Fig. 1. Plots summarizing important dynamic properties of saccades. (A) Plot of peak velocity vs amplitude of vertical saccades. Data points are saccades from 10 normal subjects. The data are fit with an exponential equation; also plotted are the 5% and 95% prediction intervals. The + indicate vertical saccades from a patient with PSP, which lie outside the prediction intervals for normals. (B) Plot of duration vs amplitude. The data from 10 normal subjects are fit with a power equation. The + indicate vertical saccades from a patient with PSP, which have greater duration than control subjects.
Aside from measurement of saccadic dynamics, substantial effort has been put into using saccades as a behavioral index of motor programming in basal ganglia and associated cortical disorders (12). Thus, although the frontal and parietal eye fields project directly to the brainstem centers, such as the superior colliculus and pontine nuclei, a second pathway running through the basal ganglia plays an important role, and comprises the caudate, substantia nigra par reticulata (SNpr), subthalamic nucleus, and superior colliculus (Fig. 2). A simplified view of this basal ganglia pathway is that it is composed of two serial, inhibitory links: a caudate-SNpr inhibition, which is only phasically active, and a SNpr-collicular inhibition, which is tonically active (13). If frontal cortex causes caudate neurons to fire, then the SNpr-collicular inhibition is removed and the superior colliculus is able to activate a saccade. In addition, the subthalamic nucleus contains neurons that discharge in relation to saccades and
excites (SNpr), which in turn inhibits the superior colliculus. Animal studies indicate that this pathway appears important for programming of saccades to targets for which there is an expectation of reward (14,15). The caudate nucleus also probably contributes to smooth pursuit (16).
For these reasons, studies of the effects of human diseases affecting basal ganglia have focused on behaviors such as memory-guided or predictive saccades (Fig. 3). Memory-guided saccades are made in darkness several seconds after a visual target has been flashed. Predictive saccades are made in anticipation of a target appearance or jump. In the anti-saccade task, the subject is required to look in the opposite direction (mirror image position) to a visual stimulus. Thus, a reflexive, visually guided saccade must be inhibited and a saccade to an imagined target made instead (17). Such testing is still mainly a research tool, but it has provided insights into the pathogenesis of parkinsonian disorders, as we will mention in discussing each type of disorder.
IDIOPATHIC PARKINSON'S DISEASE (TABLE 2)
Most patients with PD show relatively minor abnormalities at the bedside that may also occur in healthy elderly subjects. For example, steady fixation may be disrupted by saccadic intrusions (square-wave jerks) (18-20), but these are also seen in some normal elderly subjects. Moderate restriction of the range of upward gaze is common in elderly individuals (4), with or without parkinsonism, and has been attributed to changes in the orbital tissues (5). Similarly, smooth pursuit can be impaired in PD but is also abnormal in some healthy normals (21). Convergence insufficiency is common and sometimes symptomatic (22). Patients with PD often have lid lag. Patients with advanced PD may show some slowing of vertical saccades, but PSP should always be considered in such cases.
A characteristic sign in PD is that hypometria becomes more marked when patients are asked to rapidly perform self-paced refixations between two continuously visible targets (e.g., a finger of the examiners right and left hand about 60-80° apart; the normal horizontal ocular motor range is about 45° to either side) (video 1).
Laboratory Findings in PD
Saccades in PD usually undershoot the target (i.e., they are hypometric), especially vertically (20,21). Patients may show a "stair-case" of saccades to acquire the target (especially with remembered targets); this "fragmentation" has been interpreted as a robust correction mechanism to compensate for the underlying hypometria (23). It has been possible to investigate the pathogenesis of the hypometria, which becomes more marked when patients are asked to make self-paced refixations between two continuously visible targets. This phenomenon is not simply because of the persistence of the visual targets, because saccades made in anticipation of the appearance of a target light at a remembered location are also hypometric (24,25). Patients with PD have difficulty in generating sequences of memory-guided saccades (26-28), whereas saccades made reflexively to novel visual stimuli are normal in size and promptly initiated (7). Furthermore, visually guided adaptation of saccades is preserved whereas memory guided adaptation of saccades is impaired (29). Thus, it appears that PD patients are unable to generate internally guided saccades to accurately shift gaze (7,30). Despite this hypometria, patients can still shift their gaze with a series of saccades to the location of a briefly flashed target; this indicates a retained ability to encode the location of objects in extrapersonal space (20,24).
The reaction time (latency) of saccades made in response to nonpredictable target jumps may be normal or mildly increased (20,30). During self-paced refixations between two visible targets, intersaccadic intervals increase above the latency of responses to nonpredictable target jumps (30,31) If the fixation light is turned out 100 msec before a target light appears ("gap" paradigm—Fig. 3) PD patients are able to make short-latency (100-130 ms) "express saccades" like normal subjects (7).
The pathophysiology of saccadic disorders in PD is not fully understood. One possible mechanism is via the subthalamic nucleus (Fig. 2), which contains neurons that discharge in relation to saccades. The subthalamic nucleus is hyperactive in PD, and excites the substantia nigra, pars reticulata (SNpr), which in turn inhibits the superior colliculus. It may be that excess activity in SNpr in PD leads to a defect in generation of the more voluntary, internally guided saccades such as those during prediction and to memorized targets. Functional imaging studies have suggested that the basal ganglia are important for processing of temporal information (32), which may be important for generating a regular series of saccades. Furthermore, during predictive visuomanual tracking, there is an underactivity of sensorimotor cortex, but increase in premotor areas, such as pre-SMA (supplementary motor area), which may represent compensation or impaired suppression (33). Finally, PD also affects the dopaminergic
Summary of Disordered Eye Movements in Some Basal Ganglia Disorders
Mildly affected PD patients differ little from age-matched control subjects in their smooth-pursuit performance (21,35). During tracking of a target moving in a predictable, sinusoidal pattern, eye speed is less than target speed, leading to catch-up saccades (20,36). In addition, the catch-up saccades are hypometric; thus, the cumulative tracking eye movement is less than that of the target (35). Despite these impairments, the phase relationship between eye and target movement is normal,30 implying a normal predictive smooth tracking strategy. This is in contrast to saccadic tracking of predictive target jumps which, as described earlier, is deficient.
Both caloric and low-frequency rotational vestibular responses, in darkness, may be hypoactive in patients with PD (37,38). However, at higher frequencies of head rotation, and particularly during visual fixation, the vestibular ocular (VOR) reflex adequately compensates for head perturbations, which accounts for the lack of complaint of oscillopsia in patients with PD.
Patients with advanced PD may show greater defects on more demanding tests, such as making memory-guided saccades, and on the anti-saccade tasks (Fig. 3), which requires inhibiting a reflexive saccade, and looking in the opposite direction to the target (its mirror location). In addition, patients with advanced disease may show some slowing of vertical or horizontal saccades.
In general, L-dopa treatment of PD does not seem to improve the ocular motor deficits except for improvement of saccadic accuracy (i.e., saccades become larger) (36,39). Some newly diagnosed patients with idiopathic PD may show improved smooth pursuit after the institution of dopaminergic therapy (39). Memory-guided saccades are reported to be impaired after pallidotomy for PD (40), but improved with subthalamic nucleus stimulation (41), possibly by improving learning abilities in the corticobasal ganglia network (42). Pallidotomy increases saccadic intrusions on steady fixation (square-wave jerks) (43,44).
In patients with parkinsonism owing to methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tox-icity, saccadic latency is shortened and saccadic accuracy improved by dopaminergic agents; in addition, reflex blepharospasm was improved (45). In monkeys that received MPTP, saccadic abnormalities, including increased latency, increased duration, decreased rate of spontaneous saccades, and inappropriate saccades, were all reversed by dopaminergic therapy (46,47).
PSP is a degenerative disease of later life characterized by abnormal vertical saccades; the early appearance of falls, usually within a year of onset, owing to disturbance of tone and posture; difficulties with swallowing and speech; and mental slowing (48). Median survival time is about 6 yr. The disturbance of eye movements is usually present early in the course, but occasionally develops late, or is sometimes not noted by the patient's physicians (49). Patient may complain of blurred vision, double vision, or photophobia (48), and have often been fitted with several different spectacle refractions, without improvement. On direct questioning, it is usually possible to determine that these visual complaints are a result of loss of the ability to voluntarily shift gaze in the vertical plane so that, for example, patients cannot look down to see a plate of food, tie their shoes, or confidently navigate going down the stairs.
The initial ocular motor deficit consists of slowing of vertical saccades and quick phases, either down or up or both (see video 2 on accompanying DVD). Sometimes vertical saccades take a curved or oblique trajectory ("round the houses") (21,50). Vertical smooth pursuit is relatively preserved, but of decreased gain (51). Larger targets may elicit greater responses (52), and could be used to evaluate the range of eye movements in patients in whom neck stiffness makes testing of the VOR technically difficult. Similarly, full-field optokinetic stimuli may induce responses that are useful for analysis (11). Combined eye-head tracking may also be relatively spared. As the disease progresses, the range of movements possible with vertical saccades and pursuit declines and eventually no voluntary vertical eye movements are possible. However, the VOR is preserved until late in the disease (although a characteristic rigidity of the neck may make the vertical doll's head maneuver difficult to elicit).
Horizontal eye movements also show characteristic changes: steady fixation is disrupted by square-wave jerks (11,18,21), which are more common than in other parkinsonian disorders. Horizontal saccades are initially hypometric but normal in speed (see video 3 on accompanying DVD) (53); as the disease progresses, they also become slow. In some patients, the involvement of horizontal sac-
cades resembles internuclear ophthalmoplegia (INO), although vestibular stimulation may overcome the limitation of adduction (54). Horizontal smooth pursuit appears impaired, in part, because of square-wave jerks. Convergence eye movements are commonly impaired (55). Late in the disease, the ocular motor deficit may progress to a complete ophthalmoplegia. Patients with absent quick phases but intact vestibular eye movements may also show sustained deviation of the eyes in the orbit during body rotation, and if the head is free to move it too may deviate opposite to the direction of body rotation (56).
There are a variety of eyelid abnormalities in PSP: blepharospasm, lid-opening apraxia, eye-closing apraxia, lid retraction, and lid lag (21). Patients typically show an inability to suppress a blink to a bright light—a visual Meyerson's (glabella) sign (see video 4 on accompanying DVD) (57). A single patient may have more than one of these abnormalities. Bell's phenomenon is usually absent.
Laboratory Findings in PSP
Reliable measurements of saccades in PSP have demonstrated that vertical saccades are slower than horizontal saccades of similar size (21,58). For patients who are able to make only small saccades, it is still possible to determine whether the movements are slowed using an appropriate statistical approach (59). Vertical saccades are generated by "burst neurons" in the midbrain but horizontal saccades are generated by burst neurons in the pons. Thus, the selective involvement of vertical saccades in the early stage of PSP has indicated that the brunt of the disease initially falls on midbrain burst neurons, or their local circuitry (superior colliculus and the adjacent central mesencephalic reticular formation) (60,61).
The latency (reaction time) of horizontal saccades in PSP is prolonged in some patients, but others retain the ability to make short-latency or "express" saccades (62). Patients with PSP also make errors when they are required to look in the opposite direction to a suddenly appearing target (the antisaccade task—Fig. 3). Both the presence of express saccades and errors on the antisaccade task suggest defects in frontal lobe function and, although neuropathological changes there are mild, positron emission scanning indicates profound frontal hypometabolism (63).
Measurements of vestibular eye movements during horizontal rotation, either in darkness, or during fixation of a stationary target, confirms that PSP patients show similar slow-phase responses to normal subjects but quick phases are commonly impaired leading to tonic deviation of the eyes in the contraversive direction in the oribit during rotation in the dark (51).
Smooth-Pursuit, Optokinetic, and Vergence Movements
Smooth pursuit is usually impaired in both horizontal and vertical planes (21). In the vertical plane, no corrective "catch-up" saccades can be made. The combined impairment of vertical saccades and pursuit constitutes voluntary gaze palsy. During large-field, vertical optokinetic stimulation, PSP patients often show tonic deviation of the eyes in the direction of stripe motion, with small or absent resetting quick phases (11). When PSP patients shift their fixation point between distant and near targets, the vergence movement is slowed compared to control subjects (64).
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