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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 1-11

Evolution of eye movement abnormalities in Huntington’s disease

Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Submission21-May-2021
Date of Decision20-Jun-2021
Date of Acceptance28-Nov-2021
Date of Web Publication15-Mar-2022

Correspondence Address:
Dr. Ravi Yadav
Professor of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru - 560029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_24_21

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. Eye movement abnormalities are characteristic manifestations of HD. The clinical manifestations and eye movement disturbances progress with the natural course of illness. Eye movement abnormalities evolve in HD from the premanifest stage to the early-manifest and late-manifest stages. In the premanifest stage, voluntary saccades, i.e., memory-guided saccades and anti-saccades are predominantly affected. There is an increase in latency and error rates of voluntary saccades. Early-manifest stage of HD is characterized by abnormality in reflexive saccades, with decrease in saccadic amplitude and velocity and slow broken pursuits. In the late-manifest stage, initiation of voluntary saccades in all directions is slow, leading to difficulty in initiating voluntary eye movements. The rate of progression of the saccades, pursuits, and other ocular movement correlate with the disease progression; monitoring this helps in early disease evaluation and in evaluating novel therapies to modify the disease. In this article, we systematically review the available literature on the patterns and progression of eye movement abnormalities, from the premanifest, to manifest, and advanced stages of HD.

Keywords: Eye movement, Huntington’s disease, oculomotor, pursuits, saccades

How to cite this article:
Patel K, Kamble N, Holla VV, Pal PK, Yadav R. Evolution of eye movement abnormalities in Huntington’s disease. Ann Mov Disord 2022;5:1-11

How to cite this URL:
Patel K, Kamble N, Holla VV, Pal PK, Yadav R. Evolution of eye movement abnormalities in Huntington’s disease. Ann Mov Disord [serial online] 2022 [cited 2023 Mar 23];5:1-11. Available from: https://www.aomd.in/text.asp?2022/5/1/1/339699

  Introduction Top

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that occurs due to CAG trinucleotide repeat expansion at chromosome 4.[1] The underlying genetic abnormality was discovered in 1993. Healthy human beings have less than 40 repeats of CAG trinucleotide and expansion of more than 40 repeats; this leads to a toxic gain-of-function of the huntingtin protein, which causes selective neuronal death of medium spiny neurons of the striatum leading to development of HD.[1] Usually, patients develop the symptoms by 30–50 years.[2] Although there is an involvement of all the major organ systems of the body,[3],[4] the predominant clinical presentation is due to involuntary movements with behavioral and cognitive disturbances.[5] Significant oculomotor abnormality is the hallmark of motor abnormality in HD. If we look at neurodegenerative disorders, eye movements are distinctly involved in spinocerebellar ataxias, progressive supranuclear palsy, Neimann–Pick type C, among others. In these disorders, the pattern of eye movement dysfunction is distinctive and helps in clinical assessments and diagnosis.

Oculomotor abnormality is a vital part of motor abnormality that is observed in HD.[6] Oculomotor aberrations are involved in early HD almost 10 years before the disease onset, and evaluation of oculomotor abnormality in the preclinical stage helps in early diagnosis of the disease.[7] Neuropathological changes in HD begin long before the disease onset,[6] and there are very few predictors of disease progression. Oculomotor aberrations predict not only disease progression but also the underlying pathological changes. Oculomotor examination including saccadic initiation, velocity, and ocular pursuits are an integral part of the Unified Huntington’s Disease Rating Scale (UHDRS) and studies like the TRACK-HD and PREDICT-HD trials, which determine the clinical and biological markers of HD.[8],[9] These studies associated the poor score of saccadic initiation to increased probability for diagnosis of HD and saccadic velocity to low striatal volume.[8]

Studies have described multiple ocular abnormalities based on electrooculographic techniques, scleral search coils, infrared laser-based eye tracker, and other eye-tracking systems, with the help of objective and subjective assessments.[5],[6],[10],[11],[12] Previous studies have used electrooculogram, electronystagmogram, and the scleral search coil technique for monitoring ocular movements; however, video nystagmography, infrared eye tracker, ultraviolet miniature video camera with headband, red helium-neon laser, and video-based pupil tracker were later used because of their high accuracy and reliability. Recently, smartphone-based applications and laptops are the new tools used for the evaluation of eye movement.[13],[14]

The clinical manifestations and eye movement disturbances progress with the natural course of the illness. In this review, we have systematically discussed the available literature on the patterns and progression of eye movement abnormalities from the premanifest stage to manifest and advanced stages. We have attempted to classify the ocular findings based on the clinical stages of HD to better understand the interaction between various ocular abnormalities occurring with the clinical progression of HD.

  Methodology Top

The literature search was performed as per the PRISMA protocol [Figure 1]. PubMed (Medline), Google Scholar, ProQuest, and other databases from April 10 to August 30, 2020, were searched using the following keywords” “Huntington’s disease,” “Premanifest” AND “eye,” “oculomotor,” “saccades,” “pursuits,” “Westphal,” “eye movements,” and “antisaccades.” All articles with entitled, “Huntington’s disease” and “oculomotor abnormality” were included from 1980 to date. The list obtained was screened at the abstract level to yield studies for inclusion by two authors (K.P, R.Y.). The following criteria were used in the review: (1) original articles and review, (2) full text available in English, and (3) studies involving human subjects. Duplicate studies were manually removed. The references of the included studies were screened, and studies relevant to the present review but missed in the initial search were included.
Figure 1: PRISMA flowchart

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A total of 95 studies were initially identified from the various databases, out of which, 24 studies were identified after removing duplicate records. Twenty-one studies that satisfied the inclusion criteria were finally selected for the review. The methodology followed for the literature search is summarized in [Figure 1].

  Normal physiological basis of eye movements and basal ganglia Top

The five major eye movements are saccade, pursuit, fixation, vestibulo-ocular reflex (VOR), and optokinetic nystagmus (OKN).[5],[15] The brainstem, thalamus, basal ganglia, and cortex are involved in eye movements and their coordinated functions form a unique circuit.[7] Many of the eye movements utilize overlapping pathways for normal function [Figure 2][Figure 3][Figure 4].
Figure 2: Pathway of voluntary saccade. Frontal eye field, supplementary eye field, and prefrontal cortex are involved in the generation of voluntary saccades by stimulating the caudate nucleus. It causes inhibition of unwanted saccades by direct inhibition of the superior colliculus. Lesion at the frontostriatal pathway affects voluntary saccade generation.
PPRF: paramedian pontine reticular formation; riMLF: rostral interstitial nucleus of medial longitudinal fasciculus

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Figure 3: Antisaccade pathway. Prefrontal cortex, frontal eye field, and supplementary eye field are involved in the generation of antisaccades. The dorsolateral prefrontal cortex is involved in the inhibition of the saccade in the direction similar to that of the stimulus and the frontal eye field generates voluntary saccades in the opposite direction.
GPe: globus pallidus externa; SNr: substantia nigra

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Figure 4: Direct and indirect basal ganglia pathway involved in saccade generation. Voluntary saccades are triggered by excitatory projections to the caudate from the frontal cortex via the indirect pathway. The caudate nucleus, in turn, phasically inhibits the substantia nigra, which tonically inhibits the superior colliculus. Therefore, excitation of the caudate nucleus could lead to disinhibition of the superior colliculus and facilitate the generation of voluntary saccades. Saccade initiation may be mediated by attenuating the inhibitory pathway to the superior colliculus via the direct pathway of the basal ganglia.

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Saccades are quick and coordinated eye movements that direct the center of gaze from one object of interest to other. They are classified as volitional saccades, predictive saccades, memory guided saccades, and antisaccades. They are further defined according to latency, saccadic amplitude, and velocity. Saccades are generated in the frontal eye field area, supplementary eye field, prefrontal eye field, and parietal eye field, which then causes excitation of the caudate nucleus.[15] The caudate nucleus causes inhibition of the substantia nigra pars reticulata, which tonically inhibits the superior colliculus, which stimulates the para median reticular formation and initiates a saccade.[4],[6] The frontal cortex causes inhibition of the superior colliculus via the direct pathway or via the indirect pathway by stimulating an inhibitory pathway through suppression of unnecessary reflexive saccades by the caudate nucleus. In addition, a reflexive saccade is inhibited through the parietal eye field. There is a hyper direct pathway from the frontal eye to the superior colliculus, which causes stimulation of the superior colliculus without passing through the basal ganglia.[1]

Antisaccade consists of suppression of voluntary saccades in the same direction of stimulus and initiation of a saccade in the opposite direction. The dorsolateral prefrontal cortex and anterior cingulate cortex play an important role in the generation of antisaccades.[16]

Basal ganglia consists of direct and indirect pathways, which generate and modulate eye movements. These two pathways act sequentially to initiate and suppress eye movements. The direct pathway causes disinhibition of the superior colliculus by decreasing the GABAergic connection from the substantia nigra pars reticulata to the superior colliculus, initiating a saccade, while the indirect pathway increases GABAergic inhibitory outflow to superior colliculus and suppresses a saccade.[6]

Pursuit is low-amplitude slow eye movement, necessary to maintain foveation of a moving target. The neuronal substrate for pursuit is the lateral geniculate nucleus, striatal cortex, neocortex (middle temporal cortex, medial superior temporal area, parietal eye field, frontal eye field, and supplementary eye field), brainstem nucleus, and cerebellar structure.[15] VOR is important in maintaining visual stability when in motion. The confluence of a visual and vestibular signal occurs at the parietal cortex and cerebellum. Fixation is maintained by pursuit and VOR, and OKN ensures stabilization of the image on the fovea, when the environment is in motion, by generating smooth pursuit in the direction of the stimulus and saccades in the opposite direction.

  Various eye movement-tracking devices Top

Oculomotor abnormality can be detected by objective and subjective assessments. In various studies, multiple eye-tracking devices have been used for the objective assessment of oculomotor dysfunction. The four main eye-tracking devices are electrooculogram, the scleral coil technique, photooculogram or videooculogram, and remote base eye-tracking devices.[17]

  • 1) Electrooculogram: Electrooculogram measures the electrical potential difference between the two poles of the eyes (cornea and retina).[6],[17],[18],[19],[20],[21] Electrodes placed around the eyes measure the potential difference. Such techniques are simple to perform, without requiring any sophisticated techniques, and they are not affected by the surrounding light condition; however, electrooculogram is extremely susceptible to noise, which reduces its accuracy.

  • 2) Scleral coil technique: The scleral coil technique is considered to be the gold standard for detection of eye movements. It uses a scleral coil, which is intraoperatively placed in the sclera or through a contact lens,[5],[17],[22],[23],[24] and eye movement can be detected when the coil enters a magnetic field. This technique is reliable, and abnormal choreic movements do not interfere with the final result. This technique is invasive and has side effects such as irritability and transient visual loss, which reduces the study duration to 30 min; therefore, it has limited utility.[22]

  • 3) Photooculography or videooculography: Videooculography measures the reflected image of an infrared source on the cornea or the pupil center with a camera attached to a head band. The subjects can wear a head band, glasses, or a helmet.[6],[10],[12],[17],[20] These devices are more comfortable and less invasive. When using this tool, the head is either fixed with a head rest or a head-tracking device is used to determine head position, which is important to determine gaze.[6] The environmental condition and pupil size do interfere with the final outcome.

  • 4) Remote eye-tracking device: Remote eye-tracking devices are used to detect eye movements from a distance, without any physical contact with a patient.[17] Data are collected through a software application installed in a computer to detect and record eye movements when subjects normally use the computer. They are more accurate, and data processing is efficient, but the mobility of the subject is restricted to the work place. Moreover, the head movements create an artefact that interferes with data processing, which can be minimized with a head and chin rest or a supporting tower.

Recently, smartphone-based applications and laptops have been increasingly used for the evaluation of eye movements. They can accurately measure saccadic latency, prosaccade, and pursuits. In addition, they are readily available and less expensive tools for the measurement and evaluation of eye movements.[13],[14]

  Eye movement abnormalities in various stages of HD Top

Many studies on patients with HD have shown the presence of eye movement impairments. Patients with HD have difficulty in initiating saccade and use head thrust or eye blinking to initiate saccadic eye movements, known as oculomotor apraxia. Studies have shown the presence of a saccadic impairment in HD in the form of slow saccade, increased saccadic latency, and decreased amplitude. Slow and broken pursuits in HD occur when the patient maintains a sustained gaze to track an object. Other eye movement impairments associated with HD are, abnormality in the fast phase of OKN and VOR, abnormal fixation, impaired convergence, increase blink rate, the elevation of eyebrow due to frontalis overactivity, eye closure or blepharospasm, and apraxia of eyelid opening and closure.[7] No studies compare the evolution of eye movement abnormality in HD from the premanifest to the late-manifest stages.

[TAG:2]Eye movement abnormalities in the premanifest stage of HD (

[Table 1])[/TAG:2]

The diagnosis of HD is centered on motor manifestations like chorea, dystonia, and other extrapyramidal symptoms, with behavioral and cognitive decline; however, oculomotor impairment is an important clinical manifestation. In addition, oculomotor abnormality is noted in asymptomatic carrier patients. In 1997, Lasker and Zee reported saccadic aberrations in 50 premanifest HD patients using the scleral search coil technique, where voluntary saccade was predominantly affected with increase in latency of saccades (170 ms in HD patients and -78 ms in the control) and reduction in mean saccadic amplitude (14.2 degrees in HD patients and 17.8 degrees in the control).[5] Kirhwood et al.[25] described a slow horizontal saccade with impaired accuracy and abnormal OKN in 216 presymptomatic gene carrier (PSGC) patients using ocular examination with abnormality in six physiological measures like visual reaction time, visual reaction with the decision, movement time, movement time with the decision, auditory reaction time, and button tapping time. Peltsch et al.[6] described abnormal memory-guided saccade and antisaccades in premanifest HD using an electrooculogram and eye tracker with an infrared camera in nine patients. HD patients have saccades with a longer duration (134 ± 14 ms) and lower peak velocity (316 ± 26°/s), with direction and timing errors in antisaccades and delayed memory-guided saccades, respectively. In 2006, Belkher et al.[26] described oculomotor abnormality in the PSGC with the soft motor sign (PSGC1) and with likely motor sign (PSGC2), which manifests as HD. Compared to the non-gene carrier (NGC), PSGC patients had an increase in error rate, and the increase in fraction of missed flashes in antisaccades task (PSGC1 vs. NGC, p < 0.008; PSGC2 vs. NGC, p < 0.006; and HD vs. NGC, p < 0.0005). Saccadic latency increased in both presymptomatic patients with a possible motor sign and soft motor signs. In addition, it showed a trend of worsening latency with advancing disease (NGC < PSGC1 < PSGC2 < HD, p < 0.0001) and impaired fixation in the HD group [Table 1].
Table 1: Studies describing eye movement abnormalities in the premanifest stage of HD

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Various studies have validated that voluntary saccades, rather than reflexive saccades, are predominantly affected in the premanifest stage of HD.[5],[10],[11],[16],[25] Voluntary saccades are goal-driven eye movements that consist of memory-guided saccades and antisaccades. The most common finding in these patients is an increase in the latency of voluntary saccades[6],[10],[11],[12],[16],[25],[26],[27] and increase in the error rate during the antisaccades.[6],[10],[12],[28] Voluntary saccades increase in latency, i.e., delay in the initiation of saccades with increase in reaction time. Increased latency is associated with low saccadic amplitude and decrease in peak saccadic velocity in HD patients.[5],[6],[25]

Antisaccades consist of direction error, i.e., initiation of saccades in the wrong direction and timing error, which indicates saccades initiated in the correct direction but before the appearance of the stimulus and combined direction and timing error in HD patients.[6] Direction errors were high in the antisaccades task than prosaccade task.[6] The proportion of incorrect trials is higher in the antisaccades than prosaccades in HD patients. The delay in saccadic reaction time and error in antisaccades correlate with disease severity, according to UHDRS and provide a sensitive indicator of disease progression in HD.[6]

The frontostriatal pathway plays a critical role in voluntary saccade initiation. Any defect in this pathway will cause a delay in saccadic initiation and an increase in saccadic latency. There are studies with neuropathological confirmation of degeneration of the brainstem with early atrophy of the frontal lobe and striatum in premanifest HD.[29] Recently, [11C] raclopride (RAC) positron emission tomography has been used to assess the loss of dopamine-receptor binding, which is predominantly affected in the premanifest stage.[30] Various brain functional MRI and positron emission tomography studies have revealed early dysfunction of the frontostriatal pathway in HD.[11],[12],[27] Oculomotor abnormalities can be associated with other frontal lobe cognitive abnormalities, such as lack of attention and executive functions; defects in planning and processing speed; impairments in inhibitory control; working memory; and mental flexibility leading to impairment in psychomotor functions, multitasking organization, problem-solving skills, implicit learning, visuospatial functions, timing and movement sequencing, face and emotion processing, and recognition.[28] Oculomotor impairment can be ascribed to executive dysfunction, but studies have proved that all cognitive abnormalities may not be related to oculomotor deficits.[16]

In conclusion, the premanifest phase of HD has a slow voluntary saccade with an increase in latency and an increase error rate of antisaccades, which are associated with frontostriatal pathway dysfunction.

  Eye movement abnormalities in the early-manifest stage of HD Top

Oculomotor impairments, i.e., reflexive saccades and pursuits are present in the early-manifest stage of HD. In late 1981, Oepen et al.[29] used electronystagmogram for studying eye movement abnormality in HD patients and discovered a decrease in velocity in the vertical saccades (up to 600 ms) compared to horizontal saccades, with slow pursuits and abnormal OKN and VOR in 14 HD patients with slow eye movement during rapid eye movement sleep compared to control. A similar result was observed by Kirkham et al.[23]in 1984 using the scleral search coil technique. In 2012, Patel et al.[7]postulated abnormal slowing in reflexive and voluntary saccades in 11 HD patients. In the above study, the infrared ISCAN RK 826 PCI eye-tracking system was used to record saccadic abnormalities. HD patients have a positive correlation between slow reflexive saccades and motor score on UHDRS (p < 0.035) and with the total chorea score (p < 0.004). In 2014, Grabska et al.[31]observed a three-times increase in latency and decreased velocity of reflexive and voluntary saccades, as well as reduced amplitude of voluntary saccades in the early-manifest stage of juvenile HD. An increase in the duration of voluntary saccades by 90% in the early-manifest stage of juvenile HD resulted in a 20% error in cued saccadic task, with an increase in distractibility; increase in the mean saccadic latency positively correlated to worsening of the motor UHDRS score and inversely correlated to verbal fluency test (p < 0.05) [Table 2].
Table 2: Studies describing eye movement abnormalities in the manifest stage of HD

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From the above studies, it can be postulated that reflexive saccades and pursuits impairment are associated with the early-manifest stage of HD.[7],[18],[23],[29],[31],[32] Among the saccades, a reflexive saccade is predominantly affected. Reflexive saccades were two times slower in onset and mean saccadic duration was prolonged.[31] Vertical saccades were more affected than horizontal saccades in the early-manifest stage of the disease;[18] however, this finding was not consistent and is not reliable. Latency of saccadic initiation is associated with increase in motor score on UHDRS.[7],[31] Abnormal thrusting movement of the head and blinking were used to compensate for difficulty in the initiation of saccades in HD patients.[18],[32] Studies were able to corelate the increase in the latency of saccades and slow velocity to longer CAG repeat length, especially in juvenile HD patients.[32]

Reflexive saccades has a decrease in saccade amplitude and mean saccadic velocity. Saccades are slower and take more time to reach the target and are interrupted and appear hypometric. Motor output for all the saccadic eye movements is through the brainstem, and aberration in reflexive saccades and pursuits pathway points towards underlying brainstem degeneration and the pattern of disease progression.[5]

Pursuits are the second-most common oculomotor deficit after saccadic abnormality in HD patients. Abnormal pursuits are present in the early-manifest stage of HD, and they are slow with decrease in gain. Pursuits are broken and disrupted, which is due to saccadic intrusion during pursuits. There is a gradual decrease in gain in pursuits, leading to slow and irregular pursuits.[5],[18],[23],[24],[29],[32] Loss of neural integrator associated with slow pursuits leads to loss of fixation and inability to sustain the gaze at the target. In addition, the fast phase of OKN and VOR are affected with reduced velocity, rhythm, and regularity[18] in the early-manifest stage of HD.

Saccadic initiation occurs after release of the inhibitory signal from the pause neurons to burst neurons. Burst neurons are present in the brainstem for both horizontal and vertical saccades, which are under the control of the supranuclear gaze centers.[15] The indirect pathway is affected in the early-manifest stage, which causes suppression of signals from the superior colliculus to brainstem oculomotor centers; therefore, it affects the initiation of a saccade. It leads to a slow saccade, with a decrease in amplitude and velocity. This is confirmed by histopathological studies, where the subcortical pathway and brainstem degeneration are present in the early-manifest phase of HD.[29] The underlying pathophysiology of slow pursuit and abnormal fixation is not known. With the involvement of the indirect pathway, there is loss of inhibition from the substantia nigra to the thalamus, which leads to chorea and other movement abnormalities.

Therefore, the early-manifest stage of HD is characterized by abnormalities in the reflexive saccade, with slow pursuits and involuntary movements and underlying abnormalities in the indirect pathway of the basal ganglia.

  Eye movement abnormalities in the late-manifest stage of HD (advanced HD) Top

The late-manifest stage of HD is symbolized by presence of parkinsonian symptoms, such as rigidity, tremors, and bradykinesia, along with oculomotor abnormalities and reduction in the severity of chorea, due to the involvement of the direct pathway along with the indirect pathway of the basal ganglia. Kirkham et al.[23] demonstrated slowing of voluntary saccades with advancing HD. Peltsch et al.[6] postulated localized cell death in the brainstem of HD patients, which leads to abnormalities in the generation of both the automatic and voluntary saccades. Patel et al.[7] demonstrated severe slowness in initiating a reflexive and voluntary saccade with increasing clinical severity in HD patients. Furthermore, Becker et al.[19] postulated saccadic slowing with worsening of difficulties in saccade initiation to an extent where patients found it impossible to initiate a saccade and shift their gaze without resorting to large head movements [Table 2].

Therefore, in the later stage of HD, there is slowing of saccades and difficulty in initiation of saccades. This is due to involvement of the direct pathway of the basal ganglia with decrease in excitability in the superior colliculus, leading to impairment in saccade initiation. It leads to the total absence of voluntary saccadic eye movements, which are compensated by abnormal thrusting movements of the head.[5],[6],[7],[19],[23],[32] Since the patient has slow initiation of saccades in all directions, it leads to impairment of all the other eye movements. Impairment of the direct pathway of the basal ganglia leads to development of  Parkinsonism More Details with rigidity and bradykinesia.

Blepharospasm is another important eye movement abnormality associated with all the stages of HD. It can cause increased blink rate, photophobia, and eyelid opening apraxia. It is caused due to loss of dopamine receptors and altered sensorimotor learning.[33] Other oculomotor abnormalities noted in HD are abnormal fixation, impaired convergence, elevation of eyebrows due to frontalis overactivity, and apraxia of eyelid opening and closure.[7]

  Future Direction Top

HD is an autosomal dominant disorder due to trinucleotide repeat expansion. The number of CAG repeats can predict the age of onset of HD but not the age at which clinical symptoms will appear.[11] Oculomotor impairments are associated with all the stages of HD and are easy to diagnose with simple and careful neurological examination. While in the premanifest stage, voluntary saccades are predominantly affected, the early-manifest stage has abnormal reflexive saccades and broken pursuits. In the late-manifest stage of HD, very slow saccades lead to the inability of initiating voluntary eye movement, as shown in [Figure 5].
Figure 5: Timeline of eye movement impairment in patients with Huntington’s disease

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Since the initial stages of HD are usually insidious and the rate of clinical progression variable, it is vital to identify biomarkers that can detect and monitor new neuropathological changes.

  Conclusion Top

Monitoring the rate of progression of saccadic and other eye movement abnormalities from premanifest, to early, and late manifest stage will enable us to track the disease severity in HD patients and evaluate novel therapies to modify the disease. Further long-term studies will help identify the markers of disease progression as well as therapeutics for disease modification.



Author contribution

KP- Literature search, data acquisition and analysis, manuscript preparation.

NK- Intellectual concept and manuscript review.

VH- Intellectual concept and manuscript review.

PKP- Intellectual concept, manuscript editing and manuscript review.

RY- Concept, design, intellectual content, manuscript editing and manuscript review.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]


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