Ocular Motor Abnormalities in Huntington's Disease ADRIAN G

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 may reflect involvement of 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 movement control in patients with various degenerative, neurological diseases or with focal cerebral hemispheral lesions. © 1997 Elsevier Science Ltd

Huntington's disease Saccades Reflexive Volitional Distractability

INTRODUCTION including within the brain stem (Bruyn, 1968; Barr et al., 1978; Vonsattel et al., 1985; Simmons et al., 1986). 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, HISTORICAL PERSPECTIVE the disease is slowly but relentlessly progressive, with While not emphasized in early reports of HD, cognitive decline and involuntary movements of the abnormalities of eye movements, especially vertical eye limbs, usually chorea, dominating the clinical picture. movements, were occasionally recognized (Westphal, The age of onset is variable, any time from the first to the 1883; Andrr-Thomas et al., 1945; Derceux, 1945; Cogan, eighth decades of life. The disease is caused by an 1974; Petit & Milbled, 1973). Patients typically had expanding polyglutamine "triplet" repeat in the IT15 or difficulties with voluntary changes of ga~,~e and would huntingtin gene (Huntington's Disease Collaborative often thrust their heads or blink their eyes to initiate eye Research Group, 1993). Because the huntingtin gene is movements and hence were thought to have an "ocular expressed ubiquitously in all body tissues it has been motor apraxia" (Markham & Knox, 1965). Starr (1967) unclear why HD is a neurological disease. Recently, was the first to clearly distinguish abnormalities among another protein (huntingtin-associated protein (HAP)-I), the different subclasses of eye movements--saccades, which is restricted to the brain, has been identified and it pursuit and vestibular--in HD. He also was the first to is perhaps that increased binding to the huntingtin gene emphasize and quantify the slowing of saccades that can occur in HD and to interpret the ocular motor product leads to toxic effects on specific brain structures abnormalities in the context of a bioengineering control (Li et al., 1995). Pathologically, there is a predilection for systems approach to eye movements. involvement of the frontal lobes and the basal ganglia More information about the extent and nature of the early in HD but eventually degeneration is widespread, 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 correspondence should 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 [email protected]]. the patient attempted to sustain tracking of a target 3639 3640 A.G. LASKER and D. S. ZEE

TABLE 1. Ocular motor abnormalities in 50 patients with Hunting- of any other LEDs appearing in the visual periphery until ton's disease* the central LED was extinguished. HD patients were Percentage unable to suppress a glance (saccade) to the novel visual of patients stimulus and hence were unable to hold steady fixation of Eye movement Nature of abnormality affected the central LED. These findings led to the hypothesis that HD initially affected structures (within the basal ganglia Fixation Steady fixation disrupted by inappropriate saccades 73 or frontal lobes) that were more important for producing Saccades Impaired initiation reflected by: voluntary, internally generated saccades than for produ- Increased latency 89 cing reflexive, externally triggered saccades. The asso- Obligatory head movement ciated defect in maintaining steady fixation was posited --in vertical plane 89 to be related to a loss of inhibition upon the superior ---in horizontal plane 92 Obligatory blink 35 colliculus (SC) by either the frontal eye fields (FEF) or Slow saccades the substantia nigra pars reticulata (SNpr), thus creating --in vertical plane 62 difficulty in suppressing reflexive responses to novel --in horizontal plane 50 extraneous visual stimuli when steady fixation was Hypometria and reduced range of required. saccadic movement --in vertical plane 56 Later on in the disease, patients with HD began to show --in horizontal plane 46 more prominent slowing of saccades, as well as pursuit Smooth pursuit Disruptedby inappropriate deficits. Eventually there was a reduced range of saccades; reduced gain in more voluntary eye movements with vertical saccades more advanced cases affected than horizontal saccades. In contrast, vestibular --in vertical plane 56 --in horizontal plane 60 slow phases and eccentric gaze holding were preserved Vergence Convergence movements usually even late in the disease. impaired because of extraneous Findings similar to those of Leigh et al. were reported saccades that took the eye off by Kirkham & Guitton (1984); Hotson et al. (1984); target 33 Beenen et al. (1986); Bollen et al. (1986); Collewijn et al. Eccentric gaze Eyes brought back to primary holding position by inappropriate (1988) and Zangemeister & Mueller-Jensen (1985). The saccades 11 last investigators also noted changes in t]ae patterns of Vestibulo-ocular Decreasedgain (eye velocity/head eye-head coordination in patients with HD, with the reflex velocity) 0 increase in latency for the eye movement component of a *Fixation behavior could not be reliably evaluated in six patients. combined gaze shift being much greater than for the head Voluntary eye movements, particularly, smooth pursuit and component. Some parameters of eye movement perfor- vergence, could not be reliably tested in l0 patients. (From Leigh mance, such as saccade latency and saccade accuracy, et al., 1983). 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 moving in a repetitive fashion. These investigators also factors in such eye movement studies, including the emphasized fixation instability, with unwanted saccadic specifics of the paradigm, instructions to the subject, use intrusions. During attempted fixation of either a sta- of medications, stage of the disease, age of the subject tionary or a moving target, the eyes were frequently taken and method of recording eye movements. away from the target requiring a corrective saccade to bring the eyes back to the target. Overall, similar results THE NATURE OF THE SACCADE INIT]LATION AND were reported by Oepen et al. (1981), who also noted a FIXATION DEFECTS IN HD convergence deficit in most patients with HI). Further quantitative studies in our own laboratory (Lasker et al., 1987, 1988) addressed the nature of the THE EYE MOVEMENT ABNORMALITY OF HD saccade initiation and fixation defects in ttD. We found Leigh et al. (1983) provided the first comprehensive that the fixation defect was best brought out in the view of the nature, extent and evolution of the eye "antisaccade" task (Hallet, 1978). When patients were movement abnormalities in HD. They examined 50 instructed to generate a saccade in the direction opposite patients in various stages of the disease and in 15, they to that of a suddenly appearing target, at its mirror quantified eye movements using the sensitive scleral location, they had marked difficulty in suppressing the search coil technique (Robinson, 1963). Their basic reflexive saccade to the novel visual stimulus, and were findings are summarized in Table 1. Early in the disease, almost invariably drawn to the visual target as part of a two defects were most prominent. Patients had difficulty "visual grasp" reflex (Fig. 1). On average, HD patients with initiation of voluntary saccades, especially on made many more errors than did the normal subjects command without a particular visual stimulus, and (60% in patients vs 17% in normals, 12 and 11 subjects in difficulty maintaining steady fixation. The latter was each group, respectively). No subjects with HD made less apparent when patients were instructed to look at a center than 20% errors (only one HD subject made less than light emitting diode (LED) and to ignore the appearance 40% errors) and only two normal subjects made more EYE MOVEMENTS IN HUNTINGTON'S DISEASE 3641

Frontal Parietal Prefrontal ]~ ~ R 20 t FEF 7a SEF l LIP

- l-t- -+- +~ ?c~p:ri?rs 1

Eye (V)

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 R21L 20tJ projections to the caudate nucleus (CN), or both. q~he CN, in turn, phasically inhibits the substantia nigra pars reticulata (SNPR), which FIGURE 1. Inability to suppress reflexive saccades in a patient with itself tonically inhibits the SC. Thus, excitation of CN could lead to HD in the MS (antisaccade) paradigm. The patient was instructed to disinhibition of the SC and facilitate the generation of voluntary look at the opposite mirror location of the target. The patient made a saccades. Suppression of unnecessary reflexive saccades could occur misdirected saccade toward the LED, but then corrected her mistake via frontal cortex by a direct inhibitory pathway to the SC or indirectly and looked in the opposite (correct) direction. The target reappeared in by an inhibitory pathway to the CN. The dashed line indicates a direct the mirror location, at which time the patient held fixation and then, frontal-brainstem pathway that probably triggers saccades when the SC when the target returned to the primary position, made a saccade to it to is removed. FEF = frontal eye fields; SEF = supplementary eye fields; await the onset of the next trial. H = horizontal; V = vertical; tic marks LIP = lateral intraparietal area. (From Tian et al., 1991). are at 1-sec intervals. (From Lasker et al., 1987).

patients with HD (Tian et al., 1991). Targets jumped back than 20% errors (25% and 40%). Thus, more than 20% and forth, i.e., left or right 10 deg about center, at a errors on the antisaccade task seems to be a sensitive frequency of 0.5 Hz. HD patients were less able to index of ocular motor dysfunction in HD. It is important generate saccades that anticipated the occurrence of the to note that the errors on the antisaccade task cannot be target light. The normal group responded with a latency attributed to a nonspecific global decline in cognition. of -78 msec, while the HD group responded with a These eye movement errors were apparent in patients latency of 170 msec. Likewise, the mean amplitude of who had no evidence of mental decline with formal anticipatory saccades was 17.8 deg in normals group, neuropsychological testing, while excellent performance while HD patients had a mean amplitude of only on other eye movement tasks, i.e. a reflexive paradigm or 14.2 deg. The predictive defect was less if auditory cues a gap-overlap paradigm, ruled out nonspecific sedation or were also used to trigger the saccade and also if auditory inattention. cues were used in the presence of continuously The defect in the initiation of voluntary saccades was illuminated targets. The possible implications of these also brought out best in the antisaccade task. The latency findings will be discussed below. of the saccades incorrectly made to the visual target by the patient and normal groups was similar, about A MODEL FOR INITIATING VOLUNTARY AND 300 msec. However, for saccades correctly made in the REFLEXIVE SACCADES opposite direction of the suddenly appearing target, the latencies of patients were 509 msec compared to the The finding that the most prominent abnormalities in latencies of the normals which were 364 msec. Differ- early HD were a defect in the initiation of voluntary ences between HD patients and normals were also present saccades, coupled with seemingly irrepressible reflexive in other saccade paradigms but least in a simple reflexive saccades taking the eyes away from the fixation target, task ("Quickly move your eyes to the new target as soon formed the basis for a hypothesis to explain the ocular as it comes on") and more so with performance on a motor abnormalities in early HD based on selective simple voluntary task ("When the fixation light goes out involvement of frontal-basal ganglia pathways that are and the auditory beep occurs, quickly move your eye to concerned with ocular motor control. The caudate the new target"). In these more voluntary tasks the nucleus (CN) and the SNpr are two strucl:ures in which greatest increase in latency in HD patients was seen in a pathological involvement in HD is prominent and they remembered target task ("When the fixation light goes are also important in the control of saccades (Hikosaka, out quickly, move your eyes to where you previously saw 1989). the target"). A hypothetical scheme is shown in Fig. 2. The SC is We also used predictive tracking paradigms to assay the final conduit through which saccade commands are for defects in the initiation of voluntary saccades in relayed to the brainstem to trigger the premotor burst 3642 A.G. LASKERand D. S. ZEE neurons in the pons and mesencephalon that generate might also lead to unnecessary reflexive saccades. It is rapid eye movements of all types, including saccades and known that lesions in the frontal lobes, presumably quick phases of nystagmus. The importance of the SC in involving the dorsolateral prefrontal cortex, which the generation of saccades in intact individuals is projects directly to the SC and possibly indirectly through supported by the observation in monkeys that acute the CN, lead to increased errors on the anl~isaccade task lesions of the SC impair their ability to generate any type (Guitton et al., 1985; Funahashi et al., 1993). of saccade. After the ablation of the SC, however, animals do eventually recover some ability to generate Initiation abnormalities saccades (Wurtz & Goldberg, 1972; Schiller et al., 1979). The finding of a greater defect in initiation of voluntary This recovery is probably mediated by direct pathways saccades than of reflexive saccades can be attributed to from the frontal lobes to the brain stem. abnormal function of frontal-basal ganglia pathways as In intact subjects more reflexive saccades are probably outlined above (Dias et al., 1995). triggered via direct projections from the parietal lobes to Abnormalities in prediction in HD presumably reflect the SC (Keating et al., 1983). Voluntary saccades are involvement in the same pathways. Curiously, the HD probably generated from frontal structures, either patients had less difficulty anticipating the next saccade if directly, or via the basal ganglia to the SC. More auditory cues were also provided. This finding suggests specifically, the SNpr, by a tonic inhibitory influence that the defect in prediction in HD may reflect a relative upon the SC, could gate reflexive and volitional saccades inability to use spatially specific information (e.g. the that are generated by the SC. The CN, by an inhibitory target lights) to abstract both timing and location projection to the SNpr, could phasically inhihit the SNpr information for anticipatory behavior, while nonspatially and thereby lead to disinhibition of the SC and "permit" a specific cues (e.g. nonlocalizable sounds) can be used saccade to occur (Hikosaka, 1991). A projection from the relatively normally to augment anticipatory behavior. frontal lobes to the CN presumably carries the signal that Furthermore, the deficits in generating predictive eye phasically excites caudate neurons and leads to inhibition movements in HD may be a specific e,xample of a in the SNpr and thus, facilitation of the generation of a more generalized defect in generating voluntary eye voluntary saccade (Hikosaka, 1991). At other times, the movements in the context of remembered or learned SNpr tonically inhibits the SC and prevents uncalled-for, behavior. reflexive saccades. Finally, there are other pieces of evidence in favor of There are, however, other potential ways by which the relative preservation of (posterior, parietal) pathways reflexive and voluntary saccades could be gated through in HD patients. Tian et al. (1991) found there was a the SC. There are direct projections from frontal normal effect upon saccade latency with the. blanking of a structures to the SC, some of which could trigger fixation light prior to the appearance of a target light voluntary saccades and others which could suppress (gap stimulus) or with the persistence of the fixation reflexive saccades. There might also be inhibitory light after the new target light appears (overlap stimulus). projections from the frontal lobes to the CN which could These stimuli led to a relative decrease and increase, serve, in effect, to increase SNpr inhibition upon the SC respectively, in saccade initiation time, both in normals and in HD patients. Likewise, HD patients showed and help prevent unnecessary saccades. Dias et al. (1995) normal effects on saccade latencies when tested in makes a strong case for the control of all voluntary paradigms that specifically probed the ability to engage saccades via the frontal eye fields. and direct both covert and overt visual attention (Tsai It must be emphasized that the frontal ~md parietal et al., 1995). lobes are reciprocally connected, allowing for each structure to influence the other, and they have common subcortical projection sites. This anatomical complexity SLOW SACCADES IN HD precludes a strict separation of function between the Saccade slowing is another characteristic feature of posited voluntary and reflexive pathways for initiation of HD. It is more prominent in patients with the early-onset saccades. Nevertheless, the scheme outlined in Fig. 2 can form of HD. Saccade slowing does not con:elate with the be used profitably to analyze the eye movement degree of initiation or of fixation deficits, suggesting abnormalities shown by patients with HD, and with other saccade slowing has a different pathophysiology. The neurological disorders that affect saccadic eye move- explanation for the saccade slowing in HD is not settled ments. and there may be several different causes. Certainly, direct involvement within the brain stem structures that Fixation abnormalities contain the so-called burst neurons that generate the The inability to suppress reflexive saccades in HD has immediate premotor commands for horizontal [pontine been attributed to loss of tonic inhibition of the SNpr paramedian reticular formation (PPRF)] and vertical upon the SC and a consequent susceptibility to making [rostral interstitial nucleus of the medial longitudinal unnecessary saccades away from the point of fixation. fasciculus (riMLF)] saccades could explain the profound The frontal lobes, too, could be at fault, by virtue of a loss slowing that eventually occurs in many patients. On the of tonic or of phasic inhibition by the frontal lobes, either other hand, slowing of saccades can al,;o occur with directly upon the SC, or indirectly via the CN, which abnormalities in the higher level circuits, including the EYE MOVEMENTS IN HUNTINGTON'S DISEASE 3643

SC, that trigger the brainstem networks that generate progression in the eye movement defects. Beenen et al. saccades (Wurtz & Goldberg, 1972). Such slowing might (1986) also re-recorded four HD patients at intervals of reflect insufficient inhibition to so-called brainstem pause 1-3 years and found decreases in saccade velocity. cells that normally act to inhibit burst neurons. When a Neither of these studies, however, provided clear data on saccade is called for, pause neurons must cease dischar- how progression in eye movement abnormalities in HD ging, in order to disinhibit burst neurons and permit them are related to changes in other aspects of motor to generate a saccade. Accordingly, slow saccades could performance or to the cognitive decline. occur if only a fraction of the pause cells were inhibited, thereby allowing only a fraction of the burst neurons to STUDIES OF AT-RISK SUBJECTS discharge. Alternatively if a portion of the direct cerebral or SC A number of studies have looked at a possible role for projections to burst neurons are affected in HD, slow eye movement studies in identifying the "preclinical" saccades might occur because only a fraction of the burst state of HD and using eye movement abnormalities as neurons would be recruited during the saccade. There markers for the disease (Petit & Milbled, 1973; Oepen et may also be higher-level nonspeciflc influences that al., 1981; Valade et al., 1984; Zangemeister & Mueller- facilitate activity on brain stem burst neurons. In any Jensen, 1985; Beenen et al., 1986; Collewiiin et al., 1988; case, the cause of the slowing of saccades that occurs Currie et al., 1992; Rothlind et al., 1993). The usual relatively early in the course of HD may not be due to question is if one can document eye movement direct involvement of brainstem burst neurons. The abnormalities before there are other signs of the disease. exceedingly slow saccades that ultimately develop in An obvious problem with these types of studies is some patients may, however, reflect a combination of deciding when an at-risk patient is no longer at-risk but is disturbed supranuclear inputs and direct involvement of mildly affected. For example, many patients who develop the burst neurons in the paramedian reticular formation of full-blown HD may have had behavioralL or cognitive the brain stem. difficulties that preceded the appearance of any gross somatic motor abnormalities. Petit & Milbled (1973) showed a high incidence of THE PATHOLOGICAL SUBSTRATE FOR SLOW abnormalities (10/28) in at-risk subjects. These included SACCADES "poor fixation" and "increased blinking". Beenen et al. Two autopsy studies have dealt with the issue of brain (1986) showed some eye movement abnormality in 22% stem involvement in HD patients with slow saccades. of 97 at-risk subjects; in 11% this was slowing of Leigh et al. (1985) studied the midbrains of four patients horizontal saccades. In contrast, Collewijn et al. (1988) with HD who had slow vertical saccades during life. In did not find early ocular motor signs of HD in at-risk only one patient was there a statistically significant subjects. In only one (out of 22) at-risk subjects was there decrease in the number of neurons within the riMLF (the definite saccade slowing; in two there was marginal location of burst neurons for generating vertical saccade slowing. These investigators were also able to saccades), suggesting to these authors that involvement document normal saccade speed and pursuit capability in of inputs to the riMLF, rather than the riMLF itself, is several patients who, 2 years later, developed clear signs more likely the cause of slowing of vertical saccades in of HD. Taken together, these studies illustrate the HD. On the other hand Koeppen (1989) found a striking necessity of having a genetic marker for at-risk subjects loss of large neurons in the nucleus pontis centralis to best classify them. Likewise, one has to choose the caudalis of nine HD patients, suggesting that slow most sensitive tests of ocular motor dysfunction in at-risk horizontal saccades might derive from direct brain stem subjects. With this in mind, we studied a group of at-risk involvement in the PPRF. However, there was no clear subjects in whom a chromosome DNA marker linked to correlation between the degree of saccade slowing and the HD phenotype was the criterion for HD risk (Rothlind pathological involvement. 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 LONGITUDINAL STUDIES without the HD gene marker. It thus remains open as to Rubin et al. (1993) recorded eye movements in 39 HD what degree, if any, ocular motor abnormalities precede patients on two occasions, 2 years apart. The recordings other manifestations of the HD phenotype,. were made as part of a study of the effect of medications on HD, in an attempt to provide quantitative objective PERSPECTIVE signs of change in ocular motor performance. They found that a decrease in saccade speed and increase in saccade The study of eye movements in Huntington's disease latency occurred in 72% and 88% of patients, respec- illustrates a successful interaction in which the fruits of tively. They also reported that an increase in latency was basic physiological and anatomical experimental inves- more apparent for large saccades, and that with tigations are combined with careful and quantitative progressive saccade slowing there was also a decrease clinical measures of (ocular) motor performance in in the ability to make large saccades. There was a human patients to advance our understanding of both a reasonable correlation between general deterioration and neurological disease and normal human behavior. The 3644 A.G. LASKER and D. S. ZEE initial observations of eye movements in HD patients in generating goal-directed saccades. 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