Eye Movements in Chorea-Acanthocytosis

Abstract

purpose. To describe the eye movement abnormalities in patients with chorea-acanthocytosis (ChAc), a form of neuroacanthocytosis. This autosomal recessive, neurodegenerative disorder with aberrant erythrocyte morphology (acanthocytosis) is caused by mutations in the VPS13A gene. In contrast to Huntington’s disease (for which ChAc has occasionally been mistaken), ocular involvement in ChAc has not been systematically studied.

methods. Three patients aged 26, 30, and 44 years with ChAc and six normal volunteers aged 31 to 48 years were included. Patients had dystonia, chorea, parkinsonism, dysarthria, dysphagia, seizures, cognitive abnormalities, and acanthocytosis. All had heterozygous VPS13A mutations and degeneration of the basal ganglia on magnetic resonance imaging (MRI) typical of ChAc. Patients had an extensive clinical and laboratory work-up. Neuro-ophthalmic examinations and eye movement recordings made with the magnetic search coil technique assessed patients’ fixation characteristics, horizontal and vertical saccades, pursuit, and antisaccades. These were compared to the data of control subjects.

results. Patients exhibited more than 30 square-wave jerks (small saccadic intrusions) per minute, versus 0 to 8 in the control subjects, as well as fractionated (multistep) and hypometric horizontal and vertical saccades. Decreased saccadic peak-velocity and reduced saccadic range were more pronounced for vertical saccades. Pursuit testing performed in two patients showed low gain. Results of antisaccade testing done in one patient were abnormal.

conclusions. The findings suggest brain stem involvement as an additional site of neurodegeneration outside the basal ganglia in ChAc. Patients with this progressive, intractable disease have pronounced ocular motor abnormalities. Eye movement recordings could assist in diagnosing ChAc, monitoring its progression and possible treatment evaluation.

Chorea-acanthocytosis (ChAc, Online Mendelian Inheritance in Man [OMIM] 200150; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD) is an autosomal recessive neurodegenerative disorder that belongs to the group of neuroacanthocytosis (NA) syndromes. ¹ These diseases combine neurologic abnormalities with an unusual spiky appearance (acanthocytosis) of the red blood cells. Other disorders in this group include aβ-lipoproteinemia (OMIM 200100), hypo-β-lipoproteinemia (OMIM 107730), and McLeod syndrome (OMIM 314850). ¹ Unlike those diseases, the level of serum β-lipoprotein in ChAc is normal, as is the expression of the red blood cell antigen Kell, which is reduced in McLeod syndrome. ¹ Mutations in the chorein gene (vacuolar protein sorting 13A [VPS13A], on chromosome 9q, region 21) are responsible for ChAc. ^{2 3} ChAc is an uncommon disease that has been reported under different names (Levine-Critchley syndrome, familial neuroacanthocytosis, or just neuroacanthocytosis). ^{4 5 6 7 8 9} Its prevalence is unknown, and only approximately 300 cases have become known so far worldwide. The disease presents at 25 to 45 years of age with choreatic movements similar to Huntington’s disease and has a progressive course. ^{1 4 8} Orofacial dyskinesia causes dysarthria, dysphagia, motor and vocal tics, and lip and tongue biting. Cognitive and behavioral changes, seizures, parkinsonism, peripheral neuropathy, and myopathy are common. Neuroimaging and autopsy studies reveal degeneration of the basal ganglia, including the caudate nuclei, putamen, and globus pallidus ^{1 5 8 9 10} ; but, unlike Huntington’s disease, the cerebral cortex is usually spared. ⁸ Laboratory testing typically reveals acanthocytosis in 5% to 50% of the red blood cells and increased serum concentrations of muscle enzymes. 

Although eye movement abnormalities have been noted in a few patients with NA syndromes, ^{8 9 11} ocular involvement in these diseases has not been systematically studied. To characterize the ocular motor abnormalities in ChAc, we examined and recorded eye movements of three patients with this rare disease and compared them to the data obtained from six normal volunteers. The pattern of eye movement abnormalities found in ChAc may assist in diagnosing this disease and indicates that its neuropathology may not be limited to the nigrostriatal system. 

Methods

Subjects

Three patients with ChAc, ages 26, 30, and 44 years, participated in the study. To compare their eye movements with the normal range, six volunteers aged 31 to 48 years, without neurologic or ocular symptoms, were also included. The research adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the National Institute of Neurologic Disorders and Stroke. Informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. 

To confirm the diagnosis, patients had a neurologic examination, brain MRI, and extensive laboratory work-up, including serum muscle enzymes levels, blood smear for detection of acanthocytosis, Kell antigen levels, and genetic testing. All patients and control subjects had a complete eye examination, including a slit lamp examination and indirect ophthalmoscopy. A neuro-ophthalmic examination included testing of visual acuity, pupillary reaction, confrontation visual fields, ocular alignment, ductions to vestibulo-ocular reflex (VOR), and versions and convergence, as well as an evaluation of fixation behavior, saccades, and pursuit. Whenever patient cooperation permitted, color vision was assessed by an Ishihara test (Kanehara Shuppan Co., Ltd., Tokyo, Japan) and visual fields by a visual field analyzer (Carl Zeiss Meditec, Dublin, CA). 

All control subjects had normal findings in an eye examination, including corrected visual acuity. Patients’ clinical characteristics are presented individually. 

Patient 1.

This 26-year-old man had begun to exhibit nervousness at age 15 and epilepsy at age 20. Increasingly, he showed chorea and vocal tics, later to be followed by dysphagia due to feeding dystonia, dysarthria, and hypophonia. His parents were distant cousins. The patient was treated with valproic acid, 750 mg/d. He had no oscillopsia or any ocular symptoms. On examination, tics, stereotypic movements, hypophonic speech, chorea including violent trunk spasms, and reduced deep tendon reflexes were noted. Visual acuity was normal as were the anterior and posterior segments of both eyes. A neuro-ophthalmic examination revealed frequent square-wave jerks (SWJs) and broken pursuit. Ductions appeared normal to horizontal and vertical VOR. Laboratory testing revealed acanthocytosis, normal lipoproteins, absence of McLeod phenotype, and elevated muscle enzymes. A brain magnetic resonance image (MRI) was significant for dilatation of the third and lateral ventricles (primarily frontal horns); atrophy of the caudate nucleus, putamen, and globus pallidus; and minimal prominence of cortical sulci (Fig. 1A) . Molecular analysis revealed mutations in VPS13A gene (Dobson-Stone C, et al., manuscript in preparation). 

Patient 2.

This 30-year-old woman had general clumsiness and uneven handwriting that developed at age 23, followed by throat clicking and teeth grinding a year later. Dysphagia and feeding dystonia were first noted at the age of 25, along with dysarthria, memory lapses and vocal tics. Tongue biting, involuntary stereotypic movements, seizures, cognitive decline, and gait difficulties developed subsequently. The patient reported no oscillopsia or other ocular symptoms. At the time of testing, she was taking no standard antiepileptic medication, except diazepam, 5 mg/d. On examination, she showed dysarthria, chorea, hyporeflexia, and ataxia. A neuro-ophthalmic evaluation revealed frequent SWJs and slightly slow horizontal and moderately slow vertical saccades. The rest of the examination including ductions to VOR and automated visual fields, and color vision was normal. Laboratory testing was significant for acanthocytosis, reticulocytosis, elevated muscle enzymes, normal lipoproteins, and absence of the McLeod phenotype. Brain MRI showed atrophy of the basal ganglia (Fig. 1B) . Genetic analysis revealed mutations in exons 14 and 56, respectively, of the two alleles of the VPS13A gene (1208_1211del and 7867C→T; case 23 of Dobson-Stone et al. ³ ). 

Patient 3.

This 44-year-old man was first noted to exhibit echolalia, lip-smacking, and teeth grinding, as well as clicking and grunting noises at the age of 27 years. He soon exhibited micrographia, deterioration of gait, and choreatic movements. Huntington’s disease was the initial diagnosis, but after detection of acanthocytes in the blood smear, the diagnosis was revised. In the years after diagnosis, the chorea gradually subsided, and at the age of 34, he began to have hypophonia, seizures, and parkinsonism. At the time of testing, the patient was treated with carbamazepine, 800 mg/d; phenytoin, 300 mg/d; oxcarbazepine, 600 mg/d; and levetiracetam 2000 mg/d. On examination, spoken language interaction was impossible, due to almost complete aphonia. The patient had hypomimia and a dystonic grin, impaired tongue movements, reduced gag and muscle tendon reflexes, unsteady gait, bradykinesia, and muscle atrophy. A neuro-ophthalmic examination revealed some slowing of the saccades, especially vertical, and broken pursuit. The extent of ductions to VOR appeared normal. Acanthocytosis, normal levels of β-lipoprotein and Kell antigen, and elevated muscle enzymes were detected. Brain MRI showed severe atrophy of the caudate nucleus and putamen (Fig 1C) . Mutations were found in exons 48 and 70, respectively, of the two alleles of the VPS13A gene (6419C→G and 9190del; case 24 of Dobson-Stone et al. ³ ). 

Eye Movement Recordings

All patients and control subjects had eye movement recordings made with the magnetic search coil technique. ¹² Subjects viewed a red-diode laser spot target, rear projected onto a tangent screen at 1 m while the horizontal and vertical positions of the right eye were recorded. The head was stabilized by a chin rest and a forehead restraint. All subjects could clearly see the bright laser target without their optical correction; therefore, no correction was used during the recordings. A computer controlled the position of the target on a dimly illuminated screen. The search coil was precalibrated on a protractor. In the beginning of the recording session, equipment calibration was done by aligning horizontal and vertical eye position to the target over the central 20°. Eye position signals were sampled at 1 kHz, digitized at 12 bits, and stored on computer for later analysis. The testing paradigm included fixation, horizontal, and vertical saccades, smooth pursuit, and antisaccades, always presented in that order. (Because of his severe neurologic impairment and dystonic movements, the testing of patient 3 was discontinued before completion of the pursuit task.) For recording fixation, the subjects looked at a stationary target projected straight ahead for at least 1 minute. For testing horizontal saccades, at least two blocks of 45 target jumps each were presented. The same paradigm was used for the vertical saccades. The target amplitudes ranged from 2.5° to 30° for horizontal saccades and from 2.5° to 20° for vertical. Horizontal and vertical smooth pursuit was recorded at three target velocities: 5, 10, and 20 deg/min, three cycles of each, presented in that order. The target waveform was a triangular wave. The amplitude of the pursuit target at each velocity was 30° (from 15° to the right to 15° to the left of center). The antisaccade testing consisted of 100 trials lasting 3.5 seconds each. During the first 1.5 seconds of each trial, a central fixation light was presented. This was followed by a saccadic target, amplitude 10°, randomly presented to the right or to the left of the fixation spot. During the recordings, the subjects were instructed to follow the red light, except for the testing of antisaccades, when they were requested to gaze in the direction opposite to the presented target. Only patient 1 was able to comprehend the task of the antisaccade testing. 

The eye movement data were analyzed with regard to fixation stability and saccadic peak velocity, duration, and latency. The main sequence of horizontal and vertical saccades of each patient was compared with the averaged main sequence of the six control subjects. The range of horizontal and vertical saccades (the mean amplitude and standard deviation of the first saccade made by the subject in response to a given target jump), and the mean gain for each saccade size (the ratio between the amplitude of subject’s first saccade and the target amplitude) were determined for each patient and the control group. An average smooth pursuit gain was calculated for each target velocity by dividing the slope of the subject’s eye movement by the slope of the target. A percentage of correct responses during the antisaccade testing was recorded. Two-tailed Student’s t-tests were used to check the differences in saccadic amplitude, latency, and velocity between the patients and control subjects under all test conditions. 

Results

Patient 1

Eye movement recordings demonstrated fixation instability, with 40 to 65 SWJs per minute (Fig. 2)compared with 0 to 8 per minute in the control group. Horizontal and vertical saccades were hypometric and fractionated (Fig. 3) , such that most large saccades were performed in two to three steps of smaller saccades. Table 1shows gain and range (mean amplitude ± SD) of the saccades made by each patient and the control group, in response to a given target jump. For patient 1, saccadic range and gain were reduced at each target size (Figs. 4A 4B) . The amplitude of this patient’s saccades was found to be significantly lower than that of the control group at all target amplitudes except 2.5° to the left (Table 1) . The gain tended to decrease as target amplitude increased and was slightly more reduced for vertical than horizontal saccades (Table 1) . For horizontal saccades, the gain was between 0.80 and 0.86 (versus 0.96–0.99 in the control group) with a 2.5° target jump and 0.46 and 0.62 (versus 0.86 in the control group) with a 20° target jump; for vertical saccades, it ranged between 0.62–0.63 (versus 0.98 in the control group) with a 2.5° target jump and 0.39 (versus 0.76–0.85) with a 20° target jump. Mean saccadic latency was slightly shorter than in the control group for horizontal saccades, but slightly longer than in the control group for vertical saccades (Table 2) . Figures 4C and 4Dshow the main sequence of horizontal and vertical saccades of each patient and the control group. For patient 1, the peak velocity was slightly reduced for horizontal and more so for vertical saccades. Table 3shows the mean peak velocity and standard deviation of the saccades made by each patient, as well as the ratio between the patient’s mean velocity and that of the control group. It can be seen that with each size of saccade, the velocity of patient 1 was significantly slower than that of the control subjects. This slowing was more pronounced with the larger-amplitude vertical saccades. For vertical saccades of approximately 7.5°, the velocity was only 0.55 to 0.68 of the mean velocity of the control group. 

Smooth pursuit testing revealed a broken pursuit with reduced gain in the horizontal and, in particular, the vertical plane. For instance, at target velocity of 10 deg/sec, the gain of patient 1 was 0.85 horizontally and 0.58 vertically (Table 4) . Antisaccade test results were abnormal: Instead of looking in the direction opposite to the target, the patient made saccades toward the target in 61% of the trials, as opposed to 3% to 9% in the control group. 

Patient 2

During fixation, a rate of 40 to 60 SWJs per minute was recorded (Fig. 2) . Horizontal and vertical saccades were hypometric and fractionated (multi-step) (Fig. 3) . Saccadic gain and range were reduced for both horizontal and vertical saccades (Figs. 4A 4B) . A statistically significant difference was found between the mean amplitude of the patient’s saccades and that of the control group at each target amplitude (Table 1) . For horizontal saccades, the gain decreased as target amplitude increased and was between 0.57 and 0.70 with a 2.5° target jump and 0.47 with a 20° target jump. A more marked reduction in saccadic gain was found for the vertical saccades, in which the gain ranged from 0.31 to 0.48 at all target amplitudes (Table 1) . Saccadic latency did not differ significantly from that in the control group for both horizontal and vertical saccades (Table 2) . The saccadic peak velocity was significantly reduced for horizontal and vertical saccades of all sizes (Figs. 4C 4D) . The ratio between mean velocity of the patient and that of the control group was 0.60 to 0.81 for horizontal saccades and 0.47 and 0.74 for vertical saccades (Table 3) . 

Smooth pursuit was broken and had a reduced gain, especially in the vertical plane (Fig. 5) . At a target velocity of 10 deg/sec, the gain was 0.77 for horizontal and 0.37 for vertical pursuit (Table 4) . 

Patient 3

Eye movement recordings revealed frequent SWJs (∼35–60 per minute), which at times occurred continuously as square-wave oscillations (Fig. 2) . Horizontal and vertical saccades were somewhat fractionated, with multiple-velocity peaks (Fig. 3) , and the vertical saccades were slightly hypometric (Figs. 4A 4B) . The mean amplitude of horizontal saccades was slightly reduced with the 2.5° to 10° targets to the right and was within normal limits in the other trials (Table 1) . A statistically significant reduction in saccadic amplitude was found for all vertical saccades made in response to a target jump larger than 2.5°, except for 20° (which did not reach the significance level because of the small number of trials). The gain of horizontal saccades was similar to that in the control subjects and measured between 0.84 and 0.97. The gain of vertical saccades was reduced, ranging from 0.85–0.93 for a 2.5° target jump to 0.49–0.71 for a 20° target jump (Table 1) . Saccadic latency was slightly shorter than that in the control group for horizontal saccades and similar to the control group for vertical saccades (Table 2) . The peak-velocity was normal for all horizontal saccades, except for 7.5° to the left and 5° to the right, where the saccadic velocity was minimally reduced (Table 3 , Fig 4C ). A slight, but statistically significant, reduction in peak velocity was measured for all vertical saccades, except 7.5° to the right, with the ratio of patient’s velocity to that of the control group being between 0.75 and 0.89 (Table 3 ; Fig 4D ). 

Due to the severe neurologic impairment and dystonic movements, the testing was discontinued before completion of the pursuit task. Only horizontal pursuit at a target velocity of 5 deg/sec was recorded and showed a normal gain of 0.98 (Table 4) . 

Discussion

We documented several ocular motor deficits in patients with ChAc that involved fixation stability, saccades, and pursuit. Although previous reports mention impaired eye movements in patients with NA syndromes, they are based only on clinical evaluations. ^{8 9 11} The present study characterized these patients’ ocular motor function using eye movement recordings. 

Hardie et al. ⁸ reported ocular motility abnormalities in 5 of the 19 patients with NA whom they described. These abnormalities varied among patients and included impaired saccades and pursuit, limited upgaze, poor convergence, blepharospasm, and gaze apraxia. Eye movements were considered normal in two patients and were not reported for the other 12 patients. Supranuclear vertical gaze palsy, blepharospasm, and apraxia of eyelid opening were described in one patient by Spitz et al. ⁹ and in another by Bonaventura et al. ¹¹ Because previous studies did not employ eye movement recordings, the studies may have underestimated the frequency of eye movement abnormalities in ChAc. Mild saccadic limitation and slowing could be difficult to detect in a clinical examination. Although our study included only three patients, their common impairment patterns suggests that ocular motor abnormalities may be part of the ChAc syndrome. Eye movement recordings in additional patients with this infrequently occurring disease are needed to validate the findings. 

Fixation instability, as evidenced by 35 or more SWJs per minute or continuous square-wave oscillations, ^{13 14} was found in all our patients. These frequent saccadic intrusions, also detected during clinical examination of patients 1 and 2, have not been previously reported in ChAc. SWJs and oscillations are a prominent clinical finding in disorders affecting the cerebellum, brain stem, and cerebral hemispheres. ^{13 15} They have also been reported in some patients with disorders of the basal ganglia, in particular, Huntington’s disease and Parkinson’s disease. ^{16 17 18} An increase in the frequency of SWJs was observed after pallidotomy in Parkinson’s disease. ¹⁹ SWJs presumably result from a lapse of the inhibitory control over saccadic burst neurons in the brain stem. ²⁰ Along with the inhibitory control of the superior colliculus by the frontal eye fields, the basal ganglia are believed to contribute an indirect inhibition of the nonpurposive saccades. ²¹ Saccade-related cells within the superior colliculus are under tonic inhibition by substantia nigra pars reticulata, an output pathway of the basal ganglia. ^{22 23} Severe atrophy of the basal ganglia in NA could have interfered with the ability to suppress inappropriate saccadic intrusions in our patients. 

All our patients had broken, low-gain pursuit, as did two patients of Hardie et al. ⁸ These findings are similar to other nigral and striatal degenerations, such as Huntington’s disease and Parkinson’s disease, ¹³ and could be accounted for by the pattern of neuropathologic involvement known from autopsy cases of NA. ^{5 8}  

Only one of our patients was able to perform the antisaccade task. His inability to suppress reflexive saccades toward the target and consequent increased errors in the task are probably related to the frontal lobe problems reported in patients with ChAc. ^{1 4 24} Indeed, this patient had a mild frontal lobe atrophy on MRI. In addition, personality and cognitive changes in our patients are consistent with frontal lobe dysfunction. ²⁵ This “visual grasp” reflex has also been described in other disorders affecting the basal ganglia and in Alzheimer’s disease. ^{13 24 26} The saccadic initiation problems typically found in Huntington’s disease ²⁶ were not seen in our patients, neither were the blepharospasm and eyelid apraxia that has been reported in ChAc. ^{8 9 11} We found no consistent changes in saccadic latency, which is in contrast to the prolonged latency seen in Huntington’s disease. ²⁶  

A slowing of the saccades in our patients was more noticeable in the vertical than in the horizontal plane. Reduction of saccadic velocity is also observed in Huntington’s disease, but is atypical in parkinsonian syndromes. ¹³ Reduced range and gain, especially in a vertical plane, was a prominent saccadic abnormality in our patients. This finding is similar to findings in patients with advanced Huntington’s disease and in some individuals with parkinsonian syndromes, who may have more hypometric saccades in the vertical than in the horizontal plane. ^{26 27} Neuroimaging in ChAc shows atrophy or increased signal of the caudate nucleus and putamen. ^{8 9 10 28} Postmortem studies reveal degeneration of the striatum, globus pallidus, and substantia nigra. The thalamus may be also mildly affected, but the subthalamic nucleus, cerebral cortex, pons, medulla, and cerebellum have been reported to be spared. ^{5 8} Although saccadic slowing may occur with abnormalities in higher-level circuits that trigger the brain stem to generate saccades, ²⁹ impaired vertical saccades, suggesting vertical supranuclear palsy, may indicate midbrain involvement as an additional site of neurodegeneration outside the basal ganglia in ChAc. ^{13 30} Further neuropathologic studies are needed to reveal the underlying pathologic features. 

No correlation between the severity of basal ganglia involvement and ocular motor abnormalities was found in our study. Patient 3, who had the most pronounced atrophy of the basal ganglia on MRI, exhibited the least impaired saccades. This finding supports the notion that the neuropathologic basis for ocular abnormalities in ChAc may be distinct from the basal ganglia. Of note, in patient 3, the clinical presentation had gradually evolved from chorea into parkinsonism, which is typically associated with less severe saccadic abnormalities than are other neurodegenerative disorders. ¹³  

Although our patients were treated with neuroleptic medications, which could affect saccadic velocity and smooth pursuit, ^{13 31 32 33} several factors indicate that medications were not the dominant cause of their eye movement abnormalities. First, patient 3 who was treated with four antiseizure medications had less impaired saccades than the other patients, each of whom received a single medication. Also, patient 1 was treated only with valproic acid, which has been reported not to impair eye movements. ³¹ Moreover, to the best of our knowledge, these medications have not been shown to cause the other eye movement abnormalities found in our patients, which included fractionated saccades, reduced saccadic range and gain, more severe impairment of vertical than horizontal eye movements, fixation instability, and increased errors in antisaccades. De Kort et al. ³¹ found no association between antiepileptic drugs and hypometric saccades. Finally, the common pattern of eye movement impairment in our patients, despite the different medications, indicates that it was probably caused by the disease itself. 

In summary, we used eye movement recordings to document ocular motor abnormalities in ChAc, a syndrome that belongs to the NA family of diseases. These abnormalities imply that the neuropathology in ChAc is not limited to striatonigral system and prompt further studies elucidating its pathophysiology. Because the acanthocytosis may not be detected until late disease stages, ¹⁰ the diagnosis of NA is often delayed, as in patient 3, and, in some patients, may not be diagnosed at all. Assessment of eye movements may provide a marker for early diagnosis. Furthermore, because there are no current treatments for NA, quantitative eye movement recordings may help in natural history studies in which the pattern and severity of deficit are examined across time and eventually in the evaluation of future treatment modalities. 

 Submitted for publication May 14, 2004; revised January 28, 2005; accepted February 10, 2005.

 Disclosure: L. Gradstein, None; A. Danek, None; J. Grafman, None; E.J. FitzGibbon, None

 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

 

Figure 1.

 

Brain MRI scans of the three patients. These coronal, T2-weighted images taken at 1.5 T show cuts through the frontal horns of the lateral ventricles, the basal ganglia at the level of the septal region and at the level of the interthalamic adhesion. Arrows: caudate nucleus; stars: putamen; and diamonds: globus pallidus. (A) Patient 1. Atrophic caudate nucleus and putamen can be seen. Severely atrophic globus pallidus is unidentifiable. (B) Patient 2. Atrophy of all the basal ganglia. (C) Patient 3. Pronounced atrophy of the basal ganglia, in particular the caudate nucleus and putamen.

Figure 2.

 

Horizontal eye position traces of the three patients during fixation on a stationary target presented straight ahead. Upward deflection indicates movement to the right and downward, movement to the left. Each patient exhibited multiple square-wave jerks (SWJ; range, 35–65 per minute), which took the eye off fixation and then brought it back on. Occasionally, SWJs occurred continuously as square-wave oscillations.

Figure 3.

 

Examples of horizontal and vertical saccades of each patient. Traces (from bottom to top) correspond to horizontal eye position and velocity for horizontal saccades and vertical position and velocity for vertical saccades. Dotted line: target; solid line: patient. Patient 1: fractionated (multistep) horizontal and vertical saccades were best seen by multiple velocity peaks, especially apparent for larger amplitude saccades. Patient 2: saccades were both fractionated and hypometric (especially vertical). Patient 3: some fractionation of saccades was noted.

Table 1.

 

Saccade Gains

	20 deg	15 deg	10 deg	7.5 deg	5 deg	2.5 deg
Horizontal
Leftward
Controls	0.86 (17.2 ± 1.7)	0.84 (12.6 ± 1.4)	0.90 (9.0 ± 1.1)	0.89 (6.7 ± 0.6)	0.92 (4.6 ± 0.5)	0.96 (2.4 ± 0.4)
Patient 1	0.62 (12.4 ± 0.6)*	0.71 (10.7 ± 0.9)*	0.71 (7.1 ± 1.1)*	0.66 (5.0 ± 0.9)*	0.73 (3.7 ± 0.7)*	0.80 (2.0 ± 0.6)
Patient 2	0.47 (9.4 ± 1.6)*	0.53 (7.9 ± 0.9)*	0.48 (4.8 ± 1.5)*	0.49 (3.7 ± 0.6)*	0.53 (2.7 ± 0.8)*	0.57 (1.4 ± 0.1)*
Patient 3	0.85 (17.0 ± 0.9)	0.90 (13.5 ± 0.6)	0.85 (8.5 ± 0.4)	0.93 (7.0 ± 0.7)	0.96 (4.8 ± 0.4)	0.97 (2.4 ± 0.3)
Rightward
Controls	0.86 (17.3 ± 2.3)	0.88 (13.2 ± 1.5)	0.94 (9.4 ± 0.8)	0.99 (7.4 ± 0.7)	0.99 (5.0 ± 0.7)	0.99 (2.5 ± 0.4)
Patient 1	0.46 (9.3 ± 0.6)*	0.60 (9.0 ± 0.9)*	0.64 (6.4 ± 0.9)*	0.74 (5.6 ± 1.4)*	0.71 (3.5 ± 0.4)*	0.86 (2.2 ± 0.6)*
Patient 2	0.47 (9.4 ± 3.4)*	0.43 (6.4 ± 0.8)*	0.51 (5.1 ± 1.1)*	0.50 (3.7 ± 1.3)*	0.47 (2.3 ± 0.4)*	0.70 (1.8 ± 0.6)*
Patient 3	0.85 (17.1 ± 1.3)	0.85 (12.7 ± 0.6)	0.84 (8.4 ± 0.9)*	0.84 (5.9 ± 0.3)*	0.84 (4.2 ± 0.4)*	0.87 (2.2 ± 0.2)*
Vertical
Downward
Controls	0.85 (17.0 ± 3.4)	0.95 (14.2 ± 1.4)	0.96 (9.6 ± 1.0)	0.96 (7.2 ± 1.3)	0.98 (4.9 ± 1.5)	0.98 (2.5 ± 0.4)
Patient 1	—	0.65 (9.8 ± 1.7)*	0.58 (5.8 ± 2.0)*	0.58 (4.4 ± 1.1)*	0.61 (3.1 ± 1.1)*	0.63 (1.6 ± 0.2)*
Patient 2	0.48 (9.5 ± 0.13)*	0.38 (5.8 ± 1.3)*	0.33 (3.3 ± 1.5)*	0.43 (3.2 ± 1.0)*	0.48 (2.4 ± 1.3)*	—
Patient 3	0.71 (14.3 ± 0.7)	0.58 (8.6 ± 3.3)*	0.74 (7.4 ± 1.8)*	0.84 (6.3 ± 0.9)*	0.80 (4.0 ± 1.3)*	0.93 (2.3 ± 0.4)
Upward
Controls	0.76 (15.1 ± 3.0)	0.87 (13 ± 1.1)	0.87 (8.7 ± 1.3)	0.92 (6.9 ± 1.0)	0.90 (4.5 ± 0.9)	0.98 (2.4 ± 0.4)
Patient 1	0.39 (7.7 ± 2.2)*	0.54 (8.1 ± 3.5)*	0.56 (5.6 ± 1.7)*	0.61 (4.6 ± 1.4)*	0.59 (3.0 ± 0.8)*	0.62 (1.6 ± 0.2)*
Patient 2	0.31 (6.1 ± 0.3)*	0.35 (5.2 ± 1.3)*	0.35 (3.5 ± 1.5)*	0.31 (2.3 ± 0.6)*	0.32 (1.6 ± 0.3)*	—
Patient 3	0.49 (9.7 ± 3.0)	0.50 (7.6 ± 2.5)*	0.68 (6.8 ± 1.4)*	0.62 (4.6 ± 1.2)*	0.72 (3.6 ± 0.6)*	0.85 (2.1 ± 0.4)

 Data show saccade gain. In parentheses is the mean amplitude and standard deviation (in degrees) of the first saccades made in response to a target size indicated at the top of each column. Only target sizes of 20° or less were included, since there were too few large amplitude trials. Controls denote mean saccade gain of all subjects in the control group. —, not enough data for analysis.

*  Statistically significant difference from the control group (2 tail t test, P < 0.05).

Figure 4.

 

Range of horizontal (A) and vertical (B) saccades. The amplitude of the first saccade made after the target jump is plotted versus the target amplitude. Black symbols: mean amplitude of each patient’s saccades performed in response to a given target jump; gray symbols: mean amplitude of the control subjects. Vertical bars, SD. Negative numbers indicate leftward or downward saccades and positive, rightward or upward. For the control subjects, the saccade amplitude approximately equaled the target amplitude, whereas patients 1 and 2 were unable to execute larger-amplitude saccades. Their saccades had reduced gain and fell below the range of those in the control group. For patient 3, saccadic range was normal for horizontal (A) and slightly reduced for vertical (B) saccades. Main sequence for the horizontal (C) and vertical (D) saccades. Saccade peak velocity is plotted against saccade amplitude. Black symbols: patients’ saccades; gray symbols: average peak velocities of the saccades of the normal volunteers. Vertical bars, SD. Compared with the control subjects, patients 1 and 2 had a somewhat reduced peak velocity and hypometry, especially of the larger-amplitude vertical saccades (D). For patient 3, peak-velocity was normal for horizontal (C) and minimally reduced for vertical (D) saccades.

Table 2.

 

Saccade Latencies

	Horizontal	Vertical
Controls	0.152 ± 0.032	0.160 ± 0.034
Patient 1	0.134 ± 0.078*	0.182 ± 0.087*
Patient 2	0.156 ± 0.065	0.159 ± 0.064
Patient 3	0.137 ± 0.023*	0.162 ± 0.048

 The data (in seconds) are expressed as the mean ± SD of the latency of all saccades made by each patient and the control group in the horizontal and vertical plane.

*  Statistically significant difference from the control group.

Table 3.

 

Saccade Velocities

	7.5 deg	5 deg	2.5 deg	2.5 deg	5 deg	7.5 deg
	Horizontal
	Leftward					Rightward
Controls	(320 ± 18)	(264 ± 25)	(199 ± 28)	(176 ± 31)	(261 ± 23)	(313 ± 24)
Patient 1	0.73 (235 ± 19)*	0.75 (197 ± 21)*	0.71 (142 ± 28)*	0.80 (141 ± 22)*	0.72 (189 ± 10)*	0.79 (247 ± 28)*
Patient 2	0.78 (250 ± 25)*	0.69 (182 ± 53)*	0.60 (119 ± 42)*	0.78 (138 ± 43)*	0.74 (192 ± 40)*	0.81 (252 ± 0)*
Patient 3	0.89 (286 ± 24)*	0.92 (243 ± 32)	1.01 (200 ± 30)	1.11 (195 ± 10)	0.90 (235 ± 17)*	0.96 (300 ± 17)
	Vertical
	Downward					Upward
Controls	(280 ± 46)	(225 ± 35)	(157 ± 33)	(174 ± 36)	(248 ± 29)	(314 ± 29)
Patient 1	0.68 (189 ± 10)*	0.68 (154 ± 30)*	0.73 (115 ± 20)*	0.75 (130 ± 24)*	0.66 (163 ± 28)*	0.55 (174 ± 22)*
Patient 2	0.47 (132 ± 69)*	0.60 (134 ± 38)*	0.65 (102 ± 33)*	0.74 (128 ± 23)*	0.72 (179 ± 37)*	—
Patient 3	0.81 (228 ± 77)	0.89 (201 ± 40)*	0.87 (136 ± 27)*	0.75 (131 ± 50)*	0.81 (201 ± 58)*	0.87 (273 ± 29)*

 The numbers in parentheses show mean peak velocity and standard deviation (in degrees per second) for saccades of the amplitude listed at the top of the column ± 1.25°. Only saccades of 7.5° or less were included, since there were too few larger saccades generated for statistical analysis. Data indicate the ratio of each patient’s saccadic velocity to the mean velocity of the control group for the same amplitude saccade. —, not enough data for analysis.

*  Statistically significant difference from the control group.

Table 4.

 

Pursuit Gains

	Horizontal					Vertical
		5 deg/sec	10 deg/sec	20 deg/sec	5 deg/sec	10 deg/sec	20 deg/sec
Controls	1.00	1.00	1.00	1.00	1.00	1.00
Patient 1	0.94	0.85	0.79	0.64	0.58	0.29
Patient 2	0.84	0.77	0.65	0.48	0.37	0.23
Patient 3	0.98	—	—	—	—	—

 —, not enough data for analysis.

Figure 5.

 

Horizontal (bottom) and vertical (top) eye position traces of patient 2 tracking, respectively, a horizontal and vertical pursuit targets moving at a velocity 10 deg/min. Dotted line: target; solid line: patient. Note a broken, low-gain pursuit, especially in the vertical plane. Pursuit gain is 0.77 horizontally and 0.37 vertically.