Journal of Neuro-Ophthalmology, June 1996, Volume 16, Issue 2

Ocular Motility in North Carolina Austosomal Dominant Ataxia

The term "vestibulocerebellar ataxia" has been applied to a rare, autosomal dominant, late-onset disease with unusual ocular motility findings. We examined the ocular motility of 18 family members from two different kindreds and found 11 affected individuals. Both families in the present study, one of which was originally described by Farmer and Mustian, as well as the family reported by Farris et al., originated from Johnston County, North Carolina. We suspect that all three of these families have a common ancestral origin. The age of onset of the disorder was 31-60 years in the individuals examined. Ataxia, vertigo, diplopia, oscillopsia, and tinnitus were common complaints. Although a variety of eye movement abnormalities have previously been described in this disease, the most prominent and consistent findings in our patients were (a) abnormal smooth pursuits, (b) inability to suppress the vestibuloocular reflex (VOR), and (c) gaze-evoked nystagmus. These findings suggest that the cerebellar flocculus may be the primary site of pathology.

Journal of Neuro- Ophthalmology 16( 2): 91- 95, 1996. © 1996 Lippincott- Raven Publishers, Philadelphia Ocular Motility in North Carolina Autosomal Dominant Ataxia Kent W. Small, M. D., Stephen C. Pollock, M. D., Jeffrey M. Vance, Ph. D., M. D., Jeff M. Stajich, and Margaret Pericak- Vance, Ph. D. The term " vestibulocerebellar ataxia" has been applied to a rare, autosomal dominant, late- onset disease with unusual ocular motility findings. We examined the ocu­lar motility of 18 family members from two different kin­dreds and found 11 affected individuals. Both families in the present study, one of which was originally described by Farmer and Mustian, as well as the family reported by Farris et al., originated from Johnston County, North Carolina. We suspect that all three of these families have a common ancestral origin. The age of onset of the dis­order was 31- 60 years in the individuals examined. Ataxia, vertigo, diplopia, oscillopsia, and tinnitus were common complaints. Although a variety of eye move­ment abnormalities have previously been described in this disease, the most prominent and consistent findings in our patients were ( a) abnormal smooth pursuits, ( b) inability to suppress the vestibuloocular reflex ( VOR), and ( c) gaze- evoked nystagmus. These findings suggest that the cerebellar flocculus may be the primary site of pathology. Key Words: Vestibulocerebellar ataxia- Ocular motil­ity- Vestibuloocular reflex- Autosomal dominant in­heritance- Johnston County, North Carolina. Manuscript received January 6, 1995; accepted January 11, 1995. From the Jules Stein Eye Institute ( K. W. S.) UCLA, Los An­geles, California; Department of Ophthalmology ( S. C. P.), Di­vision of Neurology ( J. M. V., J. M. S., M. P.- V.), Duke University Medical Center, Durham, North Carolina, U. S. A. Address correspondence and reprint requests to Dr. Kent W. Small, Department of Ophthalmology, Jules Stein Eye Institute, UCLA, 100 Stein Plaza, Los Angeles, CA 90024- 7007, U. S. A. " Periodic attacks" of vertigo, diplopia, and ataxia were described in a family from rural North Carolina by Farmer and Mustian in 1963 ( 1). These " attacks" were associated with a sudden change in head position and had onset at age 23- 42 years. Many of the affected family members also com­plained of tinnitus, oscillopsia, nausea, and erne-sis. Ocular motility examination and nystagmogra­phy were described as showing left- beating nystagmus in left gaze, right- beating nystagmus in right gaze, and downbeat nystagmus. In addition, the authors recorded a dissociated horizontal nystagmus in which the nystagmus of the abduct­ing eye was larger in amplitude than that of the adducting eye. Another peculiar finding was a " vertical gain bias" in which the abducting eye would make a small vertical ( often downward) cor­rective saccade following a conjugate movement into lateral gaze. Despite these detailed motility descriptions, a recorded assessment of the pa­tients' smooth pursuit was lacking. From this clin­ical picture, the pathologic site was localized to the brainstem vestibular system. Another family with " periodic attacks" of ver­tigo, diplopia, and ataxia was described more re­cently by Farris and colleagues ( 2). They reported essentially the same phenotype as that of the fam­ily described by Farmer and Mustian except for the additional findings of skew deviation and damp­ened optokinetic responses ( OKN). Although no mention was made of a formal assessment of smooth pursuits, the observed OKN responses strongly suggested an abnormal pursuit system. No attempt was made to localize the primary pathologic region more precisely. We provide evidence that these two families are probably related and have the same disease and crystallize the salient ocular motility features of 91 92 K. W. SMALL ET AL. this disease. From these data, we hypothesize that the cerebellar flocculus is the primary site of pa­thology. METHODS A detailed family history was obtained from ( a) the original family reported by Farmer and Mus-tian, ( b) another previously unreported North Carolina family, and ( c) the family reported by Far-ris and colleagues ( 2). Thirteen of the original fam­ily members described by Farmer and Mustian ( 1) were reascertained and neuroophthalmologic ex­aminations were performed at their homes in North Carolina ( Fig. 1). Specific inquiries in the history included current medications, family his­tory, age of onset of symptoms, and the presence or absence of ataxia, oscillopsia, diplopia, tinnitus, nausea, and the ability to follow and clearly view objects in the grocery store while walking. The ex­amination included measurement of Snellen visual acuity with present spectacles at 14 inches, pupil­lary reaction to light, assessment of smooth pur­suits, saccades, OKN, nystagmus, range of eye movement, and phorias/ tropias in all fields of gaze. Ocular motility abnormalities were recorded with a home video camera. Four affected members of another family ( Fig. 2), phenotypically identical to that described by Farmer and Mustian ( 1), underwent neuro­ophthalmologic evaluations at Duke University. These were similar to the evaluations already de­scribed. In addition, motility abnormalities were recorded with a Tracoustics nystagmograph and a video camera. Three affected subjects were examined for their ability to suppress their vestibulo- ocular reflex ( VOR). This was accomplished by rotating the sub­jects in a chair while the subject attempted fixation of a small target located 2 feet in front of the face but attached to the head so that the target moved in concert with head rotation. This was accom­plished by bending a clothes hanger such that the triangular opening was made rectangular and fit­ted on the subject's head with the hook of the hanger located in front. The hook was then bent around to face the subject. On this hook, a quarter-sized piece of colored paper was placed for the subject to fix upon (" clothes hanger hat of Neil Miller"). Normal subjects, while rotating in a chair and fixing on this target, can suppress the VOR so that they smoothly track the target and no nystag­mus is observed. Additional testing was performed on one se­verely affected individual. He underwent com­puted tomography ( CT), magnetic resonance im­aging ( MRI) of the brain, and an electroencepha­logram ( EEG) all of which were entirely normal. A therapeutic trial of daily acetazolamide ( 500- mg sequels, orally twice daily, p. o. b. i. d.) was ad­ministered to eight affected family members ( 3). Because of the side effects, all but one discontin­ued the medication soon after initiation of therapy. The remaining patient initially reported mild sub­jective improvement in ataxia but no improvement in diplopia. However, after 1 month, he too elected to discontinue the medication. RESULTS The family histories obtained from the kindred reported by Farmer and Mustian ( 1) ( Fig. 1), the previously unreported kindred herein described ( Fig. 2) and the family reported by Farris and col­leagues ( 2) indicate that all three families had their genealogic roots in Johnston County, North Caro-family A " 0 & . if. ,., A i € Ob X x - affected fern ' ( ) unaffected ( fer / deceased fl proband if ¥^ FIG. 1. Pedigree of family A. Original family of Farmer and Mustian ( 1). / Neuro- Ophthalmol, Vol. 16, No. 2, 19% VESTIBULOCEREBELLAR ATAXIA 93 family B a FIG. 2. Pedigree of family B. Family pre­viously unreported. hnioM m^ o- - oo- 6 X X o 61 lina. In each kindred, the most senior individual known to be affected originated from this rural area. Of the 18 individuals examined in the present study, 11 were affected ( Table 1). The age of onset of vestibulo- ocular difficulties ranged from 31 to 60 years. In all cases, the first symptom was episodic ataxia with or without associated horizontal diplo­pia and with or without oscillopsia. Initially, these episodes appeared to be precipitated by or exacer­bated by a sudden change in head position or fa­tigue or by being in an environment in which ob­jects were moving past the observer such as occurs when one is seated in a moving automobile. Most subjects stated that lying supine with their eyes closed for 15- 30 min helped alleviate the symp­toms. With time, the episodes occurred with greater frequency until at some time the symptoms became constant, though variable. Many of these patients are now disabled, and three use devices to aid them in ambulation. Individuals were specifically questioned about whether symptoms of dizziness or vertigo were precipitated by walking down a grocery store aisle or riding in a moving car. Farris and colleagues ( 2) have termed this as the " grocery aisle sign." Eight of the 11 affected subjects had this symptom and, in addition, commented that they could not read the labels of items on the shelves until they stood still. Diplopia was a major complaint in seven of the 11 affected individuals. It was intermittent in four and constant in three. All patients with diplopia indicated that the images were separated horizon­tally and that the magnitude of the image displace­ment was greater at distance than at near. Oscil­lopsia in lateral gaze was reported by seven pa­tients. Ophthalmologic examination disclosed normal vision except in cases of age- related cataracts ( four subjects) and unsuccessful glaucoma surgery in one eye of one patient with a sensory exotropia. The most significant findings were related to ab­normal ocular motility. In all affected individuals, smooth pursuit in the horizontal and vertical planes was cogwheel to varying degrees. Abnor­mal smooth pursuit could also be inferred from the markedly dampened responses to rotation of the OKN drum. Although only three affected patients were tested with the clothes hanger hat of Neil Miller, all three were grossly unable to suppress the VOR and thus manifested horizontal jerk TABLE 1. Summary of affected subjects Pedigree A1 A103 A101 A9014 A9045 A9025 A115 B108 B101 B1 B106 Age 68 80 82 57 48 46 81 48 45 46 37 Onset 38 35 42 50 38 40 60 33 34 31 32 Diplopia Yes Yes Yes No Yes No No Yes Yes Yes Yes Ataxia Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Vertigo Yes Yes Yes No Yes Yes No No Yes Yes No Nausea Yes No No No No No No No Yes No Yes Tinnitus Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Oscilopsia Yes Yes No No Yes Yes No Yes Yes Yes Yes Motion Yes Yes Yes No Yes No No Yes Yes Yes Yes ET 4 2 2 0 2 0 0 3 3 10 10 Pursuits - 2 - 2 - 2 - 1 - 4 - 1 - 1 - 3 - 3 - 3 - 3 Age, age in years at latest examination; onset, age in years when subject noticed difficulties; diplopia, diplopia noticed by subject; ataxia, difficulty with balance, gait, tandem walk, dysmetria; oscilopsia, oscilopsia on lateral gaze; motion, subject complains of difficulty following moving objects and viewing subject is moving ( grocery aisle sign of Farris); ET, esotropia in primary gaze at 20- ft viewing distance; pursuits, dampening of smooth pursuit ( cogwheel: 0 = normal, 4 = no pursuit). / Neuro- Ophthalmol, Vol. 16, No. 2, 1996 94 K. W. SMALL ET AL. nystagmus during this maneuver. A concomitant esophoria or esotropia, greater at distance than at near, was present in eight of the 11 affected sub­jects. Nystagmus in primary gaze was not present in any of the family members. However, on gaze to the left, a left- beating nystagmus developed, whereas on gaze to the right, a right- beating nystagmus was observed. On careful observation, we were unable to discern convincingly a dissoci­ated horizontal nystagmus, nor was there a " ver­tical gain bias" as previously described. In addi­tion, downbeating nystagmus on lateral and down gaze was present in only three of the 11 affected individuals. Saccades appeared normal, and nei­ther ocular dysmetria nor reduced saccadic veloc­ity was recorded by nystagmography. DISCUSSION Despite the many varied disturbances of eye movement attributed to this disease, affected indi­viduals have only two ocular motor abnormalities clearly and consistently present: ( a) a deficit in smooth pursuits, and ( b) gaze- evoked nystagmus. The smooth pursuit deficit is manifested in sev­eral ways in our patients. It is directly observed as cogwheel ocular motion when the subject attempts to follow a smoothly moving target. Because test­ing with a hand- held OKN drum is essentially a test of the pursuit system, the dampened OKN responses of our patients and those reported by Farris and colleagues ( 2) represent another mani­festation of impaired pursuit function. Finally, ask­ing a subject to perform combined head and eye tracking of a moving object is equivalent to chal­lenging the smooth pursuit system to override the VOR. The inability of three of our subjects tested to suppress the VOR during this maneuver consti­tutes further evidence of a pursuit deficit. The neuroanatomical substrates for smooth pur­suit and gaze holding have been better defined recently and were thoroughly reviewed by Leigh and Zee ( 4). The flocculus is an important part of substrate for smooth pursuit. Electrophysiologic recordings in monkeys show that Purkinje cells in the cerebellar flocculus and paraflocculus alter their activity during ocular pursuit of a smoothly moving target ( 5- 8). These same cells are quiet when the target is stationary and the head is ro­tated ( 6). Smooth eye movements are produced by microstimulation of the flocculus ( 9), whereas ex­perimental ablation of the flocculus results in low pursuit gain ( eye velocity less than target velocity) ( 10,11,21). Reduced gain creates a need for correc­tive saccades and thus accounts for the " cog­wheel" nature of the observed pursuit move­ments. The median vestibular nucleus ( MVN) also contains neurons that discharge in relation to smooth pursuits ( 12- 14). Gaze- holding centers are situated in the brain­stem and cerebellum. The seat of mathematical integration involved in generating eye position commands for horizontal saccades and pursuits ( neural integrator) is the nucleus propositus hypo-glossi/ median vestibular nucleus complex ( NPH/ MVN). Experimental lesions of the NPH/ MVN re­sult in an inadequate eye position command and an inability to maintain the eyes in eccentric gaze. Following a conjugate eye movement to one side, the eyes consistently drift back toward primary po­sition. This requires repetitive corrective saccades in the direction of attempted gaze and is evident clinically as gaze- evoked nystagmus. Significantly, lesions at this location impair the VOR as well. The cerebellum has been hypothesized to contribute to gaze holding and neural integration by acting to stabilize an inherently " leaky" integrator. The floc­culus in particular has reciprocal neural connec­tions with the NPH/ MVN ( 18- 23). The smooth- pursuit pathways overlap with the gaze- holding centers in two regions, the cerebellar flocculus and the MVN/ NPH complex. Lesions of the MVN/ NPH typically cause VOR impairment and may be associated with rebound nystagmus, neither of which were present in any of our sub­jects. We therefore believe that the cerebellar floc­culus is the primary site of pathology in affected members. Most affected individuals were found to have a concomitant esodeviation, and several required ground- in prism in their eyeglasses to alleviate diplopia. An esotropia that is greater at distance than at near and is associated with full range of eye movement conforms to the clinical picture of di­vergence paralysis. This is also supported by the observation that these patients had normal hori­zontal saccadic velocities. The role of the flocculus in the control of vergence is unclear at this time. Symptoms of vertigo and tinnitus are clearly of noncerebellar origin, reflecting some degree of vestibular and auditory dysfunction, respectively. Acetazolamide has been used with some success in the treatment of certain forms of ataxia ( 3). Only one of our patients noted a subjective improve­ment in his ataxia. The remaining seven patients did not tolerate the side effects and did not give the medication an opportunity to be effective. It should be noted that all previously reported stud­ies on the efficacy of acetazolamide in this setting J Neuro- Ophthalmol, Vol. 16, No. 2, 1996 VESTIBULOCEREBELLAR ATAXIA 95 were uncontrolled. In addition, the " therapeutic results" were completely subjective. To study this issue properly, one must perform quantitative measurement of eye movements in a controlled masked fashion. A more precise name for this disorder is North Carolina autosomal dominant ataxia. The Farmer and Mustian family ( 1), the additional family in­cluded in this report, and the family reported by Farris and colleagues ( 2), all descended from the same county in North Carolina, suggesting a founder effect. The pedigree structure is clearly au­tosomal dominant, and this term should be in­cluded in the name of the disease. The term " fa­milial," which was included in its former name, is less accurate. Farmer and Mustian ( 1) referred to this disease as " periodic." This is imprecise since the term " periodic" implies that the time intervals between successive events are regular and there­fore predictable. Perhaps a better description would be " episodic." However, the episodic na­ture of this disease is manifest only during its early stages. Later in the course, the ataxia is relatively constant, with exacerbations and remissions being provoked by certain environmental and positional changes. The eye findings are not episodic. 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