Eye movement

abnormalities in stiff
person syndrome

VIDEO

AbstractThe authors describe a 38-year-old woman with stiff person syndrome (SPS) and gaze-holding nystagmus, limited abduction, vertical and horizontal ocular misalignment, deficient smooth pursuit, and impaired saccade
initiation. There was no evidence of ocular myasthenia, indicating that abnormalities of ocular motor function can occur as a primary manifestation of SPS,
perhaps from depletion of GABA.
NEUROLOGY 2005;65:14621464

John R. Economides, PhD; and Jonathan C. Horton, MD, PhD

Stiff person syndrome (SPS) is an autoimmune disease characterized by muscle rigidity, spasm, and
circulating antibodies against glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA.1
Surprisingly, ocular symptoms have not been described as a prominent feature of SPS, although
GABAergic neurons are critical for brainstem control
of eye movements.2 In a recent report, a patient was
described with alternating esodeviation, bilateral abduction weakness, hypometric saccades, nystagmus
and antiacetylcholine receptor antibodies.3 The authors identified four similar reports in the literature
and suggested that gaze disorders in SPS arise from
myasthenia gravis. Here we describe a patient with
eye movement abnormalities and SPS, without evidence of myasthenia gravis.
Case report. A 38-year-old woman reported that in 1993 she
developed diplopia on lateral gaze to either side and nystagmus.
Within a few years, she became disabled by progressive muscle
stiffness, cramps, and ataxia. Spinal fluid analysis was unrevealing, except for an elevated IgG synthesis rate. Tests for anti-Hu,
Yo, and Ri antibodies as well as thyroid autoantibodies were negative. In 1998, electromyography revealed continuous motor activity in the right gastrocnemius, quadriceps, and lumbar
paraspinous muscles after brief, low-intensity stimulation of the
right ankle. The diagnosis of SPS was confirmed by a serum
anti-GAD65 antibody level of 187 nmol/L (normal 0.02), documented in 1998 by radioimmunoassay.
In 2004, our examination (see video on the Neurology Web site
at www.neurology.org) showed mild deficiency of abduction in
each eye. In primary gaze, there was an alternating esotropia of
about 8 degrees and a right hypertropia of 1 to 2 degrees, with a
left-eye fixation preference. Horizontal smooth pursuit had a low

Additional material related to this article can be found on the Neurology

Web site. Go to www.neurology.org and scroll down the Table of Contents for the November 8 issue to find the title link for this article.

From the Beckman Vision Center, University of California, San Francisco,

CA.
Supported by the National Eye Institute (EY015343, EY10217, and
EY02162), the Larry L. Hillblom Foundation, and Research to Prevent
Blindness.
Disclosure: The authors report no conflicts of interest.
Received April 1, 2005. Accepted in final form July 12, 2005.
Address correspondence and reprint requests to Dr. Jonathan C. Horton,
Beckman Vision Center, University of California San Francisco, 10 Koret
Way, San Francisco, CA, 94143-0730; e-mail: horton@itsa.ucsf.edu
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Copyright 2005 by AAN Enterprises, Inc.

gain and was asymmetric. Horizontal saccades were often initiated with a blink. When the patient was instructed to avoid blinking, the saccades became hypometric. Gaze-holding nystagmus
was present on eccentric gaze in all directions. Vertical saccades
and pursuit were normal. There was no ptosis. Serological testing
revealed no evidence for antiacetylcholine receptor antibodies
(0.1 nmol/L). A chest CT scan was normal. A repeat determination of the anti-GAD antibody level yielded a value 30 nmol/L.
An MRI was normal, except for subtle midline atrophy of the
cerebellar cortex (figure 1).
Methods. The patients eye movements were recorded binocularly while she was seated with her head in a chin rest facing a
tangent screen. Computer-controlled spots (size 0.5 degrees;
Cambridge Research Systems, England) were rear-projected onto
the screen to control the patients fixation behavior. Eye movements were monitored at 60 Hz with a spatial resolution of 1
degree using two infrared video eye-tracking cameras (SensoMotoric Instruments, Germany). Analog voltages representing the
position of each eye and the target spot were recorded digitally for
offline analysis (Power1401 and Spike2, Cambridge Electronics
Design, England). The gain and offset of each eye was calibrated
independently (while the fellow eye was covered) by asking the
patient to fixate a nine-point grid of known visual field locations.
The first task involved smooth pursuit of a target moving sinusoidally in different directions at different speeds and amplitudes.
The second task involved making a saccade to a target appearing
intermittently in different locations. Eye movement traces were
smoothed with a Gaussian kernel and records of the patients
blinks were removed with a running median filter. Eye and target
velocities were computed offline using central point digital
differentiation.

Results.
Figure 2A demonstrates the change in the
magnitude of the patients horizontal misalignment with
respect to orbital location of the preferred left eye. She was
asked to fixate a target spot appearing randomly at 25
degrees left to 25 degrees right in 5-degree steps along the
horizontal meridian. Each data point represents the position of the fixating left eye plotted against the difference in
position between the two eyes (angle of esodeviation). During rightward gaze, the angle of esotropia was stable, out
to an eccentricity of 25 degrees. The mean value of the
right esodeviation was 8.5 degrees. On leftward gaze, the
eyes became progressively more crossed at eccentricities
greater than 10 degrees, indicating an incomitant ocular
misalignment. Her vertical deviation was comitant.
Figure 2B shows the effect of gaze position on nystagmus. At central fixation the eyes were relatively stable. At
30 degrees of eccentric gaze in any direction, a jerk nystagmus emerged beating in the direction of the eccentric gaze.
The velocity of the slow drifts during fixation at 30 degrees
to the left and to the right was approximately equal.
During smooth pursuit of sinusoidally oscillating target
spots (20 degrees, 0.1 to 1 Hz), the patient demonstrated
deficient gain, compensated for by catch-up saccades (fig-

ure 3A). Her deficiency in smooth pursuit gain was more

obvious on leftward pursuit. There were large rightward
nystagmic drifts that could be overcome only by making
numerous catch-up saccades to the left. Rightward pursuit
showed a higher gain with fewer catch-up saccades. However, it was also deficient compared with normal subjects.
Perhaps to compensate for deficient smooth pursuit, the
patient often switched ocular fixation while binocularly
tracking a target moving in a predictable sinusoidal trajectory. As the target moved to the left, the angle of right
esotropia increased, prompting the patient to switch fixation to her right eye (figure 3B). When the target moved
back to the right, the patient switched back to her left eye.
To investigate the possibility of myasthenia gravis, 10
mg of edrophonium chloride was injected IV during sinusoidal smooth pursuit 20 degrees to the left and right. No
change was seen in the magnitude of the right esodeviation or pursuit velocity (data not shown).

Figure 1. T1-weighted MRIs showing mild atrophy of the

cerebellar vermis. (A) Normal right cerebellar hemispheres, 2.1 cm from the sagittal plane. (B) Through the
midline, subtle vermal atrophy is revealed by the relative
prominence of the cortical folia. Scale bar 2 cm.

Discussion. The only previous study to include eye

movement recordings of a patient with SPS concluded that oculomotor deficits occur from coexisting
ocular myasthenia.3 The risk of developing a second
autoimmune disease, such as myasthenia gravis, apparently is elevated in patients with SPS. However,
our patient showed no clinical evidence of myasthenia gravis over 12 years. She had no detectable level
of antiacetylcholine receptor antibodies, no thymoma, no ptosis, and a negative edrophonium test.
Therefore, we conclude that her right esodeviation,
deficient pursuit, impaired saccadic initiation, and
nystagmus represent primary manifestations of SPS.
In normal subjects, the folia of the vermis often
appear more prominent than those of the cerebellar
hemispheres. Nonetheless, their prominence in our
patient was excessive. The Purkinje cells of the vermis encode gaze velocity during smooth pursuit.2
Their depletion, documented by neuropathological
studies,4 may explain our radiologic finding of vermal atrophy and could contribute to eye movement
abnormalities in SPS.
The gaze-evoked nystagmus that we documented

Figure 2. (A) Increasing esodeviation on

left gaze. The fixating left eyes position
is graphed on the abscissa; the ordinate
shows the amplitude of the right esotropia, determined by subtracting right eye
position from left eye position for data
sampled at 60 Hz during episodes of
attempted stable fixation (rather than
during purposeful dynamic eye movements). The exponential fit line for the
data shows an increasing eso-deviation
for leftward, but not rightward gaze.
(B) Horizontal eye position recordings
for the left eye during attempted fixation show gaze-holding nystagmus. The
three sample traces show fixation of a spot directly in front of the patient and 30 degrees to either side. Upward deflections of the eye position trace represent rightward horizontal movements of the eye. In primary position there was a slight
rightward drift (0.3 0.7 degree/second); left eccentric fixation resulted in a mean drift velocity back to the right of 6.1
1.0 degree/second, right eccentric fixation produced a mean drift velocity to the left of 8.4 1.3 degree/second.
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Figure 3. (A) Horizontal sinusoidal smooth pursuit shows deficient gain, especially on leftward pursuit. The bottom panel
shows the position of the left eye (blue trace) superimposed over the target position. The top panel shows horizontal eye
velocity (green trace) and target velocity (black trace); the purple trace is a fit line plotted through the nonsaccadic portions of the eye velocity trace and represents the smooth pursuit velocity of the eye during tracking. The eye velocity trace
is artificially clipped at 50 degrees. Note the lower peak eye velocity on leftward tracking, resulting in more catch-up
saccades. (B) Binocular horizontal eye movement recordings during smooth pursuit. The patient initially pursued the target with her favored left eye, but at eccentric leftward gaze she began to pursue with the right eye (highlighted in gray).
Near central fixation, she resumed tracking with her left eye.

may be due to an inappropriate eye position signal

originating from the brainstem. The nucleus prepositus hypoglossi (NPH) and the medial vestibular nucleus (MVN) form the horizontal neural integrator,
responsible for maintaining the eyes at eccentric orbital positions. Injections of GABAA antagonists into
the NPH and the MVN disrupt normal gaze-holding
at different eccentricities.5,6
Axons forming the cortico-ponto-cerebellar pathway subserving smooth pursuit make synapses in
the dorsolateral pontine nucleus (DLPN). The pons
signals the vestibulo-cerebellum via mossy fibers. Inactivation of the DLPN with muscimol, a GABAA
antagonist, results in ipsilateral deficits in pursuit
gain.7 The climbing fiber input to the flocculus originates from the dorsal cap of the inferior olive. It is
driven by input from the nucleus of the optic tract
(NOT). The NOT, which is thought to underlie the
slow build up of eye velocity in optokinetic nystagmus, has also been shown to mediate gaze holding
and smooth pursuit. Pharmacological manipulations
of the GABAergic neurons in the NOT leads to both
nystagmus and ipsilateral smooth pursuit asymmetry.8 In addition, other areas (including the deep cerebellar nuclei and the superior colliculus) have
GABA-mediated effects on gaze.9,10
We propose that the oculomotor deficits exhibited
by our patient were caused by dysfunction of
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November (1 of 2) 2005

GABAergic pathways. This report expands the spectrum of clinical findings in SPS to include horizontal
gaze limitation, ocular misalignment, nystagmus,
impaired smooth pursuit, and poor saccade
initiation.

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