Tratamiento Vestibular y Nistagmos 1-5 y 6-13

Therapeutic Advances in Neurological Disorders
Current treatment of vestibular, ocular motor

disorders and nystagmus
Michael Strupp and Thomas Brandt
Review
Ther Adv Neurol Disord

(2009) 2(4) 223239
DOI: 10.1177/
1756285609103120
The Author(s), 2009.
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Abstract: Vertigo and dizziness are among the most common complaints with a lifetime
prevalence of about 30%. The various forms of vestibular disorders can be treated with
pharmacological therapy, physical therapy, psychotherapeutic measures or, rarely, surgery.
In this review, the current pharmacological treatment options for peripheral and central
vestibular, cerebellar and ocular motor disorders will be described. They are as follows for
peripheral vestibular disorders. In vestibular neuritis recovery of the peripheral vestibular
function can be improved by treatment with oral corticosteroids. In Menie
`res disease a recent
study 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 principle
in the treatment of downbeat and upbeat nystagmus and episodic ataxia type 2 (EA 2).
These potassium channel blockers presumably increase the activity and excitability of
cerebellar Purkinje cells, thereby augmenting the inhibitory influence of these cells on
vestibular and cerebellar nuclei. A few studies showed that baclofen improves periodic
alternating 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 the
treatment of vestibular neuritis, downbeat and upbeat nystagmus, as well as EA 2, stateof-the-art trials must still be performed on many vestibular and ocular motor disorders,
namely Menie
`res disease, bilateral vestibular failure, vestibular paroxysmia, vestibular
migraine, and many forms of central eye movement disorders.
Keywords: vertigo, dizziness, benign paroxysmal positioning vertigo, vestibular neuritis,
Menie
`res disease, vestibular paroxysmia, vestibular migraine, episodic ataxia type 2, downbeat
nystagmus, upbeat nystagmus
Introduction
In the first part of this article, the treatment of
common peripheral and central vestibular disorders are described [Strupp et al. 2007a; Brandt
et al. 2005]. The second part focuses on the
clinically most relevant forms of nystagmus, in
particular downbeat and upbeat nystagmus,
along with their pathophysiology and topographic diagnosis, and current therapy [Leigh
and Zee, 2006; Strupp and Brandt, 2006].
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 neurology. The lifetime prevalence is almost 30%
[Neuhauser, 2007]. A survey of over 30,000 persons 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].
Vertigo and dizziness

The terms vertigo and dizziness cover a number
of multisensory and sensorimotor syndromes of
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
Correspondence to:
Michael Strupp, MD
Professor of Neurology
and Clinical
Neurophysiology,
University of Munich,
Klinikum Grosshadern,
Munich, Germany
Michael.Strupp@med.
uni-muenchen.de
Thomas Brandt
Institute of Clinical
Neuroscience, University
of Munich, Klinikum
Grosshadern, Munich,
Germany
223
Therapeutic Advances in Neurological Disorders 2 (4)

Depending on the aetiology, the various forms of
vestibular disorders can be treated with pharmacological therapy, physical therapy, psychotherapeutic 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 favourable
natural course (e.g. the peripheral vestibular
function improves or central vestibular compensation 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 disorders can be differentiated by their characteristic
signs and symptoms: (1) bilateral peripheral loss
of vestibular function (bilateral vestibulopathy),
characterised by oscillopsia during head movements 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 vestibular system, characterised by attacks of vertigo
and oscillopsia. This occurs in benign paroxysmal
positioning vertigo, but also in Menie`res 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 undermost ear elicited by extending the head or positioning the head or body toward the affected ear.
It is called benign because it often resolves spontaneously 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 nystagmus, 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
224
head positioning movements. Semont et al.

[1988] recommended that the patients 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 patients trunk and head into a headhanging position. It can also be explained by the
mechanism 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 Menieres disease).
It accounts for 7% of the patients who present
at outpatient clinics specialising in the treatment
of dizziness [Brandt et al. 2005] and has an incidence of 3.5 per 100,000 population [Sekitani
et al. 1993]. The key signs and symptoms of
vestibular neuritis are the acute onset of sustained rotatory vertigo, horizontal spontaneous
nystagmus toward the unaffected ear with a
rotational component, postural imbalance with
Rombergs sign, that is, falls with the eyes
closed toward the affected ear, and nausea.
Caloric testing invariably shows ipsilateral hyporesponsiveness or nonresponsiveness. In the past,
either inflammation of the vestibular nerve or
labyrinthine 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 with
HSV-1 [Theil et al. 2003].
A prospective randomised, double-blind, twoby-two factorial trial was performed, in which
patients with acute vestibular neuritis were randomly assigned to treatment with placebo,
methylprednisolone (100 mg/day, doses tapered
by 20 mg every third day), valacyclovir (valociclovir, 1 g t.i.d. for 7 days), or methylprednisolone plus valacyclovir. Vestibular function was
determined by caloric irrigation, with the use of
M Strupp and T Brandt

Methylprednisolone
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Vestibular paresis (%)
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Valacyclovir
Onset
Follow-up
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0
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0
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0
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Follow-up
Onset
Follow-up
Figure 1. Unilateral vestibular failure within 3 days after symptom onset and after 12 months. Vestibular function was determined
by 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 plus
valacyclovir (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 between
the right-sided and the left-sided responses [Honrubia 1994]. Follow-up examination showed that vestibular function improved in
all four groups: in the placebo group from 78.9 24.0 (mean SD) to 39.0 19.9, in the methylprednisolone group from 78.7 15.8
to 15.4 16.2, in the valacyclovir group from 78.4 20.0 to 42.7 32.3, and in the methylprednisolone plus valacyclovir group from
78.6 21.1 to 20.4 28.4. Analysis of variance revealed that methylprednisolone and methylprednisolone plus valacyclovir caused
significantly more improvement than placebo or valacyclovir alone. The combination of both was not superior to steroid
monotherapy (from Strupp et al. 2004b).
the vestibular paresis formula (to measure the

extent of unilateral caloric paresis), within 3
days after the onset of symptoms and 12
months afterwards. A total of 141 patients underwent randomisation. The mean improvement in
peripheral vestibular function at 12-month
follow-up was 39.6 percentage points in the placebo group, 62.4 percentage points in the
methylprednisolone group, 36.0 percentage
points in the valacyclovir group, and 59.2 percentage points in the methylprednisolone plus valacyclovir group (Figure 1). Analysis of variance
showed that methylprednisolone had a significant
effect, but valacyclovir did not. Therefore, this

study showed that methylprednisolone alone significantly 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, parameters other than vestibular paresis, such as postural imbalance or vertigo and dizziness, would
not help differentiate between the effects of steroids on the recovery of peripheral vestibular
225

function and on central vestibular compensation.
Second, there are no validated scales for measuring 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
`res disease
Menie`res disease is clinically characterised by
recurrent spontaneous attacks of vertigo, fluctuating 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 pathological basis of Menie`res 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 Menie`res 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 Menie`res
disease: recurrent attacks of vertigo.
There is a plethora of treatment strategies for
Menie`res disease. Destructive procedures involving the lateral semicircular canal and vestibule
have been proposed since 1904. The first endolymphatic sac decompression was performed in
1926. This method is still used in some settings
despite its evident ineffectiveness. Restricting salt
and fluid intake and diuretics were first proposed
in 1934. Salt restriction 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 intratympanic delivery has been performed since
1956 (for references see Smith et al. 2005). It is
remarkable that despite the high incidence of
Menie`res 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 significant differences in the treatment regimen of
Menie`res disease between Europe and the
US. In the US, low-salt diet, diuretics, and
226
intratympanic injection of gentamicin and corticosteroids are preferred. In Europe betahistine is

more often used, in the US rarely; it is remarkable that in a recent review on Menie`res disease
by two US authors the word betahistine does not
even appear [Sajjadi and Paparella, 2008].
A national survey among UK otolaryngologists
on the treatment of Menie`res 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: approximately two-thirds of the otolaryngologists use
this method.
Intratympanic injections of gentamicin

Several studies have been published on intratympanic gentamicin application for the treatment of
Menie`res disease. Initially multiple intratympanic 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 injections
and follow-up. Following the latter regimen, a
prospective uncontrolled study with a follow-up
time of 24 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-analysis on 15 trials with 627 patients on gentamicin
injection showed that complete vertigo control
was achieved in about 75% of patients and complete or substantial control in about 93%. The
success rate was not affected by the gentamicin
treatment 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 gentamicin is due to its damage to the hair cells.
Number of attacks/month
10
8
6
4
2
0
0
12
Months
Figure 2. Effects of betahistine dihydrochloride (low dosage (light blue line): 16 or 24 mg t.i.d. versus high
dosage (dark blue line): 48 mg t.i.d.) on the frequency of attacks of vertigo in a total of 112 MD patients. The
mean number of attacks per month (SEM) during the 3 months preceding treatment (month 0) is given
as 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) (p50.0001) in the low dosage group, and from 8.8 (5.5)
to 1.0 (0.0) (p50.0001) 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 (p12M 0.0002) (from Strupp et al. 2008).
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 the
patients reported vertigo control. Another 24%
responded to the repeat series of injections. All
in all, approximately one-half of the patients with
Menie`res disease achieved control of vertigo with
one or more courses of intratympanic injections
of corticosteroids. The safety of intratympanic
dexamethasone injections was evaluated by transient evoked otoacoustic emission. No change
was found in 26 patients after five injections of
4 mg dexamethasone [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 Menie`res disease it was

shown that a higher dosage of betahistinedihydrochloride (48 mg t.i.d.) and a long-term
treatment (12 months) seems to be more effective
than a low dosage (1624 mg t.i.d.) and shortterm treatment (Figure 2) [Strupp et al. 2008].
These data are the basis for a recently begun prospective, 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 (200600 mg per day) or oxcarbazepine 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 phenytoin is a possible alternative. Currently, a prospective, placebo-controlled, double-blind trial
is underway.
227

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 forms
of 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 symptoms 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 36 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 on
10 patients demonstrated that lamotrigine
(100 mg per day as a single dose) had a significant 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 characterised by recurrent attacks of ataxia, provoked
by stress or exercise, which last for several
hours to days [Strupp et al. 2007b; Jen et al.
2004; Griggs and Nutt, 1995]. Associated findings 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
228
the CaV21 subunit of the PQ-calcium channel

expressed mainly in the Purkinje cells. On the
basis of the functional changes of the PQ-channel
mutation, which leads to a reduced calcium current, it can be assumed that the inhibitory effect
of Purkinje cells is reduced in EA2 [Kullmann,
2002]. This causes the disinhibition of the deep
cerebellar 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-aminopyridine (5 mg t.i.d.). Attacks recurred after treatment 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 functioning 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 the
attacks characteristic of the tottering mouse via
cerebellar potassium channels by increasing the
threshold for attack initiation without mitigating
the character of the attack [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 nystagmus, 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

nystagmus, further randomised controlled trials
will be necessary to test different agents on the
basis of our current knowledge of the pathophysiology of nystagmus.
Common, clinically important forms of

nystagmus 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 see
Leigh 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.
Table 1. Frequency of congenital and/or acquired

ocular oscillations in 4854 consecutive patients who
were seen in a neurological dizziness unit. Downbeat
nystagmus was the most frequent fixation nystagmus
(from Wagner et al. 2008b).
Type of nystagmus/ocular oscillation
Downbeat nystagmus
Upbeat nystagmus
Central positional nystagmus
Pendular nystagmus
Congenital nystagmus
Torsional nystagmus
Seesaw nystagmus
Ocular flutter
Square wave jerks
Opsoclonus
Periodic alternating nystagmus
No. of
patients
101
54
26
15
12
12
8
8
7
1
1
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 oscillopsia that increases on lateral gaze. DBN is often
associated with other ocular motor, cerebellar
and vestibular disorders, predominantly smooth
pursuit deficits and impairment of the optokinetic 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 [Wagner
et al. 2008]. In 62% (n 72) of them, the aetiology was identified (secondary DBN), the most
frequent ones being cerebellar degeneration
(n 23) and cerebellar ischaemia (n 10). In
38% (n 45), no cause was found (idiopathic
DBN). A major finding was a high comorbidity
of both idiopathic and secondary DBN with
bilateral vestibulopathy (36%) and an association
with 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 bilateral ablation of the cerebellar flocculus and paraflocculus 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 upward
drift 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 otolith pathways as suggested by the finding that
DBN is gravity-dependent [Sprenger et al.
2006; Marti et al. 2002]; second, an imbalance
229
230
Cerebellum
(bilateral floccular
hypofunction);
lower brainstem
Degenerative
cerebellar disorder,
ischaemia,
idiopathic; often
associated with
bilateral
vestibulopathy
4-aminopyridine,
3,4-diaminopyridine, baclofen,
clonazepam
Sites of lesion
Etiology
Treatment
Since often transient, treatment not

necessary; baclofen,
4-aminopyridine
Ischaemia, bleeding,
Wernickes
encephalopathy
Medulla, pontomesencephalic
and cerebellum
Trihexiphenidyl,
memantine,
gabapentin
Multiple sclerosis,
ischaemia,
Wernickes
encephalopathy
Baclofen
Degenerative cerebellar disorders,

cranio-cervical
malformations,
multiple sclerosis,
ischaemia,
Cerebellum (uvula,
nodulus)
Gabapentin,
memantine
Dysfunction of the
visual system
Null zone, in which

nystagmus is minimal; often associated with a latent
nystagmus, inversion of the optokinetic nystagmus
Often associated
with dysfunction of
the visual system
Changes direction
every 60180 s
May be associated
with palatal
myoclonus
oculopalatal
myoclus (with
pseudohypertrophy
of the inferior olive)
Ponto-medullary
Special features
Variable with
variable velocity
and frequency
Mostly linear
Pendular,
sinusoidal
Jerk, linear,
increasing or
decreasing velocity
of the slow phase
Increase of intensity
during upward gaze
Jerk, linear,
increasing or
decreasing velocity
of the slow phase
Increase of the
intensity during
lateral and downward gaze
Waveform
(slow phase)
Mainly horizontal
Horizontal
Congenital
nystagmus
Mainly horizontal,
may be vertical and
torsional or mixed
Periodic alternating
nystagmus (PAN)
Upward
Acquired pendular
nystagmus (APN)
Downward, may be
diagonal at lateral
gaze
Upbeatnystagmus
(UBN)
Direction of the
nystagmus
(quick phase)
Downbeat
nystagmus
(DBN)
One may try clonazepam, gabapentin,

or memantine; not
readily treatable
Often associated
with dysfunction of
the visual system;
lesions of the optic
chiasm
Dysfunction of the
visual system
One eye: elevation

and intorsion, the
other eye: depression and extorsion
Pendular: seesaw;
jerk: hemi-seesaw
Seesaw nystagmus
Table 2. Summary of the clinical features, pathophysiology, aetiology, site of lesion, and current treatment of common forms of central nystagmus.
25
20
15
Eye position (deg)
10
5
0
5
10
15
target
20
25
eye
10
12
time (s)
Figure 3. Activation of the flocculus (red) in controls versus patients for the contrast smooth pursuit in the
downward direction (SMDOWN) fixation of a target in the middle of the display (FIXMID). Results obtained
by region of interest group analysis are superimposed onto orthogonal sections (A: coronal plane, B: sagittal
plane, C: axial plane) at Montreal Neurological Institute coordinates xyz 20, 36, 40 through a standard
brain template (p50.01). D: original recording (search-coil) of vertical pursuit (0.1667 Hz, amplitude
18 deg), which demonstrates normal upward pursuit and impaired downward pursuit in a patient with DBN
(from Kalla et al. 2006).
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-dimensional neural coordinate system for vertical saccade generation due to a defect of the neural
velocity-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 ondirections 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 tomography, 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 function [Hufner et al. 2007; Kalla et al. 2006].
Since the inhibitory influence of GABAergic
Purkinje cells is assumed to be impaired in
231

(B)
16
14
12
10
8
6
4
2
0
Control
3,4-DAP
(C)
10
8
up 10
Control
4
2
0
Control
(D)
16
5
0
5
3,4-DAP
10
5
16
14
12
10
8
6
4
2
0
Control
Placebo
up10
14
Eye position ()
Mean peak slow phase velocity (deg/s)
14
12
Eye position ()
16
(A)
12
10
8
6
10
Time (sec)
15
3,4-DAP
5
0
5
10
10
Time (sec)
15
0
Control
Placebo
Figure 4. Mean peak slow phase velocities (PSPV) of DBN measured by 2-D recordings of eye movements. The two graphs on the
left 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 the
range 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
(mean SD) before treatment to 3.1 2.5 deg/s 30 min after ingestion of the 3,4-DAP (n 17, p50.001, 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).
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 evaluated in a randomised, controlled, crossover trial
involving 17 patients with DBN due to cerebellar
atrophy, infarction, ArnoldChiari malformation,
or unknown aetiology [Strupp et al. 2003].
232
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
3.1 deg/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 paresthesia (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 excitability of the Purkinje cells (as was found in animal
experiments [Etzion and Grossman, 2001]),
Spontaneous vertical drift (/s)
2
1
0
1
2
3
4
5
6
7
PRE
POST
Control
PRE
POST
DBN I
PRE
POST
DBN II
PRE
POST
DBN III
Figure 5. Spontaneous vertical drift: vertical drift in control subjects and DBN patients due to cerebellar
atrophy (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). The
pronounced 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 Kalla
et al. 2007).
thereby augmenting the physiological inhibitory

influence of the vestibular cerebellum on the
vestibular nuclei. Meanwhile the effect of aminopyridines on the gravity dependence of DBN has
also been evaluated [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 using
the 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 restoring gaze-holding ability and neural integrator
function (Figure 5); further, as regards its aetiology-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 not
improve 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 hypothesis 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, in
particular, 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 hypotheses are that UBN is caused by an imbalance of
vertical vestibulo-ocular reflex tone or a mismatch
in the neural coordinate systems of saccade generation and neural velocity-to-position integration.
The symptoms persist as a rule for several weeks
but are not permanent in most of the patients.
Because the eye movements generally have larger
amplitudes, oscillopsia in upbeat nystagmus is
very distressing and impairs vision. Upbeat nystagmus due to damage to the pontomesencephalic
brainstem is frequently combined with a unilateral
or bilateral internuclear ophthalmoplegia, indicating that the MLF is affected. The main aetiologies
are bilateral lesions in MS, brainstem ischaemia
or tumour, Wernickes encephalopathy, cerebellar
degeneration and dysfunction of the cerebellum
due to intoxication.
233

GABAergic substances like baclofen have been
used to treat UBN and DBN, but they have
had only moderate success. One study demonstrated a beneficial effect of baclofen (510 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 commands. 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 pathways 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 imbalance are acquired pendular nystagmus, periodic
alternating nystagmus, convergence retraction
nystagmus, central positioning or positional
nystagmus (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 nystagmus 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 horizontally and changes its direction every 60180
seconds. Afflicted subjects complain of oscillopsia. 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
Alexanders law. The diagnosis requires quite a
long time of examination, otherwise one might
234
overlook PAN. Like many other forms of nystagmus, PAN is most often caused by cerebellar dysfunction, in particular by lesions of the nodulus
or the uvula. These lesions impair the velocitystorage mechanism as was shown in animal
experiments and the oscillations are assumed to
be caused by an over-compensation or instability of the optokinetic-vestibular system [Leigh
et al. 1981]. The treatment of choice is the
GABAergic drug, baclofen, in a dosage of
510 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 movements are not conjugate [Leigh et al. 2002;
Stahl et al. 2000]. The clinical features and associated 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 Whipples disease. In
patients with multiple sclerosis APN has a frequency of 36 Hz and is often associated with
other central ocular motor disorders such as
internuclear ophthalmoplegia or upbeat nystagmus. APN can also be associated with palatal
tremor 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 (unilateral) 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 doubleblind study demonstrated that only one of

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 convincing data for gabapentin from a double-blind
study by Averbuch-Heller et al. [1997]. They
found a significant improvement in visual acuity
and 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 recommend using gabapentin (300600 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 dominant, autosomal recessive and X-linked patterns
of inheritance have been reported. Linkage analysis suggested the existence of at least three distinct 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 clinically characterised by the following criteria: fixation nystagmus (i.e. no decrease of the intensity
during 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 neutral 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 diagonal nystagmus. It is important to know that
most patients do not have any complaints,
namely they have no oscillopsia despite a high
intensity 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 1040 mg per day (as well as gabapentin at a
dosage of 6002400 mg per day) caused a significant 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 prevalence of some of these disorders multicentre
trials. It is high time that these studies were
performed. Several drugs could be potentially
effective (cited in alphabetical order): acetazolamide, aminopyridines, anticholinergics (benztropine, scopolamine, trihexyphenidyl), baclofen,
barbiturates, benzodiazepines, cannabinoids, carbamazepine, gabapentin, lamotrigine, memantine, 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 specifically on certain receptors or ion channels will
also further improve our insights into the pathophysiology of the underlying disorders.
Conflict of interest statement

None declared.
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Therapeutic Advances in Neurological Disorders

Current treatment of vestibular, ocular motor

Ther Adv Neurol Disord

various aetiologies and pathogeneses, which can

Vertigo and dizziness

The prerequisite of every treatment of vertigo

Therapeutic Advances in Neurological Disorders 2 (4)

Peripheral vestibular disorders

head positioning movements. Semont et al.

M Strupp and T Brandt

Vestibular paresis (%)

Vestibular paresis (%)

Methylprednisolone plus valacyclovir

Vestibular paresis (%)

Vestibular paresis (%)

the vestibular paresis formula (to measure the

effect, but valacyclovir did not. Therefore, this

Therapeutic Advances in Neurological Disorders 2 (4)

intratympanic injection of gentamicin and corticosteroids are preferred. In Europe betahistine is

Intratympanic injections of gentamicin

M Strupp and T Brandt

A complete ablation of function, however, does

Intratympanic injections of corticosteroids

112 patients with Menie`res disease it was

Therapeutic Advances in Neurological Disorders 2 (4)

the CaV21 subunit of the PQ-calcium channel

M Strupp and T Brandt

Common, clinically important forms of

Table 1. Frequency of congenital and/or acquired

The most common presenting symptoms are

Since often transient, treatment not

Degenerative cerebellar disorders,

Null zone, in which

One may try clonazepam, gabapentin,

One eye: elevation

Therapeutic Advances in Neurological Disorders 2 (4)

M Strupp and T Brandt

of the vertical smooth pursuit tone in which the

velocity [Partsalis et al. 1995]. With functional

Therapeutic Advances in Neurological Disorders 2 (4)

Mean peak slow phase velocity (deg/s)

Mean peak slow phase velocity (deg/s)

Mean peak slow phase velocity (deg/s)

Mean peak slow phase velocity (deg/s)

DBN, several agents that act on this receptor

Mean peak slow-phase velocity of DBN was

M Strupp and T Brandt

Spontaneous vertical drift (/s)

thereby augmenting the physiological inhibitory

manifests with oscillopsia due to retinal slip of

Therapeutic Advances in Neurological Disorders 2 (4)

Other forms of nystagmus

M Strupp and T Brandt

and an increase of visual acuity [McLean et al.

Conclusions and future perspectives

Conflict of interest statement

Therapeutic Advances in Neurological Disorders 2 (4)

Dieterich, M. and Brandt, T. (1995) Vestibulo-ocular

M Strupp and T Brandt

Leigh, R.J., Das, V.E. and Seidman, S.H. (2002) A

Kalla, R., Deutschlander, A., Hufner, K. et al. (2006)

Marti, S., Straumann, D. and Glasauer, S. (2005)

Kalla, R., Glasauer, S., Buttner, U., Brandt, T. and

McLean, R., Proudlock, F., Thomas, S., Degg, C. and