated with pharmaco-logical therapy, physical therapy, surgery, and psychothera-peutic measures. Before treatment begins, the patient should be told that the prognosis is generally good, for two reasons: many forms of vertigo have a favorable natural course (e.g., the peripheral vestibular function improves or central vestibular compensation of the vestibular tonus imbalance takes place), and most forms can be successfully treated.

Vertigo and dizziness are not unique disease entities. There-fore there is no common drug available. The so-called antiver-tiginous drugs, such as dimenhydrinate (Dramamine), the belladonna alkaloid scopolamine (Transderm Scop), and ben-zodiazepine (Valium), are indicated for the symptomatic treat-ment of dizziness and nausea only in the following cases:

acute peripheral vestibulopathy (for a maximum of 1 – 3 days)•acute brainstem lesion near the vestibular nuclei•frequent and severe attacks of vertigo accompanied by •nausea and vomitingsevere benign paroxysmal positioning vertigo with nausea •and vomiting (0.5 h before the liberatory maneuvers)prevention of motion sickness•central positional/positioning vertigo with vomiting.•

It is the experience of the authors that none of these antivertiginous drugs are suitable for long-term treatment, for example, in cases of chronic (central vestibular) vertigo, archicerebellar ataxia, or certain forms of positional vertigo.

Besides these antivertiginous drugs, other pharmaceuticals are increasingly being used effectively to treat various forms of vertigo, such as beta-receptor blockers for vestibular migraine, aminopyridine for downbeat nystagmus and familial EA2, and carbamazepine for vestibular paroxysmia. There are only a few treatment studies available on vestibular migraine showing some effect of tricyclic antidepressants, zolmitrip-tan, or lamotrigine. However, a placebo-control multicenter trial is still warranted. So far only the standard treatment of migraine with aura can be recommended for vestibular migraine. Furthermore, there are several vestibular, ocular motor, and cerebellar disorders awaiting prospective, ran-domized, placebo-controlled and – due to the low prevalence of some disorders – multicenter treatment trials.

Several drugs that are potentially effective act specifically on certain receptors or ion channels, but not on others. A better understanding of the mechanisms of i) central compensation of a vestibular tonus imbalance due to uni-lateral peripheral or central vestibular lesions; and ii) aging and degeneration of vestibular and ocular motor structures will be important for future developments in the medical treatment of vestibular and balance disorders. Here, neu-rotransmitters will play a major role. Functional MRI and PET studies in animals and in humans (healthy subjects and patients with vestibular disorders) will disclose their involvement especially in the central vestibular system and their connections to the hippocampus and the autonomous centers. GABA, dopamine, and serotonin are among the most promising transmitter candidates. They could lead to new medical treatments of aging and degeneration, and to drugs that promote vestibular compensation or sensory substitution.

Declarationofinterest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



BibliographyPapers of special note have been highlighted aseitherofinterest(•)orofconsiderable interest(••)toreaders.

1. Neuhauser H, von Brevern M, Radtke A, et al. Epidemiology of vestibular vertigo: a neurootologic survey of the general population. Neurology 2005;65:898-904

2. Brandt T, Dieterich M, Strupp M. Vertigo and dizziness: common complaints. London: Springer, 2005

3. Sekitani T, Imate Y, Noguchi T, et al. Vestibular neuronitis: epidemiological survey by questionnaire in Japan. Acta Otolaryngol 1993;503(Suppl):9-12

4. Schulz P, Arbusow V, Strupp M, et al. Highly variable distribution of HSV-1-specific DNA in human geniculate, vestibular and spiral ganglia. Neurosci Lett 1998;252:139-42

5. Arbusow V, Schulz P, Strupp M, et al. Distribution of herpes simplex virus type 1 in human geniculate and vestibular ganglia: implications for vestibular neuritis. Ann Neurol 1999;46:416-9

6. Arbusow V, Theil D, Strupp M, et al. HSV-1 not only in human vestibular ganglia but also in the vestibular labyrinth. Audiol Neurootol 2000;6:259-62

7. Theil D, Arbusow V, Derfuss T, et al. Prevalence of HSV-1 lat in human trigeminal, geniculate, and vestibular ganglia and its implication for cranial nerve syndromes. Brain Pathol 2000;11:408-13

8. Theil D, Derfuss T, Strupp M, et al. Cranial nerve palsies: herpes simplex virus type 1 and varizella-zoster virus latency. Ann Neurol 2002;51:273-4

• ThepersistinglymphocyticcellinfiltrationandtheelevatedCD8andcytokine/chemokineexpressionincranialnervegangliademonstrateforthefirsttimethatlatentherpesviralinfectioninhumansisaccompaniedbyachronicinflammatoryprocesswithoutanyneuraldestruction.

9. Theil D, Derfuss T, Paripovic I, et al. Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response. Am J Pathol 2003;163:2179-84

10. Strupp M, Zingler VC, Arbusow V, et al. Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J Med 2004;351:354-61

•• Aprospective,randomized,double-blind,two-by-twofactorialtrialinwhichpatientswithacutevestibularneuritis

wererandomlyassignedtotreatment withplacebo,methylprednisolone,valacyclovirormethylprednisoloneplusvalacyclovir.Methylprednisolonesignificantlyimprovedtherecoveryofperipheralvestibularfunction.

11. Shupak A, Ussa A, Golz A, et al. Prednisone treatment for vestibular neuritis. Otol Neurotol 2008;29:368-74

12. Havia M, Kentala E, Pyykkö I. Prevalence of Menière’s disease in general population of Southern Finland. Otolaryngol Head Neck Surg 2005;133:762-8

13. Neuhauser H. Epidemiology of vertigo. Curr Opin Neurol 2007;20:40-6

14. Minor LB, Schessel DA, Carey JP. Menière’s disease. Curr Opin Neurol 2004;17:9-16

15. Yeh TH, Herman P, Tsai MC, et al. A cationic nonselective stretch-activated channel in the Reissner’s membrane of the guinea pig cochlea. Am J Physiol 1998;274:C566-76

16. van-Deelen GW, Huizing EH. Use of a diuretic (Dyazide) in the treatment of Menière’s disease. A double-blind cross-over placebo-controlled study. ORL J Otorhinolaryngol Relat Spec 1986;48:287-92

17. Smith WK, Sankar V, Pfleiderer AG. A national survey amongst UK otolaryngologists regarding the treatment of Menière’s disease. J Laryngol Otol 2005;119:102-5

18. Magnusson M, Padoan S, Karlberg M, et al. Delayed onset of ototoxic effects of gentamicin in patients with Menière’s disease. Acta Otolaryngol Suppl Stockh 1991;485:120-2

19. Lange G, Maurer J, Mann W. Long-term results after interval therapy with intratympanic gentamicin for Meniere’s disease. Laryngoscope 2004;114:102-5

20. Cohen-Kerem R, Kisilevsky V, Einarson TR, et al. Intratympanic gentamicin for Meniere’s disease: a meta-analysis. Laryngoscope 2004;114:2085-91

21. Carey JP, Hirvonen T, Peng GC, et al. Changes in the angular vestibulo-ocular reflex after a single dose of intratympanic gentamicin for Meniere’s disease. Auris Nasus Larynx 2002;956:581-4

22. Barrs DM. Intratympanic injections of dexamethasone for long-term control of vertigo. Laryngoscope 2004;114:1910-4

23. Boleas-Aguirre MS, Lin FR, Della Santina CC, et al. Longitudinal results with intratympanic dexamethasone in the treatment of Menière’s disease. Otol Neurotol 2008;29(1):33-8

• Arecentretrospectivestudyshowingthatdexamethasoneinjectiontherapyonanas-neededoutpatientbasiscanprovidevertigocontrolthatissatisfactoryinpatientswithMenière’sdisease.

24. Yilmaz I, Yilmazer C, Erkan AN, et al. Intratympanic dexamethasone injection effects on transient-evoked otoacoustic emission. Am J Otolaryngol 2005;26:113-7

25. Meyer ED. Zur Behandlung des Morbus Menière mit Betahistinmesilat (Aequamen) – Doppelblindstudie gegen Placebo (crossover). Laryng Rhinol Otol 1985;64:269-72

• Thefirst1-year,prospective,double-blindstudyshowingthatbetahistinetreatmentispreferabletonotreatment.

26. Claes J, Van-de-Heyning PH. Medical treatment of Meniere’s disease: a review of literature. Acta Otolaryngol Suppl 1997;526:37-42

27. James A, Thorp M. Meniere’s disease. Clin Evid 2004;12:742-50

28. Dziadziola JK, Laurikainen EL, Rachel JD, et al. Betahistine increases vestibular blood flow. Otolaryngol Head Neck Surg 1999;120:400-5

29. Strupp M, Huppert D, Frenzel C, et al. Long-term prophylactic treatment of attacks of vertigo in Menière’s disease: comparison of a high with a low dosage of betahistine in an open trial. Acta Otolaryngol 2008;128:520-4

• Despitetheconsiderablelimitationsofanopen,non-maskedtrail,particularlyinMenière’sdisease,ahigherdosageofbetahistinedihydrochloride(48mgt.i.d.)andlong-termtreatment(12months)seemtobemoreeffectivethana lowdosage(16–24mgt.i.d.)andshort-termtreatment.

30. Jeck-Thole S, Wagner W. Betahistine: a retrospective synopsis of safety data. Drug Saf 2006;29:1049-59

31. James AL, Burton MJ. Betahistine for Menière’s disease or syndrome. Cochrane Database Syst Rev 2001;(1):CD001873

32. Jannetta PJ. Neurovascular cross compression in patients with hyperactive dysfunction symptoms of the eighth cranial nerve. Surg Forum 1975;26:467-8

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



33. Jannetta PJ, Moller MB, Moller AR. Disabling positional vertigo. N Engl J Med 1984;310:1700-5

34. Moller MB, Moller AR, Jannetta PJ, et al. Microvascular decompression of the eighth nerve in patients with disabling positional vertigo: selection criteria and operative results in 207 patients. Acta Neurochir (Wien) 1993;125:75-82

35. Moller MB, Moller AR, Jannetta PJ, Sekhar L. Diagnosis and surgical treatment of disabling positional vertigo. J Neurosurg 1986;64:21-8

36. Moller MB. Results of microvascular decompression of the eighth nerve as treatment for disabling positional vertigo. Ann Otol Rhinol Laryngol 1990;99:724-9

37. Brandt T, Dieterich M. Vestibular paroxysmia: vascular compression of the eighth nerve? Lancet 1994;343:798-9

38. Ryu H, Yamamoto S, Sugiyama K, Nozue M. Neurovascular compression syndrome of the eighth cranial nerve: what are the most reliable diagnostic signs? Acta Neurochir (Wien) 1998;140:1279-86

39. Schwaber MK, Hall JW. Cochleovestibular nerve compression syndrome, I: clinical features and audiovestibular findings. Laryngoscope 1992;102:1020-9

40. Brackmann DE, Kesser BW, Day JD. Microvascular decompression of the vestibulocochlear nerve for disabling positional vertigo: the house ear clinic experience. Otol Neurotol 2001;22:882-7

41. McCabe BF, Gantz BJ. Vascular loop as a cause of incapacitating dizziness. Am J Otol 1989;10:117-20

42. Hüfner K, Barresi D, Glaser M, et al. Vestibular paroxysmia: diagnostic features and medical treatment. Neurology 2008;71:1006-14

• Thefirstfollow-upstudyonvestibularparoxysmiain32patients,whichprovestheusefulnessofthediagnosticcriteria,especiallyconstructiveinterferenceinsteady-statemagneticresonanceimaging,andthetherapeuticefficacyofmedicaltreatmentwithanticonvulsants.

43. Wagner JN, Glaser M, Brandt T, et al. Downbeat nystagmus: aetiology and comorbidity in 117 patients. J Neurol Neurosurg Psychiatry 2008;79:672-7

44. Leigh RJ, Zee D. The neurology of eye movements, 4th edition. Oxford, New York: Oxford University Press, 2006

45. Baloh RW, Spooner JW. Downbeat nystagmus: a type of central vestibular nystagmus. Neurology 1981;31:304-10

46. Pierrot-Deseilligny C, Milea D. Vertical nystagmus: clinical facts and hypotheses. Brain 2005;128:1237-46

47. Halmagyi GM, Rudge P, Gresty MA, et al. Downbeating nystagmus: a review of 62 cases. Arch Neurol 1983;40:777-84

48. Straumann D, Zee DS, Solomon D. Three-dimensional kinematics of ocular drift in humans with cerebellar atrophy. J Neurophysiol 2000;83:1125-40

49. Glasauer S, Hoshi M, Kempermann U, et al. Three-dimensional eye position and slow phase velocity in humans with downbeat nystagmus. J Neurophysiol 2003;89:338-54

50. Glasauer S, von LH, Siebold C, et al. Vertical vestibular responses to head impulses are symmetric in downbeat nystagmus. Neurology 2004;63:621-5

51. Glasauer S, Hoshi M, Buttner U. Smooth pursuit in patients with downbeat nystagmus. Ann NY Acad Sci 2005;1039:532-5

52. Bronstein AM, Miller DH, Rudge P, et al. Downbeating nystagmus: magnetic resonance imaging and neuro-otological findings. J Neurol Sci 1987;81:173-84

53. Zee DS, Yamazaki N, Butler PHZ, et al. Effects of ablation of flocculus and paraflocculus on eye movements in primate. J Neurophysiol 1981;46:878-99

• Experimentalproofthatablationoftheflocculuscausesdownbeatnystagmus inprimates.

54. Lisberger SG, Miles FA, Zee DS. Signals used to compute errors in monkey vestibuloocular reflex: possible role of flocculus. J Neurophysiol 1984;52:1140-53

55. Rambold H, Churchland A, Selig Y, et al. Partial ablations of the flocculus and ventral paraflocculus in monkeys cause linked deficits in smooth pursuit eye movements and adaptive modification of the VOR. J Neurophysiol 2002;87:912-24

56. Dieterich M, Brandt T. Vestibulo-ocular reflex. Curr Opin Neurol 1995;8:83-8

57. Bohmer A, Straumann D. Pathomechanism of mammalian downbeat nystagmus due to cerebellar lesion: a simple hypothesis. Neurosci Lett 1998;250:127-30

58. Marti S, Palla A, Straumann D. Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus. Ann Neurol 2002;52:712-21

59. Sprenger A, Rambold H, Sander T, et al. Treatment of the gravity dependence of downbeat nystagmus with 3, 4-diaminopyridine. Neurology 2006;67:905-7

60. Zee DS, Friendlich AR, Robinson DA. The mechanism of downbeat nystagmus. Arch Neurol 1974;30:227-37

61. Marti S, Straumann D, Glasauer S. The origin of downbeat nystagmus: an asymmetry in the distribution of on-directions of vertical gaze-velocity purkinje cells. Auris Nasus Larynx 2005;1039:548-53

• Mechanismofdownbeatnystagmus.

62. Partsalis AM, Zhang Y, Highstein SM. Dorsal Y group in the squirrel monkey. II. Contribution of the cerebellar flocculus to neuronal responses in normal and adapted animals. J Neurophysiol 1995;73:632-50

63. Kalla R, Deutschlander A, Hufner K, et al. Detection of floccular hypometabolism in downbeat nystagmus by fMRI. Neurol 2006;66:281-3

64. Bense S, Best C, Buchholz HG, et al. 18F-fluorodeoxyglucose hypometabolism in cerebellar tonsil and flocculus in downbeat nystagmus. Neuroreport 2006;17:599-603

65. Hufner K, Stephan T, Kalla R, et al. Structural and functional MRIs disclose cerebellar pathologies in idiopathic downbeat nystagmus. Neurology 2007;69:1128-35

• Mechanismofidiopathicdownbeatnystagmus.

66. Young YH, Huang TW. Role of clonazepam in the treatment of idiopathic downbeat nystagmus. Laryngoscope 2001;111:1490-3

67. Currie JN, Matsuo V. The use of clonazepam in the treatment of nystagmus-induced oscillopsia. Ophthalmol 1986;93:924-32

68. Dieterich M, Straube A, Brandt T, et al. The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus. J Neurol Neurosurg Psych 1991;54:627-32

69. Averbuch-Heller L, Tusa RJ, Fuhry L, et al. A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol 1997;41:818-25

70. Strupp M, Schuler O, Krafczyk S, et al. Treatment of downbeat nystagmus with

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.



3,4-diaminopyridine: a placebo-controlled study. Neurology 2003;61:165-70

• Firststudyoneffectivetreatment ofdownbeatnystagmuswithaminopyridine.

71. Etzion Y, Grossman Y. Highly 4-aminopyridine sensitive delayed rectifier current modulates the excitability of guinea pig cerebellar Purkinje cells. Exp Brain Res 2001;139:419-25

72. Helmchen C, Sprenger A, Rambold H, et al. Effect of 3,4-diaminopyridine on the gravity dependence of ocular drift in downbeat nystagmus. Neurology 2004;63:752-3

73. Sprenger A, Zils E, Rambold H, et al. Effect of 3,4-diaminopyridine on the postural control in patients with downbeat nystagmus. Ann NY Acad Sci 2005;1039:395-403

74. Kalla R, Glasauer S, Schautzer F, et al. 4-aminopyridine improves downbeat nystagmus, smooth pursuit, and VOR gain. Neurology 2004;62:1228-9

75. Kalla R, Glasauer S, Buttner U, et al. 4-aminopyridine restores vertical and horizontal neural integrator function in downbeat nystagmus. Brain 2007;130:2441-51

76. Glasauer S, Kalla R, Buttner U, et al. 4-aminopyridine restores visual ocular

motor function in upbeat nystagmus. J Neurol Neurosurg Psychiatry 2005;76:451-3

77. Glasauer S, Strupp M, Kalla R, et al. Effect of 4-aminopyridine on upbeat and downbeat nystagmus elucidates the mechanism of downbeat nystagmus. Ann NY Acad Sci 2005;1039:528-31

78. Cavelier P, Pouille F, Desplantez T, et al. Control of the propagation of dendritic low-threshold Ca(2 + ) spikes in Purkinje cells from rat cerebellar slice cultures. J Physiol 2002;540:57-72

79. Griggs RC, Nutt JG. Episodic ataxias as channelopathies. Ann Neurol 1995;37:285-7

80. Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurology 2004;62:17-22

81. Strupp M, Zwergal A, Brandt T. Episodic ataxia type 2. Neurotherapeutics 2007;4:267-73

82. Griggs RC, Moxley RT, Lafrance RA, et al. Hereditary paroxysmal ataxia: response to acetazolamide. Neurology 1978;28:1259-64

83. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 + channel gene CACNL1A4. Cell 1996;87:543-52

84. Kullmann DM. The neuronal channelopathies. Brain 2002;125:1177-95

85. Strupp M, Kalla R, Dichgans M, et al. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 2004;62:1623-5

• Thefirststudyoneffectivetreatmentofgeneticallyprovenepisodicataxiatype2withaminopyridine.

86. Weisz CJ, Raike RS, Soria-Jasso LE, et al. Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering. J Neurosci 2005;25:4141-5

87. Honrubia V. Quantitative vestibular function tests and the clinical examination. In: Herdman SJ, editor, Vestibular rehabilitation, 1st edition. Philadelphia: FA Davis; 1994. p. 113-64

AffiliationThomas Brandt† MD FRCP, Andreas Zwergal MD & Michael Strupp MD†Author for correspondenceLudwig-Maximilians-University, Institute of Clinical Neuroscience, Marchioninistr. 15, 81377 Munich, Germany Tel: +49 89 7095 2380 1; Fax: +49 89 7095 8855; E-mail: [email protected].

Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B d

er L

MU

Mue

nche

n on

03/

13/1

3Fo

r pe

rson

al u

se o

nly.

Medical treatment of vestibular disorders

Documents

Transcript of Medical treatment of vestibular disorders