J R Soc Med 2002;95:231-234
doi:10.1258/jrsm.95.5.231
© 2002 Royal Society of Medicine
Mechanisms underlying nystagmus
Richard V Abadi PhD
UMIST Department of Optometry and Neurosciences, PO Box 88, Manchester
M60 1QD, UK
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INTRODUCTION
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In health, there are three main control mechanisms for maintaining
steady
gaze—fixation; the vestibulo-ocular reflex; and
a gaze-holding system
(the neural integrator), which operates
whenever the eyes are required to hold
an eccentric gaze
position
1,2,3.
Failure
of any of these control systems will bring about a disruption
of
steady fixation. Two types of abnormal fixation can result—nystagmus
and
saccadic intrusions/oscillations. The essential difference
between them lies
in the initial movement that takes the line
of sight off the object of regard.
In the case of nystagmus,
it is a slow drift or ‘slow phase’ often
due to
a disturbance of one of the three mechanisms for gaze stability.
On the
other hand, with either saccadic intrusions or saccadic
oscillations, it is an
inappropriate fast movement that moves
the eyes off
target
4,5.
This paper will concern itself only
with the clinical aspects of nystagmus and
cover the possible
reasons for its presence.
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CLINICAL FEATURES OF NYSTAGMUS
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Nystagmus is an involuntary oscillation of one or both eyes
about one or
more axes. Broadly, nystagmus may be divided into
one of three categories
(
Figure 1). First, it may be
induced
physiologically (e.g. optokinetic, vestibular and end-point).
Secondly,
it can be present at birth or soon after, when it is referred
to as
congenital or infantile nystagmus. And thirdly, it may
be acquired (e.g.
neurological disease or drug
toxicity)
2,3,4,5,6,7.
Clinically, a nystagmus is characterized by the degree of conjugacy, the
plane or planes of the oscillation, the direction or directions of gaze at
which it is present, and the waveform, its amplitude and its frequency.
Although a reasonable indication of the oculomotor behaviour may be obtained
by just viewing the eyes, greater clarity and precision is gained when
oculographic techniques are used. When the eyes oscillate like a sine wave, it
is called pendular nystagmus (Figure
2a). If the nystagmus consists of drifts in one direction with
corrective fast phases, it is called jerk nystagmus
(Figure 2b-d).
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Figure 2. Schematic illustration of the most common nystagmus waveforms.
(a) Pendular nystagmus. This oscillation is often seen in infants
with congenital nystagmus, and in brainstem and cerebellar disease.
(b) Linear or constant velocity slow phase is followed by a quick
phase giving it a ‘saw tooth’ appearance. This oscillation is seen
in optokinetic and vestibular nystagmus. (c) An accelerating velocity
exponential slow phase. This is invariably seen in congenital nystagmus.
(d) A decelerating velocity exponential slow phase. This is
invariably seen in physiological end-point nystagmus, manifest latent
nystagmus and pathological gaze-evoked nystagmus.
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PHYSIOLOGICALLY INDUCED NYSTAGMUS
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In health, nystagmus occurs during self-rotation in order to
hold images of
the visual world steady on the retina and maintain
clear vision. Two forms of
nystagmus are induced by self-rotation—optokinetic
and vestibular. An
optokinetic nystagmus is an involuntary,
conjugate, jerk nystagmus that is
seen when a person gazes into
a large moving field
(
Figure 2b). The oscillations,
which are
in the plane of the moving field, are generally 3-4° in
amplitude
and 2-3 Hz in frequency. Both cortical and subcortical pathways
contribute
to the response, which is driven by the retinal image slip
velocity.
Smooth pursuit inputs are of particular
importance
1,2,8,9,10.
Vestibular nystagmus occurs during self-rotation even in darkness: the
inner ear contains motion detectors (vestibular labyrinth) which project to
the vestibular nuclei and
cerebellum1,2,3.
A vestibular nystagmus can also be induced by irrigating the ears with warm or
cold water. With unilateral irrigation the conjugate nystagmus is horizontal,
torsional or oblique, depending on the position of the head. Both a convection
mechanism and a direct temperature effect on the canal's sensory apparatus
have been proposed to account for the involuntary
oscillations2.
Lastly, many healthy individuals show a small-amplitude (<2°)
conjugate jerk nystagmus on far eccentric gaze (>40°). These
oscillations are thought to reflect the time constant of the gaze-holding
control system and in particular the cerebellar neural
integrator1,2,3,8,11,12,13
(see Acquired Nsytagmus, below).
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INFANTILE NYSTAGMUS
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The two most common types of benign nystagmus seen in infancy
are
congenital nystagmus (CN) and manifest latent nystagmus
(MLN)
4,5.
In
both, the oscillations are typically conjugate, horizontal and
jerky.
Differential diagnosis is made on the basis that the
CN slow phases are
typically of an increasing exponential velocity
form
(
Figure 2c), whereas in MLN the
slow phases are decreasing
or
linear
14,15,16,17,18
(
Figures 2b and 2d). In
addition to
its distinguishing slow phase, the fast phase of MLN always
beats
toward the viewing eye. MLN is also closely associated
with the presence of
strabismus and dissociated vertical divergence,
is strongly visually driven
and is largely dependent on the
attentional state of the
patient
18.
Both CN and MLN are associated with various disorders including albinism,
optic nerve hypoplasia and congenital
cataracts15,16,17,18,19.
CN may also occur without ocular or central nervous system abnormalities (i.e.
idiopathic CN).
Some patients with CN have near-normal vision, especially if they have
developed ‘foveation periods’—brief epochs when the eye is
still and pointed at the object of interest. CN is often suppressed during
convergence and decreased at certain gaze angles—properties that can
sometimes be used to provide optical or surgical therapies.
Over the years several mechanisms underlying CN and MLN have been proposed.
These include anomalies of the smooth pursuit, fixation and optokinetic
systems2,3,4,5,6,7.
To date, five distinct models have been specifically constructed to account
for CN. The first, proposed by
Dell'Osso20 in
1967, suggested that CN resulted from a high gain instability in the slow eye
movement control system. Some seventeen years later Optican and
Zee21 provided a
model in which the time constant of the neural integrator is lengthened by a
velocity feedback signal and, when the sign of the feedback signal is
reversed, the small post-saccadic drift velocities are amplified by the
unstable velocity feedback loop, leading to exponentially growing slow phases.
Tusa and his
colleagues22
extended this model by proposing that the fixation system has both normal and
abnormal feedback loops. Patients with CN who cannot suppress their nystagmus
either have only the abnormal feedback loop or cannot voluntarily manipulate
the normal feedback loop. Central to these two models is the need for a
neuronal mis-wiring. This seems somewhat untenable given the range of visual
disorders associated with CN in the absence of chiasmal misdirection, the
absence of an abnormal visual evoked response in idiopathic CN and the finding
of CN in achiasmic
dogs23,24
and humans25.
Fourthly, in 1995
Harris26 suggested
that CN was due to excessive gain in an internal efference copy loop in the
smooth pursuit system around a leaky neural integrator. Finally, and most
recently, Broomhead and his
colleagues27, using
a non-linear dynamics approach, proposed that the behaviour of burst cell
firing, in the form of a saccadic termination abnormality, could account for
the variety of CN waveforms that previous models were unable to create.
Since MLN occurs frequently in patients who have congenital or uniocular
visual loss, or who have experienced visual deprivation, it has been proposed
that disturbances of egocentric localization may be in part responsible for
these
oscillations28,29,
as well as the possibility of an abnormality of extraocular
proprioception30.
In summary, we do not have well-accepted hypotheses to account for infantile
forms of nystagmus, but certain properties of these oscillations present
opportunities for specific therapies.
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ACQUIRED NYSTAGMUS
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Many forms of acquired nystagmus can be attributed to disturbances
of the
three mechanisms that normally ensure steady gaze—visual
fixation, the
vestibulo-ocular reflex, and the mechanism that
makes it possible to hold the
eyes at an eccentric eye position
(e.g. far right
gaze)
1,2,3,4,5,6,7.
Diseases affecting the visual system, such as retinal disorders
causing visual loss, commonly lead to nystagmus because visual fixation is no
longer possible. Disease affecting the vestibular organ in the inner
ear causes an imbalance that leads to a mixed horizontal—torsional
nystagmus, usually associated with vertigo. Disease affecting the central
connections of the vestibular system, including the cerebellum, may cause
several forms of nystagmus. These include down-beat, torsional, periodic
alternating and see-saw nystagmus. None of these nystagmus types are, in
themselves, pathognomonic of central nervous system disease. Nonetheless,
down-beat nystagmus is usually associated with lesions of the
vestibulo-cerebellum (flocculus, paraflocculus, nodulus and uvula) and the
underlying medulla; up-beat nystagmus is most commonly reported with lesions
of the medulla, including the perihypoglossal nuclei and adjacent vestibular
nucleus (both structures are important for gaze-holding), the ventral
tegmentum and the anterior vermis of the cerebellum; periodic alternating
nystagmus is often linked to cerebellar disease (note that in this case the
horizontal jerk nystagmus spontaneously reverses direction of the quick phase
every few seconds); see-saw nystagmus is linked to parasellar lesions of the
optic chiasm (e.g. pituitary tumours) and achiasma (note that this is a rare
form of pendular nystagmus in which the torsional components are conjugate and
the vertical components are disjunctive—one eye rises and intorts while
the other falls and extorts); and gazeevoked nystagmus is commonly seen as a
side-effect of drugs, including sedatives, anticonvulsants and alcohol, as
well as cerebellar
disease2.
Lesions affecting the medial longitudinal fasciculus cause internuclear
ophthalmoplegia. A unilateral internuclear ophthalmoplegia is commonly related
to ischaemia, whilst bilateral internuclear ophthalmoplegias are associated
with multiple sclerosis. An adduction weakness on conjugate movements and a
jerk nystagmus of the abducting eye are the classic ocular motor signs
(‘dissociated nystagmus’).
An acquired pendular nystagmus can occur in any plane; it can be
monocular or have a greater intensity in one eye and typically remains
pendular in all directions of gaze. It is associated with a wide range of
brainstem and cerebellar disease including several disorders of myelin, with
the syndrome of oculopalatal myoclonus, with Wipple's disease and with drug
toxicities.
Recently Das and his
colleagues31 have
modified a neural-network model previously developed by Arnold and
Robinson32 to
account for the pendular oscillations
(Figure 2a) caused by disease
of central myelin. Their findings suggest that, in multiple sclerosis, the
pendular nystagmus arises from an instability in the feedback control of the
neural integrator.
One of the most studied and frequently seen of the acquired oscillations is
gaze-evoked nystagmus. The nystagmus is elicited when the patient
attempts to maintain an eccentric eye position. The oscillations are jerky
with a centripetal decreasing velocity exponential slow phase taking the eyes
away from the desired eye position, followed by a corrective fast phase
(Figure 2d). It is seen in
patients with cerebellar disease (particularly the flocculus), muscle palsy
and drug toxicity. A failure of the step (or tonic) eye position command from
the gaze-holding network (the neural integrator) is deemed to be the reason
for the presence of the
nystagmus2,6,12.
After the eyes are returned to the primary position, a short-lived reflex
nystagmus with quick phases opposite to the direction of the previous
eccentric gaze oscillation can typically be seen in vestibulocerebellar
diseases. It is very difficult to differentiate a physiological end-point
nystagmus from an acquired gaze-evoked nystagmus by viewing the eye movements
alone11,12,13.
Finally, no review of acquired nystagmus could be complete without mention
of the vestibular apparatus and pathway. Diseases affecting the
vestibular labyrinth or nerve (including the root entry zone) cause a jerk
nystagmus with linear or constant velocity slow phase drifts
(Figure 2b). Characteristically
the nystagmus increases when the eyes are turned in the direction of the quick
phases (Alexander's law), and can be markedly suppressed by visual fixation.
The direction of the unidirectional nystagmus is related to the geometrical
relationship of the semicircular canals with the fast phase opposite to the
side of the lesion. A change in head position often exacerbates the nystagmus.
On the other hand, a central vestibular nystagmus, which is caused by disease
of the brainstem and/or cerebellum, is not attenuated by fixation and
invariably exhibits bidirectionality to the nystagmus (i.e. left-beating on
left gaze and right-beating on right gaze).
Clearly, the mechanisms that give rise to congenital nystagmus remain to be
fully understood. Nonetheless, knowledge of the nystagmus characteristics can
often give clues to the location of the lesion, pathogenesis, and underlying
mechanisms. For example, a periodic alternating nystagmus which is seen
frequently both in
albinos33 and in
patients with cerebellar disease suggests that multiple mechanisms are at
work. The recent use of a systems approach to analyse and understand
congenital nystagmus has suggested that the dynamics in the region of
foveation are low-dimensional and
deterministic34.
Furthermore, on the basis of recent
studies13,22,27,
future control and dynamic systems models of nystagmus will almost certainly
need to incorporate attentional and adaptive loops in order to better describe
and simulate the oscillations. In parallel with these, advances in the
surgical and medical treatment of nystagmus have yielded promising
results.
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Footnotes
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Clinicians often regard nystagmus as a perplexing
subject—oscillations of the eyes that can only be understood by
neuro-ophthalmologists. Research over the past three decades has led to better
understanding of the pathophysiology of acquired forms of nystagmus,
suggesting drug therapies. Congenital nystagmus remains unexplained, but
better documentation of several factors that reduce these oscillations has led
to the development of surgical therapies. This symposium begins with a summary
of current concepts of the pathophysiology of nystagmus by RV Abadi, which
provides the background to current medical treatments (JS Stahl and
colleagues) and surgical therapies (J Lee).
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INTRODUCTION
CLINICAL FEATURES OF NYSTAGMUS
