Huntington's Disease (HD)
HD is a neurodegenerative disorder, due to an inherited autosomal dominant genetic mutation, characterized by chorea, cognitive impairment leading to dementia, and psychiatric disturbances with a clinical onset in the 30s.
Clinical Ocular Motor Findings
For HD, the challenge is to predict disease onset given that we can test for the presence of the abnormal huntingtin gene on chromosome 4. Ocular motor impairment is among the first manifestations in HD,[78] and the main abnormality involves the saccadic system to a greater extent than the pursuit system. This has been attributed to the close involvement of the basal ganglia with the saccadic control circuit.[79,80]
Research Findings
Impairment of both vertical and horizontal saccades was originally reported in patients suffering from manifest HD.[81] Contrary to earlier eye movement findings on premanifest HD individuals that reported intact performance,[82,83] a number of recent studies have reported deficits even in premanifest subjects. Initiation deficits of voluntary guided saccades, saccadic slowing, and delayed reflexive saccades were present.[84–86] When compared with controls, premanifest individuals also show impairment in the antisaccadic and memory-guided tasks and longer latencies, especially during the latter. Furthermore, the saccadometry research tool has proved valuable in separating premanifest, manifest, and controls who showed an increased incidence of early saccades with unusually short latencies.[84–89]
Manifest patients early in the course of their disease, exhibit reduced saccadic velocity,[78,81,90] impaired initiation of saccades, an increase in the frequency of square-wave jerks, and an increase in saccadic latencies, that is greater for voluntary than reflexive saccades. They have excessive distractibility during attempted fixation, even when specifically instructed to maintain fixation on a centrally located target.[78,91] HD patients also increased distractibility in the antisaccade task.[91,92] Impaired initiation of saccades was manifested by increased latency and the inability to make a saccade without head thrust or blink.[78] This behaviour is similar to that of patients with congenital ocular motor apraxia. Volitional saccades are also often hypometric.[84,93,94] In addition, saccadic hypometria has been documented in mildly affected HD patients.[78,91–93,95–99]
Later on in the disease, manifest patients usually begin to show more prominent slowing of saccades, as well as smooth pursuit deficits. Eventually, a reduced range of eye movements is observed with vertical saccades affected more than horizontal ones.[5,78,96] Patients who become manifest at an earlier stage tend to have slower velocity saccades, and it has been suggested that those patients are more likely to have inherited the gene from their paternal side.[93] Longitudinal studies of saccadic eye movements have reported significant progressive slowing and prolongation of reaction times and despite the great individual variation, impairment of the initial saccadic velocity is more prominent in younger patients.[100]
All the findings mentioned above can be attributed to the malfunction in parallel pathways that are utilised for the various saccadic eye movement behaviours in different saccadic paradigms. As Hikosaka et al[79] have described, a neurodegenerative disease affecting the frontal lobes or the caudate nucleus that inhibits the substantia nigra, pars reticulata (SNpr), the major outflow centre for saccades in the basal ganglia, may lead to difficulties in initiating voluntary saccades in tasks that might require learned or predictive behaviour. Furthermore, HD also affects the SNpr[101] and as the SNpr inhibits the superior colliculus (SC), it could therefore affect saccades to visual stimuli. Two distinct pathways project to the SC, working sequentially to suppress planned eye movements. One of them may be disrupted in HD as shown in Figure 1.
Figure 1.
Schematic illustration showing two pathways projecting to superior colliculus (SC) via pars reticulate (SNpr), termed the direct and indirect pathways. Excitatory projections to the caudate from the frontal cortex trigger saccades via the indirect pathway. CD inhibits the SNpr, which tonically inhibits the SC. Excitation of CN could lead to disinhibition of SC and thus generation of saccades. The direct pathway may mediate saccade initiation by decreasing GABAergic connections within the SC. A possible mechanism by which HD interferes with saccades is by disruption of the indirect pathway as shown at the point marked X; (−) inhibitory, + excitatory.
The strong correlation between the worsening of saccadic performance and disease severity, particularly in later stages of the disease, indicates that abnormalities in eye movements might be a useful and sensitive clinical marker not only in assessing motor and functional changes in HD individuals, but also in separating manifest from premanifest individuals.
Eye. 2015;29(2):200-207. © 2015 Nature Publishing Group
