Chapter 14. Neuro-Ophthalmology

As demonstrated by their common embryological origin, the retinas and anterior visual pathways (optic nerves, optic chiasm, and optic tracts) are an integral part of the brain, providing a substantial proportion of total sensory input. They frequently give important diagnostic clues to central nervous system disorders. Intracranial disease frequently causes visual disturbances because of destruction of or pressure upon some portion of the optic pathways. Cranial nerves III, IV, and VI, which control ocular movements, may be involved, and nerves V and VII are also intimately associated with ocular function.

The Sensory Visual Pathway

Topographic Overview (Figures 14–1 and 14–2)

Cranial nerve II subserves the special sense of vision. Light is detected by the rods and cones of the retina, which may be considered the special sensory end organ for vision. The cell bodies of these receptors extend processes that synapse with the bipolar cell, the second neuron in the visual pathway. The bipolar cells synapse, in turn, with the retinal ganglion cells. Ganglion cell axons comprise the nerve fiber layer of the retina and converge to form the optic nerve. The nerve emerges from the back of the globe and travels posteriorly within the muscle cone to enter the cranial cavity via the optic canal.

Intracranially, the two optic nerves join to form the optic chiasm (Figure 14–1). At the chiasm, more than half of the fibers (those from the nasal half of the retina) decussate and join the uncrossed temporal fibers of the opposite nerve to form the optic tracts. Each optic tract sweeps around the cerebral peduncle toward the lateral geniculate nucleus, where it will synapse. All of the fibers receiving impulses from the right hemifields of each eye thus make up the left optic tract and project to the left cerebral hemisphere. Similarly, the left hemifields project to the right cerebral hemisphere. Twenty percent of the fibers in the tract subserve pupillary function. These fibers leave the tract just anterior to the nucleus and pass via the brachium of the superior colliculus to the midbrain pretectal nucleus. The remaining fibers synapse in the lateral geniculate nucleus. The cell bodies of this structure give rise to the geniculocalcarine tract. This tract passes through the posterior limb of the internal capsule and then fans into the optic radiations that traverse parts of the temporal and parietal lobes en route to the occipital (calcarine, striate, or primary visual) cortex.

Analysis of Visual Fields in Localizing Lesions in the Visual Pathways

In clinical practice, lesions in the visual pathways may be localized by examination of the central and peripheral visual fields. The technique (perimetry) is discussed in Chapter 2.

Figure 14–3 shows the types of field defects caused by lesions in various locations of the pathway. Lesions anterior to the chiasm (of the retina or optic nerve) cause unilateral field defects; lesions anywhere in the visual pathway posterior to the chiasm cause contralateral homonymous defects (affecting the same side of the visual field in each eye). Chiasmal lesions usually cause bitemporal defects.

Test objects of different intensities, sizes, and possibly colors are used to evaluate field defects thoroughly. A sloping border (ie, larger field defect to a dimmer, smaller or colored rather than white test object) suggests edema or compression. Ischemic or vascular lesions tend to produce steep borders (ie, the field defect is the same size no matter what the intensity, size, or color of the test object).

The more congruous the homonymous field defects (ie, the more similar the defect in size, shape, and location in the two eyes), the farther posterior the lesion is likely to be in the visual pathway. A lesion in the occipital region tends to cause identical defects in each field, whereas optic tract lesions tend to cause incongruous (dissimilar) homonymous field defects.

Particularly in lesions of the occipital cortex, where the central field is represented posteriorly and the upper field inferiorly (Figure 14–4), there is a correlation between the visual field defect and the location of the lesion. Owing to the dual vascular supply to the occipital lobe—from the middle and posterior cerebral circulation—occipital infarcts may spare or damage the occipital pole. This leads to sparing or loss of the central field on the side of the hemianopia, respectively referred to as macular sparing (Figure 14–5) and macular splitting. Occipital lesions may also produce the phenomenon of residual sight, in which responses to movement, for example, may be demonstrable in the hemianopic field in the absence of form vision.

A complete homonymous hemianopia, wherever the site of the lesion, should still have intact visual acuity in each eye since macular function is still present in the retained visual field.

A wide variety of diseases affect the optic nerve (Table 14–1). Clinical features particularly suggestive of optic nerve disease are an afferent pupillary defect, poor color vision, and optic disk changes. It is important to remember that the optic disk may be normal in the early stages of disease affecting the retrobulbar optic nerve, particularly compression by an intracranial lesion, even when there has been severe loss of visual acuity and field. Axons can be dysfunctional long before they become atrophic.

Optic disk swelling occurs predominantly in diseases directly affecting the anterior portion of the optic nerve but also occurs with raised intracranial pressure and compression of the intraorbital optic nerve. Optic disk swelling can be a crucial clinical sign, such as in the diagnosis of anterior ischemic optic neuropathy, in which optic disk swelling must be present in the acute stage for the diagnosis to be made on clinical grounds. Central retinal vein occlusion, ocular hypotony, and intraocular inflammation can produce optic disk swelling, and hence the misleading impression of optic nerve disease.

Optic atrophy (Figure 14–6) is a nonspecific response to optic nerve damage from any cause. Since the optic nerve consists of retinal ganglion cell axons, optic atrophy may be the consequence of primary retinal disease, such as central retinal artery occlusion or retinitis pigmentosa. Excavation of the optic nerve head (optic disk cupping) is generally a sign of glaucomatous optic neuropathy, but it may occur with any cause of optic atrophy. Segmental pallor and attenuated retinal blood vessels are often the consequence of anterior ischemic optic neuropathy. Hereditary optic neuropathies usually produce bilateral temporal segmental disk pallor with preferential loss of papillomacular axons. Peripapillary exudates occur with optic disk swelling, due to inflammation (papillitis), ischemic optic neuropathy, raised intracranial pressure (papilloedema), or severe systemic hypertension. (The term “neuroretinitis” for retinal exudates, including a macular star, due to optic disk swelling, of whatever cause, is a misnomer in that there is no inflammation of the retina, the exudates being a response to the anterior optic nerve disease (Figure 14–7 A). The term is more reasonably applied if there is inflammation of the retina and optic nerve (Figure 14–7 B). Signs of prior disk edema are peripapillary gliosis and atrophy, chorioretinal folds, and internal limiting membrane wrinkling.

In general, there is a correlation between degree of optic disk pallor and loss of acuity, visual field, color vision, and pupillary responses, but the relationship varies according to the underlying etiology. The major exception to this rule is compressive optic neuropathy, in which optic disk pallor is generally a late manifestation.

Optic Neuritis

Inflammatory optic neuropathy (optic neuritis) may be due to a variety of causes (Table 14–1), but the most common is demyelinative disease, including multiple sclerosis. Retrobulbar neuritis is an optic neuritis that occurs far enough behind the optic disk that the disk remains normal during the acute episode. Papillitis is disk swelling caused by inflammation at the nerve head (intraocular optic nerve) (Figure 14–8). Loss of vision is the cardinal symptom of optic neuritis and is particularly useful in differentiating papillitis from papilledema, with which it may be confused on ophthalmoscopic examination.

Demyelinative Optic Neuritis

In adults demyelinative optic neuritis is usually unilateral and occurs chiefly in women (about 3:1), with onset mostly in the third or fourth decade of life. It is associated with multiple sclerosis in up to 85% of cases, depending on several factors, including gender, racial origin, and duration of follow-up. In children there is much lower risk of progression to multiple sclerosis, optic neuritis commonly following a viral infection or immunization and affecting both eyes simultaneously.

Clinical Features

Visual loss is generally subacute, developing over 2–7 days. In adults, approximately one-third of patients have vision better than 20/40 during their first attack, and slightly more than one-third have vision worse than 20/200. Color vision and contrast sensitivity are correspondingly impaired. In over 90% of cases, there is pain in the region of the eye, and about 50% of patients report that the pain is exacerbated by eye movement.

Almost any field defect is possible. With manual perimetry a central scotoma is most commonly found. Central visual field testing by automated perimetry most commonly shows diffuse loss. The pupillary light response is sluggish, and if the optic nerves are asymmetrically involved, a relative afferent pupillary defect will be present.

Optic disk swelling (papillitis) occurs in one third of adult cases and two thirds of childhood cases. Marked edema is unusual. Peripapillary flame-shaped hemorrhages occur in less than 10% of adult cases and vitreous cells in less than 5%. Retinal exudates and cotton-wool spots don't occur and are indicative of an infectious inflammatory or non-inflammatory optic neuropathy.

Without treatment vision usually improves, visual acuity being better than 20/30 within 2 weeks in the majority of adult cases.

Investigation & Differential Diagnosis

In typical cases, clinical diagnosis is adequate and no other investigation is required. If there are atypical features—particularly failure of vision to begin to recover by 6 weeks after onset—other diagnoses must be considered, especially compressive optic neuropathy, for which magnetic resonance imaging (MRI) or computed tomography (CT) should be performed. Other entities to be considered are optic neuritis due to sarcoidosis or systemic lupus erythematosus, anterior ischemic optic neuropathy, Leber's hereditary optic neuropathy, toxic amblyopia, and vitamin B12 deficiency, of which the last two usually present with symmetrical bilateral visual loss.

Papillitis needs to be differentiated from papilledema (optic disk swelling due to raised intracranial pressure) (Figure 14–9). In papilledema, which usually causes bilateral optic disk changes, there is often greater elevation of the optic nerve head, normal corrected visual acuity, normal pupillary response to light, and an intact visual field except for an enlarged blind spot. If there has been acute papilledema with vascular decompensation (ie, hemorrhages and cotton-wool spots) or chronic papilledema with secondary ischemia of the optic nerve, visual field defects can include nerve fiber bundle defects and nasal quadrantanopias. Differentiation between papilledema and papillitis is particularly difficult when papilledema is asymmetric and/or associated with visual loss or papillitis is bilateral and/or associated with minimal visual impairment. Diagnosis may depend on associated symptoms particularly headache and results of MRI and lumbar puncture, as well as subsequent clinical course.

During an acute episode of optic neuritis, MRI shows gadolinium enhancement, increased signal, and sometimes swelling of the affected nerve. The gadolinium enhancement and optic nerve swelling resolve, but the increased signal persists. Brain MRI at presentation shows white matter lesions in about 50% of patients with isolated optic neuritis (Figure 14–10). This does not establish a diagnosis of multiple sclerosis, although it does indicate an increased risk of subsequent development of clinically definite multiple sclerosis (see later in the chapter).

The visual evoked response (VER) from the affected eye may show reduced amplitude or increased latency during the acute episode of optic neuritis. This in itself is not particularly helpful in diagnosis except in distinguishing retrobulbar optic neuritis from subclinical maculopathy, in which there will be abnormalities of the electroretinogram (ERG). Following recovery of vision after an episode of optic neuritis, the VER will continue to show an increased latency in about one-third of cases, and this finding can be useful in the identification of past episodes of demyelinative optic neuritis in patients undergoing investigation for possible multiple sclerosis.

Treatment

Steroid therapy by whatever route—either intravenously (methylprednisolone, 1 g/d for 3 days with or without a subsequent tapering course of oral prednisolone), orally (methylprednisolone, 500 mg/d to 2 g/d for 3–5 days with or without subsequent oral prednisolone, or prednisolone, 1 mg/kg/d tapered over 10–21 days), or by retrobulbar injection—accelerates recovery of vision but does not influence the ultimate visual outcome. In the large multicenter Optic Neuritis Treatment Trial from the United States, oral prednisolone alone increased the risk of recurrent optic neuritis in either eye, but this result has not been replicated.

Prognosis

Vision continues to improve slowly over many months, with recovery of acuity to 20/40 or better occurring in over 90% of cases at both 1 year and 15 years from onset. Poorer vision during the acute episode is correlated with poorer visual outcome, but even loss of all perception of light can be followed by recovery of acuity to 20/20. Poor visual outcome is also associated with longer lesions in the optic nerve, especially if there is involvement of the nerve within the optic canal. In general, there is close correlation between recovery of visual acuity, contrast sensitivity, and color vision. If the disease process is sufficiently destructive, retrograde optic atrophy results, nerve fiber bundle defects appear in the retinal nerve fiber layer (Figure 14–11), and the disk becomes pale. Factors that correlate with subsequent development of multiple sclerosis include female sex, lack of optic disk swelling during the acute phase, brain MRI abnormalities, and cerebrospinal fluid oligoclonal bands. In the Optic Neuritis Treatment Trial, the overall 15-year risk of developing clinically definite multiple sclerosis following a first episode of demyelinative optic neuritis was 50%. It ranged from 25% in those with normal brain MRI at presentation to 72% in those with any white matter lesions. In men with optic disk swelling in the acute phase and no brain MRI abnormality, the 15-year risk was only 4%. Neurologic impairment in patients who develop clinically definite multiple sclerosis is generally mild and MRI abnormalities may be predictive.

In patients with a first episode of optic neuritis, which is designated a clinically isolated syndrome, and abnormal brain MRI at presentation, interferon β and glatiramer acetate have been shown to reduce the risk of clinically definite multiple sclerosis. Whether patients should be treated with such disease modifying therapy after a first episode of optic neuritis needs to be determined on an individual basis, according to their likely risk of subsequent episodes of demyelination and bearing in mind the relatively mild likely disability after further episodes and the potential side effects of treatment. The benefit is likely to increase if the patient develops frequent relapses.

Multiple Sclerosis

Multiple sclerosis is typically a chronic relapsing and remitting demyelinating disorder of the central nervous system. The cause is unknown. Some patients develop a chronically progressive form of the disease, either following a period of relapses and remissions (secondary progressive) or, less commonly, from the outset (primary progressive). Characteristically, the lesions occur at different times and in noncontiguous locations in the nervous system—that is, “lesions are disseminated in time and space.” Onset is usually in young adult life; the disease rarely beginning before 15 years or after 55 years of age. There is a tendency to involve the optic nerves and chiasm, brainstem, cerebellar peduncles, and spinal cord, although no part of the central nervous system is protected. The peripheral nervous system is seldom involved.

Clinical Features

Optic neuritis may be the first manifestation. There may be recurrent episodes, and the other eye usually becomes involved. The overall incidence of optic neuritis in multiple sclerosis is 90%, and the identification of symptomatic or subclinical optic nerve involvement is an important diagnostic clue.

Diplopia is a common early symptom, due most frequently to internuclear ophthalmoplegia that is frequently bilateral (Figure 14–12). Less common causes are lesions of the sixth or third cranial nerve within the brainstem.

Nystagmus is a common early sign, and unlike most manifestations of the disease (which tend toward remission), it is often permanent (70%).

Intraocular inflammation may occur, particularly subclinical peripheral retinal venous sheathing, which can be highlighted by fluorescein angiography.

In addition to ocular disturbances, there may be motor weakness with pyramidal signs, ataxia, limb incoordination with intention tremor, dysarthria, urinary and/or bowel disturbance, and sensory disturbance, particularly paresthesias.

Investigation

Diagnosis of multiple sclerosis traditionally relied upon clinical evidence of white matter disease of the central nervous system disseminated in time and space (Schumacher criteria), subsequently supported by MRI and cerebrospinal fluid abnormalities (Poser criteria). Increasingly, emphasis is being placed on MRI abnormalities, in the brain and spinal cord, supported by clinical features and cerebrospinal fluid abnormalities, to establish dissemination in time and space (McDonald criteria), thus facilitating earlier diagnosis.

Cerebrospinal fluid oligoclonal bands that are not present in the serum—representing intrathecal production of immunoglobulins—are characteristic but not diagnostic. There may be cerebrospinal fluid lymphocytosis or a mildly raised cerebrospinal fluid protein concentration during an acute relapse.

Retinal nerve fiber layer defects consistent with a subclinical optic neuritis can be detected in 68% of multiple sclerosis patients. The VER may help confirm involvement of the visual pathway. It has been reported to be abnormal in 80% of definite, 43% of probable, and 22% of suspected cases of multiple sclerosis.

Course, Treatment, & Prognosis

The course of disease is unpredictable. Optic neuritis rather than brainstem or spinal cord disease as the initial manifestation is associated with a better prognosis. Relapses and remissions are characteristic, permanent disability tending to increase with each relapse. Pregnancy or the number of pregnancies has no effect on disability, but there is an increased risk of relapse just after delivery. Onset during pregnancy has a more favorable outcome than onset unrelated to pregnancy. Elevation of body temperature may exacerbate disability (Uhthoff's phenomenon), particularly visual impairment.

Steroid treatment, usually oral or intravenous methylprednisolone, is useful in hastening recovery from acute relapses but does not influence the final disability or the frequency of subsequent relapses. Interferon β glatiramer acetate, mitoxantrone, and natalizumab reduce the rate and severity of relapses and slow the progression of brain MRI abnormalities but the effect on long-term disability is still being determined. Many immunosuppressant treatments have been tested for progressive disease with no significant benefit.

Other Types of Optic Neuritis

Neuromyelitis optica (Devic's disease) is characterized by recurrent optic neuritis and transverse myelitis that may resemble severe multiple sclerosis, but lesions on brain MRI are atypical for multiple sclerosis; spinal cord lesions are long and necrotic; there may be a cellular cerebrospinal fluid response; severe disability is common; and there is a specific probably pathogenic serum auto-antibody, NMO-IgG. The clinical outcome is variable. Approximately 50% of patients progress to death within the first decade due to the paraplegia, but the remainder may have a prolonged remission and, ultimately, a better prognosis than patients with multiple sclerosis. Treatment is with systemic steroids or if necessary plasmapheresis for the acute episodes, followed by long-term immunosuppression, primarily targeted at humoral immunity, according to disease activity.

Particularly in children, 1–2 weeks following a viral infection or immunization there may be an episode of optic neuritis, often with simultaneous bilateral involvement. There is no association with subsequent development of multiple sclerosis. In some cases, the acute disease causes more extensive neurologic involvement manifesting as an encephalomyelitis, which overlaps with acute disseminated encephalomyelitis, in which optic neuritis is also often bilateral.

Optic neuropathy in systemic lupus erythematosus may be immune-mediated, with features of inflammatory disease, or due to small blood vessel occlusion, with features of ischemic disease (see later in the chapter). Inflammatory optic neuropathy may occur in sarcoidosis, sometimes as the first manifestation. Generally there is rapid response to steroid therapy, but long-term treatment with steroids and/or other immunosuppressants is often required. Such disease occurring in individuals in whom no evidence of sarcoidosis or other systemic disease can be identified has been termed idiopathic granulomatous optic neuropathy or chronic relapsing inflammatory optic neuropathy (CRION).

Herpes zoster—particularly herpes zoster ophthalmicus—may be complicated by optic neuropathy. This is probably due to vasculitis as well as direct neural invasion, and the prognosis is poor even with antiviral and steroid therapy. Other types of primary infection of the optic nerve, such as by syphilis, tuberculosis, cryptococcosis, and cytomegalovirus, are becoming more common with the increasing numbers of severely immunocompromised individuals such as those with AIDS. Lyme disease and cat-scratch disease are important causes of optic neuritis associated with macular star formation.

Intraocular inflammation may lead to direct involvement of the anterior optic nerve with visual loss or to optic disk swelling without apparent reduction in optic nerve function. Optic nerve involvement is an important cause of permanent visual loss in cellulitis or vasculitis of the orbit. The association between sinusitis and optic neuritis is less strong than once thought, but the occurrence of visual loss in the presence of sphenoid or posterior ethmoid sinus disease may indicate a causal relationship, particularly if there is a sinus mucocele. In diabetic or immunocompromised patients, mucormycosis is an important cause of rapidly progressive sinus disease with optic and other cranial nerve involvement (see Chapter 13).

Anterior Ischemic Optic Neuropathy

Anterior ischemic optic neuropathy is characterized by pallid disk swelling associated with acute loss of vision; often there are one or two peripapillary splinter hemorrhages (Figure 14–13). The disorder is due to infarction of the retrolaminar optic nerve (the region just posterior to the lamina cribrosa) from occlusion or decreased perfusion of the short posterior ciliary arteries. Fluorescein angiography in the acute stage shows decreased perfusion of the optic disk, often segmental in the nonarteritic form but usually diffuse in the arteritic form and disk leakage in the late phase. There may be associated perfusion defects in the peripapillary choroid.

Nonarteritic anterior ischemic optic neuropathy occurs generally in the sixth or seventh decade and is associated with arteriosclerosis, diabetes, hypertension, and hyperlipidemia. Low optic cup to disk ratio is almost always present. Optic nerve head drusen and increased intraocular pressure are predisposing factors. Systemic hypotension during the early morning may be an important etiologic factor. The precise relationship between phosphodiesterase inhibitors for erectile dysfunction and ischemic optic neuropathy is uncertain. In younger patients, vasculitis (eg, systemic lupus erythematosus, antiphospholipid antibody syndrome, and polyarteritis nodosa), migraine, and inherited prothrombotic states (deficiencies of protein C, protein S, or antithrombin III and activated protein C resistance) should be considered and appropriately treated. The visual loss is generally abrupt, but it may be progressive over 1–2 weeks. Impairment of visual acuity varies from slight to no light perception; visual field defects are usually nasal (characteristically inferior with a relative altitudinal pattern). In over 40% of cases, there is spontaneous improvement in visual acuity. No treatment has been shown to provide long-term benefit. Low-dose aspirin therapy may reduce the risk of involvement of the fellow eye, which occurs in up to 40% of individuals. Recurrences in the same eye are rare. As the acute process resolves, a pale disk usually without “glaucomatous” cupping results.

It is particularly important to identify arteritic anterior ischemic optic neuropathy due to giant cell arteritis. This causes severe visual loss with the risk of complete blindness if treatment is delayed. It occurs in elderly people and is associated with painful and tender temporal arteries, pain on mastication (jaw claudication), general malaise, and muscular aches and pains (polymyalgia rheumatica). The diagnosis is usually based on an anterior ischemic optic neuropathy and high erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in an elderly patient, with or without associated local or systemic features, but the ESR and CRP may be normal. Other ocular manifestations of giant cell arteritis are central retinal artery occlusion, cilioretinal artery occlusion, retinal cotton-wool spots, ophthalmic artery occlusion, and diffuse ocular ischemia. Diagnosis is established by temporal artery biopsy, looking particularly for inflammatory cell infiltration, often but not always including giant cells, and prominent disruption of the internal elastic lamina.

Treatment with high-dose systemic steroids should be started as soon as a clinical diagnosis of arteritic anterior ischemic optic neuropathy has been made without waiting for the result of temporal artery biopsy, which should be performed within 1 week after starting treatment. Oral prednisolone, 80–100 mg/d, is usually adequate as a starting dose. Intravenous hydrocortisone, 250–500 mg, can be given if there is likely to be a delay in instituting oral therapy. Intravenous methylprednisolone may improve final visual outcome and certainly should be considered in patients with bilateral disease—including those with transient episodes of visual loss in the second eye—and in patients whose visual loss progresses or whose systemic manifestations and high ESR do not respond despite oral therapy. Steroid dosage can usually be reduced to about 40 mg prednisolone per day over 4 weeks but then should be more gradually tapered and discontinued after 9–12 months overall as long as there has been no recurrence of disease activity. Thirty percent of patients require long-term steroid therapy.

Diabetics occasionally develop mild, chronic, usually bilateral disk swelling with little change in visual function, so-called diabetic papillopathy. This is thought to represent microvascular disease affecting the optic disk circulation. It is sometimes confused with optic disk neovascularization because of the leakage of dye from the disk on fluorescein angiography. Posterior ischemic optic neuropathy, in which there is no optic disk swelling during the acute stage of the disease, may occur from massive blood loss, such as from trauma or bleeding peptic ulcer, nonocular surgery, particularly lumbar spine surgery in the prone position, radiotherapy, usually treatment for skull base or sinus tumors 12–18 months previously, giant cell arteritis, or mucormycosis. In general, the diagnosis of posterior ischemic optic neuropathy should not be considered until other causes, particularly a compressive lesion, have been excluded. Radiation optic neuropathy produces a characteristic pattern of gadolinium enhancement on MRI and may be helped by early hyperbaric oxygen therapy.

Papilledema (Figures 14–9 and 14–14, 14–15 and 14–16)

Papilledema is by definition optic disk swelling due to raised intracranial pressure, of which the most common causes are cerebral tumors, abscesses, subdural hematoma, arteriovenous malformations, subarachnoid hemorrhage, hydrocephalus, meningitis, and encephalitis.

In ophthalmology practice, a frequent cause is idiopathic intracranial hypertension. This is characterized by raised intracranial pressure, no neurologic or neuroimaging abnormality except for anything attributable to the raised intracranial pressure, such as sixth cranial nerve palsy, and normal cerebrospinal fluid constituents. It is a diagnosis of exclusion, and a number of other causes of the syndrome of pseudotumor cerebri must be excluded, such as cerebral venous sinus occlusion, tetracycline or vitamin A (retinoid) therapy, and particularly in men, obstructive sleep apnea.

Less common causes of papilledema are spinal tumors, acute idiopathic polyneuropathy (Guillain–Barré syndrome), mucopolysaccharidosis, and craniosynostoses, in which various factors, including decreased cerebrospinal fluid absorption, abnormalities of spinal fluid flow, and reduced cranial volume, contribute to the raised intracranial pressure.

For papilledema to occur, the subarachnoid space around the optic nerve must be patent and connect the retrolaminar optic nerve through the bony optic canal to the intracranial subarachnoid space, thus allowing increased intracranial pressure to be transmitted to the retrolaminar optic nerve. There, slow and fast axonal transport is blocked, and axonal distention, particularly noticeable at the superior and inferior poles of the optic disk, occurs as the first sign of papilledema. Hyperemia of the disk with dilated surface capillaries, blurring of the peripapillary disk margin, and loss of spontaneous venous pulsations are the signs of mild papilledema. Circumferential peripapillary retinal folds (Paton's lines) also develop. In acute papilledema, probably as a consequence either of markedly elevated or rapidly increasing intracranial pressure, there are hemorrhages and cotton-wool spots on and around the optic disk, indicating vascular and axonal decompensation with the attendant risk of acute optic nerve damage and visual field defects (Figure 14–14). There may also be peripapillary edema (which can extend to the macula), retinal exudates (Figure 14–14), and choroidal folds. In chronic papilledema (Figure 14–15), which is likely to be the consequence of prolonged, moderately raised intracranial pressure, a process of compensation appears to limit the optic disk changes such that there are few if any hemorrhages or cotton-wool spots. With persistent raised intracranial pressure, the hyperemic elevated disk gradually becomes gray-white as a result of astrocytic gliosis and neural atrophy with secondary constriction of retinal blood vessels, thus leading to the stage of atrophic papilledema (Figure 14–16). There may also be retinochoroidal collaterals (previously known as opticociliary shunts) linking the central retinal vein and the peripapillary choroidal veins, which develop when the retinal venous circulation is obstructed in the prelaminar region of the optic nerve. (Other causes of retinochoroidal collaterals are central retinal vein occlusion, optic nerve sheath meningioma (Figure 14–6), optic nerve glioma, and optic nerve head drusen.) The presence of drusen-like deposits within the swollen optic nerve head, which indicates that the swelling is likely to have been present for several months, characterizes vintage papilledema.

It takes 24–48 hours for early papilledema to occur and 1 week to develop fully. It takes 6–8 weeks for fully developed papilledema to resolve following adequate treatment. Transient visual obscurations are a characteristic symptom of papilledema. Acute papilledema may reduce visual acuity by causing hyperopia and occasionally is associated with optic nerve infarction, but in most cases vision is normal apart from blind spot enlargement. Chronic, particularly atrophic or vintage, papilledema is associated with gradual constriction of the peripheral visual field, particularly inferonasal loss. Sudden reduction of intracranial pressure or systolic perfusion pressure may precipitate severe visual loss in any stage of papilledema.

Papilledema is often asymmetric. It may even appear to be unilateral, although fluorescein angiography in such cases usually shows leakage from both disks. Papilledema occurs late in glaucoma and will not occur at all if there is optic atrophy or if the optic nerve sheath on that side is not patent. The Foster Kennedy syndrome is papilledema on one side with optic atrophy due to optic nerve compression on the other, commonly due to skull-base meningiomas. However, it can be mimicked (pseudo-Foster Kennedy syndrome) by ischemic optic neuropathy when optic disk swelling due to a new episode of ischemic optic neuropathy is associated with optic atrophy in the fellow eye due to a previous episode (Figure 14–13).

Papilledema can be mimicked by buried optic nerve head drusen, small hyperopic disks, and myelinated nerve fibers (Figure 14–17).

The treatment of papilledema must be directed to the underlying cause. Idiopathic intracranial hypertension generally affects obese young women, and maintained weight loss is then an important treatment objective. The major morbidity is visual loss due to papilledema, but headaches may also be troublesome. Oral acetazolamide—usually 250 mg one to four times daily but up to 500 mg four times daily in severe cases—or diuretics such as furosemide are usually effective in reducing optic disk swelling. Cerebrospinal fluid shunting or optic nerve sheath fenestration may be undertaken if there is severe or progressive loss of vision or if medical therapy is not tolerated. Repeated lumbar punctures are rarely indicated except as a temporary measure prior to surgical therapy. Headaches usually respond to control of intracranial pressure, but other treatments may be required. It is essential that patients with idiopathic intracranial hypertension undergo regular visual field assessments by perimetry.

Optic Nerve Compression

Optic nerve compression is often amenable to treatment, and early recognition is vital to optimal outcome. The possibility of optic nerve compression should be considered in any patient with signs of optic neuropathy or visual loss not explained by an intraocular lesion. Optic disk swelling may occur with intraorbital optic nerve compression, but in many cases, particularly when the optic nerve compression is intracranial, the optic disk shows no abnormality until optic atrophy develops or there is papilledema from associated raised intracranial pressure. (Examination for signs of optic nerve disease, particularly a relative afferent pupillary defect, is thus crucial in assessment of the patient with unexplained visual loss.) Investigation of possible optic nerve compression requires early imaging by MRI or CT. If no structural lesion is identified and meningeal disease is suspected, it may be necessary to proceed to cerebrospinal fluid examination.

Intracranial meningiomas that may compress the optic nerve include those arising from the sphenoid wing, the tuberculum sellae (suprasellar meningioma), and the olfactory groove. Sphenoid wing meningiomas also produce proptosis, ocular motility disturbance, and trigeminal sensory loss (Figure 14–18). Surgical excision is generally effective in debulking intracranial meningiomas, but complete excision is often very difficult to achieve and recurrence rates are relatively high. Radiotherapy may be indicated as adjuvant or primary treatment. Pituitary adenoma and craniopharyngioma are discussed in the section on chiasmal disease (see later in the chapter). The management of orbital causes of optic nerve compression is discussed in Chapter 13.

Primary optic nerve sheath meningioma is a rare tumor most commonly presenting, like other types of meningioma, in middle-aged women (Figure 14–19). Five percent of cases are bilateral. Visual loss is slowly progressive. The classic clinical features are a pale, slightly swollen optic disk with retinochoroidal collaterals, but in most cases the collateral vessels are not present (Figure 14–6). Stereotactic radiotherapy is the preferred treatment.

Nutritional & Toxic Optic Neuropathies

The usual clinical features of nutritional or toxic optic neuropathy are subacute, progressive, symmetrical visual loss, with central field defects (Figure 14–20), poor color vision, and the development of temporal disk pallor (Figure 14–6).

Vitamin Deficiency

Optic nerve involvement is relatively uncommon in vitamin B12 deficiency, but it may be the first manifestation of pernicious anemia. Thiamin (vitamin B1) deficiency is generally a feature of severe malnutrition, and, as discussed below, there is an overlap with tobacco-alcohol amblyopia. Folate deficiency alone is a rare cause of optic neuropathy.

Tobacco-Alcohol Amblyopia

Nutritional amblyopia is probably a more accurate term for this entity. Usually it occurs in individuals with poor dietary habits, with heavy alcohol consumption and heavy smoking often being associated. Strict vegetarianism without vitamin supplementation may contribute. Much consideration has been given to other toxic causes, such as cyanide from tobacco producing low vitamin stores and low levels of sulfur-containing amino acids, but experimental studies with cyanide in primates have not confirmed this theory. Drug-induced optic neuropathy must be excluded. Leber's hereditary optic neuropathy, pernicious anemia, methanol poisoning, the rare chronic optic neuropathy of primary progressive multiple sclerosis, or macular disease may cause diagnostic confusion.

There is bilateral loss of central vision, generally reducing visual acuity to less than 20/200, but it can be asymmetric. Central visual fields reveal scotomas that nearly always include both fixation and the blind spot (centrocecal scotoma) (Figure 14–20).

Adequate diet plus thiamine, folic acid, and vitamin B12 supplements may be effective if presentation is not delayed. Withdrawal of tobacco and alcohol is advisable and may hasten the cure, but adequate nutrition or vitamin B12 supplements can be effective despite continued excessive intake of alcohol or tobacco. Improvement usually begins within 1–2 months, although in occasional cases significant improvement may not occur for 1 year. Visual function can but may not return to normal. Permanent optic atrophy or at least temporal disk pallor can occur depending on the stage of disease at the time treatment was started (Figure 14–6). Loss of the ganglion cells of the macula and destruction of myelinated fibers of the optic nerve—and sometimes of the chiasm as well—are the main histologic changes.

Heavy Metal Poisoning

Chronic lead exposure, or thallium (present in depilatory cream) or arsenic poisoning can produce a toxic effect on the optic nerve.

Drug-Induced Optic Neuropathy

Ethambutol, isoniazid, linezolid, disulfiram, and tamoxifen can all cause optic neuropathy, which usually improves with prompt cessation of the drug with or without nutritional supplements. Quinine overdose produces optic neuropathy, narrowed retinal arterioles and irregular, poorly reactive pupils. Chloramphenicol in high doses causes optic neuropathy. Amiodarone has been associated with bilateral optic neuropathy with chronic disk swelling, but the relationship is not necessarily causal. It characteristically also induces a verticillate keratopathy. Various chemotherapeutic agents may cause optic neuropathy, especially with high-dose or intra-arterial therapy.

Chemical-Induced Optic Neuropathy: Methanol Poisoning

Absorption, usually oral, of methanol, which is used widely in the chemical industry as antifreeze, solvent varnish, or paint remover, causes visual impairment, sometimes progressing to complete blindness. Whitish, striated edema of the peripapillary retina is a characteristic sign.

Treatment consists of correction of the acidosis with intravenous sodium bicarbonate and oral or intravenous administration of ethanol to compete with, and thus prevent the slower metabolism of methanol into its byproducts. Hemodialysis is indicated for blood methanol levels over 50 mg/dL.

Optic Nerve Trauma

Direct optic nerve injury occurs in penetrating orbital trauma, including local anesthetic injections for ocular surgery, and in mid-facial fractures involving the optic canal. Visual loss due to indirect optic nerve trauma, which refers to optic nerve damage secondary to distant skull injury, occurs in approximately 1% of all head injuries. The site of injury is usually the forehead, often without skull fracture, and the probable mechanism of optic nerve injury is transmission of shock waves through the orbital walls to the orbital apex. Optic nerve avulsion usually results from an abrupt rotational injury to the globe, such as from being poked in the eye with a finger.

Surgery may be indicated to relieve orbital, subperiosteal, or optic nerve sheath hemorrhage or to treat orbital fractures. High-dose systemic steroids for direct or indirect optic nerve injury and decompression of the bony optic canal for indirect injury have been advocated, but their value is uncertain. There is no effective treatment for optic nerve avulsion.

Hereditary Optic Atrophy

Leber's Hereditary Optic Neuropathy

Leber's hereditary optic neuropathy is a rare disease characterized by sequential subacute optic neuropathy usually in males aged 11–30 years. The underlying genetic abnormality is a point mutation in mitochondrial DNA (mtDNA), with over 90% of affected families harboring a mutation at position 11778, 14484, or 3460. mtDNA is exclusively derived from the mother, and thus, in accordance with the general pattern of mitochondrial (maternal) inheritance (see Chapter 18), the mutation is transmitted through the female line—but for unexplained reasons the disease rarely manifests in carrier females. Once an individual is known to have the disorder, it is possible without further genetic testing to predict which other family members are at risk, with matrilineal nephews, that is, sons of the affected individual's sisters, being particularly at risk.

Blurred vision and a central scotoma usually appear first in one eye and later—within days, weeks, or months—in the other eye. During the acute episode, there may be swelling of the optic disk and peripapillary retina with dilated telangiectatic small blood vessels on their surface, but characteristically there is no leak from the optic disk during fluorescein angiography. Both optic nerves eventually become atrophic, and vision is usually between 20/200 and counting fingers. The 14484 mutation is associated with recovery of vision but not until many months after the initial onset of visual loss. Total loss of vision or recurrences of visual loss usually do not occur. Leber's neuropathy may be associated with a multiple sclerosis-like illness (particularly in affected females), cardiac conduction defects, and dystonia.

Diagnosis is by identification of one of the three mtDNA point mutations. No treatment is known to be effective. Because high tobacco and alcohol consumption may precipitate visual loss in susceptible individuals, carriers of a pathogenic point mutation, particularly males, should be advised not to smoke and to avoid high alcohol consumption.

Optic atrophy also occurs in other mitochondrial disorders, either as a manifestation of primary optic neuropathy—for example, myoclonic epilepsy and ragged red fibers (MERRF) and mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS)—or secondary to retinal degeneration, for example, Kearns–Sayre syndrome. Wolfram's syndrome (see later in the chapter) is also probably the result of a mitochondrial disorder.

Autosomal Hereditary Optic Atrophy

Autosomal dominant (juvenile) optic atrophy generally has an insidious onset in childhood, with slow progression of visual loss throughout life. It is often detected as mild reduction in visual acuity by childhood vision screening programs. There is characteristically a centrocecal scotoma with impaired color vision. Temporal optic disk pallor is usually present, although often mild, and mild disk cupping is occasionally seen. Diagnosis is by identification of other affected family members. The genetic defect has been mapped to the long arm of chromosome 3, but a diagnostic genetic test is not yet available. Rarely, the disease is associated with congenital or progressive deafness or ataxia.

Autosomal recessive (infantile) optic atrophy manifests as severe visual loss, present at birth or within 2 years and accompanied by nystagmus. It can be associated with progressive hearing loss, spastic quadriplegia, and dementia, although an inborn error of metabolism must first be considered. Wolfram's syndrome consists of juvenile diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Although there is a recessive pattern of inheritance, with the gene defect localized to chromosome 4, the underlying metabolic abnormality is probably a defect in cellular energy production, as in the mitochondrial diseases.

Optic Atrophy with Inherited Neurodegenerative Diseases

Various neurodegenerative diseases with onset in the years from childhood to early adult life are manifested by steadily progressive neurologic and optic atrophy to a variable extent. Examples are hereditary spinocerebellar ataxias (Friedreich's ataxia), hereditary motor and sensory neuropathy (Charcot–Marie–Tooth disease), and the lysosomal storage disorders. Most of the sphingolipidoses late in their course are associated with optic atrophy. The leukodystrophies (Krabbe's, metachromatic leukodystrophy, adrenoleukodystrophy, globoid dystrophy, Pelizaeus–Merzbacher disease, Schilder's disease) are associated with optic atrophy earlier. Canavan's spongy degeneration and glioneuronal dystrophy (Alper's disease) are associated with optic atrophy as well. In Refsum's disease, optic atrophy is secondary to the pigmentary retinopathy. Optic atrophy can occur in the mucopolysaccharidoses due to hydrocephalus from meningeal involvement or due to mucopolysaccharides in glial cells of the optic nerve.

Neoplastic Optic Nerve Infiltration

In leukemia (usually acute leukemia), non-Hodgkin's lymphoma, and disseminated carcinoma, optic nerve infiltration with marked visual loss and optic disk swelling may develop. Optic nerve glioma is discussed below, together with chiasmal glioma. Other primary neoplasms of the optic nerve include the astrocytic hamartoma of tuberous sclerosis, melanocytoma, and hemangioma, all rarely causing any visual disturbance.

Optic Nerve Anomalies

There are a large number of congenital optic nerve anomalies. They may be associated with other anomalies of the head since closure of the fetal fissure, ocular melanogenesis, and development of the optic disks occur at the same time as development of the skull and face.

Optic nerve hypoplasia, dysplasia, and coloboma have all been associated with basal encephaloceles and with varying intracranial anomalies, including agenesis of the corpus callosum (de Morsier's syndrome) and pituitary-hypothalamic dysfunction (especially growth hormone deficiency). Hypoplastic optic nerves are small, with normal-sized retinal blood vessels (Figure 14–21). They are associated with a wide range of visual acuities, astigmatism, a peripapillary halo that may have a pigmented rim (double-ring sign), and various visual field defects. Superior segmental optic nerve hypoplasia (topless optic disk) usually occurs in children born to mothers with type 1 diabetes. It is characterized by superior disk entrance of the central retinal artery, superior disk pallor (Figure 14–22), and inferior visual field loss. Dysplastic optic disks usually are associated with poor vision and show abnormal vasculature, retinal pigment epithelium, and glial tissue. They are often surrounded by a chorioretinal pigmentary disturbance. Dysplastic disks have been reported with trisomy 4q. The papillorenal syndrome has been reported with dysplastic disks and colobomas. Colobomas of the optic nerve have been called “pseudoglaucoma” because of their resemblance to glaucomatous cupping (Figure 14–23). Disk colobomas or hypoplasia when associated with chorioretinal lacunae, absence of the corpus callosum, and focal seizures constitute Aicardi's syndrome. This can also include retrobulbar cysts. Optic disk pits are usually not associated with any visual symptoms, but they can be mistaken for glaucomatous cupping, particularly if there is an associated field defect. Optic disk pits may present later in life as a consequence of serous detachment of the macula.

Tilted disks, which occur in 3% of normal subjects, may also be seen with hypertelorism or the craniofacial dysostoses (Crouzon's disease, Apert's disease). They are oval disks with usually an inferior scleral crescent and an associated area of fundus hypopigmentation (Figure 14–24). They may be mistaken for papilledema. They may also produce predominantly upper temporal field defects, which may be mistaken for bitemporal loss due to chiasmal dysfunction. Scleral crescents are particularly common in myopic eyes.

Megalopapilla may be mistaken for optic atrophy due to the prominence of the lamina cribrosa. Myelinated nerve fibers usually extend into the retina from the disk but occasionally are just seen in the retinal periphery (Figure 14–17). They always follow the course of the retinal nerve fiber layer. Remnants of the embryonic hyaloid system range from tissue fragments on the optic disk (Bergmeister's papilla) to strands extending to the posterior lens capsule. Prepapillary vascular loops are distinct from the hyaloid system and occasionally become obstructed, leading to branch retinal artery occlusion.

Optic nerve head drusen are clinically apparent in about 0.3% of the population but are found on ultrasound or histopathologic studies in up to 2%. They are exclusively found in white individuals. In children, they are usually buried within the disk substance, and thus are not visible on clinical examination but cause elevation of the disk surface and mimic papilledema. The optic disk is characteristically small, with no physiologic cup and an anomalous pattern of the retinal vessels. With increasing age and loss of overlying axons, optic nerve head drusen become exposed, being apparent as “lumpy-bumpy” yellow crystalline excrescences, highlighted by retroillumination of the disk substance (Figure 14–6). On fluorescein angiography, exposed drusen are autofluorescent and result in accumulation of dye within the disk substance (Figure 14–25). Buried drusen are best diagnosed by orbital ultrasound or thin-slice CT scanning, which detects their associated calcification. Optic nerve head drusen are usually bilateral. They can rarely cause visual loss, either by optic neuropathy or choroidal neovascularization. Hyperopic eyes may also have small elevated disks, resembling buried optic nerve head drusen and similarly mimicking papilledema (pseudo-papilledema).

In general, lesions of the chiasm cause bitemporal hemianopic visual field defects. Initially these defects are typically incomplete and are often asymmetric. As the disease progresses, the temporal hemianopia becomes complete but central visual acuity is preserved until there is also loss of the nasal visual fields or associated optic nerve dysfunction. Most diseases that affect the chiasm are neoplastic, vascular, and inflammatory processes being uncommon.

Pituitary Tumors

The anterior lobe of the pituitary gland is the site of origin of pituitary tumors (Figure 14–26), which manifest as pituitary dysfunction, loss of vision, cranial nerve palsies including extraocular muscle palsies, and a mass lesion on CT scan or MRI, arising from the pituitary sella and extending into the suprasellar and/or parasellar regions.

Visual assessment, especially documentation of visual fields, as well as endocrine assessment, is vital to decisions about management. Prolactinomas are generally treated medically in the first instance with dopamine agonists such as cabergoline, bromocriptine, or pergolide. Other pituitary macroadenomas generally undergo transsphenoidal hypophysectomy. Radiotherapy may be used as an adjuvant to surgery or for recurrent disease. Visual acuity and visual fields may improve dramatically after the chiasm is decompressed. The initial appearance of the optic nerve head does not predict the ultimate visual outcome, but optic atrophy is a poor prognostic sign.

Craniopharyngioma

Craniopharyngiomas are an uncommon group of tumors arising from epithelial remnants of Rathke's pouch (80% of the population normally have such remnants) and characteristically become symptomatic between the ages of 10 and 25 years but occasionally not until the 60s and 70s. They are usually suprasellar (Figure 14–27) but occasionally intrasellar. The signs and symptoms vary tremendously with the age of the patient and the exact location of the tumor as well as its rate of growth. When a suprasellar tumor occurs, asymmetric chiasmatic or tract field defects are prominent. Papilledema is more common than in pituitary tumors. Optic nerve hypoplasia can be seen with tumors presenting in infancy. Pituitary deficiency may result, and involvement of the hypothalamus may cause stunted growth. Calcification of parts of the tumor contributes to a characteristic radiologic appearance, especially in children.

Treatment consists of surgical removal—as complete as possible but limiting damage to the hypothalamus. Adjunctive radiotherapy is often used, particularly if there has been incomplete surgical removal.

Suprasellar Meningiomas

Suprasellar meningiomas arise from the meninges covering the tuberculum sellae and the planum sphenoidale, with a high proportion of patients being female. Visual loss, due to involvement of the optic chiasm and nerves, is often the presenting feature. Diagnosis is usually possible on the neuroimaging appearance. Treatment consists of surgical removal, possibly combined with adjuvant radiotherapy if there has been incomplete excision or the histopathology shows an aggressive tumor.

Chiasmatic & Optic Nerve Gliomas

Gliomas of the anterior visual pathway, more commonly arising in the optic nerve but sometimes arising in the optic chiasm, are rare, usually indolent disorders of children, particularly associated with neurofibromatosis 1 (see later in the chapter). About 70% of cases present before the age of 7 years, with visual loss, proptosis, strabismus, or nystagmus. Occasionally onset is sudden, with rapid loss of vision. There may be optic disk swelling, but optic atrophy is more common. Visual field defects reveal an optic nerve or chiasmal syndrome. Neuroimaging may reveal optic nerve expansion or a mass in the region of the chiasm and hypothalamus. Treatment depends on the location of the tumor and its clinical course. Chemotherapy can be given during a tumor growth spurt, irradiation being avoided because of adverse effects on the developing brain, and optic nerve resection is sometimes done when an optic nerve tumor aggressively starts to extend intracranially toward the chiasm, but generally management is conservative.

Malignant glioma of the anterior visual pathways is a rare disease of elderly men. There is a rapid clinical course to bilateral blindness and death due to invasion of the base of the brain. There is no effective treatment.

Cerebrovascular disease and tumors are responsible for most lesions of the retrochiasmatic visual pathways, although almost any intracranial disease process can involve these structures.

Retrochiasmatic lesions produce contralateral homonymous visual field defects. Anterior partial lesions, in the optic tract, lateral geniculate nucleus, or geniculocalcarine tract (optic radiation), tend to produce incongruous (or dissimilar) visual field defects with more involvement in the eye with the nasal defect. Posterior partial lesions, in the geniculocalcarine tract or occipital cortex, tend to produce more congruous visual field defects. Once any retrochiasmatic lesion becomes complete, incongruity cannot be assessed, and this sign loses its localizing ability. Any unilateral retrochiasmatic lesion should spare visual acuity since the visual pathway in the other hemibrain is intact.

Lesions of the optic tract or lateral geniculate nucleus are uncommon. After several weeks to months, the disks may become pale, more marked in the contralateral eye, with corresponding retinal nerve fiber layer defects. In optic tract lesions, there may be a contralateral relative afferent pupillary defect. The optic tract and lateral geniculate nucleus have at least a dual blood supply, so that primary vascular lesions are uncommon. Most cases are due to trauma, tumors, and arteriovenous malformations.

Lesions involving the geniculocalcarine tract do not result in optic atrophy (due to the synapse at the geniculate nucleus) unless the lesion is longstanding, usually congenital. The inferior portion of the geniculocalcarine tract passes through the temporal lobe and the superior portion through the parietal lobe, with macular function between them. Lesions of the inferior portion result in predominantly superior visual field defects. Processes affecting the anterior and midtemporal lobes are commonly neoplastic; posterior temporal lobe and parietal processes can be either vascular or neoplastic. An insidious onset with mild and multiple neurologic deficits would be more typically neoplastic, whereas an acute event would be more typically vascular.

Vascular lesions of the occipital lobe are common and account for over 80% of cases of isolated homonymous visual field loss in patients over age 50 years. Macular function is represented at the most posterior tip of each occipital lobe, the representation of increasingly peripheral visual field lying increasingly anterior. Due to the frequent presence of a dual blood supply, vascular occlusions may selectively spare the posterior cortex to produce homonymous defects with macular sparing, or conversely involve the posterior occipital cortex to produce homonymous congruous macular scotomas. The cortical centers involved in the generation of optokinetic nystagmus lie in the area between the occipital and temporal lobes and in the posterior parietal area, which are within the vascular territory of the middle cerebral artery. Optokinetic nystagmus asymmetry characteristically occurs in parietal lesions but not in occipital lesions. An asymmetric optokinetic nystagmus combined with an occipital visual field defect indicates a process not respecting vascular territories, and thus suggests a tumor (Cogan's sign). Posterior reversible encephalopathy syndrome, which can be due to severe systemic hypertension, such as in eclampsia, diabetic hyperglycemia, or drugs, including cyclosporin and tacrolimus, characteristically involves the posterior cerebral hemispheres causing homonymous hemianopia, or even cortical blindness, and visual perceptual abnormalities. CT and MRI demonstrate structural cerebral lesions with remarkable clarity (Figures 14–4, 14–5, 14–28, and 14–29). Visual disturbance with dementia is suggestive of the predominantly visual variants of Alzheimer's disease and sporadic Creutzfeldt–Jakob disease, both characterized by a paucity of imaging changes initially.

The size of the normal pupil varies at different ages, from person to person, and with different emotional states, levels of alertness, degrees of accommodation, and ambient room light. The normal pupillary diameter is about 3–4 mm, smaller in infancy, and tending to be larger in childhood and again progressively smaller with advancing age. Pupillary size relates to varying interactions between the sympathetically innervated iris dilator, with supranuclear control from the frontal (alertness) and occipital lobes (accommodation). The pupil also normally responds to respirations (ie, hippus). Twenty to forty percent of normal patients have a slight difference in pupil size (physiologic anisocoria), usually less than 1 mm. Mydriatic agents work more effectively on blue eyes than on brown eyes.

Neuroanatomy of the Pupillary Pathways

Evaluation of pupillary responses is important in localizing lesions involving the optic pathways. The examiner should be familiar with the neuroanatomy of the pathways for the pupillary responses to light and near (Figure 14–30).

Light Reflex

The pupillary response to light is a pure reflex with an entirely subcortical pathway. Whereas previously retinal photoreceptors were thought to be the sole receptors for the pupillary light reflex, melanopsin-expressing retinal ganglion cells in the inner retina are now known to be involved. The afferent pupillary fibers are included within the optic nerve and visual pathways until they exit the optic tract just prior to the lateral geniculate nucleus. Having decussated in the chiasm—in the same way as the visual sensory fibers—they enter the midbrain through the brachium of the superior colliculus and synapse in the pretectal nucleus. Each pretectal nucleus decussates neurons dorsal to the cerebral aqueduct to the ipsilateral and contralateral Edinger–Westphal nucleus via the posterior commissure and the periaqueductal gray matter. A synapse then occurs in the Edinger–Westphal nucleus of the oculomotor nerve. The efferent pathway is via the third nerve to the ciliary ganglion in the lateral orbit. The postganglionic fibers go via the short ciliary nerves to innervate the sphincter muscle of the iris.

Light shone into the right eye produces an immediate direct response in the right eye and an immediate indirect consensual response in the left eye (Figure 14–31). The intensity of this response in each eye is proportionate to the light-carrying ability of the directly stimulated optic nerve.

The Near Response

When the eyes look at a near object, three responses occur—accommodation, convergence, and constriction of the pupil—bringing a sharp image into focus on corresponding retinal points. The final common pathway is mediated through the oculomotor nerve with a synapse in the ciliary ganglion. The afferent pathway enters the midbrain ventral to the Edinger–Westphal nucleus and sends fibers to both sides of the cortex. Although the three components are closely associated, the near response cannot be considered a pure reflex, since each component can be neutralized while leaving the other two intact—that is, by prisms (neutralizing convergence), by lenses (neutralizing accommodation), and by weak mydriatic drugs (neutralizing miosis). It can occur even in a blind person who is instructed to look at his nose.

Afferent Pupillary Defect

One of the most important assessments to make in a patient complaining of decreased vision is whether it is due to an ocular problem (eg, cataract) or to a potentially more serious optic nerve problem. If an optic nerve lesion is present, the pupillary light response (both the direct response in the stimulated eye and the consensual response in the fellow eye) is less intense when the involved eye is stimulated than when the normal eye is stimulated. This phenomenon is called a relative afferent pupillary defect (RAPD) (Figure 14–32). It will be present also if there is a large retinal or severe macular lesion. Even dense cataract does not impair the pupillary light response. Other causes of unilateral decreased vision without an afferent pupillary defect include refractive error, media opacity other than cataract such as corneal opacity or vitreous hemorrhage, amblyopia, and functional visual loss. In a lesion of the brachium of the superior colliculus, it is possible for a relative afferent pupillary defect to be present when visual function is normal.

Absolute afferent pupillary defect is the term applied when there is no pupillary response to light stimulation of a completely blind (amaurotic) eye. Light shone into the normal eye would still induce a consensual response in the blind eye (Figure 14–33).

An afferent pupillary defect can still be identified if one pupil is either not visible, due to corneal disease, or is unable to respond due to structural damage or damage to its innervation, for example, third nerve palsy, by examination of the normal pupil.

Pupillary Light-Near Dissociation

The light reflex normally produces more miosis than the near response. The reverse is known as pupillary light-near dissociation. This is most commonly due to an afferent pupillary defect (such as in optic nerve disease) because the pupillary light reflex to stimulation of the affected eye is reduced but the near response is normal. It occurs also in lesions of the ciliary ganglion or of the midbrain, in which the light reflex pathway is relatively dorsal and the near response pathway relatively ventral. Causes include tonic pupil (see later in the chapter), midbrain tumors and infarcts, diabetes, chronic alcoholism, encephalitis, and central nervous system degenerative disease.

Argyll Robertson pupils, which are usually bilateral, are typically small (less than 3 mm in diameter), commonly irregular and eccentric, do not respond to light stimulation but do respond to a near stimulus, and dilate poorly with mydriatics as a consequence of concomitant iris atrophy. They are strongly suggestive of central nervous system syphilis.

Tonic Pupil

Tonic pupil is characterized by light-near dissociation, delayed dilation after a near stimulus (tonic near response), segmental iris constriction, and constriction in response to a weak (0.1%) solution of pilocarpine (denervation hypersensitivity). It results from damage to the ciliary ganglion or the short ciliary nerves. In the acute stage, the pupil is dilated and accommodation is impaired. The pattern of recovery is influenced by fibers in the short ciliary nerves subserving the near response outnumbering those subserving the light reflex by 30:1. Accommodation usually recovers fully, but incomplete reinnervation of the iris results in segmental iris constriction and pupillary light-near dissociation. The pupil usually becomes smaller than the pupil in the fellow eye.

Tonic pupil is usually an isolated benign entity, presenting in young women. It may be associated with loss of deep tendon reflexes (Adie's syndrome). Subsequent involvement of the other eye over a period of 10 years occurs in 50% of individuals, but bilateral tonic pupils may be due to autonomic neuropathy. Tonic pupil may occur after retinal laser photocoagulation.

Horner's Syndrome

Horner's syndrome is caused by a lesion of the sympathetic pathway either (1) in its central portion, which extends from the posterior hypothalamus through the brainstem to the upper spinal cord (C8–T2); or (2) in its preganglionic portion, which exits the spinal cord and synapses in the superior cervical (stellate) ganglion; or (3) in its postganglionic portion, from the superior cervical ganglion via the carotid plexus and the ophthalmic division of the trigeminal nerve, by which it enters the orbit. The sympathetic fibers then follow the nasociliary branch of the ophthalmic division of the trigeminal nerve and the long ciliary nerves to the iris and innervate Müller's muscle and the iris dilator. Iris dilator muscle paresis causes miosis, which is more evident in dim light. Melanocyte maturation in the iris depends on sympathetic innervation; thus, a less pigmented (bluer) iris occurs in congenital or longstanding acquired Horner's syndrome. Paresis of Müller's muscle produces ptosis. Unilateral miosis, ptosis, and absence of sweating on the ipsilateral face and neck make up the complete syndrome. Sweating on the face is normal in postganglionic lesions because postganglionic fibers to the face for sweating follow the external rather than the internal carotid artery.

Central Horner's syndrome may be due to brainstem infarction, particularly lateral medullary infarction (Wallenberg's syndrome), syringomyelia, or cervical cord tumor. Preganglionic Horner's syndrome may be due to cervical rib, cervical vertebral fractures, apical pulmonary lesions—particularly bronchogenic carcinoma (Pancoast's syndrome)—or brachial plexus injuries. Postganglionic Horner's syndrome may be due to carotid artery dissection, skull base tumors, or cluster headache. The localization of central and preganglionic Horner's syndrome is often apparent from the associated clinical features. Sudden-onset isolated painful Horner's syndrome, particularly with a recent history of neck trauma or associated with pain in the neck or jaw, necessitates urgent investigation for carotid dissection, which may lead to thrombotic or embolic stroke. Horner's syndrome associated with chronic facial pain, particularly if associated with fifth, sixth, third, fourth, or second cranial nerve palsy, requires investigation for skull-base tumor. In most cases of isolated congenital Horner's syndrome no etiology is identified. Birth trauma is a commonly identified cause and neuroblastoma is occasionally responsible. Unexplained acquired Horner's syndrome in infants requires imaging for neuroblastoma.

Pharmacologic testing with topical cocaine in the conjunctival sac differentiates Horner's syndrome, in which the pupil does not dilate, from physiologic anisocoria. Topical apraclonidine, which causes dilation of the affected but not the normal pupil, can also be used. Testing with hydroxyamphetamine drops differentiates central and preganglionic from postganglionic lesions, but they are difficult to obtain.

This section deals with the neural apparatus that controls eye movements and causes them to move simultaneously, up or down and side to side, as well as in convergence or divergence.

The neural control of eye movements is ultimately controlled by alterations in activity in the nuclei and nerve fibers of the oculomotor, trochlear, and abducens nerves. These are referred to as the nuclear and infranuclear pathways. Coordination of eye movements requires connections between these ocular motor nuclei, the internuclear pathways. The supranuclear pathways are responsible for generation of the commands necessary for the execution of the appropriate movement, whether it be voluntary or involuntary.

Classification & Examination of Eye Movements

Eye movements are either fast or slow. Fast eye movements include voluntary or involuntary refixation movements (saccades) and the fast phases of vestibular and optokinetic nystagmus (see later in the chapter). The fast eye movement system is tested by command refixation movements and by the fast phase of vestibular and optokinetic nystagmus.

Slow eye movements include pursuit movements, which track a slowly moving target once the saccadic system has placed the target on the fovea and which are tested by asking a patient to follow a slow, smoothly moving target, the slow phase movements generated by vestibular stimuli, the slow phase of optokinetic nystagmus, and vergence movements, which, unlike all the other forms of eye movements, involve dysconjugate movements of the two eyes.

Under physiologic conditions, vestibular stimulation occurs from head movements. The resulting slow eye movements, known as the vestibulo-ocular responses (VOR), compensate for the head motion such that the position of the eyes in space remains static and steady visual fixation can be maintained. The doll's head maneuver is a clinical method of testing the VOR. The patient is asked to fixate on a target while the examiner moves the head in a horizontal or vertical plane. If the VOR is deficient, the compensatory eye movements are insufficient and must be supplemented by saccadic movements to maintain fixation. The head motion must be rapid; otherwise, pursuit mechanisms dominate the ocular motor response. In the unconscious patient, the doll's head maneuver is used to assess brainstem function. Since the pursuit and saccadic systems are not operative, the head movements can be slow. Absence of the VOR leads to failure of the eyes to move within the orbit. Other methods of vestibular stimulation are whole body rotation and caloric testing (see later in the chapter).

Generation of Eye Movements

Physiology

1. Fast eye movements—Understanding of the control of eye movements is most complete in the case of saccadic movements. Similar mechanisms are thought to apply to the fast phases of nystagmus. The generation of a saccade involves a pulse of increased innervation to move the eye in the required direction and a step increase in tonic innervation to maintain the new position in the orbit by counteracting the visco-elastic forces working to return the eye to the primary position. The pulse is produced by the burst cells of the saccadic generator. The step change in tonic innervation is produced by the tonic cells of the neural integrator, so called because it effectively integrates the pulse to produce the step. There is a close relationship between the amplitude of movement and its peak velocity, larger movements having greater peak velocities. Loss of the saccadic generator function leads to slowing of saccades. Loss of the neural integrator function leads to a failure of maintenance of the desired final position, ie, a failure of gaze holding. Clinically, this usually manifests as a gaze-evoked nystagmus, with a drift of the eyes toward the primary position followed by a corrective saccade back to the desired position of gaze.

2. Slow eye movements—The slow phase movements generated by vestibular stimuli are a direct response to the detection of movement by the semicircular canals. The canals are acceleration detectors, but their output is integrated to produce a velocity signal that is then conveyed to the ocular motor nuclei. The generation of pursuit movements is less well understood. The slow phase of optokinetic nystagmus is in part a pursuit movement, but there is also an additional specific optokinetic movement generated by the perception of movement of the background of the visual scene. This optokinetic movement appears to be generated by the pathways involved in generating slow-phase vestibular movements but with an input from the retina, either via cortical centers or directly via a subcortical pathway. Vergence eye movements are generated in response to retinal disparity, that is, stimulation of noncorresponding retinal loci by the object of regard. Electromyography has established divergence as an active process, not a relaxation of convergence.

Anatomy

1. Brainstem centers for fast eye movements— The saccadic generator for horizontal eye movements lies in the paramedian pontine reticular formation. The output from this structure is channeled through the abducens nucleus, which contains both the motor neurons for the abducens nerve and the cell bodies of inter-neurons, which pass via the medial longitudinal fasciculus to innervate the motor neurons in the contralateral medial rectus subnucleus of the oculomotor nerve. The neural integrator for horizontal eye movements appears to be located close to the paramedian pontine reticular formation in the nucleus prepositus hypoglossi.

   The saccadic generator for vertical movements is in the rostral interstitial nucleus of the medial longitudinal fasciculus in the rostral midbrain. The pathway to the ocular motor nuclei for upward movements involves the posterior commissure, dorsal to the cerebral aqueduct, and its nucleus. The corresponding pathway for downward eye movements is less well defined. Neural integration for vertical eye movements seems to take place in both the interstitial nucleus of Cajal, close to the rostral interstitial nucleus of the medial longitudinal fasciculus in the midbrain and in the vestibular nuclei in the medulla.

2. Cortical centers for fast eye movements—Voluntary saccades are initiated in the frontal lobe (frontal eye field area 8). The pathway descends through the basal ganglia and the anterior limb of the internal capsule into the brainstem, terminating in the midbrain pretectal area for vertical movements and crossing to the paramedian pontine reticular formation in the opposite side of the pons for horizontal movements. The generation of involuntary (reflexive) saccades, in response to a target appearing in the peripheral field of vision, depends on activity within the superior colliculus, which receives information from the occipital cortex and also directly from the retina in a purely subcortical pathway.

3. Brainstem centers for slow eye movements—The processing of information from the semicircular canals occurs in the vestibular nuclei, which then connect directly to the ocular motor nuclei. These pathways from the vestibular nuclei in the medulla to the pons and midbrain pass in a number of fiber tracts, including the medial longitudinal fasciculus.

4. Cortical centers for slow eye movements—Pursuit movements originate in the occipital cortex. The pathway descends through the posterior limb of the internal capsule to the midbrain and ipsilateral paramedian pontine reticular formation. The slow phase of optokinetic nystagmus is likely to be generated at least in part in area V5 (or MT) at the junction of the occipital and temporal lobes, which is involved in motion detection. The descending pathway probably accompanies the pathway for pursuit movements. Vergence eye movements are generated in the occipital cortex, and the pathway also probably descends via the posterior limb of the internal capsule, together with the pathway for pursuit movements, to terminate in the rostral midbrain near or in the oculomotor nucleus. Impulses then pass directly to each medial rectus subnucleus and via the medial longitudinal fasciculus to the abducens nuclei. It is not clear whether convergence and divergence are controlled by the same or separate brainstem centers.

Abnormalities of Eye Movements

Owing to the multiplicity of pathways involved in the supranuclear control of eye movements, with origins in different areas of the brain and an anatomic separation in the brainstem of the horizontal and vertical eye movement systems, disorders of the supranuclear pathways characteristically produce a dissociation of effect upon the various types of eye movements. Thus, the clinical clues to a supranuclear lesion are a differential effect on horizontal and vertical eye movements or upon saccadic, pursuit, and vestibular eye movements. In diffuse brainstem disease, such features may not be apparent, and differentiation from disease at the neuromuscular junction or within the extraocular muscles on clinical grounds can be difficult.

Disease of the internuclear pathways results in a disruption of the conjugacy of eye movements. In infranuclear disease, the pattern of eye movement disturbance usually complies with that expected of a lesion involving one or more cranial nerves or their nuclei.

Lesions of the Supranuclear Pathways

Cerebral Hemispheres

A seizure focus in the frontal lobe may cause involuntary turning of the eyes to the opposite side. Destructive lesions cause transient deviation to the same side, and the eyes cannot be turned quickly and voluntarily (saccadic movement) to the opposite side. This is called frontal gaze palsy, and recovery occurs when the opposite frontal eye field substitutes. Ocular pursuit to the opposite side is retained. There is no diplopia.

Smooth ocular pursuit may be lost with posterior lesions of the hemispheres. The patient is unable to follow a slowly moving object in the direction of the gaze palsy. The command (fast) eye movement is not lost, so pursuit is “saccadic.”

Phenytoin can significantly affect saccades. Sedative agents and carbamazepine can alter smooth pursuit eye movements.

Brainstem

Lesions of the posterior commissure of the midbrain cause impairment of conjugate upgaze. Lesions dorsal and medial to the red nuclei produce a downgaze paresis.

Dorsal midbrain syndrome (Parinaud's syndrome) is characterized by loss of voluntary upward gaze, convergence-retraction nystagmus, pupillary light-near dissociation, and eyelid retraction (Collier's sign). There may also be insufficiency or spasm of convergence and/or accommodation, and loss of voluntary downward gaze. Conjugate horizontal ocular movements are usually not affected. The syndrome results from tectal or pretectal lesions affecting the periaqueductal area. Pineal tumors, hydrocephalus, midbrain infarcts or arteriovenous malformations, and trauma may be responsible.

Lesions of the paramedian pontine reticular formation produce an ipsilateral horizontal gaze palsy affecting saccadic and pursuit movements. Vestibular slow-phase movements are preserved owing to the direct pathway from the vestibular nuclei to the abducens and oculomotor nuclei.

Lesions of the brainstem that cause gaze palsies include vascular accidents, arteriovenous malformations, multiple sclerosis, tumors (pontine gliomas, cerebellopontine angle tumors), and encephalitis.

Spasm of the Near Response

Spasm of the near response, also known as convergence or accommodative spasm, is usually caused by functional disease, but it may be caused by a midbrain lesion. It is characterized by convergent strabismus with diplopia, miotic pupils, and spasm of accommodation (induced myopia).

In functional disease, the features are usually intermittent and provoked by eye movement examination. Cyclopentolate 1%, one drop in each eye twice daily, with reading glasses to compensate for loss of accommodation may be helpful. Psychiatric consultation may be indicated.

Convergence Insufficiency

Convergence insufficiency is characterized by diplopia for near vision in the absence of any impairment of adduction on monocular testing, refractive error, particularly presbyopia, having been excluded. It is caused by functional disease or dysfunction of the supranuclear pathway for convergence in the midbrain. In organic lesions, pupillary miosis still occurs when convergence is attempted, whereas in functional disease, it does not.

Internuclear Ophthalmoplegia

The medial longitudinal fasciculus is an important fiber tract extending from the rostral midbrain to the spinal cord. It contains many pathways connecting nuclei within the brainstem, particularly those concerned with extraocular movements. The most common manifestation of damage to the medial longitudinal fasciculus is an internuclear ophthalmoplegia, in which conjugate horizontal eye movements are disrupted owing to failure of coordination between the abducens nerve nucleus in the pons and the oculomotor nerve nucleus in the midbrain. The lesion in the brainstem is ipsilateral to the eye with the adduction failure and contralateral to the direction of horizontal gaze that is abnormal. In the mildest form of internuclear ophthalmoplegia, the clinical abnormality is restricted to a slowing of saccades in the adducting eye, producing transient diplopia on lateral gaze. In the most severe form, there is complete loss of adduction on horizontal gaze, producing constant diplopia on lateral gaze (Figure 14–12). Convergence is characteristically preserved in internuclear ophthalmoplegia except when the lesion is in the midbrain, when the convergence mechanisms may also be affected. Another feature of internuclear ophthalmoplegia is nystagmus in the abducting eye on attempted horizontal gaze, which is at least in part a result of compensation for the failure of adduction in the other eye. In bilateral internuclear ophthalmoplegia, there may also be an upbeating nystagmus on upgaze due to failure of control of gaze holding in the upward direction, and the eyes may be divergent; this is known as the wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome.

Internuclear ophthalmoplegia may be due to multiple sclerosis (particularly in young adults), brainstem infarction (particularly in older patients), tumors, arteriovenous malformations, Wernicke's encephalopathy, and encephalitis. Bilateral internuclear ophthalmoplegia is most commonly due to multiple sclerosis.

A horizontal gaze palsy combined with an internuclear ophthalmoplegia, due to a lesion of the abducens nucleus or paramedian pontine reticular formation extending into the ipsilateral medial longitudinal fasciculus, affects all horizontal eye movements in the ipsilateral eye and adduction in the contralateral eye. This is known as a “one-and-a-half syndrome,” or paralytic pontine exotropia.

Nuclear & Infranuclear Connections

Ocular Motor Nerve Palsies

Ocular motor nerve palsies result in impairment of eye movements, the pattern being determined by which extraocular muscles are involved, ocular misalignment, which at least in the acute stage also varies in severity with different gaze positions according to which muscles are paretic, and ptosis if there is palsy of the levator palpebrae superioris muscle. Misalignment of the visual axes results in diplopia, unless there is suppression, which more commonly develops in children than adults. Dizziness or disequilibrium may be associated but disappears with monocular patching. Abnormal head posture may develop. In sixth nerve palsy, there is head turn to the side of the palsy, and in fourth nerve palsy, there is head tilt to the opposite side. Paresis of an extraocular muscle can be simulated by restriction of action of the yoke muscle, for example limitation of abduction may be due to medial rectus restriction rather than lateral rectus paresis. Assessment of saccadic velocity may be helpful, but forced duction tests may need to be performed. Saccadic velocity may also help identify which muscle is paretic, for instance in differentiating superior oblique from inferior rectus palsy.

There is wide variation in the site of damage and etiology in ocular motor nerve palsies. Nuclear lesions have specific localizing features. Fascicular lesions within the brainstem resemble peripheral nerve lesions but usually can be differentiated on the basis of other brainstem signs. Any extraocular muscle palsy that occurs with minor head trauma (subconcussive injuries) should be investigated for an intracranial lesion. In ischemic (microvascular) palsies, recovery by 4 months is the rule. Palsies that have not started to recover by then—especially those involving the sixth nerve—should be evaluated for another cause, particularly a structural lesion. Urgent investigation should be undertaken when there is evidence of multiple cranial nerve dysfunction or for any extraocular muscle palsy in a young adult. Assessment of any ocular motor nerve palsy must include assessment of second, fifth, and seventh cranial nerve function.

Oculomotor Nerve (III)

The motor fibers arise from a group of nuclei in the central gray matter ventral to the cerebral aqueduct at the level of the superior colliculus. The midline central caudal nucleus innervates both levator palpebrae superioris muscles. The paired superior rectus subnuclei innervate the contralateral superior rectus. The efferent fibers decussate immediately and pass through the opposite superior rectus subnucleus. The subnuclei for the medial rectus, inferior rectus, and inferior oblique muscles are also paired structures but innervate the ipsilateral muscles. The fascicle of the oculomotor nerve courses through the red nucleus and the inner side of the substantia nigra to emerge on the medial side of the cerebral peduncles. The nerve runs alongside the sella turcica, in the outer wall of the cavernous sinus, and through the superior orbital fissure to enter the orbit. The superior branch innervates the levator palpebrae and superior rectus muscles and the inferior branch of all other muscles and the sphincter.

The parasympathetics arise from the Edinger–Westphal nucleus just rostral to the motor nucleus of the third nerve and pass via the inferior division of the third nerve to the ciliary ganglion. From there the short ciliary nerves are distributed to the sphincter muscle of the iris and to the ciliary muscle.

Oculomotor Palsy

Lesions of the third nerve nucleus typically affect the ipsilateral medial and inferior rectus and inferior oblique muscles, both levator muscles, and both superior rectus muscles. There will be bilateral ptosis and bilateral limitation of elevation as well as limitation of adduction and depression ipsilaterally.

From the fascicle of the nerve in the midbrain to its eventual termination in the orbit, third nerve palsy produces purely ipsilateral dysfunction. The exact pattern depends on the extent of the palsy, but in general the ipsilateral eye is turned out by the intact lateral rectus muscle and slightly depressed by the intact superior oblique muscle. The eye may only be moved laterally. (Incyclotorsion from the action of the intact superior oblique muscle can be observed by watching a small blood vessel on the medial conjunctiva as depression of the eye is attempted.) There can be a dilated fixed pupil, absent accommodation, and ptosis of the upper lid, often severe enough to cover the pupil. The pattern of pupil abnormality may be influenced by concomitant Horner's syndrome (sympathetic paresis) resulting in a relatively small unreactive pupil or aberrant regeneration (see later in the chapter).

Ischemia, intracranial aneurysm, head trauma, and intracranial tumors are the most common causes of third nerve palsy in adults. Causes of ischemic (microvascular) palsy include diabetes mellitus, hypertension, hyperlipidemia, and systemic vasculitis. Aneurysm usually arises from the junction of the internal carotid and posterior communicating arteries. Intracranial tumor may cause oculomotor palsy by direct damage to the nerve or due to mass effect. Pupillary dilation, initially unilateral and then bilateral, is an important sign of herniation of the medial temporal lobe through the tentorial hiatus (tentorial herniation) due to a rapidly expanding supratentorial mass. Bilateral peripheral third nerve palsies can be caused by interpeduncular lesions, such as basilar artery aneurysm.

A useful guide clinically is that in ischemic lesions the pupillary responses are spared, whereas in compression, including aneurysmal, the pupil is involved, initially loss of reactivity and then also dilation. Less than 5% of vascular third nerve palsies are associated with complete pupillary palsy, and in only 15% there is partial pupillary palsy. Painful isolated third nerve palsy with pupillary involvement necessitates emergency investigation for ipsilateral posterior communicating artery aneurysm. Such investigation may also be indicated in painful isolated third nerve palsy without pupillary involvement and in young patients with painless isolated third nerve palsy with pupillary involvement.

Monocular elevator paralysis—inability to elevate one eye in both abduction (superior rectus) and adduction (inferior oblique)—can be due to paresis of the superior division of the third nerve (tumor, sinusitis, postviral) but also occurs as a congenital defect or in thyroid ophthalmopathy, orbital myositis, orbital floor fracture, myasthenia gravis, and midbrain stroke.

Third nerve palsies in children may be congenital or may be due to ophthalmoplegic migraine, meningitis, or postviral.

Oculomotor Synkinesis (Aberrant Regeneration of the Third Nerve)

This phenomenon is characterized by inappropriate activation of muscles innervated by the oculomotor nerve, including (1) lid dyskinesias due to inappropriate activation of levator palpebrae superioris either on horizontal gaze (eyelid elevates on attempted adduction) or on vertical gaze (eyelid elevates on attempted depression (“pseudo-Graefe's sign”); (2) adduction or retraction on attempted upgaze due to inappropriate activation of medial rectus or inferior rectus; (3) pupillary constriction on attempted adduction or depression; and (4) a monocular vertical optokinetic nystagmus response (due to coactivation of superior rectus, inferior oblique and inferior rectus muscles fixing the involved eye, allowing only the normal eye to respond to the moving target).

Oculomotor synkinesis most commonly occurs in congenital third nerve palsy or during recovery from acute third nerve palsy due to trauma or aneurysmal compression (secondary oculomotor synkinesis). It may also occur as a primary phenomenon in chronic compression, usually due to an internal carotid aneurysm or meningioma in the cavernous sinus. Oculomotor synkinesis is not a feature of ischemic oculomotor palsy.

Cyclic Oculomotor Palsy

Cyclic oculomotor palsy can complicate congenital third nerve palsy; it is a rare, predominantly unilateral event, with a typical third nerve palsy showing cyclic spasms every 10–30 seconds. During these intervals, ptosis improves and accommodation increases. This phenomenon continues unchanged throughout life but decreases with sleep and increases with greater arousal.

Marcus Gunn Phenomenon (Jaw-Winking Syndrome)

This rare usually congenital condition consists of elevation of a ptotic eyelid upon movement of the jaw. Acquired cases occur after damage to the oculomotor nerve with subsequent innervation of the lid (levator palpebrae superioris) by a branch of the fifth cranial nerve.

Trochlear Nerve (IV)

Motor (entirely crossed) fibers arise from the trochlear nucleus just caudal to the third nerve at the level of the inferior colliculus; they then run posteriorly, decussate in the anterior medullary velum, and wind around the cerebral peduncles. The fourth nerve travels near the third nerve along the wall of the cavernous sinus to the orbit, where it supplies the superior oblique muscle. The fourth nerve is unique among the cranial nerves in arising from the dorsal brainstem.

Trochlear Palsy

Congenital trochlear palsy is probably not usually neurogenic in origin but due to developmental anomaly within the orbit. It may present in childhood with an abnormal head posture (see later in the chapter) or in childhood or adult life with eyestrain or diplopia due to reduced ability to overcome the vertical ocular deviation (decompensation). Acquired trochlear palsy is commonly traumatic. The nerve is vulnerable to injury at the site of exit from the dorsal aspect of the brainstem. Both nerves may be damaged by severe trauma as they decussate in the anterior medullary velum, resulting in bilateral superior oblique palsies. Acquired trochlear palsy may also be ischemic (microvascular) or secondary to posterior fossa surgery. Rarely, posterior fossa tumors may present with an isolated trochlear palsy.

Superior oblique palsy results in upward deviation (hypertropia) of the eye, which increases when the patient looks down and to the opposite side. In addition, in acquired palsy, there is excyclotropia; therefore, one of the diplopic images will be tilted with respect to the other. Thus, torsional diplopia indicates an acquired palsy and lack of torsional symptoms indicates a congenital palsy. Tilting the head toward the involved side increases the vertical ocular deviation (Bielschowsky head tilt test). Tilting the head away from the side of the involved eye may relieve the diplopia, and patients frequently adopt such a head tilt. History of an abnormal head posture during childhood, which may be confirmed by review of family photographs and a large vertical prism fusion range, are strong clues that a trochlear palsy is congenital. In bilateral traumatic palsy, there is usually a chin-down head posture. Strabismus surgery is effective in decompensated congenital palsy not controlled by prisms and for unresolved acquired palsy.

Superior Oblique Myokymia

Contrary to its name, this is an uncommon acquired tremor of the superior oblique muscle, affecting only one eye. The patient complains of episodes of torsional and/or vertical oscillopsia or double vision, which may be precipitated by looking down, such as when reading. Various anticonvulsants, typically carbamazepine, or β-blocker eye drops can be beneficial. Superior oblique muscle surgery may be undertaken. The cause may be compression of the trochlear nerve by an aberrant artery, for which intracranial surgery may be successful.

Abducens Nerve (VI)

Motor (entirely uncrossed) fibers arise from the nucleus in the floor of the fourth ventricle in the lower portion of the pons near the internal genu of the facial nerve. Piercing the pons, the fibers emerge anteriorly, the nerve running a long course over the tip of the petrous portion of the temporal bone into the cavernous sinus. It enters the orbit with the third and fourth nerves to supply the lateral rectus muscle.

Abducens Nucleus Lesion

The abducens nucleus contains the motor neurons to the ipsilateral lateral rectus and the cell bodies of interneurons innervating the motor neurons to the contralateral medial rectus. It is the final common relay point for all horizontal conjugate eye movements, and a lesion within the nucleus will produce an ipsilateral horizontal gaze palsy affecting all types of eye movement, including vestibular movements. This contrasts with a lesion of the paramedian pontine reticular formation, in which vestibular movements are preserved.

Abducens Nerve Palsy (See Also Chapter 12)

This is the most common single extraocular muscle palsy. Abduction of the eye is reduced or absent; esotropia is present in the primary position and increases with distance fixation and upon gaze to the affected side. Ischemia (arteriosclerosis, diabetes, migraine, and hypertension) is a common cause. However, increased intracranial pressure, in which the abducens palsy is a false localizing sign, intracranial tumors, particularly at the base of the skull, trauma, meningitis, demyelination, dural arteriovenous fistula, and intracranial hypotension including after lumbar puncture are other causes. Infections can produce sixth nerve palsy from direct involvement, as in middle ear infection, ischemia, or meningitis. Arnold–Chiari malformation (congenital downward displacement of the cerebellar tonsils) can produce sixth nerve palsy due to traction but can also produce a distance esotropia without limitation of abduction due to cerebellar dysfunction. A child with a sixth nerve palsy should be evaluated for a brainstem tumor (glioma) or inflammation if trauma was not present or if trauma was minimal. Möbius' syndrome (congenital facial diplegia) can be associated with a sixth nerve or conjugate gaze palsy. Pseudo-sixth nerve palsies can occur in Duane's syndrome, spasm of the near response, thyroid eye disease, myasthenia, or long-standing strabismus and in medial rectus entrapment by an ethmoid fracture.

Duane's Syndrome

Duane's syndrome is uncommon (<1% of cases of strabismus) and in almost all cases congenital. It is a stationary, nearly always unilateral condition characterized by complete or partial deficiency of abduction, with retraction of the globe and narrowing of the lid fissure on adduction. Congenital absence of the sixth nerve with coinnervation of the lateral rectus by a branch of the third nerve is the likely cause in most cases and other congenital anomalies are common. The visual handicap is seldom severe. Visual acuity is usually normal. Unless there is a marked abnormal head posture, strabismus surgery is best avoided.

Gradenigo's Syndrome

Gradenigo's syndrome is characterized by pain in the face (from irritation of the trigeminal nerve) and abducens palsy. The syndrome is produced by disease of the tip of the petrous bone and most often occurs as a rare complication of otitis media with mastoiditis or petrous bone tumors.

Syndromes Affecting Cranial Nerves III, IV, & VI

Superior Orbital Fissure Syndrome

All the ocular motor nerves pass through the superior orbital fissure and can be affected by tumor, inflammation, or trauma involving the fissure.

Orbital Apex Syndrome

This syndrome is similar to the superior orbital fissure syndrome with the addition of optic nerve signs and usually greater proptosis. It is also caused by tumor, inflammation, or trauma.

Sudden Complete Ophthalmoplegia

Complete ophthalmoplegia of sudden onset can be due to extensive brainstem vascular disease, Wernicke's encephalopathy, Fisher's syndrome, bulbar poliomyelitis, pituitary apoplexy, basilar aneurysm, meningitis, diphtheria, botulism, or myasthenic crisis.

The Cerebellum

The cerebellum has an important modulating influence on the function of the neural integrators. Thus, it is involved in gaze holding and the control of saccades, particularly the relationship between the pulse and the step of saccade generation. Cerebellar dysfunction produces gaze-evoked nystagmus, by its influence on gaze holding, and abnormalities of saccades, including saccadic dysmetria in which the saccadic amplitude is inaccurate, and postsaccadic drift due to a mismatch between the pulse and step of the saccade.

The cerebellum is also important in the control of pursuit eye movements, and cerebellar dysfunction may thus result in broken (saccadic) pursuit. It may also result in ocular misalignment, vertical due to skew deviation or horizontal.

Myasthenia gravis is characterized by abnormal fatigability of striated muscles after repetitive contraction that improves after rest and often is first manifested by weakness of the extraocular muscles. Unilateral fatiguing ptosis is a frequent first sign, with subsequent bilateral involvement of extraocular muscles, so that diplopia is often an early symptom. Unusual ocular presentations may simulate gaze palsies, internuclear ophthalmoplegias, vertical nystagmus, and progressive external ophthalmoplegia. Generalized weakness of the arms and legs, difficulty in swallowing, weakness of jaw muscles, and difficulty in breathing may follow rapidly in untreated cases. The weakness often worsens as the day progresses but can be improved by a nap. There are no sensory changes.

The incidence of the disease is in the range of 1:30,000 to 1:20,000. Myasthenia gravis usually affects young adults aged 20–40 (70% are under 40 years of age), although it may occur at any age and can be misdiagnosed as functional, especially because the weakness can be greater in exciting or embarrassing situations. Older patients are more commonly male and are more likely to have a thymoma.

The onset may follow an upper respiratory infection, stress, pregnancy, or any injury, and the disease has been noted as a transitory condition in newborn infants of myasthenic mothers. Drugs, including β-blockers (eg, propranolol), penicillamine, statins, lithium, aminoglycoside antibiotics, chloroquine, and phenytoin, may induce, unmask, or exacerbate the disease. Myasthenia gravis has been associated with hyperthyroidism (5%), thyroid abnormalities (15%), autoimmune diseases (5%), and diffuse metastatic carcinoma (7%).

In about one-third of cases, the disease is confined to the extraocular muscles at onset. In about two-thirds of these cases, the disease will become generalized with time, usually within the first year.

The differential diagnosis includes chronic progressive external ophthalmoplegia, oculopharyngeal muscular dystrophy, myotonic dystrophy, ocular motor cranial nerve palsies, and brainstem lesions including encephalitis, botulism, and multiple sclerosis.

The disease has its origin at the neuromuscular junction, especially at the postsynaptic site, primarily due to antibodies against it and the presynaptic site. Anti-acetylcholine receptor antibodies are diagnostic. They are present in 80%–90% of patients with systemic myasthenia and 40%–60% of patients with pure ocular myasthenia, but the titers do not correlate with severity of disease. Antibody-positive patients should undergo chest CT or MRI to detect thymic enlargement. Thymomas occur in 15% of patients. A large proportion of patients with generalized myasthenia gravis without acetylcholine receptor antibodies have antibodies against muscle-specific receptor tyrosine kinase (MuSK). These patients tend to be female, with predominant cranial and bulbar muscle involvement, frequent respiratory crises, and poorer response to treatment. MuSK antibody myasthenia gravis may also present with pure ocular disease.

Cholinesterase destroys acetylcholine at the neuromuscular junction, and cholinesterase-inhibiting drugs may improve the condition by increasing the amount of acetylcholine available to the damaged postsynaptic site. Intravenous edrophonium or intramuscular neostigmine can be used for diagnosis. In the edrophonium (Tensilon) test, pretreatment with intravenous atropine is recommended. Edrophonium, 2 mg (0.2 mL), is given intravenously over 15 seconds. If no response occurs in 30 seconds, an additional 5–7 mg (0.5–0.7 mL) is given. The test is most helpful when marked ptosis is present. Significant improvement in muscle function constitutes a positive response and confirms the diagnosis of myasthenia gravis. Slightly positive edrophonium tests can occur in neurogenic palsies, and there may be false-negative results when myasthenia is complicated by muscle wasting. Documented improvement of ptosis with rest or application of ice can be helpful for diagnosis.

Repetitive nerve stimulation, especially of the facial or proximal muscles, can demonstrate abnormal muscle fatigability (more than 10% decrease in the response is diagnostic of myasthenia). Variation in size and shape of motor unit potentials is noted on needle electromyography of affected muscles, and single-fiber studies show increased variability (jitter) in the temporal pattern of action potentials from muscle fibers of the same motor unit. Orbicularis oculi single-fiber electromyography is particularly useful in diagnosis of ocular myasthenia.

Myasthenia can be treated with pyridostigmine, systemic steroids, other immunosuppressants such as azathioprine, immunoglobulins, and plasmapheresis according to the severity of disease. During severe exacerbations, artificial ventilation may be necessary. Thymectomy may be indicated in patients with thymoma (although it may not influence the severity of the myasthenia) and in patients with early-onset generalized disease without evidence of thymoma—in one-third of whom it may produce complete remission without the need for immunosuppressants. Ocular myasthenia tends to respond less well to anticholinesterase agents than generalized disease, but the response to systemic steroids is usually good. Extraocular muscle surgery can be undertaken but should be delayed until the ocular motility deficit has been stable for a long time.

Myasthenia is generally a chronic disease with a tendency to pursue a relapsing and remitting course. The prognosis depends on the extent of the disease, the response to medication and thymectomy, and the careful management of severe exacerbations.

This rather rare disease is characterized by slowly progressive inability to move the eyes and severe early ptosis yet normal pupillary responses. It may begin at any age and progresses over a period of 5–15 years to complete external ophthalmoplegia. It is a form of mitochondrial myopathy and may be associated with other manifestations of mitochondrial disease, such as pigmentary degeneration of the retina, deafness, cerebellar-vestibular abnormalities, seizures, cardiac conduction defects, and peripheral sensorimotor neuropathy, in which case the term “ophthalmoplegia-plus” may be applied. Onset before 15 years of age of chronic progressive external ophthalmoplegia, heart block, and pigmentary retinopathy constitutes the Kearns–Sayre syndrome. Chronic progressive external ophthalmoplegia is associated with deletions of mitochondrial DNA, which are more frequent and more extensive in the cases with nonocular manifestations.

See Table 14–2

Nystagmus is defined as repetitive, rhythmic oscillations of one or both eyes in any or all fields of gaze, initiated by a slow eye movement. The waveform may be pendular, in which the movements in each direction have equal speed, amplitude, and duration; or jerk, in which the slow movement in one direction is followed by a rapid corrective return to the original position (fast component). By convention, the direction of jerk nystagmus is given as the direction of the corrective fast phase and not the direction of the primary slow phase.

Jerk nystagmus is classified as grade I, present only with the eyes directed toward the fast component; grade II, present also with the eyes in primary position; or grade III, present even with the eyes directed toward the slow component. The movements of pendular or jerk nystagmus may be horizontal, vertical, torsional, oblique, circular, or a combination of these. The direction may change depending on the direction of gaze.

The amplitude of nystagmus is the extent of the movement; the rate of nystagmus is the frequency of oscillation. Generally speaking, the faster the rate, the smaller the amplitude and vice versa. Nystagmus is usually conjugate but is occasionally dysconjugate, as in convergence-retraction nystagmus and seesaw nystagmus.

Nystagmus is also occasionally dissociated (more marked in one eye than the other), as in internuclear ophthalmoplegia, spasmus nutans, monocular visual loss, and acquired pendular nystagmus and with asymmetric muscle weakness in myasthenia gravis.

Physiology of Symptoms

Reduced visual acuity is caused by inability to maintain steady fixation. The patient may complain of illusory movement of objects (oscillopsia), which is usually indicative of acquired rather than congenital nystagmus and is particularly severe in vestibular disease. Head tilting is usually involuntary, to decrease the nystagmus. The head is turned toward the fast components in jerk nystagmus or set so that the eyes are in a position that minimizes ocular movement in pendular nystagmus. Head nodding may occur in congenital nystagmus and is a characteristic feature of spasmus nutans. Nystagmus is noticeable and cosmetically disturbing except when excursions of the eye are very small.

Physiologic Nystagmus

Three types of nystagmus can be elicited in the normal person.

End-Point (End-Gaze) Nystagmus

Normal individuals may have nystagmus on extreme horizontal gaze, which disappears when the eyes are moved centrally by a few degrees. It is primarily horizontal but may have a slight torsional component and greater amplitude in the abducting eye.

Optokinetic Nystagmus

This type of nystagmus may be elicited in all normal individuals, most easily by means of a rotating drum with alternating black and white lines but in fact by any repetitive targets in the visual field, such as repetitive telephone poles as seen from a window of a fast-moving vehicle. The slow component follows the object, and the fast component moves rapidly in the opposite direction to fixate on the succeeding object. A unilateral or asymmetric horizontal response usually indicates a deep parietal lobe lesion, especially a tumor. It occurs as a result of a deficit in the slow (pursuit) phase. Anterior cerebral (ie, frontal lobe) lesions may inhibit this response only temporarily when an acute saccadic gaze palsy is present, which suggests the presence of a compensatory mechanism that is much greater than for lesions situated farther posteriorly. Asymmetry of response in the vertical plane suggests a brainstem lesion. Since it is an involuntary response, this test is especially useful in detecting functional visual loss. A large mirror filling the patient's central field at near can be rotated from side to side and will induce an optokinetic nystagmus if vision is present.

Stimulation of Semicircular Canals

The three semicircular canals of each inner ear sense movements of the head in space, being primarily sensitive to acceleration. The neural output of the vestibular system, after processing within the vestibular and related brainstem nuclei, is a velocity signal. This is transmitted, principally via the medial longitudinal fasciculus on each side of the brainstem, to the ocular motor nuclei to produce the necessary compensatory eye movements (VOR) for maintaining a stable position of the eyes in space, and hence optimal vision. Vestibular signals also pass to the cerebellum and cerebral cortex.

Stimulation of the semicircular canals results in a compensatory eye movement. In the unconscious subject with an intact brainstem, this leads to a tonic deviation of the eyes, whereas in the conscious subject, a superimposed corrective fast-phase movement, returning the eyes back toward the straight-ahead position, results in a jerk nystagmus. These tests are useful methods of investigating vestibular function in conscious subjects and, in the case of caloric stimulation, brainstem function in comatose patients.

Rotatory Physiologic Nystagmus (BáRáNy Rotating Chair)

When the head is tilted 30° forward, the horizontal semicircular canals lie horizontally in space. Rotation, such as in a Bárány chair, then leads to a horizontal jerk nystagmus with the compensatory slow-phase eye movement opposite to the direction of turning and the corrective fast phase in the direction of turning. Owing to impersistence of the vestibular signal during continued rotation, the nystagmus abates. Once the rotation stops, there is a vestibular tone in the opposite direction, which results in a jerk nystagmus with the fast phase away from the original direction of turning (postrotatory nystagmus). Since the subject is stationary, postrotatory nystagmus is often easier to analyze than the nystagmus during rotation.

Caloric Stimulation

With the head tilted 60° backward, the horizontal semicircular canals lie vertically in space. Water irrigation of the auditory canal then generates convection currents predominantly within the horizontal rather than the vertical semicircular canals. Cold water irrigation induces a predominantly horizontal jerk nystagmus with a fast phase opposite to the side of irrigation, and warm water irrigation induces a similar jerk nystagmus with a fast phase toward the side of irrigation. (The mnemonic device is “COWS”: cold-opposite, warm-same.) Caloric nystagmus is made more obvious by the patient wearing Frenzel's spectacles, which eliminate patient fixation and provide a magnified view for the examiner. It is important to verify that the tympanic membrane is intact before performing irrigation of the external auditory canal.

Pathologic Nystagmus

Congenital Nystagmus

Congenital nystagmus is nystagmus present within 6 months after birth. Ocular instability is usual at birth, due to poor visual fixation, but this abates during the first few weeks of life. The presence of spontaneous nystagmus is always pathologic.

Congenital impairment of vision or visual deprivation due to lesions in any part of the eye or optic nerve can result in nystagmus at birth or soon thereafter. Causes include corneal opacity, cataract, albinism, achromatopsia, bilateral macular disease, aniridia, and optic atrophy. By definition, congenital idiopathic motor nystagmus has no associated underlying sensory abnormality, although visual performance is limited by the ocular instability. Typically it is not present at birth but becomes apparent between 3 and 6 months of age.

At one time it was thought that congenital pendular nystagmus was indicative of an underlying sensory abnormality whereas congenital jerk nystagmus was not. Eye movement recordings have shown this not to be true, both pendular and jerk waveforms being seen whether there is a sensory abnormality or not. Indeed, in many cases, a mixed pattern of alternating pendular and jerk waveforms is seen. Congenital nystagmus, particularly the idiopathic motor type with its potential for better visual fixation, generally undergoes a progressive change in its waveform during early childhood. There is development of periods of relative ocular stability, that is, relatively slow eye velocity, known as foveation periods since they are thought to be an adaptive response to maximize the potential for fixation, and hence to improve visual acuity. In addition, congenital nystagmus with a jerk nystagmus has a characteristic waveform in which the slow phases have an exponentially increasing velocity. This is known as CN-type waveform, and with very few exceptions its presence signifies that the nystagmus has been present since early childhood. This can be a particularly useful feature in determining that nystagmus noted in adulthood is not of recent onset.

Congenital nystagmus is usually horizontal and conjugate. Vertical and torsional components are only occasionally present. The direction of any jerk component often varies with the direction of gaze, but an important feature in comparison to many forms of acquired nystagmus is that there is no additional vertical component on vertical gaze. In most patients with congenital nystagmus, there is a direction of gaze (null zone) in which the nystagmus is relatively quiet. If this null zone is away from primary position, a head turn may be adopted to place the eccentric position straight ahead. In a few cases, the position of the null zone varies to produce one type of periodic alternating nystagmus. Congenital nystagmus is usually decreased in intensity by convergence, and some patients will adopt an esotropia (nystagmus blockage). Anxiety and increased “effort to see” will often increase the intensity of congenital nystagmus, and thus reduce visual acuity.

Once congenital nystagmus has been noted, it is important to identify any underlying sensory abnormality, if only to determine the visual potential. This may require electrodiagnostic studies. Extraocular muscle surgery is predominantly indicated for patients with a marked head turn. Supramaximal recessions of the horizontal rectus muscles reduce the intensity of congenital nystagmus, but the effect is only temporary. Gabapentin and/or memantine may be beneficial.

In general, latent nystagmus means nystagmus that increases in intensity when one eye is covered, which is a characteristic feature of congenital nystagmus. There is also a specific type of latent nystagmus, known as LN, which is predominantly seen in infantile esotropia. LN is a horizontal jerk nystagmus with the fast phase toward the side of the fixing eye—with the left eye covered, there is a rightward nystagmus, and with the right eye covered, a leftward nystagmus. LN also becomes more marked when one eye is covered, only then being apparent on clinical examination, but eye movement recordings show that the nystagmus is always present. Manifest latent nystagmus (MLN) is a particular type of LN in which the nystagmus is always apparent on clinical examination. It occurs in patients with LN when binocular function is lost, that is, the equivalent of one eye being covered. This may be because of loss of sight in one eye or even from the development of a divergent squint. If binocular function is restored, MLN will revert to LN.

Acquired Pendular Nystagmus

Any child who develops bilateral visual loss before 6 years of age may also develop a pendular nystagmus, and indeed the acquisition of a pendular nystagmus during infancy necessitates further investigation. A specific syndrome of acquired pendular nystagmus in childhood is spasmus nutans. This is a bilateral, generally horizontal (occasionally vertical), fine, dissociated pendular nystagmus, associated with head nodding and an abnormal head posture. There is a benign form, which may be familial, with onset before age 2 and spontaneous improvement during the third or fourth year. Spasmus nutans may also rarely be the first manifestation of an anterior visual pathway glioma.

In adults, acquired pendular nystagmus is a feature of brainstem disease, usually multiple sclerosis or brainstem stroke. There may be horizontal, vertical, or torsional components or even a combination of components to produce oblique or elliptical trajectories. The syndrome of oculopalatal myoclonus characteristically develops several months after a brainstem stroke. There is a pendular nystagmus with synchronous movements variably involving the soft palate, larynx, and diaphragm as well as producing head titubation. (The term “myoclonus” is a misnomer since the abnormal movements are a form of tremor.) The associated hypertrophy of the inferior olivary nucleus in the medulla and other evidence suggest a disruption of the dentato-rubro-olivary pathway between the brainstem and the cerebellum as the underlying pathogenesis. Various drug treatments have been tried for adult acquired pendular nystagmus, of which gabapentin, memantine, and baclofen have produced the best although still limited results. Base-out prisms may also be tried.

Vestibular Nystagmus

Abnormalities of vestibular tone result in abnormal activation of the vestibulo-ocular pathways and abnormal neural drive to the extraocular muscles. Loss of function in the left horizontal semicircular canal is equivalent to activation of the right horizontal semicircular canal, as would normally be produced by a rightward head turn. The oculomotor response is conjugate leftward slow-phase movement of the eyes. The corrective fast-phase response is rightward in direction, and a right-beating horizontal nystagmus is thus generated. The pattern of response to dysfunction of one or more semicircular canals can be similarly derived to give the full possible range of peripheral vestibular nystagmus, although in clinical practice it is the effect of dysfunction of the horizontal canals that usually predominates. As a general rule, peripheral vestibular lesions are destructive and the fast phase of the resulting nystagmus is away from the side of the lesion. Since the neural signal of the vestibulo-ocular pathways is a velocity signal, the slow phase of peripheral vestibular nystagmus has a constant velocity. This gives rise to the characteristic saw-tooth waveform on eye movement recordings.

Peripheral vestibular nystagmus is not dependent on visual stimuli and thus is still present in the dark, or with the eyes closed, as well as in blind individuals. It is, however, inhibited by visual fixation or, conversely, accentuated by wearing Frenzel's spectacles, and this is an important factor in the normal dampening over 2–3 weeks of peripheral vestibular nystagmus. Head position does not usually influence peripheral vestibular nystagmus except in benign paroxysmal positional vertigo, in which elicitation of the characteristic pattern of nystagmus with the Hallpike maneuver is a specific diagnostic feature. Other clinical features associated with peripheral vestibular disease are vertigo, tinnitus, and deafness, the latter two reflecting the close association between the vestibular and auditory systems. Causes of peripheral vestibular disease are labyrinthitis, Meniere's disease, trauma (including surgical destruction of one labyrinth), and vascular, inflammatory, or neoplastic lesions of the vestibular nerves.

Central vestibular nystagmus is an acquired jerk nystagmus due to disease in the central vestibular pathways of the brainstem and cerebellum. It has a variety of forms, but characteristic types are a purely torsional or vertical jerk nystagmus and the syndromes of downbeat and upbeat nystagmus, which are probably the result of imbalance in vestibular tone from the vertical semicircular canals. Central vestibular nystagmus is frequently elicited or enhanced by specific head positions, presumably as a result of modulation by input from the peripheral vestibular apparatus. It is not dampened by visual fixation and does not spontaneously abate in intensity with time. Other clinical features reflect the associated brainstem and cerebellar dysfunction and include abnormalities of smooth pursuit eye movements other than those due to the nystagmus itself. Causes of central vestibular nystagmus include lesions of the vestibular nuclei (brainstem demyelination, including multiple sclerosis, inflammation, and stroke, particularly thrombosis of the posteroinferior cerebellar artery leading to lateral medullary infarction—Wallenberg's syndrome).

Downbeat nystagmus is a downward-beating nystagmus, usually present in primary position. It is often most obvious on gaze down and to the side, when the nystagmus becomes oblique, with the horizontal component in the direction of lateral gaze. Downbeat nystagmus is characteristically associated with lesions at the cervicomedullary junction, notably Chiari malformation and basilar invagination, and all patients should undergo MRI to exclude such lesions. Other causes are cerebellar degeneration, demyelinating disease, hydrocephalus, anticonvulsants, and lithium. Clonazepam or aminopyridines may be beneficial.

Upbeat nystagmus is characterized by an upward-beating nystagmus in primary position, which usually increases, although it may reduce in intensity on upgaze. It is virtually always the result of brainstem disease but occasionally reflects cerebellar disease. It is seen in brainstem encephalitis, demyelination, and tumors and also as a toxic side effect of barbiturates, alcohol, and anticonvulsants. Baclofen or aminopyridines may be beneficial.

Gaze-Evoked & Gaze-Paretic Nystagmus

Maintenance of steady eccentric gaze is dependent on the neural integrator system, which produces the tonic extraocular muscle activity necessary to overcome the viscous and elastic orbital forces acting to return the globe to primary position. Reduction in activity of the neural integrator results in eccentric gaze being negated by a slow drift of the globe toward primary position. Since the force acting to produce this central drift reduces with decreasing eccentricity, this slow drift has an exponentially decreasing velocity. Additional corrective fast eye movements, returning the eye to the desired eccentric position, result in nystagmus beating in the direction of gaze, whether it is horizontal, vertical, or oblique.

End-point nystagmus (see earlier in the chapter) is the physiologic manifestation of the inability of the neural integrator to maintain steady eye position in extreme eccentric gaze. Gaze-evoked nystagmus is the result of pathologic failure of the neural integrator system. In its mildest form it manifests only on moderate horizontal gaze, whereas in its most severe form nystagmus is present with any movement away from primary position. In many cases of gaze-evoked nystagmus, there is also rebound nystagmus—following return of the eyes to primary position from a position of eccentric gaze, a jerk nystagmus beating away from the direction of the eccentric gaze develops after a latent period and lasts for a short period.

The neural integrator is situated in the brainstem but is highly dependent on cerebellar inputs. Thus, gaze-evoked nystagmus may be a manifestation of either brainstem or, especially, cerebellar disease. Often there are other cerebellar eye movement abnormalities, such as saccadic dysmetria and disruption of smooth pursuit. The most common causes of gaze-evoked nystagmus are cerebellar diseases, sedatives, and anticonvulsants. Cerebellopontine angle neoplasms, such as vestibular schwannomas (acoustic neuromas), may produce a combination of gaze-evoked nystagmus and a peripheral vestibular nystagmus beating toward the opposite side (Brun's nystagmus).

Reduction in the supranuclear input into the neural integrator or in the ability of the peripheral oculomotor system to facilitate its function will lead to nystagmus with the same basic characteristics as gaze-evoked nystagmus. Thus, conditions ranging from gaze palsy through oculomotor cranial nerve palsies and myasthenia gravis to extraocular muscle disease can manifest with nystagmus on eccentric gaze in the direction of the affected eye movements. This is termed gaze-paretic nystagmus and should be excluded whenever the possibility of a gaze-evoked nystagmus is being considered so as to avoid misdirected investigation.

Convergence-Retraction Nystagmus

Convergence-retraction nystagmus is a feature of the dorsal midbrain (Parinaud's) syndrome either from intrinsic lesions (tumor, hemorrhage, infarction, or inflammation) or extrinsic lesions, particularly pineal tumors and hydrocephalus. On attempted upgaze, which is usually defective, the eyes undergo rapid convergent movements with retraction of the globes. This is best elicited as the patient watches downward-moving stripes on an optokinetic tape or drum. Electromyographic studies have shown cocontraction of extraocular muscles and loss of normal agonist–antagonist reciprocal innervation. Convergence-retraction nystagmus may represent asynchronous, opposed, adducting saccades due to inappropriate activation of the medial rectus muscles.

Seesaw Nystagmus

Seesaw nystagmus is characterized by rising intorsion of one eye and falling extorsion of the other—and then the reverse. It may have a pendular or jerk waveform. Although it is uncommon, it occurs with acquired and congenital chiasmal lesions in association with a bitemporal hemianopia, and midbrain lesions. There does not appear to be a single underlying pathogenesis, but it is likely that dysfunction of the interstitial nucleus of Cajal or the rostral interstitial nucleus of the medial longitudinal fasciculus is important in the cases with midbrain disease.

Periodic Alternating Nystagmus

This is a horizontal jerk nystagmus regularly alternating between leftward and rightward directions, each phase lasting approximately 2 minutes. The acquired form usually results from cerebellar disease, such as cerebellar degenerations, congenital hindbrain anomalies, such as Chiari malformation, multiple sclerosis, or anticonvulsant therapy. It characteristically responds to baclofen. It may also occur with bilateral blindness and be suppressed if vision is restored. Periodic alternation may also be a feature of congenital nystagmus (see earlier in the chapter).

Mimics of Nystagmus

Abnormal spontaneous eye movements may be the result of unwanted saccadic eye movements (saccadic intrusions), which include square-wave jerks, macrosaccadic oscillations, ocular flutter, and opsoclonus. These are generally due to cerebellar disease. There is also a variety of abnormal eye movements that occur in coma, including ocular bobbing, ocular dipping, and ping-pong gaze. Superior oblique myokymia (see earlier in the chapter) is a tremor of the superior oblique muscle leading to episodic monocular vertical or torsional oscillopsia.

Voluntary Nystagmus

About 5% of normal individuals can generate short bursts of ocular oscillations that resemble small-amplitude, fast, horizontal pendular nystagmus. Eye movement recordings show the movements to be rapidly alternating saccades. Recognition of the entity is important to avoid unnecessary investigation.

Vascular Insufficiency & Occlusion of the Internal Carotid Artery

Transient episodes of visual loss most often result from retinal emboli (amaurosis fugax), usually from carotid disease but possibly from cardiac valvular disease or cardiac arrhythmia (see Chapter 15). They also occur in thrombotic disorders such as hyperviscosity states or antiphospholipid syndrome and from other causes of impaired ocular or cerebral perfusion such as giant cell arteritis, migraine, vertebrobasilar ischemia (see later in the chapter), severe hypotension, or shock. The visual loss from retinal emboli is characteristically described as a curtain descending across the vision of one eye, with complete loss of vision for 5–10 minutes, and then complete recovery. There may be associated transient ischemic attacks (TIAs) or completed strokes of the ipsilateral cerebral hemisphere. In other causes of transient visual loss, there may be constriction of the visual field from the periphery to the center, “graying” rather than complete loss of vision, and involvement of both eyes simultaneously. Fleeting episodes of visual loss that last a few seconds (transient visual obscurations) may occur in papilledema, affecting one or both eyes together, or monocularly with orbital tumors.

Cholesterol, platelet-fibrin, and calcific are the three main types of retinal emboli. Cholesterol emboli (Hollenhorst plaques) may be visible with the ophthalmoscope as small, glistening, yellow-red crystals situated at bifurcations of the retinal arteries. The nonreflective gummy white plugs filling retinal vessels, which characterize platelet-fibrin emboli, are less commonly seen because they quickly disperse and traverse the retinal circulation. Calcific emboli, which usually originate from damaged cardiac valves, have a duller, white-gray appearance compared with cholesterol emboli. Retinal emboli may also produce branch or, particularly in the case of calcific emboli, central retinal arterial occlusions.

In patients with amaurosis fugax, high-grade (70%–99%) stenosis of the internal carotid artery, as determined by ultrasound or angiographic studies, is an indication for carotid endarterectomy to reduce the risk of cerebral hemisphere stroke. Low-grade (0%–29%) and probably medium-grade (30%–69%) stenoses are best treated medically, usually with low-dose (81 mg/d) aspirin. Incidentally, noted cholesterol retinal emboli in asymptomatic individuals are associated with a tenfold increased risk of cerebral infarction, but the role of carotid endarterectomy in such individuals is uncertain.

In the acute stages of embolic retinal arterial occlusion, treatment with ocular massage, anterior chamber paracentesis, rebreathing into a paper bag to increase inhaled CO2 level, and intravenous acetazolamide may lead to displacement of the embolus and recovery of vision. After 12 hours, the clinical picture is usually irreversible, although many exceptions to this rule have been reported. Visual acuity better than counting fingers on presentation has a better prognosis with vigorous treatment. Embolic retinal arterial occlusion has a poorer 5-year survival rate due to attendant cardiac disease or stroke than occlusion due to thrombotic disease.

Slow flow (venous stasis) retinopathy is a sign of generalized ocular ischemia and indicative of severe carotid disease, usually with complete occlusion of the ipsilateral internal carotid artery. It is characterized by venous dilation and tortuosity, retinal hemorrhages, macular edema, and eventual neovascular proliferation. It resembles diabetic retinopathy, but the changes occur more in the retinal midperiphery than the posterior pole. In more severe cases, there may be vasodilation of the conjunctiva, iris neovascularization, neovascular glaucoma, and frank anterior segment ischemia with corneal edema, anterior uveitis, and cataract. Diagnosis is most easily confirmed by demonstration of reversal of blood flow in the ipsilateral ophthalmic artery using orbital ultrasound, but further investigation by angiography is usually required to determine the full extent of arterial disease. Carotid endarterectomy may be indicated but carries a risk of precipitating or exacerbating intraocular neovascularization. The role of panretinal laser photocoagulation in treating intraocular neovascularization is uncertain.

Occlusion of the Middle Cerebral Artery

This disorder may produce severe contralateral hemiplegia, hemianesthesia, and homonymous hemianopia. The lower quadrants of the visual fields (upper radiations) are most apt to be involved. Aphasia may be present if the dominant hemisphere is involved.

Vascular Insufficiency of the Vertebrobasilar Arterial System

Brief episodes of transient bilateral blurring of vision commonly precede a basilar artery stroke. An attack seldom leaves any residual visual impairment, and the episode may be so minimal that the patient or doctor does not heed the warning. The blurring is described as a graying of vision just as if the house lights were being dimmed at a theater. Episodes seldom last more than 5 minutes (often only a few seconds) and may be associated with other transient symptoms of vertebrobasilar insufficiency. Antiplatelet drugs can decrease the frequency and severity of vertebrobasilar symptoms.

Occlusion of the Basilar Artery

Complete or extensive thrombosis of the basilar artery nearly always causes death. With partial occlusion or basilar “insufficiency” due to arteriosclerosis, a wide variety of brainstem and cerebellar signs may be present. These include nystagmus, supranuclear oculomotor signs, and involvement of cranial nerves III, IV, VI, and VII.

Prolonged anticoagulant therapy has become the accepted treatment of partial basilar artery thrombotic occlusion.

Occlusion of the Posterior Cerebral Artery

Occlusion of the posterior cerebral artery seldom causes death. Occlusion of the cortical branches (most common) causes homonymous hemianopia, usually superior quadrantic (the artery supplies primarily the inferior visual cortex). Lesions on the left in right-handed persons can cause aphasia, agraphia, and alexia if extensive with parietal and occipital involvement. Involvement of the occipital lobe and splenium of the corpus callosum can cause alexia (inability to read) without agraphia (inability to write); such a patient would not be able to read his or her own writing. Occlusion of the proximal branches may produce the thalamic syndrome (thalamic pain, hemiparesis, hemianesthesia, choreoathetoid movements) and cerebellar ataxia.

Subdural Hemorrhage

Subdural hemorrhage results from tearing or shearing of the veins bridging the subdural space from the pia mater to the dural sinus. It leads to an encapsulated accumulation of blood in the subdural space, usually over one cerebral hemisphere. It is nearly always caused by head trauma. The trauma may be minimal and may precede the onset of neurologic signs by weeks or even months.

In infants, subdural hemorrhage produces progressive enlargement of the head with bulging fontanelles. Ocular signs include strabismus, pupillary changes, papilledema, and retinal hemorrhages.

In adults, the symptoms of chronic subdural hematoma are severe headache, drowsiness, and mental confusion, usually appearing hours to weeks (even months) after trauma. Symptomatology is similar to that of cerebral tumors. Papilledema is present in 30%–50% of cases. Retinal hemorrhages occur in association with papilledema. Ipsilateral dilation of the pupil is the most common and most serious sign and is an urgent indication for immediate surgical evacuation of blood. Unequal, miotic, or mydriatic pupils can occur, or there may be no pupillary signs. Other signs, including vestibular nystagmus and cranial nerve palsies, also occur. Many of these signs result from herniation and compression of the brainstem, and therefore often appear late with stupor and coma.

CT scan or MRI confirms the diagnosis.

Treatment of acute large subdural hematoma consists of surgical evacuation of the blood; small hematomas may be simply followed with careful observation. Without treatment, the course of large hematomas is progressively downhill to coma and death. With early and adequate treatment, the prognosis is good.

Subarachnoid Hemorrhage

Subarachnoid hemorrhage most commonly results from ruptured congenital berry aneurysms of the circle of Willis in the subarachnoid space. It may also result from trauma, birth injuries, intracranial hemorrhage, hemorrhage associated with tumors, arteriovenous malformations, or systemic bleeding disorders.

The most prominent symptom of subarachnoid hemorrhage is sudden, severe headache, usually occipital and often associated with signs of meningeal irritation (eg, stiff neck). Drowsiness, loss of consciousness, coma, and death may occur rapidly.

Treatment of intracranial aneurysm prior to rupture greatly improves prognosis. An expanding posterior communicating artery aneurysm may present with painful isolated third nerve palsy with pupillary involvement, which thus necessitates emergency investigation. Oculomotor palsy with associated numbness and pain in the distribution of the ipsilateral trigeminal nerve may be caused by supraclinoid, internal carotid, or posterior communicating artery aneurysm. Subarachnoid hemorrhage with optic nerve dysfunction suggests an ophthalmic artery aneurysm. If it occurs, papilledema develops after subarachnoid hemorrhage has occurred. Various types of intraocular hemorrhage occur infrequently (pre-retinal hemorrhages are the most common—Terson's syndrome) and carry a poor prognosis for life when they are both early and extensive, since they reflect rapid severe elevation of intracranial pressure.

Subarachnoid hemorrhage may be diagnosed by CT scan or cerebrospinal fluid examination. CT angiography (CTA) or magnetic resonance angiography (MRA) may identify intracranial aneurysm and will exclude other causes of subarachnoid hemorrhage, but cerebral angiography is usually necessary to determine appropriate treatment, of which endovascular therapy or surgical ligation of the aneurysm neck or of the parent arterial trunk are the main options. Supportive treatment, including control of blood pressure and vasodilator therapy, are important during the acute phase of subarachnoid hemorrhage.

Migraine

Migraine is a common episodic illness of unknown cause and varied symptomatology characterized by unilateral headache (which usually alternates sides), visual disturbances, nausea, and vomiting. There is usually a family history. The disease usually manifests between ages 15 and 30 years. It is more common and more severe in women. Many factors, including emotional ones, may predispose or contribute to the attacks.

Photophobia is common during a migraine attack. Visual auras characteristically consist of a repeating triangular colored pattern (“fortification spectrum”), beginning in the center of vision and moving with increasing speed across the same side of the visual field of each eye. The whole episode usually lasts 15–30 minutes. It may be followed by a homonymous hemianopia on the same side that lasts for several hours. Permanent visual field loss rarely develops. It may be due to cerebral infarction but should also arouse suspicion of an underlying arteriovenous malformation. Migrainous visual auras frequently have a less typical pattern. Migraine sufferers may also suffer episodes of transient monocular visual loss (see earlier in the chapter) thought to be due to either retinal or choroidal vasospasm.

The phakomatoses are a group of diseases characterized by multiple hamartomas occurring in various organ systems and at variable times.

Neurofibromatosis

Neurofibromatosis is a generalized hereditary disease characterized by multiple tumors of the skin, central nervous system, peripheral nerves, and nerve sheaths. Other developmental anomalies, particularly of the bones, may be associated. There are two distinct dominant conditions, both due to inactivating mutations of tumor suppressor genes. Neurofibromatosis 1 is associated with tumors primarily of astrocytes and neurons, whereas neurofibromatosis 2 is associated with tumors of the meninges and Schwann cells. There is no racial predominance. The manifestations may be present at birth but often become apparent during pregnancy, during puberty, and at menopause.

Neurofibromatosis 1 (Recklinghausen's disease) is characterized by multiple café au lait spots (six or more greater than 1.5 cm in diameter) (99%), peripheral neurofibromas, which are usually nodular but may be diffuse (plexiform) and usually cutaneous but may involve deep structures, axillary freckling, and Lisch nodules (iris hamartomas) (93%). Its gene lies on chromosome 17. The frequency is 1:3000 live births, with 100% penetrance but variable expressivity. When lesions are confined to the skin, the prognosis is good. The disease tends to be fairly stationary, with only slow progression over long periods of time. Neurofibromas may need to be removed, for instance to relieve spinal nerve root compression. They may undergo sarcomatous degeneration.

A defining feature of neurofibromatosis 2 is bilateral vestibular schwannomas (Figure 14–34), but unilateral vestibular schwannoma, other intracranial or spinal schwannoma, multiple intracranial or intraspinal meningiomas, or gliomas may occur. Café au lait spots and peripheral neurofibromas may be present. Its gene lies on chromosome 22. The frequency is 1:35,000.

Ophthalmic Features

In neurofibromatosis 1, as well as Lisch nodules, there may be neurofibromas of the lids, either cutaneous nodular or subcutaneous plexiform (rubbery “bag of worms”). Corneal nerves are often prominent. There may be congenital glaucoma. Anterior visual pathway glioma (see earlier in the chapter) is particularly associated with neurofibromatosis 1, bilateral optic nerve disease being pathognomonic, and many are asymptomatic (30%–80%). A subgroup with nerves having a thickened nerve core and a low-density perineural proliferation are more likely to be symptomatic. Treatment depends on disease location and progression, which is probably less severe than in patients without neurofibromatosis 1.

About 75% of patients with neurofibromatosis 2 have early posterior subcapsular lens opacities. Epiretinal membranes, combined pigment epithelial and retinal hamartomas, optic disk gliomas, and optic nerve sheath meningiomas occur with increased frequency in neurofibromatosis 2.

Von Hippel–Lindau Disease

Usually presenting in the second decade and rarely after age 45, von Hippel–Lindau disease is due to a mutation on chromosome 3. Inheritance is autosomal dominant with high penetrance. The incidence is approximately 1:40,000. The most common manifestation is retinal capillary hemangioma. Other manifestations are cerebellar hemangioblastoma; cysts of the kidneys, pancreas, and epididymis; pheochromocytoma; and renal cell carcinoma.

Retinal capillary hemangioma usually develops in the peripheral retina (Figure 10–36). Occasionally, it develops adjacent to the optic disk (juxtapapillary). In the peripheral retina, it initially manifests as dilation and tortuosity of retinal vessels, followed by development of an angiomatous lesion with hemorrhages and exudates. A stage of massive exudation, retinal detachment, and secondary glaucoma occurs later and will cause blindness if left untreated. Among all patients with retinal capillary hemangioma, about 80% have von Hippel–Lindau disease, and they usually have multiple lesions. Among patients with solitary retinal capillary hemangioma, the prevalence of von Hippel–Lindau disease is about 45%. The diagnosis is usually obvious by personal or family history but may become apparent after screening for associated lesions or after genetic testing. Sporadic retinal capillary hemangioma not associated with von Hippel–Lindau disease usually presents in the fourth decade. Any patient with bilateral retinal capillary hemangiomas or multiple lesions in eye—either at presentation or developing during follow-up—must be assumed to have von Hippel–Lindau disease.

Treatment & Prognosis

Retinal capillary hemangiomas may be treated with laser photocoagulation, cryotherapy, or plaque radiotherapy. All patients, particularly those with von Hippel–Lindau disease, need regular screening for detection of new lesions. Patients with von Hippel–Lindau disease also need regular screening for development of central nervous system and abdominal disease. Presymptomatic detection of the lesions of von Hippel–Lindau disease greatly improves the prognosis. First-degree relatives of patients with von Hippel–Lindau disease also need to undergo regular screening. Genetic testing increasingly allows identification of individuals specifically at risk.

Sturge–Weber Syndrome

This uncommon nonfamilial disease with unknown inheritance is recognizable at birth by a characteristic nevus flammeus (port wine stain, or venous angioma) on one side of the face. There is corresponding angiomatous involvement (leptomeningeal angiodysplasia) of the meninges and brain, which causes seizures (85%), mental retardation (60%), and cerebral atrophy. Since the cortical lesions calcify, they can be seen on plain skull x-rays after infancy. Unilateral infantile glaucoma on the affected side frequently develops if there is extensive involvement of the conjunctiva with hemangioma of the episclera and anterior chamber anomalies. Lid or conjunctival involvement nearly always implies ultimate intraocular involvement and glaucoma. Forty percent of patients with a port wine stain on the face develop choroidal hemangioma, usually diffuse rather than circumscribed, on the same side.

Treatment & Prognosis

There is no effective treatment for Sturge–Weber syndrome. The glaucoma is difficult to control. Choroidal hemangioma may require treatment with laser photocoagulation or radiotherapy.

Wyburn–Mason Syndrome

Wyburn–Mason syndrome is a rare disorder of multiple arteriovenous malformations, variably involving the retina, other portions of the anterior visual pathway, the midbrain, the maxilla, and the mandible, all on the same side of the head.

Headaches and seizures are the common presenting symptoms. Large, tortuous, dilated vessels covering extensive areas of the retina are an important diagnostic clue and can cause cystic retinal degeneration with decreased vision. Optic atrophy without retinal lesions can also occur.

Ataxia–Telangiectasia

Ataxia–telangiectasia is an autosomal recessive disorder characterized by skin and conjunctival telangiectases, cerebellar ataxia, and recurrent sinopulmonary infections. All signs and symptoms are progressive with time, but the ataxia appears first as the child begins to walk, and the telangiectases appear between 4 and 7 years of age. Mental retardation also occurs. The recurrent infections relate to thymic deficiencies and corresponding T-cell abnormalities as well as to deficiency of immunoglobulins. Saccadic and eventually pursuit abnormalities produce a supranuclear ophthalmoplegia.

Tuberous Sclerosis (Bourneville's Disease)

Tuberous sclerosis is characterized by the triad of adenoma sebaceum, epilepsy, and mental retardation, although 40%–50% of affected individuals have normal intelligence. Adenoma sebaceum (angiofibromas) occur in 90% of patients over the age of 4 years, and the number of lesions increases with puberty. These flesh-colored papules are 1–2 mm in diameter and have a butterfly distribution on the nose and malar area; they can also occur in the subungual and periungual areas. Ashleaf-shaped hypopigmented ovals can be present on the skin even of neonates and are best seen under Wood's (ultraviolet) light.

Retinal astrocytomas appear as oval or circular white areas in the peripheral fundus and, like optic nerve astrocytomas, characteristically have a mulberry-like appearance (Figure 10–35). Renal hamartomas occur in 70%–80% of patients. Subependymal nodules in the periventricular areas of the brain can calcify and appear as candle-wax gutterings or drippings on radiologic studies. MRI can show actively growing subependymal nodules. These can become astrocytomas. Seizures occur in 70% of patients, often starting within the first year of life.

The disease is inherited sporadically (80%) or as an autosomal dominant disorder with low penetrance. The prevalence may be 1:7000 if patients with the incomplete form of the disease are included. Vision is generally normal, and progression of retinal hamartomas is rare. The prognosis for life relates to the degree of central nervous system involvement. In severe cases, death can occur in the second or third decade; if there is minimal central nervous system involvement, life expectancy should be normal.

The genetically determined (autosomal recessive) lysosomal storage disorders may affect the neural elements of the retina. The clinical forms are classified by the age at onset and the enzyme deficiency. The pathologic changes are present prenatally. Clinical manifestations occur as a critical level of intraneuronal lipid deposition is reached, resulting in a progressive disease, including dementia, visual disturbance, and neuromotor deterioration.

The striking ocular finding of a cherry-red spot in the macula is seen in a number of lysosomal storage disorders, for example, gangliosidosis (Tay–Sachs disease, Sandhoff disease, and generalized GM1), Niemann–Pick type A (sphingomyelin lipidosis), neuraminidase deficiency (sialidosis and Goldberg syndrome), and Farber disease. A halo occurs from loss of transparency of the ganglion cell ring of the macula, which accentuates the central red of the normal choroidal vasculature. Optic atrophy is also prominent in Tay–Sachs disease and Niemann–Pick type A. Retinal degeneration without a macular cherry-red spot occurs in mucopolysaccharidoses and in the lipopigment storage disorder, neuronal ceroid lipofuscinosis.

Eye movement disorders occur in the lysosomal storage disorders, Niemann–Pick type C (vertical supranuclear gaze palsy) and juvenile (type 3) Gaucher's disease (horizontal supranuclear gaze palsy), and occasionally in Refsum's disease, a disorder of lipid metabolism, and abetalipoproteinemia, the latter two disorders more typically being associated with pigmentary retinopathy.