Clinical Vignette

A 48-year-old man was referred for sudden loss of vision in the left eye. He had noted this the morning before while shaving when he could not see the lower half of his chin with the left eye only. He had no pain, and had no preceding systemic symptoms. His past medical history was noteworthy for mild diet-controlled hypercholesterolemia and untreated labile hypertension. The affected eye had 20/40 central acuity, and an inferior central field loss that extended nasally but did not cross into the superior field. The left optic nerve showed acquired elevation and swelling, with mild peripapillary hemorrhages. The fellow nerve was small in diameter, had no physiologic cup, and had mild congenital elevation. The diagnosis of idiopathic (nonarteritic) anterior ischemic optic neuropathy (AION) was made. Over the next 6 weeks, the left optic nerve swelling abated and was replaced by mild pallor noted superiorly. The vision did not recover.

The optic nerve is not a peripheral nerve but rather a central nervous system (CNS) tract containing central myelin formed by oligodendrocytes. It is composed of long axons, whose cell bodies comprise the ganglion cell layer of the inner retina (Figs. 4-1 and 4-2). The axons run in the retina’s nerve fiber layer to gather at the optic disk.

Figure 4-1 The Retina and the Photoreceptors.

Figure 4-2 Retinal Architecture and Perimetry.

The optic nerve nominally begins when the axons of the ganglion cells (the nerve fiber layer of the retina) turn 90°, changing orientation from horizontal along the inner retinal surface to vertical, passing through the outer retina via the scleral canal (Fig. 4-3). The gathering of axons at the canal forms the optic disk (also, optic nerve head) of the fundus. Myelin is usually absent from the nerve fiber layer where the nerve exits the globe.

Figure 4-3 Anatomy of Optic Nerve (Clinical Appearance).

Vascular supply of the retina comes from the ophthalmic artery off the internal carotid artery. Proximal branches from this artery and branches off the muscular arteries constitute the posterior ciliary arteries that form a plexus of vessels around the lamina cribrosa and supply the optic disc, the adjacent optic nerve, and the outer layers of the retina. Cilioretinal branches from this plexus often supply the macula as well. Another branch of the ophthalmic, the central retinal artery, enters the distal optic nerve and emerges out the disc dividing into four arteriolar branches to supply each quadrant of retina. The proximal part of the optic nerve is supplied by a series of small vessels of the ophthalmic while the posterior optic nerve and the chiasm have additional supply from the anterior cerebral and the anterior communicating arteries.

The shape of visual field deficits due to vascular compromise of the inner retina is predictable, being consistent with the specific location of the arterial occlusion. Visual field defects are inverted in relation to the pathologic location: for example, a superior branch occlusion of the retinal artery will cause an inferior field defect. When retinal arteriolar occlusions affect the nerve fiber layer, field defects typically extend beyond the local occlusion in an arcuate or sectoral pattern, following the arc of the nerve fiber layer. Disease of the anterior optic nerve is an important health care problem. Glaucoma alone is suspected to affect 3 million patients, accounting for 120,000 cases of blindness in the United States, with an annual governmental cost of $1.5 billion in expenditures and lost revenue.

Clinical Presentations

Primary open-angle glaucoma (POAG) is a chronic, progressive, degenerative disease of the optic nerve. Its usual hallmark is high intraocular pressure (IOP; above 21 mm Hg), but glaucoma without high IOP (normal pressure or low-tension glaucoma) is occasionally seen, especially in the elderly. The typical optic nerve finding is cupping atrophy (i.e., enlargement of the disk’s central cup as nerve fibers are lost), coupled by progressive visual field loss that often starts nasally, progresses superiorly and inferiorly, and finally extinguishes the central and temporal fields (Fig. 4-4). POAG is usually bilateral and asymmetric and the visual loss is permanent. The time course is measured in years, and because of the slow pace and the late involvement of the central field, patients may remain asymptomatic until the disease is quite advanced. It is essential that all standard eye examinations include screening IOP measurements and optic disk inspection.

Figure 4-4 Optic Disc and Visual Field Changes in Glaucoma.

Glaucoma has other forms besides POAG, which may be congenital, secondary to systemic disease (e.g., diabetes), or other acquired eye conditions (e.g., trauma). Among these, acute narrow-angle glaucoma (also, acute angle closure glaucoma) may present dramatically with nausea, unilateral headache, and ipsilateral monocular visual loss. The diagnosis and treatment of glaucoma forms a significant subspecialty within ophthalmology, but treatment efforts revolve around lowering of IOP, whether by medical or surgical means. There are no restorative or neuroprotective treatments.

Central retinal artery occlusion (CRAO) results from interruption of the central retinal artery circulation with ischemia to the entire retina. If only a portion of the inner retinal circulation is affected, a more limited version, branch retinal artery occlusion (BRAO), is present. BRAO and CRAO are in effect retinal strokes, affecting the nerve fiber and ganglion cell layers. The presentation is one of sudden, painless, complete or partial monocular visual loss often described as a “curtain” obscuring the involved area. Retinal infarcts are commonly caused by emboli, and in BRAO the embolus is typically visible in the affected retinal vessel. Episodes of temporary monocular visual loss (TMVL; transient monocular blindness or TMB and also, amaurosis fugax) often herald retinal infarcts and represent temporarily compromised flow of the inner retinal arteries usually by passing clot.

Patients who present for care within the first hours after the onset of CRAO or large BRAO are usually treated with intermittent ocular massage and lowering of IOP (either by topical agents or by paracentesis of the anterior chamber) to promote movement of the embolus to a more distal arteriolar branch. Oxygen, alone or in combination with 5% CO₂ to promote arteriodilation, can also be used. Based on animal studies, it is felt that such interventions are unlikely to be helpful after 100 minutes of retinal ischemia, and in general the outlook for recovery is bleak; nevertheless, significant recovery of vision, even beyond the 100-minute window, is occasionally seen.

CRAO, BRAO, and TMVL may also serve as a warning sign of impending hemispheric stroke. Identification and treatment of the embolic source, if one can be identified, becomes the main focus of therapy after the window for acute treatment of the involved eye has passed. CRAO is often a sign of carotid stenosis, the appropriate management of which will significantly reduce long-term stroke risk (see Chapter 55, “Ischemic Stroke”). Heart embolism is another cause and a full stroke investigation is usually required. Nevertheless, up to 40% of cases remain without a definite identifiable cause with the presumed mechanism relating to intrinsic narrowing of the retinal artery due to atherosclerosis or, less commonly, other arteritides or compression.

Anterior ischemic optic neuropathy can be divided into nonarteritic and arteritic (associated with temporal arteritis [TA]) and is caused by loss of blood flow in the short posterior ciliary arteries. Patients usually experience sudden and severe painless monocular visual loss, often on awakening. Examination classically reveals an altitudinal (superior or inferior) visual field loss, with a unilaterally swollen, hemorrhagic disk (Fig. 4-5). The disk loses its swelling and becomes pale within weeks. The visual loss in most cases does not change following the event but 20% may show measurable change for better or worse over days. In contrast to retinal artery occlusions, embolic AION is extremely rare. In most cases, AION occurs in middle-aged individuals who have a congenitally small, elevated (“crowded”) optic disk, or in those with one or more vascular disease risk factors, such as diabetes, hypertension, or sleep apnea. In these cases, a transient fall in blood pressure causes hypoperfusion of the posterior ciliary circulation and subsequent ischemic damage to the optic nerve head.

Figure 4-5 Giant Cell Arteritis: Ocular Manifestations.

There is no proven treatment for AION, although a recent retrospective study suggests that acute treatment with oral steroids may improve outcome. There is a 50% risk of eventual involvement of the fellow eye. Strategies to reduce this risk have focused on identifying and treating cerebrovascular risk factors, daily aspirin, preventing systemic hypotension, and avoiding certain drugs, such as sildenafil, which may be associated with higher risk.

In older patients, AION can be a complication, and sometimes the presenting sign, of TA (also, giant cell arteritis), a systemic inflammatory process of the medium-sized arteries. TA can also produce TMVL and CRAO. Funduscopic appearance in arteritic AION often consists of pallid swelling of the disk, in contrast to the hyperemic swelling seen in idiopathic AION. In addition to an altitudinal visual loss, patients will have arteritic symptoms, including headache, scalp tenderness, jaw claudication, neck pain, malaise, loss of appetite, fevers, and morning stiffness of proximal muscles (i.e., polymyalgia rheumatica). Only rarely will a patient with arteritic AION have little or no systemic symptoms.

Untreated, TA may lead rapidly to blindness from bilateral AION, or to other serious complications including aortic dissection, myocardial infarction, renal disease, and stroke. Therefore, in any patient older than age 50 years with AION, clinical suspicion for TA is raised especially in the presence of systemic symptoms, or physical exam findings (pallid disk swelling or abnormal greater superficial temporal arteries). A high erythrocyte sedimentation rate (ESR, >45 mm/hour), high C-reactive protein (CRP, >2.45 mg/L), normocytic anemia, and thrombocytosis are supportive, but the diagnosis is established by temporal artery biopsy that reveals inflammation in the media of the arteries with disruption of the internal elastic membrane. The presence of characteristic multinucleated giant cells within the affected areas is diagnostic.

TA is treated with high-dose corticosteroids, started urgently and usually tapered over many months. Other anti-inflammatory medications, especially methotrexate, have been used in those at high risk for corticosteroid complications, but the efficacy of nonsteroidal agents has been questioned. Steroid dosage is gradually reduced over time, with the patient monitored for disease recrudescence by following symptoms and the ESR or CRP.

Papilledema (see Fig. 1-6) is bilateral optic nerve elevation and expansion due to high intracranial pressure (ICP). In mild cases, patients may have no visual symptoms. Moderate papilledema is typically accompanied by transient binocular visual obscurations, either spontaneously or during coughing, straining, or abrupt postural change. Other symptoms of high ICP may be present and include headaches (worse with recumbency) and diplopia (resulting from nonlocalizing abducens palsy; see Chapter 5). When visual loss occurs, it starts with blind spot enlargement (see Fig. 1-6), a nonspecific and often reversible change. Visual field loss resembling that of glaucoma can ensue, often over a period of many weeks. However, papilledema due to very high ICP can progress rapidly, with severe permanent visual loss within days.

Many pathophysiological mechanisms are associated with papilledema, including CNS tumor with mass effect or edema, obstructive hydrocephalus, meningitis, certain medications (e.g., tetracycline or vitamin A), and intracranial venous thrombosis or obstruction. Papilledema is occasionally seen without explanation in obese women of childbearing age and is then termed idiopathic intracranial hypertension (IIH; also, pseudotumor cerebri; see Chapter 11). Treatment involves only weight loss if the condition is mild and there is no evidence of progressive visual loss or debilitating headache. In progressive IIH, in addition to weight loss, carbonic anhydrase inhibitors such as acetazolamide (typically 1–2 g/day in divided doses) are used to reduce cerebrospinal fluid (CSF) production and optic nerve edema. When medical treatment fails, two surgical options exist: optic nerve sheath fenestration or CSF shunting either with lumboperitoneal or ventriculoperitoneal shunts.

Papilledema can be mimicked by the rare entity of optic perineuritis, which consists of monocular or bilateral optic disk swelling without central visual loss or raised ICP. Its usual cause is idiopathic optic nerve sheath swelling or inflammatory orbital pseudotumor but may be due to a systemic arteritis (Wegener or giant cell arteritis) or of an infectious (syphilitic) etiology.

Optic nerve drusen are small, translucent, usually bilateral concretions within the substance of the disk that may be observed in perhaps 1% of patients. Drusen contain calcium and can therefore be demonstrated on ultrasound and computed tomographic (CT) examinations. It is speculated that a very small scleral canal may inhibit proper axonal metabolism, causing extracellular debris to be deposited as drusen over time. Drusen of the optic nerve is often associated with visual field loss, and treatment to retard such loss is uncertain. Drusen of the nerve head are occasionally seen in patients with certain retinal disorders, such as retinitis pigmentosa.

Congenital dysplasia of the optic nerve can be seen as an isolated monocular or binocular finding, or as part of a larger disorder. The mildest form of dysplasia is “tilted” optic disks: nerve heads that are overall small with the nasal portions appearing elevated; superior temporal visual field loss (sometimes mimicking bitemporal hemianopia) is often encountered. Septo-optic dysplasia combines optic nerve hypoplasia with dysgenesis of midline brain structures, often with pituitary dysfunction. Up to a quarter of patients with fetal alcohol syndrome will have disk hypoplasia with associated inferior visual field loss, among other ocular manifestations. Optic nerve coloboma (congenital incomplete or malfusion of the globe structures including the retina and optic nerve) can be part of Aicardi syndrome, and the “morning glory” disk anomaly has been associated with several developmental syndromes.

Diagnostic Approach

As all pathologic entities in this group display abnormalities of the disc and/or retinal vessels, careful fundus examination is the essential step in diagnosis. Visual field testing typically reveals patterns of visual loss (arcuate, altitudinal, and nasal losses with a “step” at the horizontal meridian) that localize the lesion to the anterior optic nerve, does not often guide the diagnosis. Sector losses can suggest branch arterial occlusion (any location), optic nerve hypoplasia (typically inferior), optic disk tilt, or coloboma (these last two often producing superior losses).

Additional information can be obtained by special imaging of the ocular fundus. Fluorescein angiography of the fundus reveals vascular occlusions and areas of edema caused by incompetent blood vessels. Optical coherence tomography, scanning laser ophthalmoscopy, and scanning laser polarimetry provide precise measurement of the nerve fiber layer in the peripapillary retina and can help define subtle cases of disk edema or atrophy and changes in disk appearance over time.

Clinical Vignette

A 26-year-old woman presented with right monocular visual loss and headache after a car accident. She said she had suffered “whip-lash,” without bruising impact to the head. The visual loss had started 2 days after the accident. The headache was centered at the right orbit, with eye movement among its aggravating factors. Subjective visual acuity was 20/80 right eye, and visual field testing revealed nonphysiologic responses, indicating the patient was inattentive to the test, in both eyes. Fundus examination of both eyes was entirely normal; however, pupillary examination suggested a mild relative afferent papillary defect on the right. A magnetic resonance imaging (MRI) examination was obtained revealing multiple white-matter lesions. A diagnosis of multiple sclerosis (MS) presenting as optic neuritis was eventually confirmed based on spinal fluid assays and subsequent clinical course.

After leaving the eye, the fibers of the optic nerve become myelinated. The optic nerve sheath invests the nerve, starting at the sclera and becoming contiguous with the intracranial dura. CSF is present within the sheath. The optic nerve lies in the central orbit within the extraocular muscle cone and exits the orbit through the optic canal before traveling a short distance intracranially to join the chiasm. Vascular supply is via branches of the ophthalmic artery.

Diseases that affect the orbital optic nerve give characteristic central visual field loss. It is believed that the nerve fibers corresponding to central vision, among the most metabolically active cells in the visual system, occupy a central position in the optic nerve, farthest away from the exterior blood supply. The central fibers, therefore, are the most prone to dysfunction or injury due to varying mechanisms, including compression, ischemia, metabolic disease, and toxic insult. Within the bony optic canal, the optic nerve is confined in a small space and is relatively immobile, making it susceptible to quite small tumors or inflammatory processes as well as shear injury produced by deceleration head trauma.

Multiple sclerosis (see Chapter 46), however, remains the chief cause of orbital optic nerve disease and is the initial manifestation in approximately 20% of patients. An additional 20% will eventually experience it throughout the course of the disease. It is estimated that more than 90% of patients suffering “isolated” optic neuritis will eventually receive a diagnosis of MS. Diagnostic testing in optic neuritis naturally mirrors that for MS, with brain MRI and CSF analysis being the primary tools.

Clinical Presentations

Optic neuritis is the clinical syndrome of subacute painful, monocular visual loss. The pain often precedes visual loss by a day or more and is a periorbital ache made worse with eye movements. Ensuing visual loss is often sudden and severe, with perceived worsening over several days. The degree of visual field loss varies, but a central scotoma is the classic finding (Fig. 4-6). Examination may also demonstrate loss of central acuity, contrast sensitivity, and color perception in the affected eye.

Figure 4-6 Multiple Sclerosis: Ocular Manifestations.

Initially, funduscopic appearance of the affected disk is normal, but only the presence of a relative afferent pupillary defect and visual loss confirms that optic neuropathy is present. Occasionally, mild ipsilateral disk swelling is seen, and in all cases some degree of optic pallor, usually localized to the temporal quadrant of the disk, appears within weeks. Incomplete recovery of vision, mostly in the first 3 months, is expected with central acuity recovering better than other parameters, often to near normal.

As with other manifestations of MS, emphasis is on early diagnosis so that patients may begin treatment with immunomodulating medications to reduce disease activity and associated morbidity. Intravenous methylprednisolone (1 g/day for 3 days, followed by an oral prednisone taper for 11 days) has been shown to accelerate visual recovery in optic neuritis, although the final level of recovery is unaffected. The same study showed a reduced risk of MS exacerbations for 2 years following methylprednisolone pulse treatment. It is unclear if the drug provides additional protection beyond 2 years and whether it affects outcome in the long run. Oral prednisone alone is contraindicated in typical demyelinating optic neuritis.

Optic neuritis can also be seen as part of Devic neuromyelitis optica, an MS-like disease defined by episodes of optic neuritis and transverse myelitis. The immunopathogenesis appears distinct from MS and the preferred therapies are parenteral corticosteroids and plasmapheresis acutely, with long-term immunosuppressive agents, such as azathioprine, used to prevent relapses. The presence of a hallmark serum immunoglobulin (NMO-IgG directed against the aquaporin-4 protein) is central to diagnosis.

Optic neuritis can occasionally be idiopathic, with prolonged surveillance never leading to a diagnosis of MS. In rare cases, optic neuritis can be mimicked by treponemal infection, or by inflammatory disease (e.g., sarcoidosis).

Posterior ischemic optic neuropathy presents as sudden, painless monocular visual loss without acute change in the ocular fundus and disk. Over weeks, disk pallor becomes evident. Classically seen in chronically anemic patients after major gastrointestinal hemorrhage, it has been more recently found in one of three clinical settings: as bilateral visual loss after major surgery; and as unilateral visual loss, either as a complication of TA or of peripheral vascular disease. There is no definitive test for posterior ischemic optic neuropathy, and diagnostic workup is directed toward ruling out arteritis and occlusive carotid disease.

Indirect traumatic optic neuropathy can occur in the setting of sudden frontal head impact or deceleration. It differs from direct trauma in that no foreign object or displaced fracture has impinged upon the nerve. It is also distinct from deceleration injuries that avulse the nerve from the globe, or that damage the chiasm. The exact mechanism and location of indirect nerve injury is uncertain, but interest centers at the optic canal. An international treatment trial was unable to prove benefit of either surgical decompression of the canal or parenteral corticosteroids at dosages used for spinal cord injury. Despite the lack of rigorous evidence, parenteral steroids are often still used in selected cases.

Metabolic and toxic optic neuropathies typically affect the orbital optic nerve. The high metabolic rate of the central vision fibers and their relatively tenuous blood supply at the center of the orbital optic nerve are considered important factors placing these cells at risk.

Leber hereditary optic neuropathy (LHON) is a representative metabolic optic neuropathy. Sudden, painless monocular visual loss, typically occurring in the third or fourth decade of life, is then followed by involvement of the fellow eye after a period of weeks to years. The involved eye initially displays a hyperemic disk, with fluorescein angiography showing no extravasation of dye from peripapillary telangiectatic vessels. A family history of similar loss is often present: the disease, resulting from a mutation defect in one of several mitochondrial proteins, is passed maternally in the mitochondrial DNA with variable penetrance. The exact clinical presentation depends to some degree on the specific mutation involved. Neuronal damage is presumed to result from superoxide formation in the impaired mitochondria. Patients with first-eye involvement, or identified as having the mutation, are often advised to avoid substances (e.g., tobacco smoke, alcohol, and certain medications) that deplete systemic reductases, and to consider dietary supplementation of vitamin B₁₂, which, if deficient, can precipitate LHON. Use of the topical neuroprotectant brimonidine was not shown to be effective. LHON is an attractive candidate for eventual gene therapy.

Dominant optic atrophy (also, Kjer optic atrophy) is a dominantly inherited, progressive optic neuropathy, which presents in childhood and usually stabilizes by the third decade of life. It, too, is caused by defective mitochondrial metabolism, but the four known mutations are in autosomal genes. Additional, related mutations can cause optic atrophies with X-linked and recessive inheritance.

Hypovitaminosis, especially thiamine, folic acid, and cyanocobalamin, can produce a progressive bilateral optic neuropathy. Hypovitaminosis is seen in malnutrition (especially in the elderly, or in conjunction with alcoholism), in gut malabsorption syndromes, and occasionally in those following strict vegan diets. The drug methotrexate inhibits the metabolism of folic acid and has been associated with metabolic optic neuropathy.

Methanol (wood alcohol) poisoning occurs acutely as liver enzymes convert the ingested methanol to formaldehyde and formic acid. Exposure is usually accidental, sometimes in connection with homemade alcohol (“moonshine”). The special sensitivity of the optic nerve is not well understood, but optic neuropathy occurs at exposure levels far below those that are generally cytotoxic. Treatment consists of intravenous ethanol (to slow the conversion of methanol) and hemodialysis.

Other substances are either known or suspected to produce toxic optic neuropathies. These include the drugs ethambutol and isoniazid, both of which are increasingly used in the treatment of atypical mycobacteria, such as mycobacterium avium-intracellulare. Visual field monitoring is occasionally recommended for patients taking ethambutol or isoniazid, but the efficacy of monitoring in preventing or limiting visual loss has not been shown. Amiodarone is suspected of contributing to an optic neuropathy that may mimic AION, but the association remains unclear. A larger list of medications is suspected of being able to “trigger” optic neuropathy in patients predisposed to it, such as those with an LHON mutation.

Paraneoplastic optic neuropathy is a rare disease in which autoantibodies directed against cancer cells cross-react with optic nerve proteins, such as antibodies to the CRMP-5 (collapsin response-mediating) protein. Treatment is uncertain.

Compressive optic neuropathy is characterized by central vision loss. It can, on occasion, arise suddenly (e.g., traumatic orbital hematoma), or more commonly by slowly growing tumors. In sudden compression, urgent decompression is required to minimize permanent optic nerve injury. However, in the case of slow compression by tumor, visual loss, which often precedes optic pallor by months, may be reversible when compression is relieved.

Proptosis or defect of extraocular movements suggests an orbital mass. If optic atrophy has not yet occurred, fundus examination may be normal, but may reveal signs of scleral indentation with posterior chorioretinal folds, or signs of chronic central retinal vein compression and optociliary venous shunting. MRI with gadolinium is generally preferred for imaging of orbital masses, although bone structure and abnormalities (hypertrophy with meningioma, destruction with cancers, and remodeling with large benign tumors) are better seen on CT scanning.

Typical orbital tumors compressing the optic nerve are cavernous hemangioma (the most common benign orbital tumor), optic nerve sheath meningioma, and optic nerve glioma. Cavernous hemangiomas are relatively easy to address surgically, except when at the orbital apex. Optic nerve meningioma generally cannot be removed surgically without severe loss of vision, and the preferred treatment, once optic nerve compression begins, is fractionated stereotactic external beam radiation to limit tumor growth. Glioma of the optic nerve cannot be resected short of excising the nerve, causing immediate blindness in the affected eye. Therefore, the gliomas are generally left in place, with excision indicated only if severe proptosis with eye exposure or extension of the glioma toward the chiasm, threatening vision in the other eye, occurs. Stereotactic radiation can be used. Attention to the possibility of rare, aggressive gliomas requiring early excision is a cause for frequent reimaging initially when following these tumors. Multiple gliomas, typically slow-growing, are a common feature of von Recklinghausen neurofibromatosis (NF-1).

The enlarged extraocular muscles of thyroid-related orbitopathy are a common cause of proptosis, but in rare instances may also cause optic nerve compression. Patients with thyroid-related orbitopathy are monitored by serial central vision and visual field testing. Thyroid-related optic nerve compression is often treated initially with systemic corticosteroids, with definitive treatment of orbital decompression to quickly follow.

Orbital cellulitis produces an obvious clinical picture with acute pain, proptosis and periorbital edema. Because of the risk to vision posed by this acute disease, patients are often hospitalized for close monitoring and intravenous antibiotic therapy. Etiology of orbital cellulitis in adults is typically from recent penetrating periorbital trauma, from contiguous spread of facial sinusitis or from hematogenous seeding from facial soft tissue infections. Idiopathic orbital inflammation (also, orbital pseudotumor) resembles orbital cellulitis, but does not respond to antibiotic therapy, and lacks clear traumatic or infectious prodrome. A dramatic response to systemic corticosteroids is a key diagnostic feature. Orbital cellulitis can also be mimicked by Wegener granulomatosis or invasive fungal sinusitis.

Diagnostic Approach

The orbit represents the most anterior location where examination of the eye itself may not provide clues to the etiology of visual loss. Nevertheless, complete eye examination, with attention to central acuity, visual fields, pupil, and optic disk, remain central to diagnosis. External examination of the orbit, looking for proptosis, resistance to retropulsion of the globe, and limitation of ocular movement, may suggest an orbital tumor or mass. Details in the history of present illness (abruptness of onset, accompanying pain, etc.) will suggest the most likely etiologies.

In some diseases of the orbital optic nerve, optic disk changes may be present, as in the disk hyperemia of LHON. Additional fundus imaging may then be appropriate to better define the abnormalities

However, for the orbit—and for all more posterior etiologies of visual loss—eye examination must be coupled with appropriate imaging. MRI of the orbits is usually recommended, and is done with fat-suppression and gadolinium paramagnetic contrast to enhance tumors such as hemangiomas and meningiomas. Inclusion of the brain, especially fluid-attenuated inversion recovery (FLAIR) sequences, in cases of optic neuritis, helps to assess for additional white-matter lesions, suggestive of MS. However, as mentioned above, CT scanning can reveal diagnostic orbital bone changes missed by MRI. Timing of imaging is usually predicated on the acuteness of the visual loss.

When a specific diagnosis is suggested, additional studies may be indicated, as spinal fluid analysis for optic neuritis or mitochondrial genetic testing in LHON. In cases where examination and imaging do not suggest specific etiology, screening for systemic disease may be needed.

Clinical Vignette

A 51-year-old woman presented with worsening vision over many months. She reported no other significant medical history. While confirming normal central acuity, the examiner discovered that the patient could see only the left half of the eye chart with her right eye and only the right half with her left eye. A gross confrontation visual field check confirmed a dense bitemporal hemianopia. The examiner also noted that the woman had facial hypertrichosis and enlargement of her brow, nose, lips, and jaw and that the patient’s rings and shoes no longer fit properly. Acromegaly, from abnormally high circulating levels of human growth hormone produced by a pituitary tumor, was diagnosed. MRI confirmed the lesion compressing the optic chiasm.

Bitemporal hemianopia is the characteristic field abnormality of optic chiasm disease. The chiasm (from the Greek letter x) represents the “Great Divide” of the afferent visual system, separating clinical field defects into three anatomic areas. Prechiasmatic defects affect the visual field of the ipsilateral eye only and typically result from retinal or optic nerve pathology. Chiasmatic disorders classically lead to bitemporal hemianopia (also, hemianopsia), with loss of the right lateral field in the right eye and left lateral field in the left eye. Postchiasmatic defects produce homonymous hemianopias, with defects appearing more congruous (equal for both eyes) the farther posteriorly the lesion is located.

The optic chiasm is the intersection of the optic nerves from each eye and is located above the pituitary body that lies within the sella turcica of the sphenoid bone, and covered by the diaphragm sellae (Fig. 4-7). The chiasmatic cistern is located between the chiasm and the diaphragm sella. Superior to the chiasm is the third ventricle. The internal carotid arteries flank the optic chiasm laterally and then bifurcate into the anterior and middle cerebral arteries. The anterior cerebral arteries and the anterior communicating artery are anterior to the optic chiasm.

Figure 4-7 Anatomy and Relations of Optic Chiasm.

Within the chiasm, axons from the temporal retina (nasal field) comprise its lateral aspect and remain ipsilateral as they pass through the chiasm to the optic tract. In contrast, the nasal retinal fibers decussate, carrying temporal visual field information to the contralateral side. Inferior nasal fibers decussate within the chiasm more anteriorly than superior ones. As the inferior nasal retinal fibers approach the posterior aspect of the chiasm, the fibers shift to occupy the lateral aspect of the contralateral optic tract (see Fig. 4-7).

The arterial blood supply of the optic chiasm is derived from the circle of Willis, particularly, the superior hypophyseal arteries, derived from the supraclinoid segment of the carotid arteries. A “prechiasmatic plexus,” the hypophyseal portal system, and branches of the anterior cerebral arteries also contribute to the chiasmatic blood supply. Venous drainage goes to two primary areas: blood from the superior chiasm flows into the anterior cerebral veins, whereas the inferior aspect drains into the infundibular plexus and thus to the paired basal veins of Rosenthal.

The location of the chiasm renders it vulnerable to compression from vascular structures (e.g., aneurysm near the origin of the anterior communicating artery or the ophthalmic artery), from tumors of the meninges, from sphenoid sinus masses, and most important from the pituitary (Fig. 4-8).

Figure 4-8 Pituitary Macroadenoma.

Clinical Presentations

Central chiasmatic lesions most commonly produce a bitemporal hemianopia (Fig. 4-9A) that ensues when the optic chiasm is compressed or damaged midsagittally at its decussation. Such lesions preferentially affect the crossing nasal retinal fibers responsible for temporal vision, as in the vignette in this chapter.

Figure 4-9 Disorders Affecting Optic Chiasm.

Variants on the classic bitemporal hemianopia are seen with compression of the optic nerve at its entrance to the anterior chiasm, resulting in a junctional scotoma, with central visual loss in the ipsilateral eye and a superotemporal defect in the other. The field loss in the contralateral eye reflects involvement of the opposite inferior nasal optic nerve fibers that swing forward into the ipsilateral anterior chiasm (Willebrand knee) before decussating to the optic tract (Fig. 4-9B).

Posterior optic chiasm lesions lead to a posterior junctional scotoma, which displays the features of chiasmatic and optic tract lesions. The classic finding is incongruous (less dense in the ipsilateral eye) hemianopic visual field loss contralateral to the lesion from involvement of the anterior optic tract and an inferotemporal visual field loss in the ipsilateral eye—from pressure on the posterior chiasm affecting the late-crossing superotemporal retinal fibers (Fig. 4-9C). Such defects occur in lesions located near the anterior aspect of the third ventricle that approach the chiasm posteromedially. The incongruous nature of the hemianopsia is caused by the incomplete intermixing of the decussating fibers entering the optic tract with their corresponding uncrossed fibers from the contralateral eye.

Progressive visual field loss from an expanding sellar tumor characteristically begins in the upper temporal fields, likely from preferential compression of the inferior chiasm as the underlying pituitary tumor exerts pressure through the diaphragm sellae. Early, the superotemporal defects may be paracentral with sparing of the far periphery. As the tumor enlarges, the superotemporal quadrantanopsia extends to the periphery, and the inferotemporal field becomes affected. Later, the inferonasal quadrant, and eventually all vision, will be lost.

Most commonly, chiasmatic compression results from a benign pituitary adenoma (see Chapter 52). These are common brain tumors, and with high-resolution MRI imaging are detected in 10% of patients. Tumors smaller than 10 mm, termed microadenomas, are generally too small to place significant pressure on the optic chiasm. and are usually discovered because of the effects of excess pituitary hormone (e.g., prolactin) secretion. Small nonsecreting adenomas can be found as an incidental finding on brain MRI obtained for other reasons. Once a tumor grows sufficiently and obliterates the 10 mm distance from diaphragm sella to the chiasm, the potential for visual loss exists. Typically, the chiasm can accommodate slowly growing tumors, so that chiasmatic impingement or displacement by such tumors may be seen without any field defect. When the macroadenoma, however, reaches 20–25 mm, field defects are likely. The usual indications for surgical excision are continued tumor growth or the presence of visual compromise. Prolactinomas can often be treated medically using bromocriptine or cabergoline to shrink the tumor. Similarly, mitotane has been used for adrenocorticotropic hormone–secreting tumors, and somatostatin analogues for tumors secreting human growth hormone. Failure of medical therapy leaves the options of transsphenoidal surgical excision, or perhaps precision radiotherapy (e.g., gamma-knife).

Many other sellar masses cause bitemporal hemianopia and include benign or malignant intrinsic tumors (glioma and glioblastoma), extrinsic tumors (benign meningioma and craniopharyngioma or malignant chordoma and lymphoma), and inflammatory granulomas. Aneurysm (especially of the carotid, ophthalmic, or anterior communicating artery), demyelinating disease or MS, and deceleration head trauma are other important etiologies.

Pituitary apoplexy is defined as sudden expansion of a pituitary tumor from infarction or hemorrhage, with subsequent edema and necrosis. Patients typically present with rapid and painful visual loss, often accompanied by alteration of consciousness and ocular motor palsy. Death from pituitary insufficiency can supervene if replacement corticosteroids are not instituted. Prompt surgical decompression of the chiasm is recommended, although improved visual outcomes has not been rigorously proven.

MRI scanning with attention to the sella is recommended in any patient presenting with bitemporal hemianopia. Patient presenting with acute bilateral visual loss should receive urgent MRI or CT scanning to look for pituitary apoplexy or aneurysm.

Clinical Presentations

Posterior to the chiasm, any insult to the afferent visual system is immediately recognizable by the resulting contralateral homonymous (same laterality and region in each eye) visual loss. It is commonly found that in pure hemianopias without optic nerve or chiasm contribution, central visual acuity for individual letters is unaffected; however, the “macular splitting” that results from total hemianopia can cause difficulty with reading text.

Optic tract lesions are unique in that they cause homonymous hemianopias combined with pupillary abnormalities and optic disk pallor. Total lesions of the optic tract affect the pupillary afferents within the tract and produce a mild relative afferent pupillary defect in the contralateral eye because more crossed fibers exist within the tract from the contralateral eye than uncrossed fibers from the ipsilateral eye. When wallerian degeneration ensues, pallor characteristic of optic tract lesions develops in the optic disks. The ipsilateral eye, losing axons from the retina temporal to the fovea, has chiefly superior and inferior polar atrophy, whereas the contralateral eye, losing the interior of the papillomacular bundle and the axons from the retina nasal to the optic nerve, has pallor in the temporal and nasal poles (“bow-tie” atrophy).

For the optic tract, the field loss affects both eyes and is contralateral to the affected tract. The loss depends on the extent of the tract lesion and is either a complete or incomplete homonymous hemianopia. Incomplete tract hemianopias are often incongruous (i.e., the defects in each eye do not match exactly) wedge-shaped defects, with the point of the wedge encroaching on the center, a “dagger into fixation” or “sectoranopia.” As with the chiasm, neoplasms, aneurysms, and trauma are the typical lesion in this region; strokes are relatively uncommon.

Posterior to the optic tract, visual field loss is not accompanied by pupillary change or optic atrophy. However, specifics of the hemianopia can assist in localizing the lesion. LGN lesions produce field defects similar to those of the optic tract. Lesions confined to the temporal lobe can reach only the Meyer loop portion of the optic radiations, with the resulting visual field defect typically as a homonymous, incongruous superior wedge—one side located at the vertical meridian and the second edge being less sharp. This defect, resembling a “slice” removed from the superior visual field, has been termed the pie-in-the-sky defect. When encountered, it provides strong evidence of a temporal lobe pathogenesis. Often, other findings of temporal lobe dysfunction confirm the localization.

Conversely, if a parietal lesion affects the optic radiations anteriorly, an inverse lesion sparing the temporal lobe “wedge” occurs; however, such lesions are rarely encountered. Occasionally, larger or far posterior parietal lesions can affect all of the optic radiations after the Meyer loop has rejoined the other fibers, producing a complete homonymous hemianopia. Pathologic entities affecting the posterior visual afferents are most commonly stroke, tumor, demyelination, and trauma.

Differential and Diagnostic Approach

Complete homonymous hemianopias cannot be reliably localized as to the level of the optic tract, lateral geniculate body, parietal lobe, or occipital lobe. Other than the visual fields, a broader ophthalmologic examination may provide hints to the site of the lesions. For example, optic tract lesions produce a mild contralateral relative afferent pupil defect and bow-tie atrophy of the optic disks. The parietal lobe contributes to pursuit eye movements, and patients with a complete homonymous hemianopia from a parietal lesion may show altered or absent optokinetic nystagmus in the direction of the lesion.

As with any visual loss, the diagnostic course for hemianopic visual loss includes complete eye examination, visual fields with attention to assessment of central acuity, pupillary reactions, pursuit movements, and funduscopy. The presence of additional neurologic or systemic symptoms and the speed of onset may help both localize the lesion and suggest an etiology. Review of past medical history may reveal if the patient has known risks for some etiologies, such as stroke, demyelination, or metastasis. The most important ancillary test is diagnostic imaging. Typically, MRI examination is recommended as best able to detect, and distinguish among, the potential pathologies. Diffusion-weighted images can be particularly useful in defining recent stroke (see Chapter 55). Management and therapy are dictated by the etiology.

Clinical Vignette

A 64-year-old gynecologist, while operating, suddenly had difficulty seeing to the right. He had to turn his head to see the full operative field. The next day, he saw his ophthalmologist, who found evidence of a dense right homonymous hemianopia.

A subsequent neurologic consultation was otherwise unremarkable. MRI demonstrated a positive diffusion-weighted lesion in the left occipital lobe. ECG and transesophageal echocardiography results were normal. A 48-hour Holter monitor documented seven periods of intermittent atrial fibrillation. Anticoagulation was initiated. The patient was advised to stop driving.

Axons of the optic radiations synapse with the primary visual cortex. A unique white stripe or stria (stripe or line of Gennari for the discovering anatomist) represents a myelin-rich cortical layer; it is easily seen in gross sections through the cortex and bespeaks the layered, highly structured organization of V1 (also known as the primary visual cortex, the striate cortex, or Brodmann area 17). Primarily located on the mesial surface of the occipital lobe within and surrounding the calcarine fissure, the most posterior aspect of V1 typically wraps around the posterior (occipital) pole for a short distance (Fig. 4-13).

Figure 4-13 Occipital Cortex and Projections.

Microscopically, the visual cortex is arranged in six laminae, running from the surface to a depth of slightly greater than 2 mm. The most superficial, layer I, primarily contains glial cells. Layers II and III contain pyramidal cells and small interneurons. The thickest stria is layer IV, comprising almost half the depth of the visual cortex. Highly branched stellate cells exist superficially within layer IVa. The Gennari stripe comprises layer IVb, containing myelinated axons from afferent visual (geniculate) cells and cortical association fibers. Pyramidal and granule cells and giant pyramidal (Meynert) cells occur more deeply at IVc. Layer V is a densely cellular region with variously sized pyramidal cells. Layer VIa is a less cellular superficial portion, and layer VIb contains a varied neuronal population.

The blood supply of the striate cortex primarily derives from the calcarine artery, a branch of the posterior cerebral artery, and sometimes the middle cerebral artery, or anastomoses from it (Fig. 4-14).The calcarine artery is a major supply to the visual area; however, in 75% of cases, other arteries contribute as well: the posterior temporal or parietooccipital arteries, and, occasionally, anastomotic connections from the middle cerebral artery.

Figure 4-14 Arteries of Brain (Lateral and Medial Views).

Specific anatomic correlations are the primary clinical features pertinent to the striate cortex: visual information from the left visual field in each eye is projected to the right visual cortex (and conversely); the superior visual field is projected into the inferior half of V1 (and conversely); and the most central visual field is projected most posteriorly, whereas the peripheral field is located anteriorly within V1.

“Cortical magnification” in V1 results in much more cortex dedicated to the central area than to the periphery. Up to 50% of the cortex may correspond to the central 10° of vision; in fact, the most central 1° of vision uses as much cortex posteriorly as the most peripheral 50°. Cortical magnification is considered a reflection of the evolutionary importance of precise central vision to human survival.

Ocular dominance columns run at right angles to the cortical surface. Within a column, visual input is derived from one eye only; in the immediate neighboring cortical surface, perhaps 0.5 mm away, another column deriving input from the other eye is encountered.

Monocular occlusion in animal experiments during the early postnatal period demonstrates that the columns of the occluded eye grow smaller, whereas the columns of the open eye enlarge. Subsequent uncovering of the occluded eye does not restore the equality of the columns, which is considered central to understanding critical periods in visual development. The failure of that development is designated amblyopia.

A hierarchy exists to the processing of visual information at a cellular level. The striate cortex has different cell types that respond to increasingly specific stimuli. Simple cells have the same light–dark, center–surround response profile as retina and LGN cells. Complex and hypercomplex cells respond best to a light stimulus that is not a spot but a line at a particular angle or a specific length to achieve an optimal cell response.

This hierarchical structure suggests that additional cell types, probably located in extrastriate association cortices, respond to more specific and complex stimuli until, eventually, there may be “higher” association cortices, with groups of cells producing specific patterns of neuronal activation that represent the anatomic correlate for a specific perceptual recognition.

Brodmann areas 18 and 19, immediately adjacent to area 17, in the area surrounding the calcarine fissure, were termed the parastriate or association visual cortex on the assumption that they function to “associate” the visual data from V1 with brain areas regarding spatial orientation, recognition, and language.

The economic implications of hemianopic visual loss can be estimated by looking at its primary etiology, stroke. It has been estimated that 15% of stroke patients suffer homonymous visual loss. Overall, stroke costs in the United States will reach $2.2 trillion in the next 45 years, with hemianopia representing perhaps $300 billion.

Clinical Presentations

The vignette at the beginning of this section typifies an embolus to the left posterior cerebral artery causing a left occipital lobe infarct. Although occasionally such patients improve, often individuals have no substantial resolution of function. Driving restriction is essential in this case because of the total inability to perceive objects in the densely lost field.

Striate cortex lesions, like other neurologic lesions, can be classified into ischemic, neoplastic, demyelinating disease, and rare infections. Clinical characteristics of V1 visual field defects provide diagnostic anatomic localization even before imaging procedures are done. Incomplete hemianopias from V1 lesions show congruent deficits in each eye’s visual field. The small size and close proximity of the left and right ocular dominance columns make it impossible to selectively damage the visual field of only one eye.

Features of homonymous hemianopias that suggest occipital lobe origin include extremely congruous partial defects between eyes, macular sparing, central homonymous defects, keyhole defects, as well as temporal crescent defects. Because of the specialized nature of V1, lesions in it affect only the vision, without other neurologic dysfunction (except, occasionally, headache). In addition to the above, striate cortex lesions produce no signs of anterior visual pathway involvement such as optic pallor or relative afferent papillary defect. Typically, central acuity in the preserve field is normal (Fig. 4-15).

Figure 4-15 Left Posterior Cerebral Infarction.

The extreme temporal visual field of each eye represents an exception to the above principle of symmetric homonymous defects. Because the nasal visual field extends only approximately 65°, the remaining 25% of the lateral field on each side is supplied solely by the ipsilateral eye. This “temporal crescent” of the visual field corresponds to the most anterior aspect of V1, abutting the occipitoparietal fissure, where ocular dominance columns are absent, because all input comes solely from the contralateral nasal retina. Therefore, lesions of the anterior striate cortex may result in a “monocular temporal defect.”

Rarely, bilateral occipital cortical lesions occur simultaneously or in quick succession. Generalized systemic hypotension, such as from a cardiac arrest or basilar or bilateral posterior cerebral artery occlusion, can cause bilateral ischemic damage. Similarly, both occipital poles can be injured by direct trauma or contrecoup mechanisms during skull injury. Initially, bilateral occipital pole lesions may be confused with bilateral optic nerve lesions because an apparent “central scotoma” is found in each eye. However, careful visual field mapping along the vertical axis demonstrates a discontinuity, or a vertical step. The vertical step is expected because cortical injuries should not be absolutely symmetric and the extent of clinical visual field loss should vary in size between the left and right hemifields. The size difference is easily recognized at the vertical meridian, resulting in a “keyhole defect.” Like temporal crescent defects, keyhole defects are characteristic of occipital lobe lesions.

The most central visual field is represented widely on the posterior pole rather than only in the mesial occipital surface of V1 and is often supplied by the middle rather than the posterior cerebral artery. This means that even lesions affecting most of V1 may miss the most anterior, central vision area and produce a pattern of macular sparing in homonymous hemianopia with incomplete striate cortex lesions. However, when there is total loss of the cortex (e.g., surgical removal), macular sparing is not expected.

Parietal lesions differ from the isolated loss of visual field seen in V1 occipital disease in that both homonymous contralateral field loss and abnormal eye movements are usually detected. The loss of visually guided horizontal saccades to the side away from the lesion is best seen as an abnormal opticokinetic nystagmus response: when the drum is rotated toward the side of the lesion, the eyes, unable to saccade and pick up the next stripe on the drum, drift toward the affected side.

The clinical presentations of extrastriatal cortical lesions continue to be defined. Cerebral achromatopsia (impaired color perception due to occipital insult) has been described. The pathologies producing more complex visual deficits, typically termed visual agnosias, reach beyond the parastriate cortices. Prosopagnosia, for example, is typically caused by lesions encompassing the occipital and temporal lobes.

Diagnostic Approach

Visual fields, ocular, and neurologic examinations will often serve to localize the visual problem to the occipital cortex. The etiology is suggested by the tempo of onset, accompanying symptoms, and presence of risk factors for a specific disease entity. MR imaging however remains standard for better specifying the pathologic process.

Cases of diffuse cerebral dysfunction may occasionally present with poor vision as the chief complaint. Electroencephalography and positron emission tomographic (PET) scanning may help in diagnosing patients with the Heidenhain variant of Creutzfeldt–Jakob disease, where visual symptoms predominate and MRI is normal in the early course. In the visual variant of Alzheimer disease, however, neuropsychological testing and PET scanning with hypometabolism of the bilateral parieto-occipital cortices and the frontal eye fields probably provide the best diagnostic strategy.

Treatment

Treatment for most types of homonymous hemianopia is unavailing. If there is no improvement in visual deficits after the first 2 weeks, visual loss due to stroke is generally permanent. Surgical removal of an arteriovenous malformation or tumor is usually expected to leave significant residual visual loss.

Therefore, mainstays of treatment are stabilization of vision (e.g., stroke prevention if stroke was the etiology) and visual rehabilitation. Rehabilitation efforts resemble those in other areas of post-stroke rehabilitation, with focus on developing strategies to return to activities of daily living (e.g., reading and avoiding obstacles while ambulating) in spite of the hemianopic visual loss. Much of the improvement generally seen over time is usually attributed to increased visual scanning on the side of the blind hemifield, utilizing saccades and head turns to that side. Protection of the patient who is unable to see obstacles in one hemifield may be improved by use of a cane on the hemianopic side and a brimmed or billed hat to detect obstacles before collision.

The possibility of “visual restoration” after stroke or traumatic brain injury using a computer-based, stimulus-detection paradigm is being explored. Data suggesting an average of 12% increase in “stimulus detection” after 6 months of therapy have been reported, but how and whether such testing improvement translates into practical functional improvement or reorganization on a neuronal basis remains unclear.

The use of a split prismatic spectacle correction, which presents part of the “blind” hemifield to the patient’s remaining vision with less head turning, may aid selected patients by providing a way to monitor the area of visual loss more easily. Except in cases of quite minor loss, returning to driving after hemianopic visual loss is generally impossible, even if prismatic spectacles or visual restoration attempts are employed.