Vision Res., Vol. 37, No. 24, pp. 3639-3645, 1997

Pergamon

© 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0042-6989/97 $17.00 + 0.00

PII: S0042-6989(96)00169-1

Ocular Motor Abnormalities in Huntington's Disease ADRIAN G. LASKER,*~" DAVID S. ZEE* Received 29 February 1996; in revised form 8 May 1996

We review here the eye movements in patients with Huntington's disease (HD), concentrating upon saccades as they show the most prominent abnormalities. Inability to suppress reflexive glances to suddenly appearing novel visual stimuli and delayed initiation of voluntary saccades, including predictive saccades, are early and consistent findings. These two abnormalities can be interpreted in the context of a model, based upon the idea that the frontal lobes and basal ganglia contribute more to the control of voluntary than to reflexive types of saccades. Most patients eventually also show slow saccades but they are most prominent when the disease is early-onset. Slowhig of saccades m a y reflect involvement o f both the higher-level cerebral centers that trigger saccade.s and the areas in the brain stem that produce premotor saccade commands. The study of eye movements in HD has led to a fruitful interaction between basic science and clinical investigation, and has served as a paradigm for examining higher-level defects in saccadic eye m o v e m e n t control in patients with various degenerative, neurological diseases or with focal cerebral hemispheral lesions. © 1997 Elsevier Science Ltd Huntington's disease

Saccades

Reflexive

Volitional

INTRODUCTION Huntington's Chorea, better known now as Huntington's disease (HD) is one of the classical familial degenerative neurological diseases. Inherited in a dominant fashion, the disease is slowly but relentlessly progressive, with cognitive decline and involuntary movements of the limbs, usually chorea, dominating the clinical picture. The age of onset is variable, any time from the first to the eighth decades of life. The disease is caused by an expanding polyglutamine "triplet" repeat in the IT15 or huntingtin gene (Huntington's Disease Collaborative Research Group, 1993). Because the huntingtin gene is expressed ubiquitously in all body tissues it has been unclear why HD is a neurological disease. Recently, another protein (huntingtin-associated protein (HAP)-I), which is restricted to the brain, has been identified and it is perhaps that increased binding to the huntingtin gene product leads to toxic effects on specific brain structures (Li et al., 1995). Pathologically, there is a predilection for involvement of the frontal lobes and the basal ganglia early in HD but eventually degeneration is widespread,

Distractability

including within the brain stem (Bruyn, 1968; Barr et al., 1978; Vonsattel et al., 1985; Simmons et al., 1986). HISTORICAL PERSPECTIVE

While not emphasized in early reports of HD, abnormalities of eye movements, especially vertical eye movements, were occasionally recognized (Westphal, 1883; Andrr-Thomas et al., 1945; Derceux, 1945; Cogan, 1974; Petit & Milbled, 1973). Patients typically had difficulties with voluntary changes of ga~,~e and would often thrust their heads or blink their eyes to initiate eye movements and hence were thought to have an "ocular motor apraxia" (Markham & Knox, 1965). Starr (1967) was the first to clearly distinguish abnormalities among the different subclasses of eye movements--saccades, pursuit and vestibular--in HD. He also was the first to emphasize and quantify the slowing of saccades that can occur in HD and to interpret the ocular motor abnormalities in the context of a bioengineering control systems approach to eye movements. More information about the extent and nature of the eye movement abnormalities in HD was. provided by Avanzini et al. (1979), who reported that HD patients *Department of Neurology,Johns Hopkins Hospital, 600 North Wolfe showed not only slowing but also hypometria of Street, Baltimore, MD 21267, U.S.A. saccades. They also pointed out that HD patients had a tTo whom all correspondenceshould be addressed at: Johns Hopkins particular difficulty in initiating more voluntary types of Hospital, Department of Neurology, Eye Movement/Vestibular saccades, e.g. on command. Pursuit abno~analities were Testing Laboratory, Pathology 2-210, 600 North Wolfe Street, Baltimore, MD 21287, U.S.A. [Fax: +1 410 614 1746; Email: also noted and were seemingly more pronounced when the patient attempted to sustain tracking of a target [email protected]]. 3639

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A.G. LASKER and D. S. ZEE

TABLE 1. Ocular motor abnormalities in 50 patients with Huntington's disease*

Eye movement Fixation Saccades

Smooth pursuit

Vergence

Eccentric gaze holding Vestibulo-ocular reflex

Nature of abnormality

Percentage of patients affected

Steady fixation disrupted by inappropriate saccades Impaired initiation reflected by: Increased latency Obligatory head movement --in vertical plane ---in horizontal plane Obligatory blink Slow saccades --in vertical plane --in horizontal plane Hypometria and reduced range of saccadic movement --in vertical plane --in horizontal plane Disruptedby inappropriate saccades; reduced gain in more advanced cases --in vertical plane --in horizontal plane Convergence movements usually impaired because of extraneous saccades that took the eye off target Eyes brought back to primary position by inappropriate saccades Decreasedgain (eye velocity/head velocity)

73 89 89 92 35 62 50 56 46

56 60

33 11 0

*Fixation behavior could not be reliably evaluated in six patients. Voluntary eye movements, particularly, smooth pursuit and vergence, could not be reliably tested in l0 patients. (From Leigh et al., 1983).

moving in a repetitive fashion. These investigators also emphasized fixation instability, with unwanted saccadic intrusions. During attempted fixation of either a stationary or a moving target, the eyes were frequently taken away from the target requiring a corrective saccade to bring the eyes back to the target. Overall, similar results were reported by Oepen et al. (1981), who also noted a convergence deficit in most patients with HI). THE EYE MOVEMENT ABNORMALITY OF HD Leigh et al. (1983) provided the first comprehensive view of the nature, extent and evolution of the eye movement abnormalities in HD. They examined 50 patients in various stages of the disease and in 15, they quantified eye movements using the sensitive scleral search coil technique (Robinson, 1963). Their basic findings are summarized in Table 1. Early in the disease, two defects were most prominent. Patients had difficulty with initiation o f voluntary saccades, especially on command without a particular visual stimulus, and difficulty maintaining steady fixation. T h e latter was apparent when patients were instructed to look at a center light emitting diode (LED) and to ignore the appearance

of any other LEDs appearing in the visual periphery until the central LED was extinguished. HD patients were unable to suppress a glance (saccade) to the novel visual stimulus and hence were unable to hold steady fixation of the central LED. These findings led to the hypothesis that HD initially affected structures (within the basal ganglia or frontal lobes) that were more important for producing voluntary, internally generated saccades than for producing reflexive, externally triggered saccades. The associated defect in maintaining steady fixation was posited to be related to a loss of inhibition upon the superior colliculus (SC) by either the frontal eye fields (FEF) or the substantia nigra pars reticulata (SNpr), thus creating difficulty in suppressing reflexive responses to novel extraneous visual stimuli when steady fixation was required. Later on in the disease, patients with HD began to show more prominent slowing of saccades, as well as pursuit deficits. Eventually there was a reduced range of voluntary eye movements with vertical saccades more affected than horizontal saccades. In contrast, vestibular slow phases and eccentric gaze holding were preserved even late in the disease. Findings similar to those of Leigh et al. were reported by Kirkham & Guitton (1984); Hotson et al. (1984); Beenen et al. (1986); Bollen et al. (1986); Collewijn et al. (1988) and Zangemeister & Mueller-Jensen (1985). The last investigators also noted changes in t]ae patterns of eye-head coordination in patients with HD, with the increase in latency for the eye movement component of a combined gaze shift being much greater than for the head component. Some parameters of eye movement performance, such as saccade latency and saccade accuracy, have been reported to be affected by some experimenters but not by others. This seeming variabiliql points to the necessity of controlling for potentially confounding factors in such eye movement studies, including the specifics of the paradigm, instructions to the subject, use of medications, stage of the disease, age of the subject and method of recording eye movements. THE NATURE OF THE SACCADE INIT]LATION AND FIXATION DEFECTS IN HD Further quantitative studies in our own laboratory (Lasker et al., 1987, 1988) addressed the nature of the saccade initiation and fixation defects in ttD. We found that the fixation defect was best brought out in the "antisaccade" task (Hallet, 1978). When patients were instructed to generate a saccade in the direction opposite to that of a suddenly appearing target, at its mirror location, they had marked difficulty in suppressing the reflexive saccade to the novel visual stimulus, and were almost invariably drawn to the visual target as part of a "visual grasp" reflex (Fig. 1). On average, HD patients made many more errors than did the normal subjects (60% in patients vs 17% in normals, 12 and 11 subjects in each group, respectively). No subjects with HD made less than 20% errors (only one HD subject made less than 40% errors) and only two normal subjects made more

EYE MOVEMENTS IN HUNTINGTON'S DISEASE

~

R

20t

Frontal Prefrontal ]~ FEF SEF

3641 Parietal l

7a LIP

- l-t- -++

~

?c~p:ri?rs 1

Eye (V)

R21t L 20J

FIGURE 1. Inability to suppress reflexive saccades in a patient with HD in the MS (antisaccade) paradigm. The patient was instructed to look at the opposite mirror location of the target. The patient made a misdirected saccade toward the LED, but then corrected her mistake and looked in the opposite (correct) direction. The target reappeared in the mirror location, at which time the patient held fixation and then, when the target returned to the primary position, made a saccade to it to await the onset of the next trial. H = horizontal; V = vertical; tic marks are at 1-sec intervals. (From Lasker et al., 1987).

than 20% errors (25% and 40%). Thus, more than 20% errors on the antisaccade task seems to be a sensitive index o f ocular motor dysfunction in HD. It is important to note that the errors on the antisaccade task cannot be attributed to a nonspecific global decline in cognition. These eye m o v e m e n t errors were apparent in patients who had no evidence o f mental decline with formal neuropsychological testing, while excellent performance on other eye m o v e m e n t tasks, i.e. a reflexive paradigm or a gap-overlap paradigm, ruled out nonspecific sedation or inattention. The defect in the initiation o f voluntary saccades was also brought out best in the antisaccade task. The latency o f the saccades incorrectly made to the visual target by the patient and normal groups was similar, about 300 msec. However, for saccades correctly made in the opposite direction of the suddenly appearing target, the latencies o f patients were 509 msec compared to the latencies o f the normals which were 364 msec. Differences between H D patients and normals were also present in other saccade paradigms but least in a simple reflexive task ("Quickly m o v e your eyes to the new target as soon as it comes on") and more so with performance on a simple voluntary task ( " W h e n the fixation light goes out and the auditory beep occurs, quickly m o v e your eye to the new target"). In these more voluntary tasks the greatest increase in latency in H D patients was seen in a remembered target task ( " W h e n the fixation light goes out quickly, m o v e your eyes to where y o u previously saw the target"). W e also used predictive tracking paradigms to assay for defects in the initiation o f voluntary saccades in

FIGURE 2. Hypothetical scheme of interactions among the frontal and parietal lobes, the basal ganglia, and the superior colliculus (SC) in the generation of saccades. Parietal-SC pathways presumably trigger reflexive saccades. Voluntary saccades are triggered from the frontal lobes by direct excitatory projections to the SC, by excitatory projections to the caudate nucleus (CN), or both. q~he CN, in turn, phasically inhibits the substantia nigra pars reticulata (SNPR), which itself tonically inhibits the SC. Thus, excitation of CN could lead to disinhibition of the SC and facilitate the generation of voluntary saccades. Suppression of unnecessary reflexive saccades could occur via frontal cortex by a direct inhibitory pathway to the SC or indirectly by an inhibitory pathway to the CN. The dashed line indicates a direct frontal-brainstem pathway that probably triggers saccades when the SC is removed. FEF = frontal eye fields; SEF = supplementary eye fields; LIP = lateral intraparietal area. (From Tian et al., 1991).

patients with H D (Tian e t a l . , 1991). Targets j u m p e d back and forth, i.e., left or right 10 deg about center, at a frequency of 0.5 Hz. H D patients were less able to generate saccades that anticipated the occurrence o f the target light. The normal group responded with a latency o f - 7 8 msec, while the H D group responded with a latency of 170 msec. Likewise, the mean amplitude o f anticipatory saccades was 17.8 deg in normals group, while H D patients had a mean amplitude o f only 14.2 deg. The predictive defect was less if auditory cues were also used to trigger the saccade and also if auditory cues were used in the presence of continuously illuminated targets. The possible implications o f these findings will be discussed below.

A MODEL FOR INITIATING VOLUNTARY AND REFLEXIVE SACCADES

The finding that the most prominent abnormalities in early H D were a defect in the initiation o f voluntary saccades, coupled with seemingly irrepressible reflexive saccades taking the eyes away from the fixation target, formed the basis for a hypothesis to explain the ocular motor abnormalities in early HD based on selective involvement o f frontal-basal ganglia pathways that are concerned with ocular motor control. The caudate nucleus (CN) and the SNpr are two strucl:ures in which pathological involvement in H D is prominent and they are also important in the control o f saccades (Hikosaka, 1989). A hypothetical scheme is shown in Fig. 2. The SC is the final conduit through which saccade c o m m a n d s are relayed to the brainstem to trigger the premotor burst

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A.G. LASKERand D. S. ZEE

neurons in the pons and mesencephalon that generate rapid eye movements of all types, including saccades and quick phases of nystagmus. The importance of the SC in the generation of saccades in intact individuals is supported by the observation in monkeys that acute lesions of the SC impair their ability to generate any type of saccade. After the ablation of the SC, however, animals do eventually recover some ability to generate saccades (Wurtz & Goldberg, 1972; Schiller et al., 1979). This recovery is probably mediated by direct pathways from the frontal lobes to the brain stem. In intact subjects more reflexive saccades are probably triggered via direct projections from the parietal lobes to the SC (Keating et al., 1983). Voluntary saccades are probably generated from frontal structures, either directly, or via the basal ganglia to the SC. More specifically, the SNpr, by a tonic inhibitory influence upon the SC, could gate reflexive and volitional saccades that are generated by the SC. The CN, by an inhibitory projection to the SNpr, could phasically inhihit the SNpr and thereby lead to disinhibition of the SC and "permit" a saccade to occur (Hikosaka, 1991). A projection from the frontal lobes to the CN presumably carries the signal that phasically excites caudate neurons and leads to inhibition in the SNpr and thus, facilitation of the generation of a voluntary saccade (Hikosaka, 1991). At other times, the SNpr tonically inhibits the SC and prevents uncalled-for, reflexive saccades. There are, however, other potential ways by which reflexive and voluntary saccades could be gated through the SC. There are direct projections from frontal structures to the SC, some of which could trigger voluntary saccades and others which could suppress reflexive saccades. There might also be inhibitory projections from the frontal lobes to the CN which could serve, in effect, to increase SNpr inhibition upon the SC and help prevent unnecessary saccades. Dias et al. (1995) makes a strong case for the control of all voluntary saccades via the frontal eye fields. It must be emphasized that the frontal ~md parietal lobes are reciprocally connected, allowing for each structure to influence the other, and they have common subcortical projection sites. This anatomical complexity precludes a strict separation of function between the posited voluntary and reflexive pathways for initiation of saccades. Nevertheless, the scheme outlined in Fig. 2 can be used profitably to analyze the eye movement abnormalities shown by patients with HD, and with other neurological disorders that affect saccadic eye movements. Fixation abnormalities

The inability to suppress reflexive saccades in HD has been attributed to loss of tonic inhibition of the SNpr upon the SC and a consequent susceptibility to making unnecessary saccades away from the point of fixation. The frontal lobes, too, could be at fault, by virtue of a loss of tonic or of phasic inhibition by the frontal lobes, either directly upon the SC, or indirectly via the CN, which

might also lead to unnecessary reflexive saccades. It is known that lesions in the frontal lobes, presumably involving the dorsolateral prefrontal cortex, which projects directly to the SC and possibly indirectly through the CN, lead to increased errors on the anl~isaccade task (Guitton et al., 1985; Funahashi et al., 1993). Initiation abnormalities

The finding of a greater defect in initiation of voluntary saccades than of reflexive saccades can be attributed to abnormal function of frontal-basal ganglia pathways as outlined above (Dias et al., 1995). Abnormalities in prediction in HD presumably reflect involvement in the same pathways. Curiously, the HD patients had less difficulty anticipating the next saccade if auditory cues were also provided. This finding suggests that the defect in prediction in HD may reflect a relative inability to use spatially specific information (e.g. the target lights) to abstract both timing and location information for anticipatory behavior, while nonspatially specific cues (e.g. nonlocalizable sounds) can be used relatively normally to augment anticipatory behavior. Furthermore, the deficits in generating predictive eye movements in HD may be a specific e,xample of a more generalized defect in generating voluntary eye movements in the context of remembered or learned behavior. Finally, there are other pieces of evidence in favor of the relative preservation of (posterior, parietal) pathways in HD patients. Tian et al. (1991) found there was a normal effect upon saccade latency with the. blanking of a fixation light prior to the appearance of a target light (gap stimulus) or with the persistence of the fixation light after the new target light appears (overlap stimulus). These stimuli led to a relative decrease and increase, respectively, in saccade initiation time, both in normals and in HD patients. Likewise, HD patients showed normal effects on saccade latencies when tested in paradigms that specifically probed the ability to engage and direct both covert and overt visual attention (Tsai et al., 1995). SLOW SACCADES IN HD Saccade slowing is another characteristic feature of HD. It is more prominent in patients with the early-onset form of HD. Saccade slowing does not con:elate with the degree of initiation or of fixation deficits, suggesting saccade slowing has a different pathophysiology. The explanation for the saccade slowing in HD is not settled and there may be several different causes. Certainly, direct involvement within the brain stem structures that contain the so-called burst neurons that generate the immediate premotor commands for horizontal [pontine paramedian reticular formation (PPRF)] and vertical [rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF)] saccades could explain the profound slowing that eventually occurs in many patients. On the other hand, slowing of saccades can al,;o occur with abnormalities in the higher level circuits, including the

EYE MOVEMENTS IN HUNTINGTON'SDISEASE SC, that trigger the brainstem networks that generate saccades (Wurtz & Goldberg, 1972). Such slowing might reflect insufficient inhibition to so-called brainstem pause cells that normally act to inhibit burst neurons. When a saccade is called for, pause neurons must cease discharging, in order to disinhibit burst neurons and permit them to generate a saccade. Accordingly, slow saccades could occur if only a fraction of the pause cells were inhibited, thereby allowing only a fraction of the burst neurons to discharge. Alternatively if a portion of the direct cerebral or SC projections to burst neurons are affected in HD, slow saccades might occur because only a fraction of the burst neurons would be recruited during the saccade. There may also be higher-level nonspeciflc influences that facilitate activity on brain stem burst neurons. In any case, the cause of the slowing of saccades that occurs relatively early in the course of HD may not be due to direct involvement of brainstem burst neurons. The exceedingly slow saccades that ultimately develop in some patients may, however, reflect a combination of disturbed supranuclear inputs and direct involvement of the burst neurons in the paramedian reticular formation of the brain stem. THE PATHOLOGICAL SUBSTRATE FOR SLOW

SACCADES Two autopsy studies have dealt with the issue of brain stem involvement in HD patients with slow saccades. Leigh et al. (1985) studied the midbrains of four patients with HD who had slow vertical saccades during life. In only one patient was there a statistically significant decrease in the number of neurons within the riMLF (the location of burst neurons for generating vertical saccades), suggesting to these authors that involvement of inputs to the riMLF, rather than the riMLF itself, is more likely the cause of slowing of vertical saccades in HD. On the other hand Koeppen (1989) found a striking loss of large neurons in the nucleus pontis centralis caudalis of nine HD patients, suggesting that slow horizontal saccades might derive from direct brain stem involvement in the PPRF. However, there was no clear correlation between the degree of saccade slowing and pathological involvement. LONGITUDINAL STUDIES Rubin et al. (1993) recorded eye movements in 39 HD patients on two occasions, 2 years apart. The recordings were made as part of a study of the effect of medications on HD, in an attempt to provide quantitative objective signs of change in ocular motor performance. They found that a decrease in saccade speed and increase in saccade latency occurred in 72% and 88% of patients, respectively. They also reported that an increase in latency was more apparent for large saccades, and that with progressive saccade slowing there was also a decrease in the ability to make large saccades. There was a reasonable correlation between general deterioration and

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progression in the eye movement defects. Beenen et al. (1986) also re-recorded four HD patients at intervals of 1-3 years and found decreases in saccade velocity. Neither of these studies, however, provided clear data on how progression in eye movement abnormalities in HD are related to changes in other aspects of motor performance or to the cognitive decline. STUDIES OF AT-RISK SUBJECTS

A number of studies have looked at a possible role for eye movement studies in identifying the "preclinical" state of HD and using eye movement abnormalities as markers for the disease (Petit & Milbled, 1973; Oepen et al., 1981; Valade et al., 1984; Zangemeister & MuellerJensen, 1985; Beenen et al., 1986; Collewiiin et al., 1988; Currie et al., 1992; Rothlind et al., 1993). The usual question is if one can document eye movement abnormalities before there are other signs of the disease. An obvious problem with these types of studies is deciding when an at-risk patient is no longer at-risk but is mildly affected. For example, many patients who develop full-blown HD may have had behavioralL or cognitive difficulties that preceded the appearance of any gross somatic motor abnormalities. Petit & Milbled (1973) showed a high incidence of abnormalities (10/28) in at-risk subjects. These included "poor fixation" and "increased blinking". Beenen et al. (1986) showed some eye movement abnormality in 22% of 97 at-risk subjects; in 11% this was slowing of horizontal saccades. In contrast, Collewijn et al. (1988) did not find early ocular motor signs of HD in at-risk subjects. In only one (out of 22) at-risk subjects was there definite saccade slowing; in two there was marginal saccade slowing. These investigators were also able to document normal saccade speed and pursuit capability in several patients who, 2 years later, developed clear signs of HD. Taken together, these studies illustrate the necessity of having a genetic marker for at-risk subjects to best classify them. Likewise, one has to choose the most sensitive tests of ocular motor dysfunction in at-risk subjects. With this in mind, we studied a group of at-risk subjects in whom a chromosome DNA marker linked to the HD phenotype was the criterion for HD risk (Rothlind et al., 1993). Using saccade latency on a predictive tracking task, and errors on the antisaccade task, we found no differences between at-risk subjects with and without the HD gene marker. It thus remains open as to what degree, if any, ocular motor abnormalities precede other manifestations of the HD phenotype,. PERSPECTIVE

The study of eye movements in Huntington's disease illustrates a successful interaction in which the fruits of basic physiological and anatomical experimental investigations are combined with careful and quantitative clinical measures of (ocular) motor performance in human patients to advance our understanding of both a neurological disease and normal human behavior. The

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initial observations of eye m o v e m e n t s in H D patients were analyzed in the context of results from basic science and lead to a specific hypothesis about the nature of the eye m o v e m e n t defects in H D patients. V o l u n t a r y saccades were thought to be more affected than reflexive saccades, because of selective i n v o l v e m e n t in the frontal lobes and basal ganglia. W h i l e an oversimplification, the idea that there is a separation of the control of saccades within the cerebral hemispheres into more voluntary and more reflexive pathways has b e e n a useful hypothesis with which to study the ocular motor defects in HD. F o l l o w i n g u p o n this suggestion, new results from basic science and further clinical studies of the functional and anatomical defects in H D could be combined, in an iterative process, to develop better paradigms for testing eye m o v e m e n t s in patients, to infer further bow eye m o v e m e n t s are controlled by the basal ganglia in n o r m a l h u m a n beings. As the molecular basis and cellular pathology of H u n t i n g t o n ' s disease b e c o m e s further understood, one can expect further insights into n o r m a l ocular motor physiology, at both a behavioral and n e u r o n a l level.

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Acknowledgement--NIH grant P01 NS 16375.