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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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Onset Follow-up Onset Follow-up
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Onset Follow-up Onset
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V e s t i b u l a r p a r e
s i s ( % )
Controls Methylprednisolone
Methylprednisolone plus valacyclovirValacyclovir
Follow-up
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.
0
0
2
4
6
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10
3 6 9 12
Months
N u m b e r
o f a t t a c k s / m o n t h
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).
M Strupp and T Brandt
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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
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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
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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).
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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).
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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).
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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
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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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