Neuro-Ophthalmology

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[edit] Neuro-Ophthalmology

Barry Skarf

Vision, and thus the discipline of ophthalmology, involves more than just the eyes and their supporting structures. The eyes form extensive connections with the brain, and normal visual function depends on the development and maintenance of connections to visual, sensory, and motor centers. The field of neuro-ophthalmology deals with those disorders of neurologic function that can affect vision: diseases of the central nervous system (CNS) and of the cranial nerves as well as systemic conditions that affect the CNS. Representative conditions that affect vision through their CNS action include multiple sclerosis, cerebrovascular disease, intracranial and intraorbital tumors, and generalized systemic diseases (e.g., syphilis, sarcoidosis).

Neuro-ophthalmology is divided into two broad divisions: sensory and motor. The sensory visual system directly subserves sight; disorders affecting it can cause profound visual disturbances. This system is made up of the retinas, the optic nerves and chiasm, the optic tracts, both lateral geniculate nuclei of the thalamus, the optic radiations (which connect the lateral geniculate nucleus to the visual cortex), and those regions of the cerebral cortex, primarily in the occipital lobe, that subserve vision. Neuro-ophthalmology deals with diseases that affect all portions of this pathway, excluding disorders that involve only the eye and retina. The second division of neuro-ophthalmology involves the ocular motor system and its disorders. Essential to the normal function of vision is the ability to execute appropriate, coordinated eye movements. Disturbances of eye movements and of ocular alignment can seriously degrade vision and visual function. The ocular motor system includes the eye muscles and the nerves that control them, as well as the brainstem and cortical centers, which direct eye movements. The principal symptoms that result from ocular motor system disorders are blurring of vision, diplopia, and difficulty achieving or maintaining appropriate fixation.

The neuro-ophthalmologist is concerned with conditions causing visual disturbances for which no obvious intraocular pathology exists. This category includes a variety of transient visual disturbances, functional complaints, and factitious visual loss, as well as conditions that cause optic nerve swelling (edema) and systemic conditions that affect vision and CNS structures.

[edit] SENSORY VISUAL SYSTEM

[edit] Patient Evaluation

[edit] History.

Visual loss is the principal manifestation of disease involving the sensory visual system. Patients who note an unexplained change in vision will present to their primary care physician, optometrist, or ophthalmologist. When the change in vision is sudden and dramatic or accompanied by a headache or other systemic disturbance, the physician is consulted preferentially. Usually the visual loss is spontaneous, but a history of trauma and antecedent ocular, neurologic, or systemic disease should be elicited. The visual loss may be transient or persistent and may affect one or both eyes. Loss of central vision and a decrease of peripheral vision may occur. Most important, visual loss may be acute, having occurred instantaneously or over a few days, or it may have developed much more gradually.

Patients with true sensory pathway dysfunction often complain of blurred vision, dim vision, or a decrease in the brightness of colors. Although a detailed history is essential, care must be taken in its interpretation, since patients are often unclear or even incorrect about the nature of their visual loss. For example, a patient with a right homonymous hemianopsia may describe visual loss in the right eye. In fact, the patient has lost vision in the right hemifield of both eyes, but this can be determined only through appropriate examinations. Also, a patient claiming acute visual loss in one eye may have been unaware of a gradual loss of vision in the eye until this loss is “discovered” when the good eye is inadvertently covered. The nature of the visual loss, whether transient or permanent, can be invaluable in making a diagnosis and determining suitable management.

Frequently, patients present with transient photopsias or complaints of seeing flashing lights or various other positive visual phenomena not associated with visual loss. These complaints must be taken seriously because they could relate to incipient retinal detachment or retinal tear, migrainous visual auras, or more serious CNS diseases (e.g., arteriovenous malformations, brain tumors).

[edit] Examination.

Objective clinical findings may be difficult to obtain in neuro-ophthalmic disease. The most reliable sign of monocular visual loss caused by neuro-ophthalmic disease is the relative afferent pupillary defect (Marcus Gunn pupil), as determined by the swinging flashlight test. When this clinical sign is absent in a patient complaining of persistent uniocular visual loss, the examiner should look for an abnormality of the eye itself (e.g., refractive error, media opacity, mild retinal edema). If tests for these conditions are negative, factitious visual loss must be considered. The presence of a relative afferent pupillary defect, however, confirms the patient's visual deficit and is usually indicative of a serious problem (see Chapter 172 ).

[edit] Optic Nerve Disease

Funduscopic examination of the optic nerve heads is an established part of any complete medical examination, especially in patients who complain of headaches, other neurologic problems, or visual disturbances. Abnormal optic nerves can reflect a variety of local, neurologic, and systemic diseases. It is important to emphasize, however, that the optic nerve head may be abnormal in only one of three ways: (1) swollen (edematous); (2) pale in color, which is usually a sign of optic atrophy; and (3) morphologically or structurally abnormal or anomalous, such as optic disc cupping in glaucoma and optic disc drusen (calcific bodies embedded within the optic nerve substance). The primary care physician must determine whether the appearance of each optic nerve is normal or abnormal and categorize them appropriately. When visual loss is caused by retrobulbar optic neuropathy (neuritis), the optic nerve head may appear normal. Because optic nerve pathology can be difficult to recognize, consultation with an ophthalmologist or neuro-ophthalmologist should be obtained whenever the appearance of the optic nerve heads is suspect.

[edit] Optic Disc Swelling.

Disorders associated with optic disc swelling can be divided into those without significant visual loss and those with visual loss.

[edit] No Visual Loss.

Patients complaining of headache associated with transient visual disturbances may have bilateral disc swelling or edema. Bilateral disc edema usually implies papilledema, a term reserved exclusively for disc edema secondary to elevated intracranial pressure (ICP). Visual function is usually preserved, except for enlarged blind spots. Patients may describe shadows or photopsias in the temporal portion of the visual field. Central vision may be slightly disturbed, but patients can usually achieve normal or near-normal acuity. Although true papilledema is usually bilateral, it may be asymmetric. Papilledema should be considered a medical emergency requiring computed tomography (CT) or magnetic resonance imaging (MRI) to rule out an intracranial mass lesion. The patient's medical history must include detailed information on trauma, illness, infection, and other neurologic symptoms. Because papilledema can result from severe hypertension, blood pressure must be checked.

Another common cause of papilledema is pseudotumor cerebri, or benign intracranial hypertension (BIH). BIH typically affects middle-aged, overweight women who have had children. Patients with BIH often have headaches, although BIH may occur without headache and may be discovered only when a routine examination reveals papilledema. Because BIH is a diagnosis of exclusion, patients must have MRI or CT scan to rule out an intracranial mass. If a space-occupying lesion is not found, the patient should have a lumbar puncture to obtain cerebrospinal fluid (CSF) for laboratory studies as well as to determine CSF pressure.

Unfortunately, many normal optic nerves appear elevated with blurred margins, giving them a “swollen” appearance. When exaggerated, prominent disc elevation and blurred disc margins represent pseudopapilledema, a congenital variation that mimics true papilledema. This anomaly is often associated with intrapapillary calcium deposits known as optic disc drusen. The examining physician must distinguish between pseudopapilledema, a benign condition, and papilledema, as well as among other causes of disc edema.

True disc edema, including papilledema, can be recognized because the swollen edge of the optic disc obscures some of the small and medium-sized vessels that transverse the disc margin. This clinical picture can occur relatively early in the development of disc edema before elevation of the disc is obvious. If the optic discs show marked elevation with blurred margins, but all vessels traversing the disc margin (including small capillaries) are well defined and are not obscured by edema, the patient probably has pseudopapilledema. Fluorescein angiography of the fundus, which results in leakage of dye into and around the optic disc, can help distinguish true edema.

Occasionally, unilateral disc swelling, indistinguishable from papilledema, is noted; in rare cases, this can be true papilledema caused by elevated ICP. More frequently, however, it is caused by localized optic nerve disease. Unilateral causes of optic disc edema in the absence of significant visual loss include (1) compressive optic neuropathies (i.e., tumor compression of the optic nerve obstructing venous drainage and causing disc swelling) and (2) papillophlebitis, an idiopathic condition that usually causes only slight visual loss and mild to moderate disc swelling, mainly in young, otherwise healthy patients. Unilateral optic disc swelling may also result from ocular hypotony, which can occur after a perforating injury of the globe, including ocular surgery. This condition is seen most frequently after cataract extraction.

[edit] Visual Loss.

Patients presenting with visual loss (usually in one eye) and mild to moderate swelling of the optic disc may have a number of different disorders. Papillitis is the most common cause of visual loss associated with disc swelling in patients younger than 40. In this form of optic neuritis the anterior portion of the optic nerve becomes inflamed and the optic nerve head is swollen. Occasionally the disc swelling may be accompanied by retinal swelling and exudates, a condition known as neuroretinitis. Retrobulbar optic neuritis presents acutely without any change in the appearance of the nerve head. Neuroretinitis, papillitis, and retrobulbar optic neuritis, however, are essentially the same type of inflammatory condition involving different segments of the optic nerve.

Anterior ischemic optic neuropathy (AION) is the most common cause of visual loss associated with optic disc swelling in patients older than 50. This condition represents an acute infarction of the optic nerve head. Typically, patients present with sudden, painless loss of vision in one eye, but mild orbital pain may precede or accompany the event. Both eyes are rarely involved simultaneously. Usually the visual loss is central or altitudinal, but patients may complain of seeing a shadow to one side, above, or below their fixation. The typical fundus appearance shows a swollen optic disc; a portion of the disc is hyperemic, with the remaining portion somewhat paler in appearance. Frequently, one or a few streaky nerve fiber layer hemorrhages surround the disc.

The two major pathologic types of AION are the idiopathic, nonarteritic form and the arteritic form, associated with temporal arteritis. In addition, a variety of vasculitides, coagulopathies, and systemic diseases can contribute to the development of AION (Box 177-1). Occasionally, ischemic optic neuropathy develops within a few days of cataract surgery. All patients with ischemic infarction of the optic disc should undergo the following laboratory tests: complete blood count (CBC), platelets, erythrocyte sedimentation rate (ESR), glucose, antinuclear antibody (ANA), Venereal Disease Research Laboratories (VDRL), prothrombin time (PT), partial thromboplastin time (PTT), and cardiolipin antibodies. Neuroimaging studies are not indicated.

Idiopathic AION is more common than the arteritic form and generally occurs in patients older than 45. Hypertension is an accepted risk factor, a diabetic relationship exists and persons with small, crowded optic discs seem predisposed. AION affects men more than women and results in a permanent visual deficit. Approximately one third of patients experience progressive visual loss, and another one third improve. Recovery is usually modest, although if central vision is involved, substantial improvement in visual acuity can occur.

Although no treatment for AION has proved successful, patients should take one tablet of aspirin daily. Risk factors such as hypertension should be treated appropriately. With time, optic disc swelling subsides, but the patient has residual sectoral optic atrophy. Once visual loss stabilizes, there is little chance of recurrent infarction in the same optic nerve head. Bilateral involvement occurs in approximately 25% of affected individuals, although the second eye may not succumb for months or years.

AION associated with temporal (giant cell) arteritis is a treatable medical emergency; without appropriate medical management, visual loss can progress rapidly in both eyes, resulting in blindness. This arteritic form of AION occurs in elderly patients, who often appear cachectic. Although known to occur in younger individuals, temporal arteritis is unusual in patients younger than 65. Visual loss in the arteritic form of AION frequently develops in stages and becomes catastrophic with severe reduction in field and acuity. The entire optic disc is swollen and pale. Untreated patients have increased risk of rapid progression with involvement of the second eye.

To identify this treatable condition and to help establish the diagnosis of AION, the primary care physician should obtain an immediate ESR on every patient over 50 who presents with sudden visual loss and a swollen optic disc. The patient should be questioned carefully about constitutional symptoms suggesting temporal arteritis (Box 177-2). Persons in their 70s or 80s are particularly vulnerable, and it is always best to obtain an ESR, even when the diagnosis of AION is uncertain. If temporal arteritis is suspected based on the ESR or clinical history, immediate therapy with oral prednisone (1 mg/kg/day) must be initiated. If the diagnosis is uncertain, it is best to begin treatment (unless steroids are contraindicated) and arrange for a temporal artery biopsy. Histopathologic examination of a segment of the superficial temporal artery usually confirms the diagnosis; in rare situations, however, a normal biopsy may be obtained in a patient with temporal arteritis. Once again, clinical judgment is crucial. The principal goal of therapy is to prevent further visual loss and to preserve vision in the second eye. Unfortunately, high-dose corticosteroids do not promote recovery once vision is lost.

Several features of retinal vein occlusion, which occurs mainly in patients over 40, resemble those seen in AION. Acute visual loss is common, although patients often complain of a “sputtering” of their vision before they develop a persistent visual deficit. Fundus examination reveals a swollen disc with peripapillary hemorrhages. The veins are extremely dilated, but unlike AION, the hemorrhages extend along the affected vascular tree outward toward the periphery. If the central vein is involved, multiple hemorrhages are scattered along both upper and lower arcades of the fundus. If a branch vein is occluded, hemorrhage is found only in the territory of the involved branch.

Papillophlebitis is a milder form of vein occlusion that occurs in younger individuals. It is characterized by moderate swelling of the optic discs, moderate engorgement of the veins, and a few hemorrhages. Visual deficits are usually minimal.

All patients with retinal venous occlusive disease should be examined for causes of increased serum viscosity, including dysproteinemia, polycythemia, hemoglobinopathy, diabetes, and leukemia. These patients are at risk for developing a secondary form of glaucoma and must be followed closely by an ophthalmologist.

Neoplasms can cause optic nerve swelling and loss of vision through a variety of mechanisms. Externally, they compress the optic nerve causing venous congestion, which in turn leads to disc swelling. Primary optic nerve tumors (meningiomas or gliomas) can produce the same effect (see later). Leukemia, lymphoma, and meningeal carcinomatosis may infiltrate the optic nerve causing optic disc swelling either by direct tumor extension into the optic nerve head or by producing venous congestion. Visual loss occurs rapidly with optic nerve infiltration but may be gradual and insidious when there is optic nerve compression. Optic nerve swelling and visual loss also can occur in advanced dysthyroid ophthalmopathy when greatly enlarged extraocular muscles compress the optic nerve at the apex of the orbit. Any patient with optic nerve swelling and visual loss who does not fit a typical description of optic neuritis or ischemic optic neuropathy should undergo neuroimaging studies, as should any patient with a history of slowly progressive visual loss over weeks to months.

Leber's hereditary optic neuropathy superficially resembles papillitis. It tends to occur in young healthy individuals, who present with subacute visual loss and optic nerve swelling. Several features, however, differentiate this condition from optic neuritis. Visual loss is always painless and optic nerve hyperemia is marked, with engorgement of the peripapillary capillaries and small retinal vessels. The contralateral optic nerve may appear swollen as well, even when visual function is normal. At a minimum the small vessels in the contralateral peripapillary region are prominent. Leber's neuropathy is transmitted by mitochondrial deoxyribonucleic acid (DNA) from mothers to their children (never through the paternal line). Men are twice as likely to be affected as women. Several markers on mitochondrial DNA have been linked to Leber's hereditary optic neuropathy. Patients with bilateral visual loss from optic neuropathy have tested positive for these markers, even in the absence of the characteristic fundus appearance. The second eye is almost always affected within weeks to months; however, the visual loss may be asymmetric. Patients tend to have permanent central visual loss, although some improve several years after the acute episode. Patients may have a cardiac myopathy, and an electrocardiogram (ECG) should be obtained to rule out a preexcitation syndrome. No effective treatment exists for Leber's hereditary optic neuropathy.

[edit] Optic Atrophy.

Retrobulbar optic neuritis is one of the most common causes of subacute visual loss in young adults, especially young women ages 18 to 45, although it also occurs in older individuals. Pain and discomfort in or around the affected eye, often exacerbated by eye movements, are common symptoms. A few days after the onset of ocular discomfort, the patient generally notes progressively decreasing visual acuity. This disturbance can vary from mild blurring or dimming of vision, with colors taking on a washed-out appearance, to complete blindness. Visual field deficits and an afferent pupillary defect are present in the affected eye. In acute retrobulbar optic neuritis, examination of the fundus is completely normal, with no evidence of swelling or pallor of the optic disc. Papillitis and neuroretinitis are also forms of optic neuritis, but in adults these forms occur much less frequently than the retrobulbar form. Clinically, however, all forms of optic neuritis have similar natural histories. After a few weeks, most patients notice improving vision, followed by slow recovery for up to 1 year. Optic atrophy usually develops after a few weeks.

Retrobulbar optic neuritis is closely associated with multiple sclerosis. Frequently, questioning reveals a relationship to systemic demyelinating disease. Other patients may have no previous history, but MRI shows multiple small lesions scattered in the brain's white matter. A positive MRI may indicate the development of multiple sclerosis in otherwise idiopathic cases of optic neuritis.

Treatment of retrobulbar optic neuritis is still controversial. Results of the Optic Neuritis Treatment Trial sponsored by the National Institutes of Health (NIH) have shown that oral steroids are of no value but that intravenous (IV) methylprednisolone can promote a more rapid recovery and may delay the development of multiple sclerosis. The established dose is 250 mg of IV methylprednisolone every 6 hours for 3 days, followed by 11 days of oral prednisone (1 mg/kg/day). The prednisone is then tapered. Vision usually begins to improve within 1 month with or without treatment. Patients who do not improve within 6 weeks or who continue to worsen after the first 2 weeks should be investigated fully for other causes of optic neuropathy.

Gliomas of the visual pathway, including optic nerve and chiasm, are primarily childhood phenomena frequently associated with neurofibromatosis. Proptosis, visual loss, disc swelling, or optic atrophy may occur; however, not all optic nerve and chiasmal gliomas produce visual deficits. Some cause asymptomatic optic nerve enlargement that can remain stable for many years.

Optic nerve sheath meningiomas are the second major primary tumor of the optic nerve. They are most prevalent in young to middle-aged women but can occur in older individuals. Although they tend to occur in an older population than gliomas and usually have a distinct radiologic appearance, occasionally it may be difficult to differentiate between the two tumors. Patients with optic nerve sheath meningiomas usually present with proptosis and slowly progressive visual loss. Optic disc swelling, optic atrophy, and optociliary shunt vessels on the optic disc are common.

Treatment of primary optic nerve tumors remains controversial and depends on the extent of visual loss and location of the tumor. Management of these tumors is best referred to a neuro-ophthalmologist or neurosurgeon familiar with current treatment.

Intracranial meningiomas growing along the sphenoid ridge or plane frequently involve the chiasm and optic nerves. They may infiltrate the orbit along the optic nerve sheath and can compress optic nerve, causing swelling and visual loss similar to that seen with primary optic nerve sheath meningiomas. En plaque meningiomas are particularly common in women between 40 and 60 years of age. They may be associated with hyperostosis, which can lead to proptosis, often the presenting sign. Neuroimaging is mandatory, and the patient should be referred to a neurosurgeon once the diagnosis is made.

Optic atrophy is thought to be present from birth. Mild to moderate reduction in visual acuity and decreased color vision are common. Both eyes usually are affected symmetrically, but some variation may be present. Family members are affected in a dominantly inherited pattern. Expression of the abnormality is variable, with some patients manifesting only a mild color vision deficit and better than 20/100 vision. Those with more severe disease may develop nystagmus.

Nutritional optic neuropathy is typically associated with inadequate B-complex vitamins and folate in the diet. These nutritional factors are frequently exacerbated by excessive consumption of alcohol and use of tobacco products, producing classic tobacco-alcohol amblyopia. Most significant, however, is the nutritional inadequacy that usually accompanies a diet in which most calories are obtained from alcohol. Resultant visual loss, usually central, can be rapid or insidious.

Toxic optic neuropathy can result from exposure to a variety of drugs and toxic substances. The extensive list of causative medications and environmental substances includes many chemotherapeutic agents (e.g., vincristine, mevatricate, BCNU), ethambutol, fluoroquinolones, isoniazid, quinine, streptomycin, and sulfacetamides. Among the environmental toxins are ethylene glycol mercury and methyl alcohol. To diagnose toxic optic neuropathy, patients must be questioned carefully about their working environment, medications, and drug and alcohol use.

Toxic and nutritional optic neuropathies are typically bilateral and symmetric. If unilateral involvement occurs, another diagnosis should be suspected. In addition to central visual loss, there may be generalized constriction of the visual field. Optic atrophy can develop, color vision is lost, and visual acuity may decrease to recognition of hand movements only. In nutritional amblyopia, visual acuity can improve if proper diet is restored.

Traumatic optic neuropathies occur after closed head injuries or skull fractures. Although the ocular examination may be normal, sudden or subacute visual loss occurs. Visual loss in closed head injury is attributed to shearing forces at the optic canal or microfractures in the skull base that produce optic nerve ischemia and swelling in the canal. When visual loss is sudden, recovery is unlikely. Visual recovery is more likely with subacute visual loss, which can develop within hours to days after injury. Aggressive treatment with IV corticosteroids or surgical decompression of the optic canal may benefit patients with progressive visual loss documented over time.

Radiation optic neuropathy occurs months to years after radiotherapy treatment for primary or secondary intracranial tumors. Because visual loss is typically delayed, a relationship to radiation therapy is not always apparent. Usually the only finding is decreased vision, with a field defect and mild optic disc pallor indicating atrophy. In acute cases, disc pallor may be absent initially. Physicians should consider radiation optic neuropathy in any patients with a history of radiotherapy to the head. When the eyes have been included in the irradiated field, the diagnosis becomes easier because characteristic radiation retinopathy, with neovascularization, microaneurysms, soft exudate, and arteriolar narrowing, is associated with optic disc pallor. Usually the dose of radiation must exceed 5000 cGy. No effective treatment can reduce radiation injury to the optic nerves.

[edit] Optic Nerve Anomalies.

Congenital anomalies that alter the appearance of the optic nerve head can create diagnostic confusion. Some of these anomalies are associated with reduced vision or visual field defects, complicating the diagnosis even more. The most common and important anomaly is pseudopapilledema (see earlier), in which the optic nerve head appears elevated and enlarged with blurred margins. Moderate blind spot enlargement and subtle field defects also may be present. Unlike papilledema, however, pseudopapilledema is not associated with elevated ICP, the retinal venules are not distended, and spontaneous venous pulsations are frequently present. In pseudopapilledema, hemorrhages around the optic nerve are very unusual. Pseudopapilledema is usually bilateral and benign, reflecting a local process at the optic nerve head and not intracranial pathology. Often, optic disc drusen are noted, and the diagnosis is straightforward; otherwise, distinguishing pseudopapilledema from papilledema can be difficult. An expert opinion should be obtained before proceeding with an extensive neuroradiologic investigation.

Other congenital anomalies that affect the shape and size of the optic disc develop when the eye and optic nerve are formed. These include tilted optic discs, optic nerve colobomas and pits, and hypoplasia (congenitally underdeveloped optic nerves). Each anomaly has a characteristic morphology and spectrum of severity. Eyes with the worst anomalies also may be associated with developmental CNS abnormalities and usually have poor vision. Mildly anomalous optic nerves are compatible with normal acuity and mild to moderate peripheral visual field defects. An optic disc anomaly should be suspected when the optic discs appear abnormal in an otherwise healthy individual with no complaints, especially when the rest of the examination is unremarkable and the condition is bilateral and fairly symmetric. Except for the unusual optic disc appearance, the fundus shows no evidence of swelling, hemorrhage, infarct, or edema.

[edit] Chiasmal Compression and Syndrome

Most lesions at the optic chiasm are compressive, producing visual loss in both eyes. The most common cause of chiasmal compression is a pituitary tumor arising from within the sella turcica and extending upward to stretch and compress the chiasm. Most pituitary tumors are adenomas. In premenopausal women they cause amenorrhea and are discovered early, usually before producing any visual loss. In contrast, nonsecreting pituitary tumors and those in men and postmenopausal women are usually not detected until they produce visual loss. Other tumors (e.g., craniopharyngiomas, meningiomas, gliomas, aneurysms) also cause a similar pattern of visual loss by compressing the chiasm. Pituitary tumors cause slowly progressive, painless, usually asymmetric visual loss and characteristic bilateral, typically bitemporal and asymmetric visual field defects that assume several forms. Occasionally, if hemorrhage or infarction occurs within a pituitary tumor, visual loss can be rapid and associated with severe headache and even loss of consciousness (pituitary apoplexy).

Patients with pituitary tumor often present with endocrinologic disturbances such as amenorrhea and galactorrhea (women) or impotence and decreased libido (men). A hormonal workup, particularly for prolactin levels, is critical in evaluating patients with suspected pituitary tumor. Patients must be asked about endocrine functions (e.g., menstrual cycles), symptoms of acromegaly, and thyroid dysfunction. When the condition has evolved slowly, the optic nerves appear atrophic, and occasionally a characteristic horizontal band of atrophy may be noted across the optic disc. Changes in the optic nerve may be subtle, even in the presence of a large visual field defect. A normal-appearing optic nerve suggests a good potential for visual recovery, often after surgical decompression in patients with a chiasmal syndrome. Occasionally, tumors of this region may extend into the patient's cavernous sinus, causing palsies of the third, fourth, and sixth cranial nerves and resulting in diplopia.

All patients suspected of having chiasmal syndrome must undergo formal perimetry. If perimetry confirms a characteristic pattern of visual field loss, usually bitemporal, with some portion of the field deficit in at least one eye respecting the vertical meridian, the next step is neuroimaging. MRI is generally more effective than CT in evaluating lesions of the chiasmal region. If a pituitary tumor is demonstrated, management depends on tumor size and whether it secretes prolactin. Prolactin-secreting adenomas can be treated with bromocriptine, which should shrink the tumor and improve symptoms. When this treatment is inappropriate or inadequate, however, a neurosurgeon should be consulted. Most pituitary tumors, even those with marked suprasellar extension, can be decompressed via a transsphenoidal approach. Depending on the degree of optic atrophy and type of tumor involved, vision often improves after treatment. Some patients, however, require lifetime hormonal replacement.

Although chiasmal compression by extrinsic tumor is the most common cause of the chiasmal syndrome, visual loss at the chiasm also may result from compression by an aneurysm, mucocele, abscess, or glioma (chiasmal or hypothalamic). Demyelinating lesions of the optic chiasm, ischemic and traumatic lesions, traction from chiasmal arachnoiditis, postradiation neuropathy, and prolapse of the chiasm into an empty sella may also be associated with visual loss.

[edit] Postchiasmatic Disease

Retrochiasmal lesions involving the optic tract, optic radiations, and cerebral cortex produce homonymous hemianopsia. These lesions can be caused by stroke, tumor, vascular malformations, demyelinating lesions, and abscesses. Patients who develop a partial or complete homonymous hemianopsia may be unaware of the extent of their visual loss. They may have a vague sense of visual disturbance on the affected side, which they may attribute to a problem with the ipsilateral eye. They may complain of difficulty reading or of bumping into objects on that side. Visual acuity is unaffected in unilateral hemispheric lesions. Occasionally, patients with a tumor or an arteriovenous malformation will experience visual hallucinations contralateral to the affected hemisphere. These may resemble migrainous aura but are always present on the same side. Visual field examination is mandatory in the diagnosis of retrochiasmal disease. Thus patients with normal visual acuity should be referred for visual field testing if they complain of difficulty reading or difficulty with vision to one side. A visual field obtained on confrontation often can establish the diagnosis with minimal effort.

Although a complete homonymous hemianopsia is nonlocalizing, partial hemianopsias can localize the lesion to the temporal, parietal, or occipital lobes. Visual field defects produced by occipital lesions are exquisitely congruent in both eyes. Patients with occipital lobe lesions also may demonstrate macular sparing; that is, they may have a complete hemianopsia except for a small region of the hemifield extending from central fixation into the hemianopic field. This condition occurs when an infarction of the occipital cortex spares the most posterior portion of the occipital lobe, which is quite common in strokes of this region. Macular sparing is virtually pathognomonic for an infarction of the occipital cortex. Cortical blindness can result from bilateral occipital lobe lesions. When the patient denies blindness, the condition is termed Anton's syndrome. Temporal lobe lesions tend to produce visual field defects that are more dense superiorly in the visual field; parietal lobe lesions tend to produce defects that are denser inferiorly. Temporal and parietal defects are less congruent than those produced by occipital lobe lesions and are usually associated with other neurologic deficits. The least congruent homonymous hemianopsias result from lesions of the optic tract, which occur infrequently.

CT scan, or preferably MRI, is required in any patient who has a complete or partial homonymous hemianopsia. These examinations usually demonstrate an infarct, tumor, or other CNS lesion. Appropriate management of these neurologic conditions can then be arranged.

[edit] Transient and Subjective Visual Disturbances

Patients frequently complain of transient, temporary, and vague visual disturbances that frighten or concern them. It is important to distinguish potentially serious disturbances from the multitude of symptoms that are usually benign. Because objective signs are rare and symptoms frequently have passed, physicians must rely on the patient's history of the event(s).

The duration of the visual disturbance is critical. Momentary spots or flashes of light indicate vitreous traction or a retinal tear but are not characteristic of pathology along the retrobulbar visual pathway. Transient visual obscurations lasting less than a minute can occur in papilledema. Transient monocular visual loss that results from vascular occlusion of the retinal or optic nerve circulation (amaurosis fugax) usually lasts several minutes but may last a half hour. The positive and negative visual disturbances that accompany migraine typically last 15 to 20 minutes. They rarely last less than 5 minutes or more than 45 minutes.

Although it is crucial to determine whether the visual loss is monocular or binocular, patients often are unable to make this determination. Patients may also attribute visual loss in one hemifield to a visual disturbance in the ipsilateral eye. For these reasons, care must be taken in interpreting patient descriptions.

The mode of onset and evolution of the visual disturbance further define the pathophysiology. Common symptoms in patients with visual disturbances include dimming or darkening of vision in all or part of the visual field, photopsias, shimmering lights, rings, and arcs of light that can obscure vision. The patient's activity at the onset, changes during the visual loss, and nature and duration of the recovery help define the visual disturbance. Also, neurologic symptoms (e.g., lightheadedness, weakness, numbness, paresthesias, dizziness, unsteadiness) can help localize the disturbance to the anterior or posterior visual pathway.

Amaurosis fugax usually is caused by carotid artery stenosis, which produces decreased vascular perfusion of the retina and optic nerve. The carotid artery also can be a source of platelet-fibrin emboli, which may obstruct the central retinal artery or any of its branches. Patients complain of “darkening” or dimming of vision. They often describe a curtain or shade that may rise or fall to obscure part or all of the vision in the affected eye. The onset is usually rapid, and the episode may last seconds or minutes. On examination, whitish Hollenhorst plaques may be seen in the retinal circulation. When amaurosis fugax is suspected, patients should report any symptoms suggestive of other transient ischemic attacks, with or without visual loss. Frequently, vascular risk factors, including stroke, are present. Transient neurologic symptoms (paresthesia, weakness) or a carotid bruit may indicate a high-grade stenosis of the carotid artery. These patients are at significant risk of stroke and permanent visual loss. Management requires a complete cardiovascular and cerebrovascular workup and possible treatment with antiplatelet agents, anticoagulants, or endarterectomy.

When similar episodes of transient monocular visual loss occur in a young person in the absence of any risk factors, they can be attributed to retinal migraine. Transient visual loss in retinal migraine is thought to be produced by vasospasm of the retinal artery and is rarely associated with risk of permanent deficit. Carotid artery dissection, which can cause similar transient visual loss, must be excluded. Patients presenting with transient photopsias describe flashing lights or spots of light in one eye that last moments but occur sporadically. They should be asked whether their symptoms are more noticeable in the dark and whether they are aggravated by head or eye movement. Movements that induce flashes suggest vitreous traction on the retina or, more seriously, retinal tear or detachment. These patients should be referred immediately for dilated ophthalmologic examination, even when they have normal vision and no other complaints.

Photopsias that last from 5 to 45 minutes more typically represent migrainous phenomena. They usually are binocular but can be monocular if caused by retinal migraine. Patients typically refer binocular photopsias occurring in one hemifield to the ipsilateral eye. A typical history for a migraine is a scintillating scotoma or fortification scotoma that expands or contracts, lasts 15 to 40 minutes, and is followed by a headache. Patients not currently experiencing headache must report any history of migrainelike headaches. In older patients, migrainelike symptoms can be caused by vertebrobasilar insufficiency, although this problem is usually associated with other neurologic symptoms (e.g., dizziness, ataxia, diplopia). If the episodes are always unilateral, an arteriovenous malformation or other intracranial pathology must be suspected, and neuroimaging studies should be ordered.

Patients who complain of blurred vision that changes from day to day may have diabetes, with a fluctuating, poorly controlled blood sugar level. Other causes of bilateral blurred vision are vasculopathies, hyperviscosity and hypercoagulation syndromes, and seizures.

Patients may report a variety of visual experiences in which they see distorted or illusory objects as well as hallucinations. Visual illusions and distortions are the altered visual perception of real objects. These phenomena can arise from optical as well as central mechanisms. Hallucinations, on the other hand, are visual perceptions that have no basis in reality. They are generated centrally, although they may be triggered by an external sensory stimulus. They may be related to seizure disorders, intake of a variety of medications and toxic substances, various disease processes, or altered states of consciousness.

Occasionally a patient presents with factitious visual loss, which may be psychogenic or may represent malingering. Differentiation of factitious visual loss from true deficits caused by organic disturbances can be difficult. Primarily the physician must demonstrate that the pattern of visual loss is inconsistent with normal physiologic constraints by uncovering various inconsistencies in the pattern and degree of visual dysfunction. The physician must rule out an underlying organic defect and demonstrate that visual function exceeds that claimed by the patient.

[edit] OCULAR MOTOR SYSTEM

An intact ocular motor system is essential for normal vision. Eye movements are responsible for capturing and locking onto a visual object of interest and for maintaining fixation on that object even during head and body movements. This requires an elaborate supranuclear control system involving extensive connections among the visual, vestibular, and oculomotor centers. Disturbances of this system profoundly affect vision and bring patients to their physicians with complaints of double vision, blurred vision, jumpy vision, and more general complaints of unsteadiness, dizziness, and vertigo.

[edit] Functions

The functions of the ocular motor system can be categorized into five subgroups: saccades, fixation, smooth pursuit movements, vestibuloocular mechanism, and vergence mechanism. Saccades are rapid eye movements that are used to refixate from one object of regard to another. They rapidly execute a foveation reflex, which captures items of interest onto the fovea. The fixation mechanism enables the maintenance of foveation or fixation on an object once it has been “captured.” Smooth pursuit movements are slow movements that allow an object to be followed as it moves from place to place. The vestibuloocular mechanism produces reflex eye movements driven by the semicircular canals, which detect head movement. A combination of the smooth pursuit, fixation, and vestibuloocular mechanisms allows continued steady fixation of moving targets during head or whole body movement. All these mechanisms generate conjugate eye movements; that is, they move both eyes equally and symmetrically in the same direction. In contrast, the vergence mechanism produces disconjugate movement, principally horizontal, which adjusts the position of the two eyes with respect to each other so that fixation is maintained by both eyes on the object of interest. During normal activity, all these mechanisms operate simultaneously to produce a seamless pattern of eye movements.

[edit] Evaluation.

To evaluate oculomotor function clinically, it is best to test each of these mechanisms separately. Fixation maintenance and smooth pursuit mechanisms are tested by asking the patient to fixate on a target while slowly moving the target to extreme positions of gaze. During this process it is important to observe the steadiness of eye position and fixation. If the target motion is slow and steady, any instability in eye movement is abnormal, except in the most extreme positions, where physiologic nystagmus can occur. Saccades can be tested by having patients refixate back and forth from a central to a peripheral target held successively up, down, and to each side. The vestibuloocular reflex can be tested by having the patient make rapid head movements (side to side and up and down) while fixating on a distant target. This test does not rely only on the vestibuloocular reflex because visual feedback exists; if head movements are rapid, however, the principal mechanism driving the eye movements is vestibular. Vergence mechanisms can be tested by having a patient refixate between distant and near targets. When evaluating the oculomotor system, ocular alignment must also be tested by covering first one eye and then the other while looking for movement of the uncovered eye. This test should be performed with the eyes in the primary position and to the left, right, up, and down.

[edit] Symptoms

Double vision, or diplopia, is one of the most frequent complaints related to the oculomotor system. Diplopia can be monocular or binocular; therefore the physician should determine whether double vision disappears when one eye is covered. If double vision persists with monocular viewing, the patient has monocular diplopia, which is never caused by an oculomotor disturbance. Various optical and ocular diseases can combine to cause monocular diplopia; infrequently it can result from CNS pathology. True binocular diplopia always disappears when either eye is covered. Occasionally, patients do not recognize diplopia and simply complain of blurred vision or of letters, print, or sentences running together.

Once it is determined that a patient has true binocular diplopia, the patient should be asked (1) whether two perceived images are displaced horizontally, vertically, or obliquely; (2) whether one image is tilted with respect to the other; (3) which direction of gaze results in the greatest separation of the images and which produces the least; and (4) whether the diplopia is worse at distance or at near. Typically, lateral rectus muscle weakness produces an esodeviation (inturning eye), which is worse at distance; weakness of the medial rectus muscle produces an exodeviation (outturning eye), which is worse at near. However, patients may be troubled more by double images close to each other than by those widely separated. Diplopia is most frequently caused by a benign process and often resolves spontaneously; however, it also can be a medical emergency. Therefore any patient who presents with acute diplopia must be evaluated immediately by a neuro-ophthalmologist or neurologist.

Nystagmus (an involuntary rhythmic oscillation of the eyes) is a cardinal sign of oculomotor dysfunction. Often, patients do not recognize that they have nystagmus, which is discovered by friends or family. These patients typically complain of blurred vision or actual jumpiness of objects, a phenomenon termed oscillopsia.

Oculomotor dysfunction and diplopia also may cause unsteadiness or a sense of dizziness or may be associated with true vertigo. In certain oculomotor disorders, patients may have difficulty looking to either side or up or down and difficulty looking at their feet or at a plate of food. Appropriate questioning is often necessary to reveal a history of this type of disorder. The patient may complain of difficulty reading, but when tested, visual acuity at distance and near will be perfect. Reading is adversely affected by the patient's inability to make precise movements from one word to another. This problem can occur with oculomotor disturbances that affect saccadic eye movements.

[edit] Disorders of Ocular Motility

Disturbances of eye movement can be divided topographically into two categories: infranuclear disorders and central or supranuclear disorders. Infranuclear disorders result from lesions in the cranial nerves, extraocular muscles, or the tissue supporting the eyes and their muscles. They frequently affect only one eye and generally present with diplopia. Central disorders upset the control of eye movements and create problems with conjugate gaze. That is, they affect the saccadic, pursuit, or convergence movements of both eyes and may upset the balance or alignment between them.

[edit] Infranuclear Disorders

[edit] Orbital and Systemic Diseases.

Diseases that involve the orbital contents can cause disturbances in ocular motility. They can restrict the range of normal eye movements both mechanically and physiologically, producing diplopia.

Thyroid ophthalmopathy is the most common disease affecting orbital tissues and resulting in oculomotor symptoms. This condition occurs in a high percentage of patients with Graves' disease; however, approximately 10% of patients with thyroid ophthalmopathy are clinically euthyroid. Typical signs of thyroid ophthalmopathy include exophthalmos, lid retraction, lid lag, and limitation of eye movement, particularly on attempted upgaze. Patients may or may not have a previous history of thyroid disease. Thyroid ophthalmopathy may simulate other causes of ophthalmoplegia. Typically, however, the abnormal eye movement cannot be explained on the basis of a single or even multiple oculomotor nerve palsies. The diagnosis is established by endocrine investigation, by other signs of hyperthyroidism, and by restriction of eye movements and enlargement of the eye muscles on CT scan of the orbits. Thyroid ophthalmopathy can pose difficult management problems. Sensory visual function and diplopia must be monitored carefully by an ophthalmologist with experience in managing and treating this condition.

Besides thyroid disease, other causes of mechanically restricted eye movements include orbital trauma, most often an orbital floor fracture and entrapment of the inferior rectus muscle. The medial rectus muscle also can be caught in a medial wall fracture. Infiltrative diseases (inflammatory or neoplastic) can enlarge one or more orbital muscles, causing limitation of eye movement. Orbital myositis can involve one muscle or several muscles and is associated with pain and discomfort. Orbital pseudotumor is a more extensive inflammatory condition affecting the eye muscles, as well as other orbital soft tissue, causing severe pain and limitation of movement. Less frequently the muscles and soft tissues of the orbit may become infiltrated with lymphoma or an inflammatory process such as sarcoidosis, polymyositis, or Wegener's granulomatosis. Neoplasm can infiltrate the orbit by direct extension from adjacent sinuses and periorbital tissues or by metastatic spread from distant sites.

[edit] Chronic Progressive External Ophthalmoplegia (CPEO).

CPEO is a group of syndromes that result in gradual loss of eye movements. Progressive bilateral ptosis is an early sign, with patients developing a generalized ophthalmoplegia over many years. Diplopia may not occur because the eyes can remain aligned in the primary position, although their movements become extremely limited. A variety of associated conditions coexist with CPEO, including heart block, pigmentary retinopathy, ataxia, myopathy, and weakness elsewhere. Patients may complain only of bilateral ptosis and may have a vague sense of difficulty looking to the side. Most forms of chronic, progressive external ophthalmoplegia are related to mitochondrial disease, and muscle biopsy reveals ragged red fibers characteristic of mitochondrial myopathy. Because a risk of heart block and sudden death exists, CPEO is potentially life threatening.

[edit] Myasthenia Gravis.

A condition that can affect all skeletal muscles, myasthenia gravis is prone to affect the extraocular muscles, particularly those that elevate the eyelids. Isolated ocular myasthenia occurs in 20% of patients and can pose a diagnostic challenge to physicians. Myasthenia gravis can mimic almost any oculomotor disorder, from single-nerve palsies to complete ophthalmoplegias. Its distinguishing characteristics, however, are fatigability and variability. The ptosis that occurs in myasthenia varies with the time of the day and usually worsens toward evening. Patients often relate that their lids open normally in the mornings but become increasingly ptotic as the day progresses. Diplopia, when present, may also worsen later in the day. Fatigue is demonstrated when the examiner has the patient look steadily upward for several minutes, without blinking. The eyelids will gradually descend over the globe in affected individuals. Diplopia, when present, may also worsen later in the day.

Myasthenia gravis results from defective synaptic transmission at the motor end plates because of antibodies to the acetylcholine receptors. The diagnosis can be confirmed by (1) demonstrating an elevation of circulating acetylcholine receptor antibodies; (2) testing with Tensilon, which produces a transient improvement in lid position; or (3) having the patient rest the eyes for a half hour and noting improvement in lid position and ocular alignment. Further confirmation can be obtained by demonstrating characteristic electromyographic disturbances in skeletal or ocular muscles. Definitive diagnosis and treatment are best handled by a neurologist. Treatment is usually oral pyridostigmine (Mestinon), but in resistant cases, corticosteroids or azathioprine can be added. A CT scan of the chest determines whether the thymus gland is enlarged. If it is, surgical resection is recommended.

[edit] Oculomotor Palsies.

Three paired cranial nerves are responsible for innervating the extraocular muscles and producing eye movements. A dysfunction in any of these nerves can cause diplopia in one or more positions of gaze. Of the numerous causes of such dysfunction, some affect more than one of the nerves, whereas others are specific for a particular nerve. Patients may present with single or multiple nerve palsies that affect movements in one or both eyes.

[edit] Sixth nerve palsy.

The most easily recognized isolated ocular nerve palsy involves the sixth cranial nerve producing weakness in the ipsilateral lateral rectus muscle. Patients complain of horizontal double vision that worsens when they look toward the side of the affected nerve. On examination a limitation of abduction is seen when the patient looks in the direction of the weak lateral rectus muscle. Lateral rectus weakness can be caused by any of the orbital diseases already described; however, if no evidence suggests orbital involvement, a diagnosis of sixth nerve palsy can be made.

The sixth nerve passes through the cavernous sinus and can be compromised by diseases of this region. Intracavernous carotid artery aneurysm or fistula, meningioma, metastatic disease, infection, and inflammation (e.g., the Tolosa-Hunt syndrome) can cause sixth nerve dysfunction. Nasopharyngeal carcinoma and pituitary tumors also can invade the cavernous sinus from adjacent regions. Tracing the course of the sixth nerve proximally, it turns caudally to descend down the clivus toward the pons. This segment of the nerve can be compromised by tumor, head trauma, or elevated ICP. Meningeal carcinomatosis can also involve the sixth nerve in the prepontine portion of its course. Gradenigo's syndrome, which develops when an otitis media spreads to involve the sixth nerve, occurs principally in children. Finally, CNS disease (e.g., tumor, stroke, multiple sclerosis) can affect the sixth nerve fasciculus within the pons; usually other brainstem structures are involved, with coexisting oculomotor and neurologic abnormalities.

The most common etiology of an acute isolated sixth nerve palsy is idiopathic. Presumably, these cases result from small-vessel infarction along the course of the sixth nerve, most probably in its intracavernous portion. This infarction occurs more frequently in patients with vasculopathic histories, including diabetes and hypertension. Usually, idiopathic sixth nerve palsies resolve spontaneously within 2 to 3 months.

Congenital abnormalities and those acquired early in childhood can sometimes be confused with sixth nerve palsies. Patients with Möbiuss' syndrome may appear to have bilateral sixth nerve palsies, but they also have facial diplegia, clubfoot, branchial malformations, and abnormalities of pectoral muscles. Patients with Duane's syndrome have unilateral or occasionally bilateral absence of the sixth nerve, with limitation of abduction and sometimes adduction. The globe retracts on attempted adduction.

[edit] Fourth nerve palsy.

The fourth nerve is the only cranial nerve to exit from the dorsal surface of the brain. It leaves the posterior midbrain, crosses to the opposite side, and travels beneath the tentorium and then through the cavernous sinus to innervate the contralateral superior oblique muscle.

Patients with fourth nerve palsy complain of vertical or oblique double vision, which becomes worse when they look downward. They may assume a characteristic head posture in which their head is turned and titled away from the affected side. Because of its relationship to the tentorium, the fourth nerve is subject to physical injury during head trauma, and palsies are often associated with trauma.

Idiopathic fourth nerve palsies, attributed to microvascular infarction along the nerve, usually resolve spontaneously with time. Tumors rarely cause fourth nerve palsy, although myasthenia and orbital disease can occasionally mimic this disorder. Patients with congenital fourth nerve palsies have a long history of abnormal head posture, which can be revealed by examining old photographs. The fourth nerve also can be compromised by the same cavernous sinus and brainstem diseases that produce sixth nerve palsies.

[edit] Third nerve palsy.

The third nerve is the largest and most important cranial nerve involved with eye movements. It innervates the superior, inferior, and medial rectus muscles, as well as the inferior oblique and levator palpebrae. It also innervates the pupil and ciliary body, producing pupillary constriction and accommodation. Thus a complete third nerve palsy immobilizes most eye movements, although patients often develop a partial third nerve palsy that does not affect all its components. Patients usually complain of horizontal or oblique diplopia but may not have diplopia if the ptotic eyelid covers the eye. In partial third nerve palsies, myasthenia gravis or orbital disease must be considered, especially if the pupil is spared.

Orbital or cavernous sinus diseases can cause third nerve palsies, but typically one or more of the fourth, fifth, or sixth cranial nerves are also involved. Of greatest concern, third nerve palsies may result from compression by an aneurysm of the posterior communicating artery or from uncal herniation. Strokes, demyelinating disease, and brainstem tumors can cause lesions of the third nerve nucleus or fasciculus in the midbrain. These lesions usually produce other neurologic abnormalities. Nuclear lesions produce bilateral ptosis and weakness of the contralateral superior rectus muscle.

One of the most common causes of third nerve palsy is microvascular infarction, which typically spares the pupil; however, some patients can have partial pupillary involvement. Small-vessel infarction tends to affect the interpeduncular or intercavernous portions of the nerve and generally resolves within 2 to 3 months. It is much more common in patients with diabetes, hypertension, and other vasculopathies.

[edit] Multiple oculomotor nerve palsies.

As previously stated, diseases affecting the cavernous sinus and orbital apex frequently cause multiple oculomotor nerve palsies. The optic nerve and trigeminal nerve also may be involved. These diseases may mimic myasthenia gravis and other orbital diseases that cause multiple extraocular muscle dysfunction. In the absence of clinical signs of these diseases, however, evaluation of the cranial nerves traversing the cavernous sinus and neuroimaging are mandatory when a combination of oculomotor palsies occur. If there is associated pain, inflammatory disease of the cavernous sinus (Tolosa-Hunt syndrome) should be suspected.

Another condition that may produce multiple oculomotor nerve palsies is the Fisher variant of the Guillain-Barré syndrome. Patients develop acute onset of diplopia and ptosis, often after an upper respiratory tract infection, resulting from involvement of multiple extraocular muscles bilaterally. Pupillary involvement is variable and distinguishes this condition from myasthenia gravis. Associated neurologic abnormalities include ataxia and loss of the deep tendon reflexes. The condition resolves spontaneously but may last several months.

[edit] Evaluation.

Isolated fourth and sixth nerve palsies are rarely emergencies. Microvascular infarction is the most frequent cause in the absence of a history suggesting trauma. Tests include a blood glucose to rule out diabetes and an ESR to check for temporal arteritis in patients older than 50. If myasthenia gravis is considered in the differential diagnosis, a Tensilon test should be arranged and acetylcholine antibodies measured. Neuroimaging studies should be performed only in patients with other cranial nerve involvement or other neurologic abnormalities or with suspected orbital disease. Acute third nerve palsies, on the other hand, can be much more serious, particularly when they are caused by aneurysm. If the pupil is involved, neuroimaging studies and cerebral angiography should be obtained immediately in acute cases. If the pupil is spared, and particularly with a history of diabetes or hypertension, the patient may be observed and a broader differential diagnosis considered. As already indicated, multiple oculomotor nerve palsies are virtually synonymous with cavernous sinus disease. Multiplanar MRI with gadolinium can uncover cavernous sinus involvement that is otherwise difficult to demonstrate. Consideration also must be given to myasthenia gravis and thyroid disease, which mimic multiple oculomotor nerve palsies.

[edit] Central (Supranuclear) Disorders.

CNS disorders (e.g., stroke, brain tumor) affect the conjugate movements of both eyes and also may disturb the balance or alignment between the eyes and the coordination of eye movements. In contrast, peripheral oculomotor nerve disorders generally affect one eye or, if they involve both eyes, tend to affect them asymmetrically. Eye movement abnormalities produced by lesions in the CNS include disorders of both horizontal and vertical conjugate gaze, skew deviations, ocular dysmetria, and many forms of nystagmus.

[edit] Disorders of Conjugate Gaze.

Conjugate gaze depends on a flow of impulses from centers in the brain, including the cerebral hemispheres, midbrain, pons, and cerebellum, as well as the pathways that connect them. Thus lesions of the CNS frequently produce disorders of eye movement.

The inability to move both eyes to one side is called a horizontal gaze palsy; it results from a lesion in the pons that damages either the ipsilateral paramedian pontine reticular formation (PPRF) or the ipsilateral sixth nerve nucleus. Bilateral lesions in the pons can cause a complete bilateral horizontal gaze palsy while leaving vertical movements preserved. Less complete lesions in this region may result in partial horizontal gaze palsies or in gaze-evoked nystagmus, that is, nystagmus on attempted gaze with rapid beats in the direction of gaze. Usually, other neurologic deficits are present. Hemispheric disorders and those involving the upper brainstem can produce similar horizontal gaze palsies. These are typically transient, however, and usually can be overcome by reflex horizontal eye movements generated by the vestibular nuclei with head movement (doll's eye reflex) or by caloric stimulation.

Vertical gaze depends on intact centers in the midbrain. Diseases that affect the dorsal midbrain produce up-gaze paresis and may also produce light/near dissociation of the pupils and characteristic convergence-retraction nystagmus. In the young patient this condition is typically caused by a pinealoma or hydrocephalus, whereas infarction is more common in older patients. Down-gaze paresis occurs less frequently than up-gaze and results from a bilateral midbrain lesion in the region of the red nuclei. Infarction may precipitate a sudden down-gaze palsy, but difficulty with down-gaze frequently develops slowly in association with Parkinson's disease, progressive supranuclear palsy, and a variety of diffuse neurodegenerative diseases.

Midbrain lesions also can cause a vertical misalignment between the two eyes (skew deviation). Skew deviation is a term reserved for vertical oculomotor imbalances that result from supranuclear (i.e., central) disorders. A skew deviation may resemble a fourth nerve palsy superficially but usually does not have all the characteristics. In addition, skew deviations rarely occur in isolation and usually are accompanied by other central disorders of ocular motility and other neurologic signs.

Internuclear ophthalmoplegia (INO) is a common central disorder of ocular motility that results from a lesion of the medial longitudinal fasciculus between the pons and midbrain. It causes weakness of the medial rectus muscle on the ipsilateral side and produces a partial or complete adduction palsy accompanied by abducting nystagmus of the contralateral eye. INO can be unilateral or bilateral and may occur in relative isolation. In young adults and especially women, acute bilateral INO is highly suggestive of multiple sclerosis. Unilateral INO in elderly patients is more typical of a small lacunar infarct and is frequently associated with diabetes, vasculitides (e.g., systemic lupus erythematosus), aneurysm, and other conditions.

Central disorders can selectively disrupt rapid or slow eye movements. Disturbances of rapid refixation eye movement (saccades) produce ocular dysmetria, which can cause the patient to undershoot or overshoot the intended visual target. More severe disorders of saccadic movement can generate ocular flutter (brief bursts consisting of reversing saccades) and, in the worst cases, opsoclonus (back-to-back, continuous unrestrainable saccades, “saccadomania”). Saccadic dysmetria, flutter, and opsoclonus occur in cerebellar and brainstem disease. Specifically, opsoclonus can be a component of a paraneoplastic syndrome such as neuroblastoma in children or oat cell carcinoma in adults. Loss of rapid eye movements occurs in a variety of degenerative disorders, such as Wilson's disease, spinocerebellar degenerations, and progressive supranuclear palsy.

Children may manifest a congenital absence of rapid eye movements called congenital ocular motor apraxia. During the first 2 years of life, these children develop head thrusts that compensate for their inability to make normal refixation movements. As indicated earlier, saccadic palsies that occur with lesions in the cerebral hemispheres and brainstem, whether partial or incomplete, also may result in an inability to initiate refixation movements or in slowed or hypometric saccades.

Disorders impairing slow eye movements used in smooth pursuit result in jerky movements termed saccadic pursuit. This finding is not always indicative of disease but may be caused by fatigue, drugs, or lack of attention. When asymmetric, saccadic pursuit is likely caused by an organic disease of the brainstem, cerebellum, or parietooccipital junction of the cerebrum.

Vergence system dysfunction is frequently psychogenic, and it may be difficult to separate organic disease from a factitious abnormality. A paresis of convergence can occur after infarction, demyelination, or head trauma. Patients complain of diplopia at near range only and have no obvious limitation or abnormality in their eye movements, except for the inability to converge. When this symptom is of long duration and associated with longstanding reading difficulties, it may be a true convergence insufficiency, which is congenital and not caused by neurologic disease.

Patients who continue to converge, even when attempting to fixate at a distance, may have spasm of the near reflex, which includes convergence spasm, excessive accommodation, and pupillary constriction. Excessive accommodation causes these patients to complain of blurred vision. Although convergence spasm is associated with organic diseases (e.g., neurosyphilis, trauma, encephalitis), it is also related to stress and psychogenic causes.

Divergence palsy occurs rarely and results in the acute onset of esotropia and diplopia, with full preservation of eye movements. It may follow systemic illness and is usually benign and self-limited; however, it also can be caused by demyelinating disease, neurosyphilis, encephalitis, and trauma.

[edit] Evaluation.

Patients with central disorders of ocular motility may present with vague symptoms that may not easily characterize their oculomotor disturbance. Diplopia may be a prominent symptom, but other patients may complain of blurred vision, difficulty looking to one side, difficulty reading, running together of words, blurred vision when looking to one side, difficulty focusing at near gaze, or jumpiness of targets (oscillopsia). Any time a patient's symptoms suggest a central disorder affecting eye movements, the physician should assess for other neurologic symptoms. A complete oculomotor examination is essential. Fixation must be observed in all positions and a cover test performed to evaluate ocular alignment. The range of eye movements in all directions, steadiness of fixation, saccadic refixations, smooth pursuit movements, and convergence should be tested. Finally, reflex eye movements should be evaluated by observing the doll's head response to head rotation and Bell's phenomenon (elevation of the globe during forced eye closure).

[edit] Nystagmus

The term nystagmus describes a group of involuntary ocular movements that are rhythmic and oscillatory. The two major categories of nystagmus are jerk nystagmus, which consists of a slow phase in one direction followed by a fast phase in the opposite direction, and pendular nystagmus, in which movements in both directions are equal in velocity. Ocular oscillations that are involuntary and recurrent but not rhythmic also occur; these are called nystagmoid movements.

[edit] Physiologic Nystagmus.

Extreme gaze in any direction can result in end-point nystagmus, a jerk nystagmus with fast phase in the direction of gaze. Optokinetic nystagmus is a jerk nystagmus that develops when a subject views a repetitive visual stimulus. The slow phase of the nystagmus occurs when the subject follows the moving target; this phase is interrupted by fast phases as the eyes return to refixate on to another target entering the visual field. Vestibular-induced nystagmus can result from the effect of whole-body rotation or caloric stimulation on the semicircular canals.

[edit] Congenital Motor Nystagmus.

Resulting from a primary oculomotor system abnormality, congenital motor nystagmus may be pendular or jerk. Typically, complex cycles of repetitive eye movements are generated. The amplitude of the nystagmus decreases with convergence. Acuity is mildly reduced, and patients do not complain of oscillopsia.

An early infantile form of nystagmus can result from sensory (visual) deprivation. This sensory form of “congenital” nystagmus usually develops between 2 and 3 months of age in a child with abnormally decreased central vision. Sensory deprivation nystagmus is typically pendular and also may decrease with convergence.

[edit] Latent Nystagmus.

Demonstrated only when one eye is occluded, latent nystagmus is a jerk form that beats away from the occluded eye. It is seen frequently in children with strabismus and amblyopia and may be bilateral or unilateral.

The physiologic, congenital, and latent forms of nystagmus are benign and differ from the pathologic forms. Patients with congenital or physiologic nystagmus may be unaware of their condition and do not have symptoms of oscillopsia. They may have decreased central vision, but this is longstanding.

[edit] Acquired Nystagmus.

Most forms of acquired nystagmus produce ocular oscillations that involve both eyes about equally; however, some forms of nystagmus may produce asymmetric nystagmus or exclusive involvement of only one eye. Acquired nystagmus is usually of the jerk form and can be divided into two major subcategories: nystagmus caused by disorders of the peripheral vestibular apparatus and nystagmus caused by disorders of the CNS.

Peripheral nystagmus develops after loss of vestibular function and is usually purely horizontal or horizontal and rotatory. Purely vertical or tortional nystagmus is unusual with peripheral vestibular disease. Peripheral nystagmus is frequently acute in onset and associated with severe vertigo. Symptoms can be recurrent, transient, and last days to weeks but usually resolve with time. Postural effects and hearing deficits can occur. The common causes are infectious disease involving the labyrinth (labyrinthitis) or the vestibular nerve (neuronitis), Meniere's disease, or trauma.

Central nystagmus is much more variable and usually is not associated with severe vertigo. Symptoms may be transient or permanent. The nystagmus may beat in both directions depending on eye position, and in some forms the direction may change over time. Central nystagmus often is a result of a brainstem or cerebellar lesion caused by demyelinating disease, vascular infarction, or tumor.

The pattern of nystagmus has many variations, some of which have particular pathognomonic or localizing significance. Acquired nystagmus should always be investigated by a neurologist, ophthalmologist, or otolaryngologist familiar with its variations. Many rhythmic oscillations, including vertical forms, can affect the eyes and are usually pathognomonic for lesions in specific regions of the brainstem. These special forms of nystagmus include up-beating and down-beating vertical nystagmus, ocular myoclonus, ocular bobbing, convergence-retraction nystagmus, rebound nystagmus, and periodic alternating nystagmus. Some forms of nystagmus respond to medications, but most are resistant to therapy.

[edit] The Pupil

[edit] Pupillary Response.

Observation of the pupillary response is one of the most important components of the routine physical and ophthalmic examinations (see Chapter 172 ). Pupil size should be evaluated in both bright and dim illumination while the patient fixates on a distant object. Any difference in pupil size (anisocoria) should be noted, with particular attention to whether the difference increases in bright or dim light. The light response of each pupil should then be evaluated independently. Next, the pupils are examined for a relative afferent pupillary defect (Marcus Gunn pupil) by alternating a flashlight between eyes while noting pupillary responses. Both eyes must be stimulated equally and symmetrically. If the pupils are unequal initially, it may be helpful to observe the reaction of one pupil to stimulation of the ipsilateral and contralateral eyes during the swinging flashlight test. The examiner also observes pupillary reaction when the eyes converge and accommodate onto a near target. Use of eyedrops and oral medications may affect pupillary response and size.

[edit] Dilated or Nonreacting Pupil.

If a patient's larger pupil does not constrict well to a light stimulus and the anisocoria increases with greater light levels, the patient has a form of pupillary sphincter palsy. Once local disease in the eye is ruled out (e.g., history of trauma, ocular inflammation), only three causes for dilated pupil remain: (1) compression or other lesion of the third cranial nerve, (2) parasympathetic denervation of the pupil due to injury or lesion in the ciliary ganglion that produces an Adie's pupil, and, (3) pharmacologic block of the pupillary sphincter. Therefore, when confronted with a dilated pupil, the physician must search for other signs of a third nerve palsy, such as ptosis, diplopia, or oculomotor paresis. Even when these conditions are not present, a dilated, sluggish, or nonreactive pupil can be a sign of third nerve compression, which can result from uncal herniation or posterior communicating artery aneurysm. Therefore, if recent in onset or acute, a dilated pupil is considered a medical emergency, particularly when accompanied by headache or other neurologic signs. If the pupil has been dilated for at least a few weeks, however, and the reaction to a near stimulus produces slow constriction, followed by an even slower redilation after the near stimulus is removed, the diagnosis is likely Adie's pupil, or tonic pupil. This benign condition is usually unilateral but may be bilateral. Adie's pupil is supersensitive to dilute solutions of pilocarpine and can be positively identified if 0.1% pilocarpine constricts the pupil. Patients with tonic pupil may complain of difficulty reading because of accommodative paresis, but usually the dilated pupil is an incidental finding. The condition is believed to result from damage to the ciliary ganglion caused by infectious (viral) or vascular disease.

Sometimes patients introduce substances into the eye that dilate the pupil pharmacologically. These pupils react poorly to both light and near stimulation and do not react to 1% pilocarpine. Thus they can be distinguished from Adie's pupil and the dilated pupil seen with lesions of the third nerve, both of which constrict with pilocarpine. A dilated pupil may also result from direct or indirect trauma. The pupillary sphincter may be damaged during surgery or by penetrating injury or blunt trauma to the globe. Trauma to the iris usually can be detected by slit-lamp examination. Depending on the extent of damage, the pupil may constrict to pilocarpine. Occasionally the pupil remains dilated as a result of previous intraocular disease (e.g., inflammation, rubeosis, trauma, surgery). Other less common causes of an unreactive pupil are congenital anomalies, central iris atrophy, and tumors involving the anterior chamber.

[edit] Constricted or Small Pupil.

If the two pupils are unequal in size and the pupillary light reaction appears normal, the anisocoria is physiologic or the patient may have Horner's syndrome. Physiologic anisocoria occurs in 20% of the normal population. Also, many elderly individuals have involutional ptosis, which also may be asymmetric.

Horner's syndrome is characterized by a slight ptosis of the ipsilateral upper lid and a minor elevation of the lower lid causing narrowing of the palpebral fissure. Patients may complain that their eye appears smaller. In addition to the ptosis and miosis, patients with Horner's syndrome may have anhydrosis (decreased sweating on the ipsilateral forehead region). Horner's syndrome is suspected by observing an increase in anisocoria in dim light and a decrease in bright light. Pharmacologic testing for Horner's syndrome is performed by instilling 4%, 5%, or 10% cocaine drops in both eyes. Normal pupils dilate over 40 minutes, but in Horner's syndrome the pupil dilates much less, if at all. Thus the anisocoria increases. The response to cocaine may be minimal in both eyes of patients with dark irides. If the anisocoria does not increase with the cocaine test, the patient does not have Horner's syndrome. If the anisocoria increases after instillation of cocaine, the diagnosis of Horner's syndrome is confirmed, implying a lesion of the sympathetic pathway. Hydroxyamphetamine (1% drops) can be used on a subsequent visit to determine whether the lesion in the sympathetic pathway is preganglionic or postganglionic. Postganglionic lesions are distal to the superior cervical ganglion, whereas preganglionic lesions are more proximal or central. Hydroxyamphetamine does not dilate a miotic pupil resulting from a postganglionic lesion but does dilate the pupil if there is a preganglionic lesion.

Horner's syndrome is frequently observed in asymptomatic patients and may be longstanding. It is helpful to review old photographs of the patient to determine the duration of the ptosis and the anisocoria. Congenital Horner's syndrome can result from birth trauma, but it is also associated with a lightly pigmented iris on the affected side. In the absence of a history of birth trauma, a child with Horner's syndrome should undergo radiologic studies to exclude the presence of a tumor in the mediastinum or cervical region. In adults a postganglionic Horner's syndrome is almost always benign and is frequently associated with a history of migraine headaches. Preganglionic lesions are more ominous and are often a result of neoplasm affecting the cervical region or brainstem. Because preganglionic lesions can be a sign of internal carotid dissection, a high order of suspicion is appropriate when a patient presents with severe radiating neck pain, headache, and new-onset Horner's syndrome.

When caused by a central lesion, Horner's syndrome usually is associated with other neurologic abnormalities. Patients with preganglionic lesions therefore require a complete neurologic examination, including neck and thyroid gland. Imagining studies of the mediastinum, neck, and brain are recommended to rule out neoplasm. If carotid dissection is suspected, magnetic resonance angiography selective cerebral arteriography is required. If old photographs establish that the Horner's syndrome has been present for years, however, investigation is not indicated, even in preganglionic cases.

[edit] Other Pupillary Abnormalities.

Episodic dilation of the pupil lasting minutes to hours can occur in otherwise healthy patients. It may be associated with headache, blurred vision, or photophobia. Patients are rarely seen during episodes but usually are normal when examined. The condition is considered benign, and further investigation is not indicated.

Patients with severe neurologic lesions or taking certain drugs may have small but reactive pupils. Light/near dissociation, or a good response to an accommodative target but a poor response to light stimulation, can affect any patient with severe visual impairment. With normal vision, however, dissociation occurs in patients who have midbrain lesions, a long history of diabetes, alcoholism, or late syphilis (Argyll-Robertson pupils).

[edit] ADDITIONAL READINGS

• RM Burde, PJ Savino, D Trobe: Clinical decisions in neuro-ophthalmology ed 2. St Louis: Mosby; 1992:
• TR HedgesIII: Consultation in ophthalmology Philadelphia: Decker; 1987:
• WAJ Heuven, JT van Zwaan: Decision making in ophthalmology Philadelphia: Decker; 1992:
• NM Newman: Neuro-ophthalmology: a practical text New York: Appleton & Lange; 1992: