Clinical manifestations

Many movement disorders and most neurodegenerative diseases are associated with a variety of visual and ocular motor impairments that may be troublesome for the patients and adversely impact their quality of life (132; 88; 128). These ophthalmologic symptoms may arise from problems with visual processing, impaired subcortical and cortical control of eye motility, and other still poorly understood mechanisms. The neuro-ophthalmologic features of some of the most common movement disorders are discussed in this article and summarized in Table 1.

Ophthalmologic signs of disorders with parkinsonism include the following:

Parkinson disease. Ophthalmologic sensory and motor symptoms in patients with Parkinson disease can result from dysfunction at several anatomic levels, including ocular and orbital structures, subcortical pathways, and cortical centers involved in regulation of ocular motility and visual processing. In an observational study of 848 patients with Parkinson disease and 250 healthy controls, one or more ophthalmologic symptoms were reported by 82% of patients and 42% of healthy adults (19). Ophthalmologic symptoms interfered with daily activity in 68% of patients. Subjective dry eye symptoms were reported in 61% of patients with Parkinson disease (93). Other common ocular complaints reported by about two thirds of patients with Parkinson disease are photophobia, tearing, eye pain, or gritty eye sensation suggestive of ocular surface irritation (16; 19). Reduced blink rate can contribute to precorneal tear film dysfunction and worsen eye discomfort in patients with Parkinson disease. This ocular surface irritation on a background of primary basal ganglia dysfunction has been implicated in the development of peripherally induced blepharospasm (60; 52; 67). Blepharospasm with or without apraxia of eyelid opening, characterized by difficulties opening the lids after voluntary closure, is more common in advanced idiopathic Parkinson disease or atypical parkinsonism with progressive supranuclear palsy, leading the group of parkinsonian disorders associated with prominent eyelid motility dysfunction (16; 134; 105). In patients with Parkinson disease and other parkinsonian syndromes, reduced blink rate often co-exists with glabellar reflex, or Myerson sign, and is characterized by nonsuppression of blinking with repetitive tapping of the glabella. This reflex is a relatively sensitive sign of Parkinson disease and atypical parkinsonism, but it lacks specificity to differentiate between particular parkinsonian disorders (22). Blink rate can be influenced by the corneal sub-basal nerve density, and the latter was found to be markedly reduced in 15 patients with Parkinson disease as compared to healthy controls (91). Previous studies have reported that the spontaneous eyeblink rate correlated with the dopamine levels in the brain and plasma levodopa levels; therefore, it might serve as a potential biomarker of the dopaminergic brain function and motor fluctuations in patients with Parkinson disease (64).

Search for potential biomarkers of Parkinson disease in tear chemical profile revealed significantly elevated levels of oligomeric α-Synuclein, CCL2 (a secreted chemokine induced by TNF- α), and lactoferrin in reflex tears (tears in response to stimulation of sensory nerves of the ocular surface) in patients with Parkinson disease relative to healthy controls (55; 110). Other changes in tear biochemistry found in search for potential biomarkers of Parkinson disease include decreased levels of total alpha-synuclein, increased levels of norepinephrine, dopamine, and alpha-2-macroglobulin compared to tears from healthy controls (76). Proteins involved in immune response, lipid metabolism, oxidative stress, collagen degradation, protein synthesis, lipid transport were found to be deregulated in tears of patients with Parkinson disease (76). A study of proteome profiles of 24 patients with idiopathic Parkinson disease, three carriers of E46K mutation in alpha-synuclein gene (SNCA), and 27 healthy controls identified six deregulated proteins in patients with Parkinson disease (01). These proteins were associated with alterations in lysosomal autophagy, apoptosis, retrograde axonal transport, and demyelination. Three of those proteins showed good capability to differentiate patients with Parkinson disease from healthy controls – cathepsin D, acid ceramidase, and cytoplasmic dynein 1.

Impaired eye motility is another common ophthalmologic finding in patients with Parkinson disease (103). This group of symptoms includes convergence insufficiency, abnormal saccades (rapid eye movements that shift gaze from one location to another), impaired smooth pursuit, upgaze limitation, and square-wave jerks (inappropriate saccades that take the eye off the target, followed by inter-saccadic interval, and another corrective saccade that brings the eye back to the target). Although reflexive, visually-guided saccades (prosaccades) are usually preserved in early stages of disease, voluntary saccades represented by anti-saccades (saccades in the opposite direction to a stimulus) and memory-guided saccades (saccades for a remembered target that has subsequently disappeared) are commonly impaired in early Parkinson disease (21; 118). Prosaccadic latency is significantly affected (prolonged) by dopaminergic medication. On the contrary, antisaccadic latency is affected largely by the disease state with no medication effect (86). Impaired smooth pursuit is observed in more advanced Parkinson disease and characterized by deficit in smooth pursuit gain, intrusion of catch-up saccades, decreased peak velocity, and progressive displacement reduction with repetitive movements similar to that seen with other motor tasks in Parkinson disease (80). The latter phenomena could be potentially explained by easy fatigability in Parkinson disease rather than direct disruption of ocular smooth pursuit pathways as they are not directly connected to the basal ganglia (75). Visual exploration strategies that consist of alternating runs of saccades and gaze fixations were found to be impaired in patients with Parkinson disease versus healthy controls, and more affected in Parkinson disease patients with cognitive impairment versus Parkinson disease with normal cognitive function (08). Convergence insufficiency (inability to maintain binocular eye alignment on an object as it approaches from distance to near) is another common neuro-ophthalmologic feature of Parkinson disease. Decreased convergence amplitude (measured by placing increasing base out prism over one eye until a patient develops diplopia due to inability to fuse near target) can be accompanied by normal near point of convergence in early Parkinson disease (16) or more remote near point later in the course of the disease (02). Convergence insufficiency in association with presbyopia can be worsened by base-out effect (prism rotation towards the ear) from bifocal lenses often prescribed to older people. On the other hand, monocular vision using a simple eye-patch over one eye may actually facilitate reading in patients with Parkinson disease with marked convergence insufficiency. Patients with Parkinson disease also frequently have mild restriction of upgaze as opposed to limitation of downward gaze in another parkinsonian disorder, progressive supranuclear palsy. Deficits in ocular fixation, manifesting as pervasive oscillatory eye movements while attempting to fixate on a still object, is another characteristic ocular phenomenon in Parkinson disease, named ocular tremor, with no difference between medicated versus nonmedicated patients (47). The controversy remains around ocular tremor being a presentation of Parkinson disease tremor similar to limb tremor and often having the same frequency versus just vestibulo-ocular reflex induced by head oscillations transmitted from a tremulous limb (47; 34; 74; 48).

Visual perception is also impaired in Parkinson disease affecting visual acuity, color discrimination, contrast sensitivity, and perception of motion (71; 102; 30; 92; 122; 07; 95; 17; 11). The Survey of Health, Ageing, and Retirement in Europe (SHARE) study of 115,240 individuals 50 years of age and older conducted in 27 countries reported increased odds of impaired overall (odds ratio 2.67), distance (odds ratio 2.55), and near (odds ratio 2.07) eyesight in patients with Parkinson disease compared to nondiseased individuals (54). Electroretinography and optical coherence tomography, coupled with pathological findings of thinning of the retinal nerve fiber layer, provide evidence for retinal foveal deficit in Parkinson disease (17). Some studies have suggested retinal thinning in patients with Parkinson disease, partly due to dopaminergic neuronal loss (18). Retinal nerve fiber layer thinning may be associated with visual hallucinations and risk of dementia (79; 83; 126). Impaired color discrimination was found mainly along red-green axis in the contrast to aging-dependent color vision impairment affecting mainly blue-yellow axis or retinal disease where all color axes are affected (07; 95). Contrast sensitivity and color discrimination impairment often worsens with progression of Parkinson disease but may improve with levodopa (61; 23). Decreased sensory visual function in Parkinson disease can be a consequence of retinal and postretinal dysfunction. Primary deficiency of retinal dopaminergic circuits with reduced dopamine level in retina was found in patients with Parkinson disease (94; 57). Previous studies reported thinning of inner retina even in early Parkinson disease, with alpha-synuclein accumulation discovered in the postmortem eyes of some but not all patients with Parkinson disease (28; 51; 18; 24). Degree of foveal thinning and retinal nerve fiber atrophy were correlated with Parkinson disease duration and severity in studies (113). Thinning of the retinal nerve fiber layer was found to be more significant in the temporal and inferior quadrants of the retina in patients with Parkinson disease compared to healthy controls, especially in the eye contralateral to the side of the body most affected by Parkinson disease (78; 136). Similar pattern of retinal pathology with predominant temporal fibers atrophy is observed in axonal optic neuropathies associated with mitochondrial disorders involving complex I defect, such as Leber hereditary optic neuropathy. This observation might support the hypothesis of mitochondrial dysfunction in the pathogenesis of Parkinson disease (78). It is not well known if retinopathy alone or its combination with affected subcortical visual pathways and cortical visual processing centers can be implicated in sensory visual dysfunction in Parkinson disease (07). Changes in choroid layer thickness and choriocapillaris vascular flow density in the eye of patients with Parkinson disease were identified with the use of optical coherence tomography (31; 135). Some studies reported decrease of the choroid thickness in Parkinson disease and attributed it to blood flow irregularities and atrophy (36). On the contrary, other studies using a different method of measuring choroid thickness found thickened macular and peripapillary choroid in Parkinson eyes (114). The authors suggested the alterations in perivascular connective tissue density and not hypoperfusion alone to be the mechanisms behind the changes in the choroid layer in Parkinson disease. The study evaluating macular thickness and peripapillary retinal nerve fiber layer in 28 healthy controls, 48 patients with Parkinson disease, 18 with progressive supranuclear palsy, and 38 with multiple system atrophy found different patterns of retinal changes in all groups, thus suggesting that optical coherence tomography could be a biomarker for differential diagnosis of parkinsonian disorders (87). Macular thickness and volume were markedly thinner in multiple system atrophy than in Parkinson disease, whereas patients with progressive supranuclear palsy had increased retinal nerve fiber thickness in temporal sector compared to other patients and healthy controls.

Visual hallucinations are common among patients with Parkinson disease and could be at least partially related to impaired visual processing (40; 126). Functional brain imaging in Parkinson disease patients with visual hallucinations identified global loss of connectivity affecting attention and perception (58). The majority of hallucinations are minor, such as illusions, sensation of presence, or sideways passage of a live object. Formed visual hallucinations are less frequent. Risk factors for hallucinations in Parkinson disease are advanced disease, significant cognitive decline, ocular disorders, and sleep-wake cycle disturbance (40). Although use of dopaminergic and anticholinergic medications without other contributors was thought not to be an important risk factor for hallucinations (40; 90), anti-Parkinson disease medications, particularly dopamine agonists, levodopa, and anticholinergic medications, clearly play an important role in visual hallucinations as reduction in dosage or discontinuation leads to improvement or resolution of this symptom, and this strategy is recommended in management. Visual hallucinations early in the course of the disease might suggest evolution into dementia with Lewy bodies (40).

Several case reports described corneal edema as a side effect of amantadine, which is often used for treatment of motor symptoms of Parkinson disease (42; 89). Relative risk of corneal edema was estimated at 1.7 among the patients on amantadine, and it was usually observed within the first year of amantadine use. The exact mechanism of corneal edema remains unclear. Because only a small number on patients treated with amantadine develop corneal edema, it was suggested that the variable distribution of the dopamine receptors in the endothelial cells of the cornea might explain increased sensitivity to dopamine in some but not all patients. Few cases of reversible corneal edema linked to the use of ropinirole were also reported (89).

Recognition and treatment of the ophthalmologic symptoms in patients with Parkinson disease can significantly improve their quality of life. Inadequate corneal lubrication can be improved with the use of artificial tears. In severe cases of dry eyes, punctal occlusion might be beneficial. Botulinum toxin injections are used in the treatment of blepharospasm with or without apraxia of eyelid opening. Visual perception in patients with Parkinson disease with abnormal contrast sensitivity and color discrimination can be improved by the use of ample ambient light while reading (16). Reading glasses with base-in rather than base-out lenses should be prescribed to patients with convergence insufficiency. If comfortable binocular vision cannot be achieved with appropriate lenses, patients can use monocular occlusion while reading or using a computer. Visual hallucinations may require modification of Parkinson disease medications. Atypical neuroleptics or pimavanserin, a selective serotonin 5-HT2A inverse agonist, might be prescribed to the patients with Parkinson disease who have persistent hallucinations (29; 27).

Progressive supranuclear palsy. Impaired eye motility is a cardinal feature of progressive supranuclear palsy that helps to differentiate this disorder from similar neurodegenerative diseases with parkinsonism. Slowing of vertical, particularly downward, saccades even in the presence of full range of vertical gaze, best elicited by moving an optokinetic tape in an upward direction, is one of the earliest neuro-ophthalmological signs of progressive supranuclear palsy. Slowing of horizontal saccades, hypometric saccades, impaired antisaccades and smooth pursuit, abnormal downward optokinetic nystagmus with impaired slow phase response, and slow quick phase combined with square-wave jerks are also among the earliest ocular motor features of progressive supranuclear palsy, often preceding the development of characteristic supranuclear gaze palsy or other motor signs (123; 108; 44; 56; 10). Square-wave jerks are much more prevalent in progressive supranuclear palsy as compared to healthy controls and patients with Parkinson disease. The volumes of the midbrain measured with Voxel-based morphometry MRI were not correlated with the square-wave jerk rate (04). Instead, associations were found for atrophy in the superior, middle, and inferior temporal gyri. The findings indicate that supratentorial cortical structures located mainly in the temporal lobe are deeply involved in the generation of abnormally high square-wave jerk rates in patients with progressive supranuclear palsy. With progression of the disease, vertical eye movement limitation occurs with downgaze palsy developing before upgaze restriction, followed by limitation of lateral eye movements, sometimes preceded by internuclear ophthalmoplegia, and eventually progressing to complete ophthalmoplegia. Another characteristic sign of progressive supranuclear palsy is the "round the houses" sign (104; 100). The patient exhibiting this sign is unable to make pure vertical saccades along a straight line in the midline; instead, his eye makes a lateral arc, which creates a curve course of oblique saccades.

Ability to overcome ophthalmoparesis with an oculocephalic maneuver is lost in the late stages of progressive supranuclear palsy (nuclear ophthalmoplegia), indicating involvement of brainstem nuclei in the pathological process (63). Degeneration of the subcortical pathways and cortical centers of eye motility are implicated in the prominent ocular motor symptoms of progressive supranuclear palsy (53; 130). Although ophthalmoparesis is the clinical hallmark of progressive supranuclear palsy, pathologically documented cases of progressive supranuclear palsy without ophthalmoparesis have been reported (25). On the other hand, it is important to remember that supranuclear ophthalmoparesis can occur in other disorders, such as corticobasal degeneration, dementia with Lewy bodies, postencephalitic parkinsonism, Wernicke encephalopathy, Whipple disease, stiff-person syndrome, neuroacanthocytosis, progressive external ophthalmoplegia, hydrocephalus, Kufor-Rakeb syndrome, and other neurologic disorders.

Abnormal eyelid motility in progressive supranuclear palsy, including decreased blink rate, eyelid retraction, blepharospasm and apraxia of eyelid opening and closure, can be present already in early stages of the disease (43; 50). Apraxia of eyelid movements is often attributed to supranuclear inhibition of levator palpebrae muscle (81), loss of reciprocal relationship between levator palpebrae and pretarsal portion of the orbicularis oculi muscles (101), or eyelid freezing similar to sudden freezing of the other movements in parkinsonian disorders (65). Eyelid reflexes are also impaired, including acoustic blink reflex (a brief eye closure in response to a sudden sound) (46). Abnormal eyelid and ocular motility combined with “worried” or “astonished” facial expression, partly due to contraction of the procerus and possibly corrugator muscles (so called “procerus sign”), create a characteristic facial appearance of a patient with progressive supranuclear palsy that can be distinguished from other parkinsonian disorders (111).

Other less known but not uncommon ophthalmologic features of progressive supranuclear palsy are decreased pupillary diameter in the dark (115), involuntary persistence of ocular fixation (absent suppression of ocular fixation to allow gaze shifts), and difficult suppression of the vestibule-ocular reflex (106). Patients with progressive supranuclear palsy might have vertical jerky eye oscillations during oculographic testing that might be interpreted as “downbeat nystagmus.” However, Ticku and colleagues have observed that those oscillations were phase-locked and frequency-matched with subtle head jerks and that they could be eliminated by adequate head stabilization (121). Therefore, such vertical eye oscillations were interpreted as “pseudonystagmus” representing vestibulo-ocular reflex.

Other parkinsonian disorders. In addition to Parkinson disease and progressive supranuclear palsy, blepharospasm may be a disabling symptom in patients with multiple system atrophy (16; 72). Dry eyes, conjugate eye movement abnormalities, and ocular misalignment are the most common findings in patients with multiple system atrophy (45). The disease is also often associated with a variety of ocular motor abnormalities, including spontaneous and gaze-evoked nystagmus, square wave jerks, slow and hypometric saccades, diminished vestibular-ocular reflex suppression, internuclear ophthalmoparesis, reduced vestibulo-ocular reflex suppression, and impaired vertical gaze (05; 37). Gorges and colleagues studied smooth pursuit and visually guided reactive saccades compared to the microstructural alterations on the brain diffusion tensor imaging in patients with Parkinson disease, progressive supranuclear palsy, and multiple system atrophy (49). Smooth pursuit was impaired in patients with multiple system atrophy with “catch-up” saccades, resulting in significantly reduced pursuit gain. The shape of saccadic pursuit was correlated with alterations on diffusion tensor imaging in the middle cerebral peduncle. Peak eye velocity was markedly reduced in patients with progressive supranuclear palsy and correlated significantly with microstructural impairment in the midbrain.

In corticobasal degeneration, horizontal saccades commonly have prolonged latency correlating with “apraxia score” but normal speed of saccadic eye movements (123). Vertical saccades are usually preserved or only minimally impaired on upward gaze.

One of the most prominent features of dementia with Lewy bodies is the presence of visual hallucinations early in the course of the disease. Patho-anatomical studies identified nonspecific neurodegenerative changes without alpha-synuclein inclusions in postmortem retinas of patients with dementia with Lewy bodies, but Lewy bodies were identified in substantia nigra and neocortex (28). Furthermore, amplitude, velocity, and latency of saccades are typically impaired in dementia with Lewy bodies (73).

Ophthalmologic signs of hyperkinetic movement disorders include the following:

Huntington disease. Impaired saccadic eye movements are among the earliest signs of Huntington disease and are characterized by increased saccade latency with increased variability of saccade latency, slowing of vertical and horizontal saccades, and difficulty suppressing reflexive saccades. Abnormal saccadic latency in Huntington disease demonstrates more systematic and steady worsening year-to-year than progression of other motor abnormalities, thus, highlighting the importance of this ocular sign in tracking disease progression (06). Voluntary saccades, including antisaccades and memory-guided saccades, were shown to be more consistently affected early in the course of disease than reflexive saccades; but both reflexive and voluntary eye motor control in patients with Huntington disease has been shown to decrease with increased disease severity, suggesting that simple tasks, such as prosaccades and antisaccades, can serve as quantitative biomarkers of disease progression in Huntington disease (98).

Increased saccadic latency and error rates can be observed in the premanifest stage of Huntington disease in proportion to the predicted age of the disease onset (59). Correlation was also found between latency of vertical antisaccades and degree of atrophy in the left superior frontal gyrus, left inferior parietal lobule, and bilateral caudate nuclei (112). Coppen and colleagues reported correlation between oculomotor dysfunction and cortical volume loss on brain MRI, especially in occipital regions, whereas chorea was mainly associated with subcortical volume loss (26). Other ocular motor findings in Huntington disease include increased blink rate and impaired smooth pursuit, but despite loss of balance, the vestibulo-ocular reflex appears to be preserved. Blepharospasm and apraxia of eyelid opening and closing are rare ocular signs of Huntington disease.

Significant reduction in macular retinal thickness and inferior peripapillary retinal nerve fiber layer thickness was found in Huntington disease patients compared to healthy controls with 25 subjects in each study arm (03). Another study of 41 Huntington patients and 41 healthy controls reported diffuse retinal changes in retinal nerve fiber layer and macula in the diseased group but concluded that the changes were too small and not suitable to be considered as biomarkers of the disease (33).

Dystonia and other facial spasms. Blepharospasm is a type of focal dystonia affecting eyelids and often can be a part of cranial-cervical dystonia. Many patients with blepharospasm present with the complaints suggestive of ocular surface irritation, such as dry eye, photophobia, or sensation of foreign object in the eye (52; 97). Before the development of sustained eyelid spasms that are characteristic features of blepharospasm, about one third of the patients recall having excessive blinking. As the disorder progresses, the patients develop clonic and later tonic (sustained) contractions of orbicularis oculi muscles causing forceful closure of the eyelids. This should be differentiated from ptosis caused by weakness of the levator palpebrae. Blepharospasm is usually an idiopathic disorder, a form of primary focal dystonia; however, it can occur as secondary dystonia in the setting of tardive dystonia, structural brain lesions (such as stroke or multiple sclerosis), or as a symptom of some neurodegenerative disorders (eg, atypical parkinsonism, Huntington disease). Blepharospasm may be associated with apraxia of eyelid opening or closure, particularly in patients with atypical parkinsonism.

In primary blepharospasm, apraxia of eyelid opening was reported in 4% of patients (99). Botulinum toxin injections are very effective in the treatment of blepharospasm, but apraxia of eyelid opening is much more difficult to treat with botulinum toxin unless the latter is triggered by the blepharospasm (66; 68). Transient improvement of blepharospasm was observed in seven patients treated with apraclonidine, an alpha-2 adrenergic receptor agonist that causes contraction of superior tarsal (Müller) muscle resulting in improvement of blepharospasm-related eyelid closure (124).

Oculogyric crisis is a type of focal dystonia characterized by sustained contractures of ocular muscles, resulting in conjugate tonic ocular deviation usually up or to one side. Oculogyria was a prominent ophthalmologic sign of encephalitis lethargica and subsequent postencephalitic parkinsonism, a disorder that is rarely seen in present days (125). Today, oculogyric crisis is usually indicative of drug-induced acute and tardive dystonic reaction as a complication of dopamine-blocking medication use (41). This symptom can also be observed in a group of inherited disorders of monoamine metabolism, such as aromatic amino acid decarboxylase deficiency, tyrosine hydroxylase deficiency, and pterin metabolism defect (77; 131). Because inherited metabolic disorders often manifest in childhood, it is important to differentiate oculogyric crisis from a relatively benign childhood condition called paroxysmal tonic upgaze of infancy (84). Infants present with paroxysmal conjugate deviation of the eyes upward associated with neck flexion, downbeat saccades on attempted downgaze, mild ataxia or otherwise normal neurologic examination and ancillary tests, and ultimate resolution of the symptoms without residual deficit or with minor oculomotor symptoms and borderline cognitive disability.

Hemifacial spasm is not classified as focal dystonia but rather a peripherally induced movement disorder involving facial muscles, including periorbital muscles and eyelids, and often causing eye closure that can resemble blepharospasm (133). In contrast to blepharospasm, hemifacial spasm is almost always unilateral. Another feature that can help to distinguish these two disorders from each other is ipsilateral eyebrow elevation by frontalis contraction in hemifacial spasm, so-called “other Babinski sign” (119), as opposed to depression of the eyebrows in blepharospasm due to contraction of the procerus, corrugator, and orbicularis oculi muscles.

Hemifacial spasm is most frequently caused by facial nerve compression by a blood vessel at the exit of the nerve root, but it can be encountered in patients with demyelinating CNS disease, structural lesions in the middle, or posterior cranial fossa. Botulinum toxin injections are considered the treatment of choice for hemifacial spasm, although surgical vascular decompression of the facial nerve is still used in some cases.

Tourette syndrome. Motor tics in Tourette syndrome often involve ocular or eyelid movements (69). Excessive blinking is one of the most common simple clonic tics. Oculogyric deviations seen in 28% of patients with Huntington disease and blepharospasm (15% of patients) are the examples of simple dystonic tics (70).

Patients with Tourette syndrome also demonstrate higher rate of antisaccades errors than healthy controls (38). Although dopamine-blocking or dopamine-depleting drugs are often used in the management of tics, botulinum toxin injections can provide additional benefit for blinking tics and blepharospasm associated with Tourette syndrome.

Movement disorders with ataxia. Movement disorders with ataxia as a main component of clinical presentation include multiple types of hereditary spinocerebellar atrophy, ataxia-telangiectasia syndrome, episodic ataxias, multiple system atrophy, alcohol-related cerebellar degeneration, and other disorders (15). Gaze-evoked and spontaneous nystagmus, ocular dysmetria with hypermetric saccades (overshoot of eye movements), square-wave jerks, and impaired smooth pursuit with saccadic intrusions are common ophthalmologic signs of heterogeneous diseases with cerebellar pathway dysfunction independent of etiology.

Some ocular symptoms are observed mostly or exclusively in certain types of spinocerebellar ataxias (96). Slow saccades occur in spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, and spinocerebellar ataxia type 7. Spinocerebellar ataxia type 3 can be associated with supranuclear ophthalmoparesis, rebound nystagmus, lid retraction with bulging eyes, and decreased blink rate. Retinal changes with thinning of peripapillary retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer were found in patients with spinocerebellar ataxia type 3 compared to healthy controls (107). Retinal layers thickness negatively correlated with ataxia severity rating scales. Downbeat positional nystagmus and rebound nystagmus are often seen in spinocerebellar ataxia type 6. Spinocerebellar ataxia type 7 is the only spinocerebellar atrophy syndrome with prominent visual disturbances, including retinal degeneration and pigmentary retinopathy with optic atrophy leading to blindness. Visual disturbance might precede other neurologic symptoms in spinocerebellar ataxia type 7 (96). Progressive ophthalmoplegia is another characteristic feature of spinocerebellar ataxia type 7. Retinal nerve fiber layer thinning and optic nerve atrophy were documented in patients with spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, and spinocerebellar ataxia type 3 (96).

Ataxia-telangiectasia is an autosomal-recessive disorder with early ocular signs, such as conjunctival telangiectasia and oculomotor apraxia, manifested by loss of volitional saccades so that the patients thrust their heads in the direction of interest to bring the eyes into alignment with the object of interest (109). Other neuro-ophthalmological signs associated with ataxia-telangiectasia include impaired fixation, accommodation deficiency, impaired smooth pursuit, hypometric saccades, nystagmus, increased blink rate, and photophobia.

Episodic ataxia type 1 is a channelopathy involving potassium channels often presenting with periorbital myokymia, which persists even between the ataxia attacks (127). Episodic ataxia type 2 is a calcium channelopathy disorder with characteristic downbeat nystagmus along with bouts of ataxia often with diplopia.

Wernicke encephalopathy is a neurologic disorder secondary to thiamine deficiency that manifests as a triad of altered mental status, ataxia, and ocular motor abnormalities; however, many patients present with an incomplete clinical triad. Nystagmus is the most common ophthalmologic presentation of Wernicke encephalopathy. It ranges from gaze-evoked, nonsustained horizontal nystagmus in early stages of the disease to sustained nystagmus with gaze-holding failure in later stages (62). Primary gaze upbeat nystagmus is observed in Wernicke encephalopathy, and it sometimes switches to permanent downbeat nystagmus that is thought to indicate a chronic state and poor prognosis for recovery (62). Other ocular motor signs include bilateral abducens nerve palsy followed by conjugate gaze palsy with horizontal gaze affected more than vertical. Complete ophthalmoplegia is an uncommon presentation of Wernicke encephalopathy. Vision loss is an uncommon symptom of the disease that might be the result of optic neuropathy with disc edema and retinal hemorrhages. Most ophthalmologic findings in Wernicke encephalopathy are reversible and improve dramatically with thiamine replacement treatment.

Hyperkinetic movement disorders in diabetes. Chorea, athetosis, ballism, or their combination are uncommon but often disabling conditions in patients with poorly controlled diabetes and can present as acute, chronic, or paroxysmal movement disorders (85). It has been suggested that the presence and degree of diabetic retinopathy can be an indirect marker of striatopallidal microangiopathy in patients with diabetes because both the retina and striatum/globus pallidus pars externa lack collateral blood circulation. Therefore, patients with a more advanced diabetic retinopathy have a higher risk of hyperkinetic movement disorders of diabetic striatopathy and a poorer prognosis for recovery (85).

Ophthalmologic signs of other movement disorders include the following:

Wilson disease. The best-known ophthalmologic feature of Wilson disease is the Kayser-Fleischer ring, which is a clinically asymptomatic brown or green deposition of copper in the peripheral Descemet membrane around the iris, best visualized with a slit lamp. Sunflower cataract is another ocular sign of Wilson disease associated with copper deposition in the lens capsule, but it usually does not affect vision (129). Saccades, smooth pursuit, and range of ocular motility can also be affected, although these findings are not specific for Wilson disease (82).

Neurodegeneration with brain iron accumulation and neuroacanthocytosis. Neurodegeneration with brain iron accumulation disorders and neuroacanthocytosis often have prominent ophthalmologic features, including abnormal eye motility, such as impaired saccades and smooth pursuit; convergence insufficiency; gaze palsy; and apraxia of gaze (32; 116). Patients with neurodegeneration with brain iron accumulation can also present with visual dysfunction (retinitis pigmentosa and optic nerve atrophy resulting in diminished vision) and pupillary abnormality (eg, Adie pupils) (35).

Psychogenic movement disorders. Ocular symptoms, including complaints of blindness, double vision that often persists with monocular occlusion, psychogenic blepharospasm and hemifacial spasm, opsoclonus, and oculogyric movements, are frequently seen in psychogenic disorders (14). Convergence spasm was reported in 69% of patients with psychogenic movement disorders (39). This ocular sign is characterized by transient ocular convergence, miosis, and accommodation associated with dysconjugate gaze that mimics abducens palsy.

It is important to remember that convergence spasm can occur in healthy individuals as well as in organic neurologic and ophthalmologic disorders, such as strabismus, metabolic encephalopathy, encephalitis, genetic disorders of dopamine metabolism, multiple sclerosis, and brainstem ischemia; therefore, interpretation of this neuro-ophthalmologic finding should be conducted in the appropriate clinical context.

Whipple disease. Whipple disease is an infectious disorder caused by Tropheryma whipplei with multisystem involvement including prominent neuro-psychiatric presentation. Oculomasticatory myorhythmia is one of the most distinguishing features of Whipple disease and is characterized by pendular vergence oscillations of the eyes and concurrent contractions of masticatory muscles (117; 12). Other ocular symptoms of Whipple disease include retinitis, uveitis, vitreitis, papilledema, optic nerve atrophy, and nystagmus.

Opsoclonus-myoclonus syndrome. Opsoclonus-myoclonus syndrome (or dancing eyes-dancing feet syndrome) is an immune-mediated syndrome characterized by acute to subacute onset of neurologic and ocular symptoms including ataxia, abnormal eye movements (such as bizarre, non-rhythmic, involuntary horizontal and vertical eye movements/opsoclonus), myoclonic jerks, and behavioral changes (13). Parainfectious opsoclonus-myoclonus syndrome is usually associated with West Nile virus, cytomegalovirus, Epstein-Barr virus, HIV and Herpes viruses, and some bacterial infections. Paraneoplastic opsoclonus-myoclonus can manifest in children with neuroblastoma or in adults with squamous cell carcinoma or adenocarcinoma (09). Some of these disorders are associated with loss of peripheral vestibular function resulting in nystagmus and oscillopsia (illusion that the environment is moving), particularly during walking (120). Early diagnosis and treatment of the primary diseases is of paramount importance in the management of movement disorders of infectious or autoimmune etiology.

Oculopalatal tremor is a rare condition resulting from any interruption of a brainstem circuitry within the Guillain-Mollaret triangle formed by the contralateral dentate nucleus, ipsilateral red nucleus, and inferior olivary nucleus (20; 12). The disorder manifests as a combination of pendular nystagmus synchronous with rhythmical, 1 to 3 Hz, contractions of the soft palate and pharynx. Although palatal or pharyngeal tremor (also referred to as “palatal myoclonus”) is almost always asymptomatic, oscillopsia (visual illusion of to-and-fro movement of the environment) is usually disturbing to the patients.

Treatment with gabapentin or memantine might be effective in oculopalatal tremor (20).

Table 1. Neuro-Ophthalmologic Features in Movement Disorders