Neurodegenerative Diseases

PD is the most common of the synucleinopathies, a group of neurodegenerative diseases characterized by toxic accumulation of the protein α-synuclein. More than 1 million individuals in the United States have PD, which affects 1% of the population over age 60. Although the average age of symptom onset is 57, up to 10% of patients have early onset PD, with symptoms beginning before the age of 50.

PD is identified by the presence of motor symptoms such as bradykinesia, rigidity, resting tremor, and postural instability. The presence of any 2 of these signs comprises parkinsonism. Idiopathic PD accounts for 75% of parkinsonism; the remainder is associated with other neurodegenerative disorders, medications, cerebrovascular disease, or postinfectious etiologies. The motor signs of PD are largely attributable to reduced dopaminergic transmission in the basal ganglia, owing to the loss of dopaminergic neurons in the substantia nigra pars compacta. The chief pathologic feature is the Lewy body, an α-synuclein-containing, eosinophilic cytoplasmic inclusion that is present in affected neurons.

The ophthalmic manifestations of PD are usually mild and nonspecific, and often go untreated. Nevertheless, in the course of PD, visual complaints such as blurred vision, double vision, photophobia, ocular discomfort, asthenopia, and difficulty reading occur commonly. Table 3 presents an acrostic of ophthalmic problems in PD patients, modified from Dr. J. Lawton Smith’s writing.

Visual hallucinations occur in 25% to 40% of treated PD patients, most often in the elderly, those with low vision, and those taking dopaminergic or anticholinergic medications. Hallucinations early in the disease, unrelated to medication use, are unusual in PD and suggest the possibility of an atypical parkinsonian syndrome such as diffuse Lewy body disease.

The finding that dopamine is present in visual sensory pathways—particularly amacrine and interplexiform cells of the retina, lateral geniculate nucleus, and visual cortex—has spurred research on visual sensory deficits in PD. Evidence for retinal involvement in PD includes the presence of levodopa-responsive abnormalities on pattern electroretinograms (ERGs), visual evoked potentials (VEPs), and contrast sensitivity (CS) testing. Visual acuity in PD patients, after appropriate refraction and corneal lubrication, is similar to that of age-matched controls. Color vision, visual fields, and fundus appearance also are normal in PD patients. Visual CS in PD patients is severely reduced at intermediate and high spatial frequencies. These CS abnormalities in PD differ from those of normal aging in that they tend to be orientation-specific (ie, the CS abnormality is greater for horizontal than for vertically oriented gratings). Since orientation selectivity is a property of visual cortex cells, this finding implicates cortical dysfunction, which may contribute to impaired depth perception.

Up to 75% of patients with idiopathic PD have some ocular motor abnormalities, but eye signs are usually mild. Indeed, the presence of prominent ocular motor abnormalities should arouse suspicion of another parkinsonian syndrome. Limited upgaze reported in older studies may reflect the high prevalence of postencephalitic PD at the time, age-related upgaze defects, and/or the inclusion of cases that were not confirmed by autopsy. Saccades to novel stimuli usually remain unaffected, but saccades to remembered locations (antisaccades) may be slowed and hypometric. Saccadic initiation deficits and hypometric saccades occur, with the initial saccade followed by a series of small saccades before fixation on the target is achieved. Some patients need to blink in order to change saccadic direction. Saccadic amplitudes and accuracy tend to normalize with levodopa. Patients with levodopa-induced dyskinesias, however, may exhibit dyskinetic eye movements, with frequent hypermetric saccades. Smooth pursuit eye movements can become jerky, with catch-up saccades leading to “cogwheel” pursuit, reminiscent of the ratchety limb movements in PD. Although square-wave jerks may occur in up to 18% of PD patients, particularly in the levodopa “on” state, the presence of square-wave jerks in excess of 6 per minute suggests atypical parkinsonism. Nystagmus does not occur in idiopathic PD, but it was common in postencephalitic parkinsonism. Oculogyric crises, consisting of uncomfortable involuntary tonic deviation of the eyes upward or up-and-laterally, are seen with postencephalitic parkinsonism or use of neuroleptics, but have not been described in idiopathic PD.

Impaired head-eye coordination occurs in PD because of poor image stabilization along with postural instability and imbalance. Accommodative paresis and convergence insufficiency occur, sometimes as a side effect of anticholinergic medications. Divergence insufficiency is less common. Eyelid abnormalities include blepharospasm, apraxia of the eyelid opening (AEO), infrequent blink rate (as low as 1 to 2 blinks/minute; normal is 16) and eyelid retraction reflecting hypokinesia of the levator palpebrae, but these are less common than in PSP. Blepharospasm presents as involuntary blinking and squeezing of the lids, reflecting excessive orbicularis excitation. In contrast, AEO describes the inability to open the eyelids once closed. The likely mechanism is abnormal supranuclear inhibition of the pathways responsible for levator palpebrae function.

DLBD, another α-synucleinopathy, is characterized by parkinsonism with dementia, but it is less common than PD and Alzheimer disease (AD). Cognitive deficits occur within the first year of disease and include memory loss, inattention, apraxia, and spatial disorientation. These deficits often fluctuate in severity. Hallucinations, paranoia, delusions, sleep disorders, and autonomic dysfunction are common. Lewy bodies are more widely distributed than in PD, with early and prominent cortical involvement.

Visual symptomatology in DLBD reflects mainly visual cortical dysfunction from the disease process. Visual hallucinations, formed or unformed, are present in two-thirds of DLBD patients, and illusions are also common. Hallucinations serve as an early sign of DLBD, and may precede parkinsonism. The presence of unprovoked visual hallucinations early in the disease is characteristic of DLBD and distinguishes it from both PD and AD. Patients with DLBD also experience visuospatial disturbances, illusions, and misperceptions that objects move or change shape. Evidence of the cortical basis of visual dysfunction is seen with fluoro-deoxyglucose positron emission tomography (FDG-PET), which shows diffuse hypometabolism and, in contrast to AD, affects primary and associated visual cortex. Vertical and horizontal supranuclear gaze palsies are rare in DLBD, but have been described.

MSA, another α-synucleinopathy, is characterized by various combinations of basal ganglia, cerebellar, autonomic, corticospinal, and peripheral nerve dysfunction. The clinical presentation of MSA has 2 subtypes: the parkinsonian variant (MSA-P; previously referred to as striatonigral degeneration or Shy-Drager syndrome); and the less common cerebellar variant (MSA-C). The mean age of onset of MSA is 50, younger than in PD, and the disease is more rapidly progressive, with a median survival of 6 to 9 years. Resting tremor is much less common than in PD. Sleep disorders (including sleep apnea), vocal cord paralysis, and subcortical cognitive deficits are common. Parkinsonism in MSA may be levodopa-responsive early in the disease, but the benefits are usually short-lived, and the medication is often poorly tolerated because of orthostatic hypotension. The pathologic hallmark of MSA is the glial cytoplasmic inclusion, an α-synuclein-positive inclusion found in oligodendrocytes in various brain regions.

The ophthalmic manifestations of MSA-P are mostly ocular motor and include frequent square-wave jerks and saccadic pursuit. Gaze-evoked and downbeat nystagmus occur in some patients, but are more characteristic of MSA-C. Visuospatial function and vertical saccadic velocities are normal in MSA-P. Eye movement abnormalities in MSA-C include square-wave jerks, saccadic pursuit, slowed saccades, saccadic hypometria, decreased optokinetic nystagmus (OKN) gain, and gaze-evoked nystagmus.

Described by Steele, Richardson, and Olszewski, PSP is a tauopathy characterized by axial rigidity, bradykinesia, postural instability, dysarthria, dysphagia, personality changes, pseudobulbar affect, and frontal cognitive defects. Tremor is typically absent. The most common initial symptom is postural instability, with backward falls. Supranuclear gaze palsies are the hallmark of PSP, and visual symptoms are usually prominent. PSP may be misdiagnosed as PD, because some patients with PSP initially respond to levodopa and may have preserved eye movements until late in the disease course. The average age of onset is 63 years, with typical survival of 7 years after diagnosis. Pathologic findings include tau containing neurofibrillary tangles in the basal ganglia, midbrain, cerebral cortex, dentate gyrus of the cerebellum, and spinal cord.

The most common visual symptoms in PSP include difficulty reading and walking down stairs. These symptoms reflect difficulty with downward gaze, exacerbated by axial rigidity and retrocollis that prevent compensatory flexion of the neck to compensate. Ocular motor dysfunction is prominent in PSP, and manifests as square-wave jerks and supranuclear vertical gaze palsy, with downgaze affected earlier than upgaze. Errors in antisaccades also occur early in the disease course. Slowing of vertical saccades typically precedes the development of downgaze paresis. This sign should be elicited in patients where PSP is suspected. Pursuit becomes jerky. As the disease progresses, upgaze becomes affected; then horizontal eye movements become impaired; and finally global gaze palsies develop.

Complaints of binocular diplopia are more likely caused by convergence insufficiency than by disorders of conjugate gaze. Sources of monocular diplopia and discomfort include ocular surface disease, media opacities, decreased tear production, and decreased blink rate. Fixation instability results in large, frequent square-wave jerks, which are present in 60% to 80% of PSP patients and may be continuous. Eyelid disorders are more common in PSP than in PD, and include lid retraction, blepharospasm, and AEO. Lid retraction likely occurs because of disruption of dorsal midbrain pathways. Acoustic startle and blink reflexes are absent. Visuospatial dysfunction is characteristically absent, except in cases with overlapping features of corticobasal ganglionic degeneration.

CBGD is a tauopathy with clinical features that overlap those of other tauopathies such as PSP and frontotemporal dementia. It presents in the sixth or seventh decade of life and follows a chronic, progressive course. The hallmarks of CBGD include asymmetric levodopa-resistant parkinsonism, cortical signs (eg, language disturbance, apraxia, sensory neglect, cortical sensory loss), postural and action tremor, myoclonus, hyper-reflexia, and focal limb dystonia. Patients may experience the “alien limb” phenomenon, in which a limb moves spontaneously as if not attached to the rest of the patient’s body, sometimes interfering with the use of the contralateral limb. Dystonic spasms with superimposed myoclonic jerks are common, but resting tremor is rare. Cognitive symptoms include subcortical dementia, disinhibition, and perseveration. Brain pathology shows ballooned achromatic neurons, and tau-containing inclusions in neurons and glia. These changes are asymmetric or focal in the cortex and basal ganglia.

Visual complaints in CBGD include diplopia and difficulty reading because of loss of place on the page. In contrast with PSP, there is prominent visuospatial dysfunction, which may include hemispatial neglect and Balint syndrome (ocular apraxia, optic ataxia, and simultanagnosia). Some patients substitute head thrusts for saccades. Horizontal saccade latencies are increased selectively on the side where the patient experiences apraxia. Horizontal and vertical gaze may be impaired, but not to the degree seen in PSP. Convergence insufficiency and eyelid disorders such as blepharospasm or AEO occur.

AD is the most common dementia. It is caused by pathology in the cerebral cortex, in contrast with the subcortical dementias that occur in disorders such as PSP and Huntington disease. AD is heralded by progressive memory loss and impairment of the activities of daily living. It occurs most commonly in patients over the age of 60, but younger-onset cases can begin as early as the fourth decade. The underlying pathophysiology involves abnormal aggregation of β-amyloid protein. The characteristic pathologic features are amyloid plaques and neurofibrillary tangles.

Secondary visual-processing neurons of the inferior temporal and parietal pathways are particularly vulnerable, while neurons in the primary visual cortex are relatively spared. Deficits in complex visual function such as agnosias are common, and may result in vague visual complaints early in the disease. Visual hallucinations may occur late in the disease or in association with medications, but are less common than in DLBD. The rare visual variant of AD (posterior cortical atrophy) presents with visual cortical dysfunction resulting in visual agnosia, visual field loss, or components of Balint syndrome. Deficits in visuospatial processing, visual attention, object recognition, and visual motion processing during observer movement have been documented at all stages of AD.

Ocular motor dysfunction is common and includes an inability to maintain steady visual fixation on a target, arising from a combination of poor attention, ocular apraxia, delayed and hypometric saccades, and impaired smooth pursuit. Visual acuity and visual fields are generally preserved, but testing becomes unreliable in the late stages of disease. Optical coherence tomography (OCT) demonstrates thinning of the retinal nerve fiber layer, and post-mortem studies prove extensive optic nerve degeneration. However, the color vision defects that occur appear to be of central etiology.

FTD refers to a group of diseases characterized by neurodegeneration in the frontal and temporal lobes, some of which is caused by abnormal neuronal accumulation of tau proteins. The age of onset is in the 50s or early 60s, younger than in most other dementing disorders, and progression is more rapid than in AD. Clinical manifestations vary depending on the brain regions most involved and may overlap with those of other tauopathies such as PSP and CBGD. Behavioral symptoms such as personality changes, impulsivity, inappropriate social conduct, apathy, emotional blunting, loss of insight, changes in eating habits, and perseveration are prominent early in the disease course. Some variants of FTD are characterized by language disturbance and relative sparing of other cognitive and behavioral domains. Parkinsonism may occur in FTD, and is particularly characteristic of the FTDP-17 variant, an inherited disorder associated with mutations in the MAPT gene encoding tau protein on chromosome 17. FTD may also be associated with CBGD-like symptoms (referred to as corticobasal syndrome) or with motor neuron disease. Ocular motor dysfunction in patients with FTD includes increased saccadic latency, jerky pursuit, and increased errors on antisaccadic tasks. Specific subtypes of FTD exist, such as semantic dementia, in which ocular motor function is characteristically preserved.

Sporadic CJD is a rare spongiform encephalopathy caused by accumulation of abnormal prion proteins. Onset is typically in the sixth or seventh decade. The diagnostic clinical triad includes rapidly progressive dementia, myoclonic jerks, and an EEG pattern of periodic sharp wave complexes that develops in the middle to late stages of disease. Initial symptoms may include nonspecific changes in mood, behavior, or sleep; anorexia and muscle wasting; dizziness and memory loss; and sometimes a sudden-onset focal cortical symptom such as aphasia, vertigo, or homonymous hemianopia. Alternatively, patients may experience rapid deterioration in cortical functions, such as memory, reasoning, and judgment, followed by signs of sensory, cerebellar, pyramidal, extrapyramidal, and/or lower motor neuron dysfunction. CJD often involves the occipital cortex, cerebellum, and supranuclear pathways. Progression to an akinetic-mute state culminates in death within 6 to 12 months.

Ten percent of patients with sporadic CJD have visual symptoms at presentation. This increases to 50% over the course of the disease. Abnormal eye movements are common and include internuclear ophthalmoplegia, periodic alternating nystagmus, and centripetal nystagmus, implicating the cerebellum. Skew deviation, limitation of vertical gaze, and slowed vertical saccades are seen. Visual sensory dysfunction may figure as the presenting complaint, with visual loss, visual hallucinations, diplopia, oscillopsia, or difficulty focusing. Occipital cortical involvement may manifest as cortical blindness, visual field defects, impaired color vision, palinopsia, or Balint syndrome. The Heidenhain (occipital) variant of sporadic CJD presents with prominent isolated visual complaints such as blurred vision, visual field constriction, metamorphopsia, or cortical blindness.

The SCAs are an expanding group of nearly 30 dominantly inherited disorders characterized by progressive gait ataxia and incoordination of movement from neurodegeneration of selected tracts in the cerebellum and spinal cord. The SCAs are autosomal-dominant triplet-repeat disorders that usually present in adulthood. Disease-specific manifestations of SCAs include ophthalmoplegia, retinopathy, dementia, dysarthria, deafness, parkinsonism, and peripheral neuropathy. There is significant overlap in the clinical manifestations of the SCAs, as well as marked phenotypic variability among patients of a given SCA genotype. For that reason, genetic testing is required for diagnosis.

Visual symptoms of SCAs include oscillopsia, diplopia, and difficulty focusing due to nystagmus and other cerebellar ocular motility disturbances. Optic atrophy, when present, is usually mild. Therefore, visual impairment is not common, and may only be manifest as constriction of the visual fields. The notable exception is SCA7, which causes pigmentary retinopathy as well as optic atrophy, with loss of visual acuity and color vision. Ocular motor dysfunction in SCAs also tends to be subtype-specific. Refer to Table 2 for a summary of the ophthalmic findings associated with each of the SCAs.

This inherited disease is an autosomal recessive disorder resulting from a trinucleotide repeat expansion mutation in the noncoding region of the FRDA gene, on chromosome 9, which encodes the production of frataxin protein. Decreased production of this protein results in oxidative stress. Clinical manifestations include progressive ataxia and incoordination, weakness of the limbs and trunk, proprioceptive and vibratory sensory deficits in the limbs, loss of deep tendon reflexes, presence of extensor plantar reflexes, scoliosis, dysarthria, intention tremor, and often comorbid cardiac disease and/or diabetes. The onset is usually in adolescence. Typically, ambulation is lost 15 years after disease onset, and death occurs in the fourth or fifth decade.

Optic atrophy occurs in up to half of patients with Friedreich ataxia, but severe visual loss is unusual. VEPs are abnormal in two-thirds of patients, typically displaying prolonged latency and reduced amplitude. Eye movement abnormalities include increased square-wave jerks, increased saccadic latency with normal velocity, saccadic hypermetria (more common than hypometria), and jerky pursuit with an inability to maintain eccentric gaze, resulting in gaze paretic nystagmus and rebound nystagmus. VOR is impaired, but OKN is relatively preserved.

HD is an autosomal dominant disorder resulting from a trinucleotide repeat expansion in the HTT gene on chromosome 4, which encodes the huntingtin protein. The earliest manifestations are usually psychiatric, but progressive abnormal involuntary movements and cognitive deficits are also major features. Psychiatric manifestations include depression, mania, impulsivity, anxiety, psychosis, obsessive-compulsiveness, aggressive behavior, and sleep disorders. Choreoathetosis is the most prominent movement disorder, but dystonia and parkinsonism also occur. Parkinsonism is particularly characteristic of juvenile-onset cases (Westphal variant). Cognitive symptoms include deficits in executive function, verbal fluency, attention, visuospatial processing, and abstract reasoning. Gait ataxia, dysarthria, and dysphagia are also common. Pathologic changes are most prominent in the frontal lobes, striatum (particularly the caudate nucleus), and basal ganglia.

The most common visual complaint of patients with HD is difficulty reading because they lose their place on the page. Patients frequently drop their eyeglasses because of involuntary choreoathetoid movements. Ocular motor findings such as delayed reflexive saccades and impaired initiation of voluntary-guided saccades appear early in the disease, and may be detected in presymptomatic patients. At later stages of disease, patients have difficulty initiating saccades and suppressing reflexive saccades. They exhibit slowing of horizontal and vertical saccades, jerky pursuit, and decreased OKN gain. Convergence insufficiency, blepharospasm, and apraxia of eyelid closure sometimes occur. VOR is preserved.

Wilson disease, also called hepatolenticular degeneration, is an autosomal recessive neurodegenerative disorder caused by abnormal copper accumulation in the liver, eye, and/or brain due to a mutation in a copper transport protein responsible for its excretion. Although serum copper levels are elevated, ceruloplasmin, the serum copper transport protein, is low. Cerebral involvement is characterized by abnormal accumulation of copper in the basal ganglia, cerebellum, and white matter. The peak age of diagnosis is 21 years. Neuropsychiatric manifestations include dysarthria, dystonia, rigidity, postural instability, tremor, gait abnormalities, and psychosis.

The classic ophthalmic finding in Wilson disease is the Kayser-Fleischer (KF) ring, a deposition of copper seen in the Descemet membrane of the cornea, forming a pigmented perilimbal ring (Figure 1). The KF ring is present in nearly all cases in which there is central nervous system involvement and is a pathognomonic sign of Wilson disease. Less commonly, deposition of copper in the lens forms a sunflower cataract. Ocular motor abnormalities are present in 90% of patients with central nervous system involvement. They include saccadic vertical pursuit, impaired vertical OKN, jerky horizontal pursuit, slow saccades, difficulty reading, accommodative deficit, and gaze distractibility.