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Therapeutic Advances in Neurological Disorders Review

Current treatment of vestibular, ocular motor

disorders and nystagmus

Michael Strupp and Thomas Brandt

Abstract : Vertigo and dizziness are among the most common complaints with a lifetimeprevalence of about 30%. The various forms of vestibular disorders can be treated withpharmacological therapy, physical therapy, psychotherapeutic measures or, rarely, surgery.In this review, the current pharmacological treatment options for peripheral and centralvestibular, cerebellar and ocular motor disorders will be described. They are as follows forperipheral vestibular disorders. In vestibular neuritis recovery of the peripheral vestibularfunction can be improved by treatment with oral corticosteroids. In Meniè re’s disease a recentstudy showed long-term high-dose treatment with betahistine has a significant effect on the

frequency of the attacks. The use of aminopyridines introduced a new therapeutic principlein the treatment of downbeat and upbeat nystagmus and episodic ataxia type 2 (EA 2).These potassium channel blockers presumably increase the activity and excitability ofcerebellar Purkinje cells, thereby augmenting the inhibitory influence of these cells onvestibular and cerebellar nuclei. A few studies showed that baclofen improves periodicalternating nystagmus, and gabapentin and memantine, pendular nystagmus. However,many other eye movement disorders such as ocular flutter opsoclonus, central positioning,or see-saw nystagmus are still difficult to treat. Although progress has been made in thetreatment of vestibular neuritis, downbeat and upbeat nystagmus, as well as EA 2, state-of-the-art trials must still be performed on many vestibular and ocular motor disorders,namely Menière’s disease, bilateral vestibular failure, vestibular paroxysmia, vestibularmigraine, and many forms of central eye movement disorders.

Keywords : vertigo, dizziness, benign paroxysmal positioning vertigo, vestibular neuritis,Menière’s disease, vestibular paroxysmia, vestibular migraine, episodic ataxia type 2, downbeatnystagmus, upbeat nystagmus

Introduction

In the first part of this article, the treatment of

common peripheral and central vestibular disor-

ders are described [Strupp et al . 2007a; Brandt

et al . 2005]. The second part focuses on theclinically most relevant forms of nystagmus, in

particular downbeat and upbeat nystagmus,

along with their pathophysiology and topo-

graphic diagnosis, and current therapy [Leigh

and Zee, 2006; Strupp and Brandt, 2006].

Vertigo and dizziness

The terms vertigo and dizziness cover a number

of multisensory and sensorimotor syndromes of

various aetiologies and pathogeneses, which can

be elucidated only with an interdisciplinary

approach. After headache, it is one of the most

frequent presenting symptoms, not only in neu-

rology. The lifetime prevalence is almost 30%[Neuhauser, 2007]. A survey of over 30,000 per-

sons showed that the prevalence of vertigo as a

function of age lies around 17% and rises up to

39% in those over 80 years of age [Davis and

Moorjani, 2003].

The prerequisite of every treatment of vertigo

and dizziness is a correct diagnosis, which can

be simply made in most patients on the basis of

the patient history and the clinical examination

even without any laboratory examinations.

http://tan.sagepub.com 223

Ther Adv Neurol Disord

(2009) 2(4) 223–239

DOI: 10.1177/1756285609103120

The Author(s), 2009.

Reprints and permissions:http://www.sagepub.co.uk/ journalsPermissions.nav

Correspondence to:

Michael Strupp, MD

Professor of Neurologyand ClinicalNeurophysiology,University of Munich,

Klinikum Grosshadern,Munich, GermanyMichael.Strupp@med.

uni-muenchen.de

Thomas Brandt

Institute of ClinicalNeuroscience, Universityof Munich, KlinikumGrosshadern, Munich,Germany


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Depending on the aetiology, the various forms of

vestibular disorders can be treated with pharma-

cological therapy, physical therapy, psychothera-

peutic measures or, rarely, surgery. Before

beginning any treatment, the patient should be

told that the prognosis is generally good for two

reasons: (a) vertigo often takes a favourablenatural course (e.g. the peripheral vestibular

function improves or central vestibular compen-

sation of the vestibular tone imbalance takes

place) and (b) most forms can be successfully

treated (mainly with drugs or physiotherapy).

Several agents are now available for the specific

treatment of certain forms of vestibular and

ocular motor disorders.

Peripheral vestibular disorders

Three typical forms of peripheral vestibular dis-orders can be differentiated by their characteristic

signs and symptoms: (1) bilateral peripheral loss

of vestibular function (bilateral vestibulopathy),

characterised by oscillopsia during head move-

ments and instability of gait and posture; (2)

acute/subacute unilateral failure of vestibular

function (most often caused by vestibular

neuritis), characterised by a rotatory vertigo,

oscillopsia, and a tendency to fall toward the

affected ear; and (3) paroxysmal, inadequate

stimulation or inhibition of the peripheral vestib-

ular system, characterised by attacks of vertigo

and oscillopsia. This occurs in benign paroxysmalpositioning vertigo, but also in Menière’s disease

or vestibular paroxysmia.

Benign paroxysmal positioning vertigo Benign paroxysmal positioning vertigo (BPPV) is

the most common cause of vertigo, not only

in the elderly. It is characterised by brief attacks

of rotatory vertigo and simultaneous positioning

rotatory-vertical nystagmus toward the under-

most ear elicited by extending the head or posi-

tioning the head or body toward the affected ear.

It is called benign because it often resolves spon-taneously within weeks to months; in some cases,

however, it can last for years. The canalolithiasis

hypothesis of freely floating ‘heavy otoconia’ is

compatible with all features of BPPV: latency,

duration, course of attacks, direction of nystag-

mus, reversal of nystagmus, fatigability and, most

important, the efficacy of positioning ‘liberatory

manoeuvres’ of the head [Brandt and Steddin,

1993]. Brandt and Daroff [1980] were the first

to devise an effective exercise programme which

required the simple performance of a series of

head positioning movements. Semont et al .

[1988] recommended that the patient’s position

should be changed from the inducing position by

a tilt of 180 degrees to the opposite side. Epley

[1994] proposed another variation that involved

turning the patient’s trunk and head into a head-

hanging position. It can also be explained by themechanism of canalolithiasis. The liberatory

maneuvers according to Semont et al . [1988] or

Epley [1992] are successful in more than 95% of

the patients if performed correctly [Strupp et al .

2007a; Brandt et al . 2005].

Vestibular neuritis Vestibular neuritis is the third most common

cause of peripheral vestibular vertigo (the first

and the second are BPPV and Meniére’s disease).

It accounts for 7% of the patients who presentat outpatient clinics specialising in the treatment

of dizziness [Brandt et al . 2005] and has an inci-

dence of 3.5 per 100,000 population [Sekitani

et al . 1993]. The key signs and symptoms of

vestibular neuritis are the acute onset of sus-

tained rotatory vertigo, horizontal spontaneous

nystagmus toward the unaffected ear with a

rotational component, postural imbalance with

Romberg’s sign, that is, falls with the eyes

closed toward the affected ear, and nausea.

Caloric testing invariably shows ipsilateral hypo-

responsiveness or nonresponsiveness. In the past,

either inflammation of the vestibular nerve orlabyrinthine ischaemia was proposed to cause

vestibular neuritis. Currently a viral cause is

favoured. The evidence, however, remains

circumstantial. Herpes simplex virus type 1

(HSV-1) DNA has been detected on autopsy

with the use of polymerase chain reaction in

about two-thirds of human vestibular ganglia

[Theil et al . 2002, 2000; Arbusow et al . 2000,

1999; Schulz et al . 1998]. This, as well as

the expression of CD8-positive T-lymphocytes,

cytokines and chemokines, indicates that the

vestibular ganglia are latently infected withHSV-1 [Theil et al . 2003].

A prospective randomised, double-blind, two-

by-two factorial trial was performed, in which

patients with acute vestibular neuritis were ran-

domly assigned to treatment with placebo,

methylprednisolone (100 mg/day, doses tapered

by 20 mg every third day), valacyclovir (valoci-

clovir, 1 g t.i.d. for 7 days), or methylpredniso-

lone plus valacyclovir. Vestibular function was

determined by caloric irrigation, with the use of

Therapeutic Advances in Neurological Disorders 2 (4)

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the vestibular paresis formula (to measure the

extent of unilateral caloric paresis), within 3days after the onset of symptoms and 12

months afterwards. A total of 141 patients under-

went randomisation. The mean improvement in

peripheral vestibular function at 12-month

follow-up was 39.6 percentage points in the pla-

cebo group, 62.4 percentage points in the

methylprednisolone group, 36.0 percentage

points in the valacyclovir group, and 59.2 percen-

tage points in the methylprednisolone plus vala-

cyclovir group (Figure 1). Analysis of variance

showed that methylprednisolone had a significant

effect, but valacyclovir did not. Therefore, this

study showed that methylprednisolone alone sig-nificantly improves the recovery of peripheral

vestibular function in patients with vestibular

neuritis, whereas valacyclovir is not required

[Strupp et al . 2004b]. Symptom outcome at 12

months was not addressed for two reasons. First,

animal experiments show that steroids improve

central vestibular compensation. Thus, para-

meters other than vestibular paresis, such as pos-

tural imbalance or ‘vertigo and dizziness’, would

not help differentiate between the effects of ster-

oids on the recovery of peripheral vestibular

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Controls Methylprednisolone

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Figure 1. Unilateral vestibular failure within 3 days after symptom onset and after 12 months. Vestibular function was determinedby caloric irrigation, using the ‘vestibular paresis formula’ (which allows a direct comparison of the function of both labyrinths) for

each patient in the placebo (upper left), methylprednisolone (upper right), valacyclovir (lower right), and methylprednisolone plusvalacyclovir (lower left) group. Also shown are box plot charts for each group with the mean (g) SD, and 25% and 75% percentile(box plot) as well as the 1% and 99% range (x). A clinically relevant vestibular paresis was defined as 425% asymmetry betweenthe right-sided and the left-sided responses [Honrubia 1994]. Follow-up examination showed that vestibular function improved inall four groups: in the placebo group from 78.9 24.0 (meanSD) to 39.019.9, in the methylprednisolone group from 78.7 15.8to 15.416.2, in the valacyclovir group from 78.420.0 to 42.7 32.3, and in the methylprednisolone plus valacyclovir group from78.6 21.1 to 20.4 28.4. Analysis of variance revealed that methylprednisolone and methylprednisolone plus valacyclovir causedsignificantly more improvement than placebo or valacyclovir alone. The combination of both was not superior to steroidmonotherapy (from Strupp et al . 2004b).

M Strupp and T Brandt



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function and on central vestibular compensation.

Second, there are no validated scales for measur-

ing vertigo and dizziness. All in all, this cheap

and well-tolerated therapy can be recommended

as the pharmaceutical treatment of choice for

vestibular neuritis.

Menie `re’s disease Menière’s disease is clinically characterised by

recurrent spontaneous attacks of vertigo, fluctu-

ating hearing loss, tinnitus and aural fullness.

Its incidence varies between 7.5 per 100,000 to

160 per 100,000 persons [Minor et al . 2004].

Endolymph hydrops is assumed to be the patho-

logical basis of Menière’s disease, either due to a

too high production or a too low absorption of

the endolymph. The increased endolymphatic

pressure causes periodic rupturing or leakage(by the opening of nonselective, stretch-activated

ion channels [Yeh et al . 1998] of the membrane

separating the endolymph from the perilymph

space. Therefore, pathophysiologically it makes

sense to reduce the production and increase

the absorption of endolymph. The clinical aims

of treatment of Menière’s disease are to stop

vertigo, reduce or abolish tinnitus, and preserve

and even reverse hearing loss. Most studies focus

on the most distressing symptom of Menière’s

disease: recurrent attacks of vertigo.

There is a plethora of treatment strategies forMenière’s disease. Destructive procedures invol-

ving the lateral semicircular canal and vestibule

have been proposed since 1904. The first endo-

lymphatic 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 and diuretics are still

recommended, although in one double-blind

study diuretics did not have any effect

[van-Deelen and Huizing, 1986]. Vestibulotoxic

drugs have been in use since 1948; local intra-tympanic delivery has been performed since

1956 (for references see Smith et al . 2005). 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 few decades, there are still only very few

state-of-the-art prospective, placebo-controlled,

double-blind trials. Moreover, there are signifi-

cant differences in the treatment regimen of

Menière’s disease between Europe and the

US. In the US, low-salt diet, diuretics, and

intratympanic injection of gentamicin and corti-

costeroids are preferred. In Europe betahistine is

more often used, in the US rarely; it is remark-

able that in a recent review on Menière’s disease

by two US authors the word betahistine does not

even appear [Sajjadi and Paparella, 2008].

A national survey among UK otolaryngologistson the treatment of Menière’s disease revealed

that 94% used betahistine, 63% diuretics, 71%

salt restriction, 52% sac decompression, and

approximately 50% insertion of a grommet

[Smith et al . 2005]. Local gentamicin instillation

has become more and more popular since its

introduction in the UK 10 years ago: approxi-

mately two-thirds of the otolaryngologists use

this method.

Intratympanic injections of gentamicinSeveral studies have been published on intratym-

panic gentamicin application for the treatment of

Menière’s disease. Initially multiple intratympa-

nic injections of gentamicin were given until

patients developed vestibular hypofunction.

This led to a good control of attacks of vertigo,

which, however, was accompanied by a high rate

of sensorineural hearing loss (approximately

50%). Especially after the demonstration of a

delayed onset of ototoxic effects [Magnusson

et al . 1991], the regimen was changed in two

ways: (1) single instillations at fixed interims of

several days or weeks, or (2) single-shot injectionsand follow-up. Following the latter regimen, a

prospective uncontrolled study with a follow-up

time of 2–4 years on 57 patients showed that in

95% vertigo attacks could be controlled [Lange

et al . 2004]. Fifty-three per cent of these patients

needed only one injection of 12 mg gentamicin,

32% two or three injections. A recent meta-ana-

lysis on 15 trials with 627 patients on gentamicin

injection showed that complete vertigo control

was achieved in about 75% of patients and com-

plete or substantial control in about 93%. The

success rate was not affected by the gentamicintreatment regimen; that is, fixed versus titration

[Cohen-Kerem et al . 2004]. Hearing level and

word recognition were not adversely affected,

regardless 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 genta-

micin is due to its damage to the hair cells.




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A complete ablation of function, however, does

not seem necessary in order to control vertigo

[Carey et al . 2002].

Intratympanic injections of corticosteroids

In a retrospective chart review, Barrs [2004]

evaluated the effects of intratympanic injections

of dexamethasone in 34 patients. After a single

course of weekly injections of 10 mg/ml

dexamethasone for 1 month, only 24% of thepatients reported vertigo control. Another 24%

responded to the repeat series of injections. All

in all, approximately one-half of the patients with

Menière’s disease achieved control of vertigo with

one or more courses of intratympanic injections

of corticosteroids. The safety of intratympanic

dexamethasone injections was evaluated by tran-

sient evoked otoacoustic emission. No change

was found in 26 patients after five injections of

4 mg dexamethasone [Yilmaz et al . 2005].

Betahistine

In Europe betahistine is more often used, mainly

on the basis of a study by Meier in 1985 and

more recent meta-analyses [James and Thorp,

2004; Claes and Van-de-Heyning, 1997].

Betahistine is an H1 agonist and H3 antagonist.

It improves the microcirculation by acting on the

precapillary sphincters of the stria vascularis

[Dziadziola et al . 1999]. 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) seems to be more effective

than a low dosage (16–24 mg t.i.d.) and short-

term treatment (Figure 2) [Strupp et al . 2008].

These data are the basis for a recently begun pro-

spective, randomised, double-blind dose-finding

study comparing placebo with 16 mg and 48 mg

t.i.d. betahistine-dihydrochloride. Finally, 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.

Vestibular paroxysmia Vestibular paroxysmia is characterised by short

attacks of rotatory or to-and-fro vertigo. These

attacks last for seconds to minutes and may

occur up to 30 times a day. Like in trigeminal

neuralgia, hemifacial spasm or superior oblique

myokymia, it is assumed that a neurovascular

cross-compression of the eighth cranial nerve is

the cause of vestibular paroxysmia [Brandt and

Dieterich, 1994]. Therapy with low doses of

carbamazepine (200–600 mg per day) or oxcar-

bazepine has an early therapeutic onset, and

thus provides a positive response useful in the

diagnostics of the disease. This was demonstrated

in an open trial. [Hufner et al . 2008]. In case of

intolerance, gabapentin, valproic acid, or pheny-

toin is a possible alternative. Currently, a pro-

spective, placebo-controlled, double-blind trial

is underway.

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Figure 2. Effects of betahistine dihydrochloride (low dosage (light blue line): 16 or 24 mg t.i.d. versus highdosage (dark blue line): 48 mg t.i.d.) on the frequency of attacks of vertigo in a total of 112 MD patients. Themean number of attacks per month (SEM) during the 3 months preceding treatment (month 0) is givenas well as the number per month during therapy (month 3, 6, 9, 12). After 12 months the mean (median)number of attacks dropped from 7.6 (4.5) to 4.4 (2.0) ( p 50.0001) in the low dosage group, and from 8.8 (5.5)to 1.0 (0.0) (p 50.0001) in the high dosage group. The number of attacks after 12 months was significantly

lower in the high dosage group than in the low dosage group ( p 12M¼ 0.0002) (from Strupp et al . 2008).




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Central vestibular, ocular motor, and

cerebellar disorders

In this review the pharmacological treatment of

the most important central vestibular, ocular

motor, and cerebellar disorders will be presented,

namely vestibular migraine, episodic ataxia

type 2, and downbeat, upbeat and other formsof nystagmus.

Vestibular migraine Vestibular migraine is the most common cause of

central recurrent attacks of vertigo. Characteristic

features include recurrent attacks of various

combinations of vertigo, ataxia of stance and

gait, visual disorders, and other brainstem symp-

toms accompanied or followed by occipitally

located head pressure, pain, nausea or vomiting

[Neuhauser and Lempert, 2004; Furman et al .

2003; Brandt and Dieterich, 1994]. There is,however, an ongoing debate as to whether it is a

clinical entity. Treatment is the same as for

migraine with aura; that is, for prophylactic

therapy the use of betablockers (metoprolol or

propranol), valproic acid or topiramate for at

least 3–6 months. A few treatment studies on

vestibular migraine have been performed.

Tricyclic antidepressants in combination with

diet showed a good response in a trial on

81 patients [Reploeg and Goebel 2002]. For

zolmitriptan the response rate in acute attacks

was 38% versus 22% in a study on 19 patients

[Neuhauser et al . 2003]. Another open trial on10 patients demonstrated that lamotrigine

(100 mg per day as a single dose) had a signifi-

cant effect on the occurrence of headache and a

more marked effect on vertigo [Bisdorff, 2004].

Again, a placebo-controlled multicentre trial is

warranted. So far, only the standard treatment

of migraine with aura can be recommended for

vestibular migraine.

Episodic ataxia type 2 Episodic ataxia type 2 (EA2) is clinically charac-

terised by recurrent attacks of ataxia, provokedby stress or exercise, which last for several

hours to days [Strupp et al . 2007b; Jen et al .

2004; Griggs and Nutt, 1995]. Associated find-

ings during the nonattack interval include central

ocular motor and vestibular dysfunction, mainly

downbeat nystagmus. Patients with EA2 can

often be successfully treated with acetazolamide

[Griggs et al . 1978]. Genetically EA2 is an

autosomal dominant hereditary disorder caused

by mutations of the calcium channel gene

CACNA1A [Ophoff et al . 1996], 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 cur-

rent, it can be assumed that the inhibitory effect

of Purkinje cells is reduced in EA2 [Kullmann,

2002]. This causes the disinhibition of the deepcerebellar nuclei and thus ataxia and downbeat

nystagmus. Since aminopyridines (as potassium

channel blockers) were shown to improve

downbeat nystagmus (see below) most likely by

increasing the inhibitory influence of the Purkinje

cells (this hypothesis was supported by animal

experiments [Etzion and Grossman, 2001]), we

evaluated its effects on the occurrence of attacks

with EA2 [Strupp et al . 2004a]. In three patients

with EA2 (two with proven mutations of the

CACNA1A gene) attacks could be prevented

with the potassium channel blocker 4-aminopyr-idine (5 mg t.i.d.). Attacks recurred after treat-

ment was stopped; subsequent treatment

alleviated the symptoms (mean follow-up time

greater than 12 months). These effects might

be due to an improvement of the impaired func-

tioning of Purkinje cells. It must be pointed out

that these three patients did not respond to the

standard treatment with acetylzolamide any

more. Again on the basis of this open trial a

placebo-controlled study is currently in progress.

The clinical findings were supported by an

animal study on the calcium channel mutant

tottering mouse. Aminopyridines blocked theattacks characteristic of the tottering mouse via

cerebellar potassium channels by increasing the

threshold for attack initiation without mitigating

the character of the attack [Weisz et al . 2005].

Nystagmus Nystagmus can be defined as periodic, most

often involuntary eye movements that normally

consist of a slow (causative or pathological)

phase and a quick eye phase, which brings the

eye back to the initial position. Nystagmus is

quite common: its prevalence lies around 0.1%[Stayte et al . 1993]. The most common forms of

acquired nystagmus are downbeat and upbeat

nystagmus. Both can be treated nowadays with

aminopyridines in their capacity as potassium

channel blockers. More rare forms are congenital

nystagmus, acquired fixation pendular nystag-

mus, and period alternating nystagmus. If they

cause symptoms, mainly involuntary movement

of the visual surrounding (oscillopsia), treatment

with mematine or gabapentin should be tried.

To improve treatment of the different forms of




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nystagmus, further randomised controlled trials

will be necessary to test different agents on the

basis of our current knowledge of the patho-

physiology of nystagmus.

Common, clinically important forms ofnystagmus and their therapy

In the following the most common and clinically

most relevant forms of nystagmus and their

pathophysiology as well as current therapy will

be described. For the frequency of the different

forms, see Table 1. In Table 2 all the features are

summarised. The treatment of nystagmus is

based on four principles: medical treatment,

optical devices, surgery to weaken certain eye

muscles, and somatosensory or auditory stimuli.

Medical treatment is the most relevant and

successful means of treatment (for reviews seeLeigh and Zee, 2006; Strupp and Brandt, 2006;

Straube et al . 2004; Leigh and Tomsak, 2003).

Downbeat nystagmus (DBN) Downbeat nystagmus (DBN) is the most

common form of acquired persisting fixation

nystagmus (Table 1) [Wagner et al . 2008]. It is

characterised by slow upward drifts and fast

downward phases. Slow-phase velocity increases

on lateral and downward gaze and convergence,

although there may be atypical presentations with

enhancement of the DBN on upward gaze or

suppression on convergence [Leigh and Zee,2006; Pierrot-Deseilligny and Milea, 2005;

Baloh and Spooner, 1981] From a clinical point

of view, it is important to look for DBN in lateral

gaze because it might otherwise be overlooked.

The most common presenting symptoms are

unsteadiness of gait and to-and-fro vertigo

[Wagner et al . 2008] On further inquiry, the

patients frequently report blurred vision or oscil-

lopsia that increases on lateral gaze. DBN is often

associated with other ocular motor, cerebellar

and vestibular disorders, predominantly smoothpursuit deficits and impairment of the optoki-

netic reflex and visual fixation suppression of

the vestibulo-ocular reflex (VOR) [Leigh and

Zee 2006; Glasauer et al . 2005a, 2004, 2003b;

Straumann et al . 2000; Halmagyi et al . 1983].

The aetiology of DBN is diverse. 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 aetiological spectrum [Wagneret al . 2008]. In 62% (n¼72) of them, the aetiol-

ogy was identified (‘secondary DBN’), the most

frequent ones being cerebellar degeneration

(n¼23) and cerebellar ischaemia (n¼10). In

38% (n¼45), 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 polyneuropathy and cerebellar ataxia even

without cerebellar pathology on MRI. From this

study one can conclude that ‘idiopathic DBN’

remains common despite improved diagnostic

techniques.

Animal studies in monkeys have shown that bilat-

eral ablation of the cerebellar flocculus and para-

flocculus result in DBN and an integrator deficit

[Zee et al . 1981], lasting deficits in pursuit eye

movements, impaired horizontal VOR adaptation

[Rambold et al . 2002; Lisberger et al . 1984]

and visual suppression of caloric nystagmus

[Takemori and Cohen, 1974]. The upward drift

of DBN consists of a gaze-evoked drift, which is

hypothesised to be due to an impaired neural

integrator function, and a spontaneous upwarddrift during gaze straight ahead [Glasauer et al .

2003a; Straumann et al . 2000]. Three different

pathomechanisms are thought to cause the

spontaneous upward drift: first, a tone imbalance

of the central vestibular pathways of the vertical

eye movements [Bohmer and Straumann, 1998;

Dieterich and Brandt, 1995; Halmagyi et al .

1983; Baloh and Spooner, 1981], including oto-

lith pathways as suggested by the finding that

DBN is gravity-dependent [Sprenger et al .

2006; Marti et al . 2002]; second, an imbalance

Table 1. Frequency of congenital and/or acquiredocular oscillations in 4854 consecutive patients whowere seen in a neurological dizziness unit. Downbeatnystagmus was the most frequent fixation nystagmus(from Wagner et al . 2008b).

Type of nystagmus/ocular oscillation No. ofpatients

Downbeat nystagmus 101Upbeat nystagmus 54Central positional nystagmus 26Pendular nystagmus 15Congenital nystagmus 12Torsional nystagmus 12Seesaw nystagmus 8Ocular flutter 8Square wave jerks 7Opsoclonus 1Periodic alternating nystagmus 1




8/17

T a b l e

2 .

S u m m a r y o f t h e c l i n i c a l

f e a t u r e s , p a t h o p h y s i o l o g y , a e t i o l o g y ,

s i t e o f l e s i o n , a n d c u r r e n t t r e a t m e n t o f c o m m o n f o r m s o f c e n t r a l n y s t a g m u s .

D o w n b

e a t

n y s t a g

m u s

( D B N )

U p b e a t n y s t a g m u s

( U B N )

A c q u i r e d

p e n d u l a r

n y s t a g m u s ( A P N )

P e r i o d i c a l t e r n a t i n g

n y s t a g m u s

( P A N )

C o n g e n i t a l

n y s t a g m u s

S e e s a w n y s t a g m u s

D i r e c t i o n o f t h e

n y s t a g m u s

( q u i c k p h a s e )

D o w n w

a r d , m a y b e

d i a g o n

a l a t l a t e r a l

g a z e

U p w a r d

M a i n l y h o r i z o n t a l ,

m a y b e v e r t i c a l a n d

t o r s i o n a l o r m i x e d

H o r i z o n t a l

M a i n l y h o r i z o n t a l

O n e e y e : e l e v a t i o n

a n d i n t o r s i o n ,

t h e

o t h e r e y e : d e p r e s -

s i o n a n d e x t o r s i o n

W a v e f o r m

( s l o w p h a s e )

J e r k ,

l i n e a r ,

i n c r e a

s i n g o r

d e c r e a

s i n g v e l o c i t y

o f t h e

s l o w p h a s e

J e r k ,

l i n e a r ,

i n c r e a s i n g o r

d e c r e a s i n g v e l o c i t y

o f t h e s l o w

p h a s e

P e n d u l a r ,

s i n u s o i d a l

M o s t l y l i n e

a r

V a r i a b l e w i t h

v a r i a b l e v e l o c i t y

a n d f r e q u e n c y

P e n d u l a r : s e e s a w ;

j e

r k : h e m i - s e e s a w

S p e c i a l f e a t u r e s

I n c r e a

s e o f t h e

i n t e n s

i t y d u r i n g

l a t e r a l a n d d o w n -

w a r d g a z e

I n c r e a s e o f i n t e n s i t y

d u r i n g u p w a r d g a z e

M a y b e a s s o c i a t e d

w i t h p a l a t a l

m y o c l o n u s ¼

o c u l o p a l a t a l

m y o c l u s ( w i t h

p s e u d o h y p e r t r o p h y

o f t h e i n f e r i o r o l i v e )

C h a n g e s d i r e c t i o n

e v e r y 6 0 – 1

8 0 s

N u l l z o n e ,

i n w h i c h

n y s t a g m u s i s m i n i -

m a l ; o f t e n a s s o -

c i a t e d w i t h a l a t e n t

n y s t a g m u s ,

i n v e r -

s i o n o f t h e o p t o k i -

n e t i c n y s t a g m u s

S i t e s o f l e s i o n

C e r e b e l l u m

( b i l a t e

r a l f l o c c u l a r

h y p o f u

n c t i o n ) ;

l o w e r

b r a i n s t e m

M e d u l l a , p o n t o -

m e s e n c e p h a l i c

a n d c e r e b e l l u m

P o n t o - m e d u l l a r y

C e r e b e l l u m

( u v u l a ,

n o d u l u s )

O f t e n a s s o c i a t e d

w i t h d y s f u n c t i o n o f

t h e v i s u a l s y s t e m

O f t e n a s s o c i a t e d

w

i t h d y s f u n c t i o n o f

t h

e v i s u a l s y s t e m ;

l e

s i o n s o f t h e o p t i c

c h i a s m

E t i o l o g y

D e g e n

e r a t i v e

c e r e b e

l l a r d i s o r d e r ,

i s c h a e

m i a ,

i d i o p a t h i c ; o f t e n

a s s o c i a t e d w i t h

b i l a t e r

a l

v e s t i b u l o p a t h y

I s c h a e m i a ,

b l e e d i n g ,

W e r n i c k e ’ s

e n c e p h a l o p a t h y

M u l t i p l e s c l e r o s i s ,

i s c h a e m i a ,

W e r n i c k e ’ s

e n c e p h a l o p a t h y

D e g e n e r a t i v e c e r e -

b e l l a r d i s o

r d e r s ,

c r a n i o - c e r v i c a l

m a l f o r m a t i o n s ,

m u l t i p l e s c

l e r o s i s ,

i s c h a e m i a ,

D y s f u n c t i o n o f t h e

v i s u a l s y s t e m

D

y s f u n c t i o n o f t h e

v i s u a l s y s t e m

T r e a t m e n t

4 - a m i n o p y r i d i n e ,

3 , 4 - d i a m i n o p y r i -

d i n e , b

a c l o f e n ,

c l o n a z

e p a m

S i n c e o f t e n t r a n s i -

e n t , t r e a t m e n t n o t

n e c e s s a r y ; b a c l o f e n ,

4 - a m i n o p y r i d i n e

T r i h e x i p h e n i d y l ,

m e m a n t i n e ,

g a b a p e n t i n

B a c l o f e n

G a b a p e n t i n ,

m e m a n t i n e

O n e m a y t r y c l o n a -

z e p a m , g a b a p e n t i n ,

o r m e m a n t i n e ; n o t

r e

a d i l y t r e a t a b l e




9/17

of the vertical smooth pursuit tone in which the

imbalance of upward visual velocity commands

results in spontaneous upward drift [Zee et al .

1974]; and third, a mismatch in the three-dimen-

sional neural coordinate system for vertical sac-

cade generation due to a defect of the neuralvelocity-to-position integrator for gaze holding

[Glasauer et al . 2003a].

Marti et al . [2005] 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 10%

of them show on-directions for upward-gaze

velocity [Partsalis et al . 1995]. With functional

magnetic resonance imaging (fMRI) and

F-fluorodeoxyglucose-positron emission tomo-

graphy, it was recently shown that patients with

DBN have diminished activation/metabolism of

both floccular lobes (Figure 3) [Bense et al .2006; Kalla et al . 2006]. This supports the view

that a functional deficiency of the flocculi causes

not only a defect in downward pursuit but also

DBN [Marti et al . 2005]. More recent studies

using voxel-based morphometry demonstrated

an atrophy in certain areas of the cerebellum,

which are mainly related to ocular motor func-

tion [Hufner et al . 2007; Kalla et al . 2006].

Since the inhibitory influence of GABAergic

Purkinje cells is assumed to be impaired in

−5

−15

−20

−25

−10

0

5

10

15

20

25

20

time (s)

4 6 8 10 12

E y e p o s i t i o n ( d e g )

target

eye

D

BA

C

Figure 3. Activation of the flocculus (red) in controls versus patients for the contrast ‘smooth pursuit in thedownward direction’ (SMDOWN) – ‘fixation of a target in the middle of the display’ (FIXMID). Results obtainedby region of interest group analysis are superimposed onto orthogonal sections (A: coronal plane, B: sagittalplane, C: axial plane) at Montreal Neurological Institute coordinates xyz ¼20, 36, 40 through a standardbrain template (p 50.01). D: original recording (search-coil) of vertical pursuit (0.1667 Hz, amplitude18 deg), which demonstrates normal upward pursuit and impaired downward pursuit in a patient with DBN(from Kalla et al. 2006).




10/17

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 [Young and Huang 2001; Currie and

Matsuo 1986]. The GABAB agonist, baclofen, is

assumed to reduce DBN [Dieterich et al . 1991],

but as was shown in a double-blind crossover trial

in a few patients, only one out of six responded to

baclofen [Averbuch-Heller et al . 1997]. Further,

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 [Averbuch-Heller

et al . 1997].

On the basis of the assumed pathomechanism of

DBN, the effects of aminopyridines were evalu-

ated in a randomised, controlled, crossover trial

involving 17 patients with DBN due to cerebellar

atrophy, infarction, Arnold–Chiari malformation,

or unknown aetiology [Strupp et al . 2003].

Mean peak slow-phase velocity of DBN was

measured before and 30 min after randomised

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

3.1deg/s 30 min after ingestion ( p50.001)

(Figure 4). The mean peak slow-phase velocity

decreased in 10 of 17 patients by more than

50%. Except for transient perioral or digital par-

esthesia (three patients) and nausea and headache

(one patient), 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 excitabil-

ity of the Purkinje cells (as was found in animal

experiments [Etzion and Grossman, 2001]),

16

14

12

10

8

6

4

2

0

16

14

12

10

8

6

4

2

0

16

14

12

10

8

6

4

2

0

16

14

12

10

8

6

4

2

0

M e a n p e a k s l o w p

h a s e v e l o c i t y ( d e g / s )

M e a n p e a k s l o w

p h a s e v e l o c i t y ( d e g / s )

M e a n p e a k s l o w p

h a s e v e l o c i t y ( d e g / s )

M e a n p e a k s

l o w

p h a s e v e l o c i t y ( d e g / s )

10

5

0

−5

−10

10

5

0

−5

−10

E y e p o s i t i o n ( ° )

E y e p o s i t i o n ( ° )

up

up

Control

Time (sec)

Time (sec)

5 10 15

5 10 15

Control Control

ControlControl Placebo Placebo

3,4-DAP 3,4-DAP

3,4-DAP

(A) (B)

(D)(C)

Figure 4. Mean peak slow phase velocities (PSPV) of DBN measured by 2-D recordings of eye movements. The two graphs on theleft show the original data of mean PSPV for each subject: (A) Control versus 3,4-diaminopyridine (3,4-DAP), (C) control versus placebo. The two graphs in the middle give the box plot charts with the mean, median, and the fiftieth percentile as well as therange for control versus 3,4-DAP (B) and control versus placebo (D). 3,4-DAP reduced mean PSPV of DBN from 7.2 4.2 deg/s(meanSD) before treatment to 3.1 2.5 deg/s 30 min after ingestion of the 3,4-DAP (n¼ 17, p 50.001, two-way ANOVA). The inset(E) shows an original recording of the vertical eye position before (upper trace) and 30 min after ingestion of the drug (lower trace)(from Strupp et al . 2003).




11/17

thereby augmenting the physiological inhibitory

influence of the vestibular cerebellum on the

vestibular nuclei. Meanwhile the effect of amino-

pyridines on the gravity dependence of DBN has

also been evaluated [Helmchen et al . 2004] and an

improvement of postural imbalance in DBN was

demonstrated [Sprenger et al . 2005].

The underlying mechanism of action of 4-AP in

DBN was also investigated in two studies usingthe magnetic search-coil technique [Kalla et al .

2007, 2004]. 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 vertical vestibulo-ocular reflex [Kalla et al .

2004] Second, 4-AP improved fixation by restor-

ing gaze-holding ability and neural integrator

function (Figure 5); further, as regards its aetiol-

ogy-dependent efficacy in DBN, 4-AP may work

best when DBN is associated with cerebellar

atrophy [Kalla et al . 2007] (Figure 5). If DBN

is caused by a structural lesion, 4-AP does notimprove DBN in most cases. A PET study

showed that 4-AP – in parallel to improving

DBN – increases the metabolic activity of the

flocculus [Bense et al . 2006] All these studies

give additional support both to the above hypoth-

esis about the pathophysiology of DBN and the

way that aminopyridines act.

Upbeat nystagmus (UBN) 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 brainstem and cerebellar

regions such as the pontomesencephalic junction,

medulla, or cerebellar vermis. Lesions in the

pathways mediating upward eye movements, inparticular, from the vestibular nuclei through the

brachium conjunctivum to the ocular motor

nuclei, might result in slow downward drift

of the eyes, which is corrected by fast upward

movements [Leigh and Zee, 2006]. Other hypoth-

eses are that UBN is caused by an imbalance of

vertical vestibulo-ocular reflex tone or a mismatch

in the neural coordinate systems of saccade gen-

eration and neural velocity-to-position integration.

The symptoms persist as a rule for several weeks

but are not permanent in most of the patients.Because the eye movements generally have larger

amplitudes, oscillopsia in upbeat nystagmus is

very distressing and impairs vision. Upbeat nys-

tagmus due to damage to the pontomesencephalic

brainstem is frequently combined with a unilateral

or bilateral internuclear ophthalmoplegia, indicat-

ing that the MLF is affected. The main aetiologies

are bilateral lesions in MS, brainstem ischaemia

or tumour, Wernicke’s encephalopathy, cerebellar

degeneration and dysfunction of the cerebellum

due to intoxication.

2

1

0

−1

−2

−3

−4

−5

−6

−7

S p o n t a n e o u s

v e r t i c a l d r i f t ( ° / s )

PRE POST PRE POST PRE POST PRE POST

Control DBN I DBN II DBN III

Figure 5. Spontaneous vertical drift: vertical drift in control subjects and DBN patients due to cerebellaratrophy (DBN I), unknown aetiology (DBN II), or other aetiologies (DBN III) before (PRE) and after (POST)administration of 4-aminopyridine (4-AP) (red lines: target visible; blue lines: target blanked). Thepronounced DBN is mainly reduced in DBN I and to a lesser degree in DBN II post-medication. Similar

effects are observed while the target is blanked. Error bars indicate 95% confidence intervals (from Kallaet al . 2007).




12/17

GABAergic substances like baclofen have been

used to treat UBN and DBN, but they have

had only moderate success. One study demon-

strated a beneficial effect of baclofen (5–10 mg

t.i.d.), but this trial was not controlled

[Dieterich et al . 1991]. In a single patient with

UBN it was shown that 4-aminopyridine (4-AP)reduced the peak slow-phase velocity in the light

from 8.6 to 2.0 deg/s [Glasauer et al . 2005b].

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 com-

mands. We propose that 4-AP helps to activate

parallel pathways that can assume the function

of the lesioned structures [Glasauer et al .

2005c]. 4-AP may strengthen these parallel path-ways by increasing the excitability of cerebellar

PCs [Etzion and Grossman 2001]. It may also

evoke complex spikes in PCs similar to those

elicited by climbing fibre stimulation [Cavelier

et al . 2002].

Other forms of nystagmus

Other forms of nystagmus which are associated

with oscillopsia and in some patients with imbal-

ance are acquired pendular nystagmus, periodic

alternating nystagmus, convergence retraction

nystagmus, central positioning or positionalnystagmus (see above) and seesaw nystagmus.

Congenital nystagmus often does not cause any

symptoms. Square wave jerks, ocular flutter

(mainly horizontal saccades), and opsoclonus

(horizontal, vertical, and torsional saccades)

belong to the saccadic intrusions or saccadic

oscillations and are not classified as a nystagmus.

In this review the features, pathophysiology, and

treatment of congenital nystagmus, periodic

alternating nystagmus and acquired fixation nys-

tagmus will be summarised, because they are the

clinically most relevant forms (see also Table 2).

Periodic, alternating nystagmus (PAN) This form of nystagmus most often beats hori-

zontally and changes its direction every 60–180

seconds. Afflicted subjects complain of oscillop-

sia. Patients often turn their head in the direction

of the quick phase and in this way bring their eyes

in the direction of the slow phase of PAN

to reduce oscillopsia – in accordance with

Alexander’s law. The diagnosis requires quite a

long time of examination, otherwise one might

overlook PAN. Like many other forms of nystag-

mus, PAN is most often caused by cerebellar dys-

function, in particular by lesions of the nodulus

or the uvula. These lesions impair the velocity-

storage mechanism as was shown in animal

experiments and the oscillations are assumed to

be caused by an ‘over-compensation’ or instabil-ity of the optokinetic-vestibular system [Leigh

et al . 1981]. The treatment of choice is the

GABAergic drug, baclofen, in a dosage of

5–10 mg t.i.d., which abolishes PAN in most

patients [Straube, 2005a, 2005b, Straube et al .

2004; Stahl et al . 2002]. There have been no

randomised, controlled trials so far.

Acquired pendular nystagmus (APN) and oculopalatal tremor Acquired pendular nystagmus may have

horizontal, vertical or torsional components.The amplitude varies, and in part the eye move-

ments are not conjugate [Leigh et al . 2002;

Stahl et al . 2000]. The clinical features and asso-

ciated symptoms, in particular palatal tremor

[Kim et al . 2007; Moon et al . 2003], often

depend on the underlying disease. The three

most common causes are multiple sclerosis,

brainstem ischaemia, and Whipple’s disease. In

patients with multiple sclerosis APN has a fre-

quency of 3–6 Hz and is often associated with

other central ocular motor disorders such as

internuclear ophthalmoplegia or upbeat nystag-

mus. APN can also be associated with palataltremor oculopalatal tremor. In such patients

there is often a synchronisation of the nystagmus

with the palatal tremor. MRI of patients in the

chronic state often reveals a pseudohypertrophy

of the inferior olivary nucleus [Deuschl and

Wilms, 2002]. In a recent correlation between

APN and MRI changes it was demonstrated

that a dissociated APN predicts asymmetric (uni-

lateral) inferior olivary pseudohypertrophy on

MRI; however, symmetric pendular nystagmus

was associated with either unilateral or bilateral

signal changes in the inferior olivary nucleus[Kim et al . 2007; Moon et al . 2003]. It is assumed

that oculopalatal tremor is caused by damage to

the paramedian tract projections and denervation

of the dorsal cap of the inferior olive, leading

to an instability of eye velocity to position

integration.

Several agents have been recommended for APN.

One is trihexiphenidyl [Jabbari et al . 1987;

Herishanu and Louzoun, 1986] but a double-

blind study demonstrated that only one of




13/17

six patients responded to this treatment [Leigh

et al . 1991]. Memantine, a glutamate antagonist,

was also recommended [Starck et al . 1997], but

its efficacy has not been proven. There are con-

vincing data for gabapentin from a double-blind

study by Averbuch-Heller et al . [1997]. They

found a significant improvement in visual acuityand reduction of nystagmus with gabapentin

in 10 of 15 patients but not with baclofen. The

retrobulbar application of botulinum toxin was

also recommended, but this was tested in only a

small series of patients [Leigh et al . 1992] and

was not always successful [Tomsak et al . 1995].

From a practical point of view, we now recom-

mend using gabapentin (300–600 mg t.i.d.) for

acquired pendular nystagmus. Memantine and

trihexiphenidyl are second and third choices,

respectively.

Congenital nystagmus Congenital nystagmus often develops during the

first months of life. Some of the cases are familial

and genetically heterogeneous. Autosomal domi-

nant, autosomal recessive and X-linked patterns

of inheritance have been reported. Linkage ana-

lysis suggested the existence of at least three dis-

tinct loci for both autosomal dominant and

X-linked forms, although so far only one disease

gene was identified on chromosome Xq26.2 [Self

and Lotery 2007]. Congenital nystagmus is clini-

cally characterised by the following criteria: fixa-

tion nystagmus (i.e. no decrease of the intensityduring fixation); nystagmus most often beating

horizontally; large variability of form and form

frequency and velocity; intensity depending on

gaze position; often a position (the so-called neu-

tral zone) with a minimal intensity which the

patient prefers and which leads to an appropriate

head turn. Examination with the optokinetic

drum often shows an inversion of the direction

or during vertical optokinetic stimulation, a diag-

onal nystagmus. It is important to know that

most patients do not have any complaints,

namely they have no oscillopsia despite a highintensity of nystagmus. This is most likely due

to an impairment of visual motion perception in

these subjects. Since most patients do not have

any medical complaints, treatment is generally

not necessary. In patients with oscillopsia,

one might try gabapentin or memantine. In a

randomised, controlled, double-blind study it

was demonstrated that memantine at a dosage

of 10–40mg per day (as well as gabapentin at a

dosage of 600–2400 mg per day) caused a signif-

icant decrease of the intensity of the nystagmus

and an increase of visual acuity [McLean et al .

2007]. This, however, was not associated with

visual acuity during regular daily activities or

improvement of the patients’ disease-related

quality of life.

Conclusions and future perspectives

Considerable progress has been made over the

last decades in the description of the clinical

characteristics of different forms of nystagmus,

its pathophysiology, and aetiology. However,

because there are several forms of nystagmus

and underlying central vestibular, ocular motor

and in particular cerebellar disorders, effective

drugs are still awaiting prospective, randomised,

placebo-controlled and – due to the low preva-

lence of some of these disorders – multicentre

trials. It is high time that these studies wereperformed. Several drugs could be potentially

effective (cited in alphabetical order): acetazola-

mide, aminopyridines, anticholinergics (benztro-

pine, scopolamine, trihexyphenidyl), baclofen,

barbiturates, benzodiazepines, cannabinoids, car-

bamazepine, gabapentin, lamotrigine, meman-

tine, phenytoin, selective serotonin reuptake

inhibitors, tricyclic antidepressants, topiramate,

triptans or valproic acid. In other words, there

is still a lot to do. Knowledge of the possible

effects of these agents – most of which act speci-

fically on certain receptors or ion channels – willalso further improve our insights into the patho-

physiology of the underlying disorders.

Conflict of interest statement

None declared.

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