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Role of Ocular Motor Assessment in Diagnosis
and Research
R. John Leigh and David S. Zee
INTRODUCTION
The clinical evaluation of eye movements can contribute substantially to the diagnosis of parkinsonian disorders, provided the physician performs a proper examination and interprets the findings
by referring to a simple scheme of the neurobiology of eye movements (1). Further diagnostic information can often be obtained by recording eye movements, which are more accessible to measurement and analysis than limb movements or gait. A good part of the neurobiological substrate of eye
movements has been defined, which makes it possible to attribute disordered properties of eye movements to dysfunction of specific neuronal populations or structures in the brain. In this chapter, first,
we review pertinent aspects of the ocular motor examination; second, we highlight some important
test paradigms and technical aspects of measuring eye movements; and third, we summarize disorders of ocular motility reported with parkinsonian disorders and diseases affecting the basal ganglia.
CLINICAL EXAMINATION OF EYE MOVEMENTS IN PARKINSONISM
The systematic examination of eye movements is summarized in Table 1. The most useful part of
the examination concerns saccades, which are the rapid eye movements by which we voluntarily
move our line of sight (direction of gaze). Saccades are perhaps the best understood of all movements
both in terms of their dynamic properties and neurobiology (1–3). It is important to differentiate
between limited range of movement, especially upward, and speed of saccades, especially vertically.
Normal elderly subjects show limited upgaze (4), and this may be because of changes in the connective tissues of the orbit (5). Nonetheless, some normal elderly subjects make vertical saccades that
have normal velocities, within their restricted range of motion (6). Range of movement is conventionally elicited as the patient attempts to follow the examiner’s moving finger, but this does not test
saccades. It is important to ask the patient to shift gaze on command between two stationary visual
targets, displaced horizontally or vertically, such as a pencil tip and the examiner’s nose. After each
verbal cue (e.g., “look at the pencil; now look at my nose”), note the time taken to initiate the saccade,
its speed, and whether it gets the eye on target, or whether further corrective saccades are needed. It
is also useful to ask parkinsonian patients to make saccades voluntarily at a rapid pace back and forth
between two stationary targets (e.g., a finger from the left and right hand of the examiner. Patients
with idiopathic Parkinson’s disease (PD) often have difficulty making such self-generated sequences
and several saccades, rather than one, are needed for the eye to reach the target (see video 1).
From: Current Clinical Neurology: Atypical Parkinsonian Disorders
Edited by: I. Litvan © Humana Press Inc., Totowa, NJ
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Table 1
Summary of Eye Movement Examination
• Establishment of the range of ocular motility in horizontal and vertical planes
• Fixation stability in central and eccentric gaze (looking for nystagmus or saccades that intrude on
steady fixation)
• Horizontal and vertical saccades made voluntarily between two fixed visual targets (noting initiation
time, speed, and accuracy)
• Horizontal and vertical pursuit of a smoothly moving target (looking for “catch-up” saccades)
• “Optokinetic nystagmus” induced with horizontal or vertical motion of a hand-held drum or tape
• Ocular alignment during fixation of a distant target, and vergence responses to smooth or stepping
motion of targets aligned in the patient’s sagittal plane
• The vestibular ocular reflex in response to smooth sinusoidal, or sudden, head rotations in horizontal
and vertical planes (looking for corrective saccades that accompany or follow the head rotation)
Another important feature of many parkinsonian disorders is inappropriate saccades that intrude
on steady fixation; the most common are small “square-wave jerks” that are most easily appreciated
during ophthalmoscopy as to-and-fro movements of the fundus. Smooth pursuit is not usually helpful, because many elderly normal subjects and even some younger subjects may have impaired pursuit that requires catch-up saccades to keep the line of sight on the moving target. Optokinetic
stimulation at the bedside may be useful in some patients who have difficulty initiating voluntary
saccades (e.g., progressive supranuclear palsy [PSP]); vertical drum motion may induce tonic vertical deviation of the eyes in affected individuals or evoke reflexive “quick phases” of nystagmus.
Vergence is also often impaired in normal elderly subjects, and identification of abnormalities may
require laboratory assessment.
A NOTE ON LABORATORY METHODS FOR STUDYING EYE MOVEMENTS
IN PARKINSONIAN DISORDERS
Perhaps the most important diagnostic contribution to be made by recording eye movements in
parkinsonian disorders concerns tests of vertical saccades (7,8). Reliable measurement of horizontal
or vertical saccades requires methods with adequate bandwidth (0–150 Hz), sensitivity (0.1°), and
linear range (±30°). DC-amplified electro-oculography (EOG) is adequate to signal horizontal eye
position and timing at the beginning and end of a saccade, but is unreliable for measuring vertical
movements. Infrared methods provide better bandwidth but inferior range to EOG, and also cannot
be used to measure vertical movements. The most reliable method is the magnetic search coil which,
in our experience, is well tolerated by frail and elderly subjects, and has the added advantage of being
calibrated independently of the patient’s voluntary range of movements (1). Fast frame-rate videobased techniques are suitable for measuring dynamic properties of horizontal and vertical saccades
(9), but their calibration depends on the ability of the patient to look at visual targets, and this may be
impaired, for example, in PSP.
Saccades show consistent relationships between their size, speed, and duration (2,10). Thus, the
bigger the saccade, the greater its peak velocity and the longer it lasts. Examples of the “main
sequence” relationships between peak velocity, duration, and amplitude are provided from normal
subjects in Fig. 1; exponential or power-function equations have been used to describe these relationships and define prediction intervals for normal subjects (2,10,11). Deviations of measured eye movements from these relationships indicate either abnormal saccades, or nonsaccadic eye movements.
Thus, in Fig. 1, we also provide an example of abnormally slow vertical saccades from a patient
with PSP.
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Fig. 1. Plots summarizing important dynamic properties of saccades. (A) Plot of peak velocity vs amplitude
of vertical saccades. Data points are saccades from 10 normal subjects. The data are fit with an exponential
equation; also plotted are the 5% and 95% prediction intervals. The + indicate vertical saccades from a patient
with PSP, which lie outside the prediction intervals for normals. (B) Plot of duration vs amplitude. The data
from 10 normal subjects are fit with a power equation. The + indicate vertical saccades from a patient with PSP,
which have greater duration than control subjects.
Aside from measurement of saccadic dynamics, substantial effort has been put into using saccades
as a behavioral index of motor programming in basal ganglia and associated cortical disorders (12).
Thus, although the frontal and parietal eye fields project directly to the brainstem centers, such as the
superior colliculus and pontine nuclei, a second pathway running through the basal ganglia plays an
important role, and comprises the caudate, substantia nigra par reticulata (SNpr), subthalamic nucleus,
and superior colliculus (Fig. 2). A simplified view of this basal ganglia pathway is that it is composed
of two serial, inhibitory links: a caudate-SNpr inhibition, which is only phasically active, and a SNprcollicular inhibition, which is tonically active (13). If frontal cortex causes caudate neurons to fire,
then the SNpr-collicular inhibition is removed and the superior colliculus is able to activate a saccade. In addition, the subthalamic nucleus contains neurons that discharge in relation to saccades and
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Fig. 2. (A) Block diagram of the major structures that project to the brainstem saccade generator (premotor
burst neurons in PPRF and riMLF). Also shown are projections from cortical eye fields to superior colliculus.
FEF, frontal eye fields; SEF, supplementary eye fields; DLPC, dorsolateral prefrontal cortex; IML, intramedullary lamina of thalamus; PEF, parietal eye fields (LIP); PPC, posterior parietal cortex; SNpr, substantia nigra,
pars reticulata.
excites (SNpr), which in turn inhibits the superior colliculus. Animal studies indicate that this pathway appears important for programming of saccades to targets for which there is an expectation of
reward (14,15). The caudate nucleus also probably contributes to smooth pursuit (16).
For these reasons, studies of the effects of human diseases affecting basal ganglia have focused on
behaviors such as memory-guided or predictive saccades (Fig. 3). Memory-guided saccades are made
in darkness several seconds after a visual target has been flashed. Predictive saccades are made in
anticipation of a target appearance or jump. In the anti-saccade task, the subject is required to look in
the opposite direction (mirror image position) to a visual stimulus. Thus, a reflexive, visually guided
saccade must be inhibited and a saccade to an imagined target made instead (17). Such testing is still
mainly a research tool, but it has provided insights into the pathogenesis of parkinsonian disorders, as
we will mention in discussing each type of disorder.
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Fig. 3. Schematic summary of stimulus paradigms that have been used to test saccades in Parkinsonian
disorders. (A) Simultaneous switching of fixation target off and visual target on (overlap paradigm). (B) Gap
paradigm, in which fixation target is switched off before visual target is switched on. (C) Memory target task.
The subject views the fixation target during the time that the visual target is flashed and after several seconds
(the memory period), the fixation light is switched off and the subject looks toward the remembered location
of the target. (D) The antisaccade task. The subject is required to look in the opposite direction when the visual
stimulus is presented. (E) Predictive task. Subject makes saccades to a target that jumps to a predictable location with predictable timing.
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IDIOPATHIC PARKINSON’S DISEASE (TABLE 2)
Clinical Findings in PD
Most patients with PD show relatively minor abnormalities at the bedside that may also occur in
healthy elderly subjects. For example, steady fixation may be disrupted by saccadic intrusions
(square-wave jerks) (18–20), but these are also seen in some normal elderly subjects. Moderate
restriction of the range of upward gaze is common in elderly individuals (4), with or without parkinsonism, and has been attributed to changes in the orbital tissues (5). Similarly, smooth pursuit can
be impaired in PD but is also abnormal in some healthy normals (21). Convergence insufficiency is
common and sometimes symptomatic (22). Patients with PD often have lid lag. Patients with advanced
PD may show some slowing of vertical saccades, but PSP should always be considered in such cases.
A characteristic sign in PD is that hypometria becomes more marked when patients are asked to
rapidly perform self-paced refixations between two continuously visible targets (e.g., a finger of the
examiners right and left hand about 60–80° apart; the normal horizontal ocular motor range is about
45° to either side) (video 1).
Laboratory Findings in PD
Saccades
Saccades in PD usually undershoot the target (i.e., they are hypometric), especially vertically
(20,21). Patients may show a “stair-case” of saccades to acquire the target (especially with remembered targets); this “fragmentation” has been interpreted as a robust correction mechanism to compensate for the underlying hypometria (23). It has been possible to investigate the pathogenesis of the
hypometria, which becomes more marked when patients are asked to make self-paced refixations
between two continuously visible targets. This phenomenon is not simply because of the persistence
of the visual targets, because saccades made in anticipation of the appearance of a target light at a
remembered location are also hypometric (24,25). Patients with PD have difficulty in generating
sequences of memory-guided saccades (26–28), whereas saccades made reflexively to novel visual
stimuli are normal in size and promptly initiated (7). Furthermore, visually guided adaptation of
saccades is preserved whereas memory guided adaptation of saccades is impaired (29). Thus, it
appears that PD patients are unable to generate internally guided saccades to accurately shift gaze
(7,30). Despite this hypometria, patients can still shift their gaze with a series of saccades to the
location of a briefly flashed target; this indicates a retained ability to encode the location of objects in
extrapersonal space (20,24).
The reaction time (latency) of saccades made in response to nonpredictable target jumps may be
normal or mildly increased (20,30). During self-paced refixations between two visible targets,
intersaccadic intervals increase above the latency of responses to nonpredictable target jumps (30,31)
If the fixation light is turned out 100 msec before a target light appears (“gap” paradigm—Fig. 3) PD
patients are able to make short-latency (100–130 ms) “express saccades” like normal subjects (7).
The pathophysiology of saccadic disorders in PD is not fully understood. One possible mechanism
is via the subthalamic nucleus (Fig. 2), which contains neurons that discharge in relation to saccades.
The subthalamic nucleus is hyperactive in PD, and excites the substantia nigra, pars reticulata (SNpr),
which in turn inhibits the superior colliculus. It may be that excess activity in SNpr in PD leads to a
defect in generation of the more voluntary, internally guided saccades such as those during prediction
and to memorized targets. Functional imaging studies have suggested that the basal ganglia are important for processing of temporal information (32), which may be important for generating a regular series
of saccades. Furthermore, during predictive visuomanual tracking, there is an underactivity of sensorimotor cortex, but increase in premotor areas, such as pre-SMA (supplementary motor area), which
may represent compensation or impaired suppression (33). Finally, PD also affects the dopaminergic
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Table 2
Summary of Disordered Eye Movements in Some Basal Ganglia Disorders
Progressive Supranuclear Palsy (PSP)
• Slow vertical saccades, especially down, with a preserved range of movement, may be the first sign of
the disorder; later, loss of vertical saccades and quick phases
• Horizontal saccades become slow and hypometric
• Disruption of steady gaze by horizontal saccadic intrusions (square-wave jerks)
• Impaired smooth pursuit, vertically (reduced range) and horizontally (with catch-up saccades)
• Smooth eye-head tracking may be relatively preserved, especially vertically
• Preservation of slow phases of vestibular ocular reflex but quick phases are affected as saccades
• Horizontal disconjugacy suggesting INO
• Loss of convergence
• Ultimately, all eye movements may be lost, but vestibular movements are the last to go
• Eyelid disorders: apraxia of lid opening, lid lag, blepharospasm, inability to suppress a blink to a
bright light.
Parkinson’s Disease
• Fixation may be disrupted by square-wave jerks
• Hypometria of horizontal and vertical saccades, especially when patients are asked to perform selfpaced refixations between two continuously visible targets
• Normal saccadic velocity except in some advanced cases
• Impaired smooth pursuit, horizontally and vertically, owing partly to inadequate catch-up saccades
• Vestibular eye movements normal for natural head movements
• Impaired convergence
• Oculogyric crises
• Lid lag
Huntington’s Disease
•
•
•
•
•
Difficulties initiating saccades (without an associated head thrust and blink)
Difficulties suppressing saccades to novel visual stimuli (especially during the antisaccade task)
Slow saccades, especially vertically, and in patients with early age of onset
Impairment of smooth pursuit
Preservation of VOR and gaze-holding
cells within the retina. PD patients have abnormalities of color vision and in detection of spatially and
temporally modulated gratings (34).
Smooth Pursuit
Mildly affected PD patients differ little from age-matched control subjects in their smooth-pursuit
performance (21,35). During tracking of a target moving in a predictable, sinusoidal pattern, eye
speed is less than target speed, leading to catch-up saccades (20,36). In addition, the catch-up saccades are hypometric; thus, the cumulative tracking eye movement is less than that of the target (35).
Despite these impairments, the phase relationship between eye and target movement is normal,30
implying a normal predictive smooth tracking strategy. This is in contrast to saccadic tracking of
predictive target jumps which, as described earlier, is deficient.
Vestibular Responses
Both caloric and low-frequency rotational vestibular responses, in darkness, may be hypoactive in
patients with PD (37,38). However, at higher frequencies of head rotation, and particularly during
visual fixation, the vestibular ocular (VOR) reflex adequately compensates for head perturbations,
which accounts for the lack of complaint of oscillopsia in patients with PD.
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Effects of Disease Course and Treatment
Patients with advanced PD may show greater defects on more demanding tests, such as making
memory-guided saccades, and on the anti-saccade tasks (Fig. 3), which requires inhibiting a reflexive
saccade, and looking in the opposite direction to the target (its mirror location). In addition, patients
with advanced disease may show some slowing of vertical or horizontal saccades.
In general, L-dopa treatment of PD does not seem to improve the ocular motor deficits except for
improvement of saccadic accuracy (i.e., saccades become larger) (36,39). Some newly diagnosed
patients with idiopathic PD may show improved smooth pursuit after the institution of dopaminergic
therapy (39). Memory-guided saccades are reported to be impaired after pallidotomy for PD (40), but
improved with subthalamic nucleus stimulation (41), possibly by improving learning abilities in the
corticobasal ganglia network (42). Pallidotomy increases saccadic intrusions on steady fixation
(square-wave jerks) (43,44).
Toxic Parkinsonism
In patients with parkinsonism owing to methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, saccadic latency is shortened and saccadic accuracy improved by dopaminergic agents; in addition, reflex blepharospasm was improved (45). In monkeys that received MPTP, saccadic
abnormalities, including increased latency, increased duration, decreased rate of spontaneous saccades, and inappropriate saccades, were all reversed by dopaminergic therapy (46,47).
PROGRESSIVE SUPRANUCLEAR PALSY
Clinical Features
PSP is a degenerative disease of later life characterized by abnormal vertical saccades; the early
appearance of falls, usually within a year of onset, owing to disturbance of tone and posture; difficulties with swallowing and speech; and mental slowing (48). Median survival time is about 6 yr. The
disturbance of eye movements is usually present early in the course, but occasionally develops late,
or is sometimes not noted by the patient’s physicians (49). Patient may complain of blurred vision,
double vision, or photophobia (48), and have often been fitted with several different spectacle refractions, without improvement. On direct questioning, it is usually possible to determine that these
visual complaints are a result of loss of the ability to voluntarily shift gaze in the vertical plane so
that, for example, patients cannot look down to see a plate of food, tie their shoes, or confidently
navigate going down the stairs.
The initial ocular motor deficit consists of slowing of vertical saccades and quick phases, either
down or up or both (see video 2). Sometimes vertical saccades take a curved or oblique trajectory
(“round the houses”) (21,50). Vertical smooth pursuit is relatively preserved, but of decreased gain
(51). Larger targets may elicit greater responses (52), and could be used to evaluate the range of eye
movements in patients in whom neck stiffness makes testing of the VOR technically difficult. Similarly, full-field optokinetic stimuli may induce responses that are useful for analysis (11). Combined
eye-head tracking may also be relatively spared. As the disease progresses, the range of movements
possible with vertical saccades and pursuit declines and eventually no voluntary vertical eye movements are possible. However, the VOR is preserved until late in the disease (although a characteristic rigidity of the neck may make the vertical doll’s head maneuver difficult to elicit).
Horizontal eye movements also show characteristic changes: steady fixation is disrupted by squarewave jerks (11,18,21), which are more common than in other parkinsonian disorders. Horizontal
saccades are initially hypometric but normal in speed (see video 3) (53); as the disease progresses,
they also become slow. In some patients, the involvement of horizontal saccades resembles inter-
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nuclear ophthalmoplegia (INO), although vestibular stimulation may overcome the limitation of adduction (54). Horizontal smooth pursuit appears impaired, in part, because of square-wave jerks.
Convergence eye movements are commonly impaired (55). Late in the disease, the ocular motor
deficit may progress to a complete ophthalmoplegia. Patients with absent quick phases but intact
vestibular eye movements may also show sustained deviation of the eyes in the orbit during body rotation, and if the head is free to move it too may deviate opposite to the direction of body rotation (56).
There are a variety of eyelid abnormalities in PSP: blepharospasm, lid-opening apraxia, eye-closing apraxia, lid retraction, and lid lag (21). Patients typically show an inability to suppress a blink to
a bright light—a visual Meyerson’s (glabella) sign (see video 4) (57). A single patient may have more
than one of these abnormalities. Bell’s phenomenon is usually absent.
Laboratory Findings in PSP
Saccades
Reliable measurements of saccades in PSP have demonstrated that vertical saccades are slower
than horizontal saccades of similar size (21,58). For patients who are able to make only small saccades, it is still possible to determine whether the movements are slowed using an appropriate statistical approach (59). Vertical saccades are generated by “burst neurons” in the midbrain but horizontal
saccades are generated by burst neurons in the pons. Thus, the selective involvement of vertical
saccades in the early stage of PSP has indicated that the brunt of the disease initially falls on midbrain
burst neurons, or their local circuitry (superior colliculus and the adjacent central mesencephalic
reticular formation) (60,61).
The latency (reaction time) of horizontal saccades in PSP is prolonged in some patients, but others
retain the ability to make short-latency or “express” saccades (62). Patients with PSP also make
errors when they are required to look in the opposite direction to a suddenly appearing target (the
antisaccade task—Fig. 3). Both the presence of express saccades and errors on the antisaccade task
suggest defects in frontal lobe function and, although neuropathological changes there are mild,
positron emission scanning indicates profound frontal hypometabolism (63).
Vestibular Eye Movements
Measurements of vestibular eye movements during horizontal rotation, either in darkness, or during fixation of a stationary target, confirms that PSP patients show similar slow-phase responses to
normal subjects but quick phases are commonly impaired leading to tonic deviation of the eyes in the
contraversive direction in the oribit during rotation in the dark (51).
Smooth-Pursuit, Optokinetic, and Vergence Movements
Smooth pursuit is usually impaired in both horizontal and vertical planes (21). In the vertical
plane, no corrective “catch-up” saccades can be made. The combined impairment of vertical saccades and pursuit constitutes voluntary gaze palsy. During large-field, vertical optokinetic stimulation, PSP patients often show tonic deviation of the eyes in the direction of stripe motion, with small
or absent resetting quick phases (11). When PSP patients shift their fixation point between distant
and near targets, the vergence movement is slowed compared to control subjects (64).
EYE MOVEMENTS IN OTHER DISORDERS CAUSING PARKINSONIAN
SYNDROMES: DIFFERENTIATION FROM PSP (TABLE 3)
The clinical challenge often posed to neurologists is to diagnose parkinsonian patients with abnormal eye movements. As noted above, most patients with PD have normal eye movements for their
age, whereas as most patients with PSP do not. In fact, a number of other parkinsonian disorders have
been reported to produce abnormal eye movements, and it is those disorders that we review in this
section, noting features that help to differentiate from PSP.
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Table 3
Comparison of Findings in Some Parkinsonian Syndromes
SWJ During Fixation
PD
Increased following
pallidotomy
Visually Guided Saccades
Laboratory Testing of Saccades
Hypometric, when self-generated and
especially when instructed to generate
successive saccades back and forth at a rapid
pace; slow vertically in advanced casedes
Difficulty generating memorized
sequences
Advanced cases make errors
on antisaccade task
Increased errors on antisaccade task
PSP
Markedly increased
Slow; hypometric; initiated with difficulty
MSA
Increased in some
patients
Slow and hypometric in some patients
CBGD
Increased in some
patients
Hypometric and increased latency; deficit more
marked in the presence of a visual
background
Increased errors on antisaccade task
HD
May be increased
Difficulty with initiation; may be slow and
hypometic
Markedly increased errors
on antisaccade task; impaired
predictive saccade tracking
Conditions that closely mimic PSP, causing slow vertical saccades, horizontal square-wave jerks,
dysphagia, and frequent falls, include multiple infarcts affecting the basal ganglia, internal capsule,
and midbrain (in the distribution of the perforating vessels arising from the proximal portions of the
posterior cerebral artery) (65), infiltrative processes such as lymphoma, and paraneoplastic syndromes
(66). Disorders causing the dorsal midbrain syndrome, such as tumor and hydrocephalus, can also
produce a clinical picture that has some similarities to PSP with vertical-gaze palsy.
Whipple’s disease can also closely mimic PSP, with vertical saccadic gaze palsy (67,68). In addition, there may be characteristic “oculomasticatory myorhythmia”— a pendular vergence oscillation
with concurrent contractions of the masticatory muscles; occasionally the limb muscles also show
rhythmic contractions (69). Whipple’s disease can now be diagnosed using polymerase chain reaction (PCR) analysis of involved tissues (70), and can be treated with antibiotics (71).
Pure akinesia is characterized by profound disturbances of speech, handwriting, and gait, so that,
for example, affected patients may suffer episodes during which they stand “frozen” for hours on end
(72). Tremor, limb rigidity, akinesia, dementia, or responsiveness to levodopa are absent. Such patients
may show slow and hypometric vertical saccades. The disorder may be a restricted form of PSP with a
longer, more benign course.
Cortical-basal degeneration (CBD) may lead to a defect in range of vertical eye movements but it
usually does not cause marked slowing of saccades; instead the defect is an increased saccadic reaction time (latency), which is evident at the bedside (21,73). Hypometria of upward saccades may
occur early in the course, and should be differentiated from restricted upward range, which is present
in elderly normal subjects. Other occasional findings in CBD include some decrease in horizontal
saccade speed in the direction of the more affected limb, and increased distractibility during the
antisaccade paradigm (looking at, instead of way from, the visual target). The other features of this
degeneration—focal dystonia, ideomotor apraxia, alien hand syndrome, myoclonus, asymmetric akinetic-rigid syndrome with late onset of gait or balance disturbances—are more important in securing
the diagnosis (74,75).
Multiple system atrophy (MSA) causes a parkinsonian syndrome with marked autonomic findings. Some patients show slowing of vertical saccades as well as hypometria (21,76), whereas other
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have cerebellar eye movement findings, including downbeat nystagmus during positional testing (77),
impaired smooth ocular and eye-head pursuit.
Dementia with Lewy bodies, which causes parkinsonism and fluctuating dementia with florid visual
hallucinations, may be associated with a vertical-gaze paralysis (78,79), but systematic measurements
of vertical saccade are not yet available.
Other basal ganglia disorders that have been reported to show features similar to PSP include
idiopathic striopallidodentate calcification (Fahr’s disease) (80), and autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration (81). Some patients with Huntington’s
disease (HD) may present with vertical saccadic palsy and axial rigidity; this condition is discussed
in a later section. Patients with the syndrome of amyotrophic lateral sclerosis (ALS), parkinsonism,
and dementia (Lytico-Bodig), which is encountered in the inhabitants of the islands of the South
Pacific Ocean, including Guam, may show more severe deficits than those with idiopathic PD, including limitation of vertical gaze (82). A variant of ALS has been described, in which slow vertical saccades, gaze-evoked nystagmus, and impaired pursuit were prominent (83). In the French West Indies,
a PSP-like syndrome thought to result from neurotoxic alkaloids is associated with ingestion of herbal
teas and fruits (84). Slow saccades, with a supranuclear gaze palsy, are also characteristic of
Creutzfeldt–Jakob disease but usually in both the horizontal and vertical planes (85). Periodic alternating nystagmus, rebound nystagmus, and centripetal nystagmus (slow phases directed eccentrically) on lateral gaze are also characteristic of this condition owing to cerebellar involvement (85,86).
DRUG-INDUCED PARKINSONISM AND OCULOGYRIC CRISIS
Drug intoxications, especially with phenothiazines such as the butyrophenones, may produce a
parkinsonian picture with slowing of saccades and an “akinetic mutism” picture. A distinct syndrome
is oculogyric crisis, which was once a common feature of postencephalitic parkinsonism, but is now
a side effect of drugs, especially neuroleptic agents (87). Oculogyric crises may also rarely be a
feature of Wilson’s disease (88), and disorders of amino acid metabolism (aromatic L-amino acid decarboxylase deficiency) (89).
A typical oculogyric crisis is ushered in by feelings of fear or depression, which give rise to an
obsessive fixation on a thought. The eyes usually deviate upward, and sometimes laterally; they
rarely deviate downward. During the period of upward deviation, the movements of the eyes in the
upper field of gaze appear nearly normal. Affected patients have great difficulty in looking down,
except when they combine a blink and downward saccade. Thus, the ocular disorder may reflect an
imbalance of the vertical gaze-holding mechanism (the “neural integrator”). Anticholinergic drugs
promptly terminate the thought disorder and ocular deviation, a finding that has led to the suggestion
that the disorders of thought and eye movements are linked by a pharmacological imbalance common
to both (87). Delayed oculogyric crises have been described after striatocapsular infarction, and with
bilateral putaminal hemorrhage (90). Oculogyric crises are distinct from the brief upward ocular
deviations that occur in Tourette syndrome (91), Rett syndrome (92), children with benign paroxysmal tonic upgaze (93), and in many patients with tardive dyskinesia (94). In some patients with
tardive dyskinesias, however, the upward eye deviations are more sustained and also have the characteristic neuropsychological syndrome of oculogyric crises (95). Episodic brief spells of tonic upgaze
have also been reported after bilateral lentiform lesions (96).
HUNTINGTON’S DISEASE
Clinical Findings
HD results from a genetic defect of the IT15 gene (“huntingtin”) on chromosome 4, causing
increased CAG triplet repeat length. Disturbances of voluntary gaze are common in this disorder
(97–100). Initiation of saccades may be difficult with prolonged latencies, especially when the sac-
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cade is made to command or in anticipation of a target that is moving in a predictable fashion. An
obligatory blink or head turn may be used to start the eye moving (101). Saccades may be slow in the
horizontal or vertical plane; this deficit can often be detected early in the disease if eye movements
are measured, but may not be evident clinically until late in the course. Longitudinal studies of saccades have documented progressive slowing and prolongation of reaction time (102). Saccades may
be slower in patients who become symptomatic at an earlier age, and it has been suggested that such
individuals are more likely to have inherited the disease from their father (99).
Fixation is abnormal in some patients with HD because of saccadic intrusions (100). This defect of
steady fixation is particularly evident when patients view a textured background. Smooth pursuit
may also be impaired with decreased gain, but often is relatively spared compared with saccades. By
contrast, gaze holding and the VOR are spared. Late in the disease, rotational stimulation causes the
eyes to tonically deviate with few or no quick phases.
Despite the near-ubiquitous finding of abnormal eye movements in HD, some individuals who
have been studied at a presymptomatic point in their disease have shown normal eye movements
(97,103,104). Thus, routine testing of eye movements cannot be regarded as a reliable method for
determining which offspring of affected patients will go on to develop the disease. Some improvement of the eye movement abnormalities in HD has been reported with sulpiride (105).
The paradoxical findings of difficulty in initiating voluntary saccades but with an excess of extraneous saccades during attempted fixation has been further elucidated using special test stimuli (Fig. 3).
These have revealed an excessive distractibility in, for example, tasks in which patients are required to
look in the opposite direction to a suddenly appearing target (antisaccade task) (106). A second finding
is that saccades to visual stimuli are made at normal latency, whereas those made to command are
delayed. These findings can be related to the parallel pathways that control the various types of
saccadic responses. On the one hand, disease affecting either the frontal lobes or the caudate nucleus,
which inhibits the SNpr, may lead to difficulties in initiating voluntary saccades in tasks that require
learned or predictive behavior (107). On the other hand, HD also affects the SNpr (108). Since this
structure inhibits the superior colliculus (nigro-collicular projection), and so suppresses reflexive
saccades to visual stimuli, one might expect excessive distractibility during attempted fixation (107).
The slowing of saccades might reflect involvement of saccadic burst neurons (109) but at least some
pathologic evidence suggests that disturbance of prenuclear inputs, such as the superior colliculus or
frontal eye fields, is responsible (110).
Disorders to be considered in the differential diagnosis of HD include neuroacanthocytosis (111),
although abnormal eye movements have not been described as an important feature of this disorder.
Dentatorubropallidoluysian atrophy, also called the Haw River syndrome (112), is another CAG
triplet repeat disease (B37, chromosome 12) and is characterized by slow saccades but more myoclonus and ataxia than in HD.
OTHER DISORDERS THAT MAY AFFECT THE BASAL GANGLION
DISORDERS AND MAY HAVE ABNORMAL EYE MOVEMENTS
Wilson’s disease, hepatolenticular degeneration, is an autosomal recessive, inherited disorder of
copper metabolism. The defect is in a copper-transporting ATPase with the gene at q14.3 on chromosome 13. CT typically shows hypodense areas, and positron emission tomography (PET) scanning
indicates a decreased rate of glucose metabolism in the globus pallidum and putamen. The classic
clinical picture is a movement disorder with psychiatric symptoms and associated liver disease. The
Kayser–Fleisher ring is typical in the posterior cornea in Descemet’s membrane, and some patients
may have a sunflower cataract. Ocular motor disorders in Wilson’s disease include a distractibility of
gaze, with inability to voluntarily fix upon an object unless other, competing, visual stimuli are
removed (e.g., fixation of a solitary light in an otherwise dark room) (113). Slow vertical saccades
have also been reported in one patient with Wilson’s disease (114), but are often normal. A lid-
Role of Ocular Motor Assessment
247
opening apraxia has also been noted (115). Oculogyric crises may occur (88). The eye movements of
Wilson’s disease, therefore, show some similarities to those described in HD and Alzheimer’s disease. The distractibility in both conditions may be owing to involvement of the inhibitory pathways
from the basal ganglia to the superior colliculus (Fig. 2).
Ataxia telangiectasia results from a defect on chromosome 11q. Characteristic eye signs include
an ocular motor apraxia with hypometria and increased latency, but normal velocity of saccades with
head thrusts (116–119). Both vertical and horizontal saccades are affected. Other features are gazeevoked nystagmus, periodic alternating nystagmus, square-wave jerks, and unusual slow smoothpursuit-like movements that are used to change gaze voluntarily when saccades are difficult to
generate. α-Feto protein levels are usually dramatically elevated.
Niemann–Pick disease (Niemann–Pick type C [2S] disease), usually presents during adolescence
with intellectual impairment, ataxia, and dysarthria, and a selective slowing of vertical saccades (120–
122). Other eye movements (including horizontal saccades) are normal. Diagonal saccades may show
a curved trajectory evident during the clinical examination. A bone marrow examination shows sea
blue histiocytes.
Caudate hemorrhage has been associated with ipsilateral gaze preference (123), consistent with
experimental dopamine depletion of this structure. Patients with bilateral lentiform nucleus lesions
show abnormalities of predictive and memory-guided saccades (both internally generated), but visually guided saccades and antisaccades (both triggered by a visual target) are normal (124). It has been
suggested that defects in the control of predictive smooth-pursuit eye movements are a feature of striatal
damage (125), consistent with demonstration of pursuit projections to the caudate nucleus (16).
Patients with Gilles de la Tourette syndrome may show abnormalities such as blepharospasm and
eye tics that include involuntary gaze deviations (91). Routine testing of saccades, fixation, and pursuit is normal, but patients show increased latency and decreased peak velocity of antisaccades, as
well as impaired sequencing of memory-guided saccades (126–131). The lid abnormalities of Tourette
syndrome must be distinguished from benign eye movement tics, which children often outgrow
(132,133). Patients with Lesch–Nyhan syndrome—a disorder of purine metabolism—show an impaired
ability to make voluntary saccades, errors on the antisaccade task, blepharospasm, and intermittent
gaze deviations similar to Tourette syndrome (134).
Patients with essential blepharospasm generally show normal eye movements (135), although
saccadic latencies may be increased in certain visually guided and memory-guided saccade tests
(136,137). Patients with spasmodic torticollis may show abnormalities of vestibular function including the torsional VOR (138,139). Whether vestibular abnormalities are the cause or a secondary
effect of spasmodic torticollis has not been settled, but affected patients do show changes in their
perceptions of the visual vertical and straight ahead (140). Patients with tardive dyskinesia may display increased saccade distractibility (141). Patients with active Sydenham’s chorea are reported to
show saccadic hypometria (142). Patients with essential tremor, which may sometimes be confused
with PD, have eye movement disorders suggestive of cerebellar dysfunction (impaired pursuit and
impaired modulation of the duration of vestibular responses by head orientation) (143).
PROSPECTS FOR EYE MOVEMENTS IN PARKINSONIAN
RESEARCH (TABLE 4)
At present, much is known about the neurobiology of eye movements, especially saccades, which
can be applied to understanding the pathogenesis of disturbed behavior in a range of movement
disorders. It can be expected that the trend of using novel paradigms (such as shown in Fig. 3) along
with functional imaging is likely to provide new insights. To the clinical movement disorder specialists, examination of eye movement remains a useful diagnostic tool that will likely become even
more important with basic science advances. As more movement disorder specialists incorporate a
systematic eye movement examination into their daily routine, not only will diagnostic accuracy
248
Leigh and Zee
Table 4
Major Issues for Eye Movement Research in Parkinsonian Syndromes
General significance:
Eye movements can contribute to a better understanding of the pathogenesis of parkinsonian disorders, and
conversely, the study of patients with parkinsonian disorders can contribute to a better understanding of how
the brain controls movement in general and eye movements in particular.
•
•
•
•
•
Many functions are accessible to bedside clinic testing.
Ease and reliability of eye movement measurement.
Eye movements, and the stimuli that drive them, are readily quantified.
Important aspects of the neurobiological substrate of eye movements have been defined.
Paradigms are readily available that can test brainstem functions as well as the role of eye move
ments in prediction, memory, learning, visual search, attention, and reward.
Specific issues that can be addressed by eye movement research
•
•
•
•
•
•
•
•
•
What is the substrate for frequent saccadic intrusions (square-wave jerks) in PSP and in PD following
pallidotomy?
What is the pathogenesis of selective slowing of vertical saccades early in the course of PSP, and what
accounts for the curved trajectories of saccades?
Why do patients with PSP smoothly track a large visual target better than a small one?
What is the role of the basal ganglia in generation of pursuit eye movements?
Why do PD patients have difficulty generating voluntary saccades between visible targets without an
external cue (such as an auditory prompt)?
What are the effects of deep brain stimulation on the full range of saccadic and pursuit dynamics?
Why do head thrusts and a blinks facilitate the generation of saccades in patients with HD?
What is the neurobiological basis for ocular motor tics?
What is the role of the basal ganglia in ocular motor learning?
increase, but there will be more insights into the pathophysiology of the ocular motor disturbances in
parkinsonian disorders and how they respond to treatment.
ACKNOWLEDGMENTS
Dr. Leigh is supported by the Office of Research and Development, Medical Research Service,
Department of Veterans Affairs; NIH grant EY06717; Evenor Armington Fund. Dr. Zee is support by
NIH grant EY01849 and the Robert M. and Annetta J. Coffelt endowment for PSP research.
VIDEO LEGENDS
Video 1: Voluntary saccades in Parkinson’s disease. During the initial part of the clip, the patient
is verbally instructed to look between two visual targets (a pen and the camera); some mild hypometria
is evident. Subsequently, the patient is instructed to make self-generate saccades between two stationary targets about 60–80° apart; hypometria becomes much more marked, as well as some delayed
in initiation.
Video 2: Vertical saccades in PSP. The patient is looking between two stationary targets about 40°
apart in the vertical plane. The movements are slow, but carry the eyes to their targets. Their trajectories are slightly oblique or curved with a horizontal correction at the end (“round the houses”) (50).
Video 3: Horizontal saccades in PSP. The patient is looking between two stationary targets separated about 60° in the horizontal plane. Horizontal saccades are faster than vertical saccades (Video 2),
but tend to be hypometric.
Role of Ocular Motor Assessment
249
Video 4: Light-induced blink response in a patient with PSP. This was tested by flashing a penlight repetitively into one eye at 1–2 Hz, as he viewed a distant target with both eyes. Unlike normals,
or patients with PD, no habituation occurred.
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