Cranial Nerve II: Optic Nerve and Visual System

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; greater than 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. 5.4 ). 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.

Glaucoma has other forms besides POAG; it 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 available for this condition at the present time.

Central retinal artery occlusion (CRAO) results from interruption of the central retinal artery circulation with resultant 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) or transient monocular blindness (TMB or amaurosis fugax ) often herald retinal infarcts and represent temporarily compromised flow of the inner retinal arteries usually by retinal emboli.

Patients who present within the first few 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% CO ₂ to promote arteriolar dilation, 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, become 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 15 , “Ischemic Stroke”). Cardiac 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.

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 suffering vision loss from a nonarteritic ischemic optic neuropathy (NAION) 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. 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 NAION is extremely rare. In most cases, NAION 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. Medications may also play a role in causing NAION. Specifically, nocturnal hypotension from taking blood pressure medications at night, phosphodiesterase type 5 inhibitor medications such as sildenafil, and amiodarone have been associated with optic nerve injury as seen in NAION.

There is no proven treatment for NAION, although oral prednisone and anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab have been tried. Unfortunately, there is no treatment that has been proven to be beneficial. There is a 30% risk of eventual involvement of the fellow eye. Strategies to reduce this risk have focused on identifying and treating cerebrovascular risk factors, treating sleep apnea, preventing systemic hypotension, and avoiding drugs, such as sildenafil, which may be associated with a 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 ( Fig. 5.5 ), in contrast to the hyperemic swelling seen in NAION. 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/hr), 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 urgently treated with high-dose steroids, typically intravenous methylprednisolone, especially if the patient has visual symptoms. TA, once initially treated with parenteral corticosteroids, is transitioned to oral prednisone tapered over many months. Other antiinflammatory medications, especially methotrexate, have been used in those at high risk for corticosteroid complications, but the efficacy of nonsteroidal agents has been questioned. The FDA has approved the use of tocilizumab (interleukin-6 [IL-6] inhibitor) in the management of GCA after studies have found that concomitant use with prednisone may allow for earlier steroid taper compared with patients who took placebo and prednisone. Steroid dosage is gradually reduced over time, with the patient closely monitored for disease recrudescence by following symptoms and the ESR or CRP.

Papilledema 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 compression of cranial nerve VI [abducens nerve] from increased ICP; see Chapter 6 ). When visual loss occurs, it starts with blind spot enlargement, 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 pathophysiologic mechanisms are associated with papilledema, including CNS tumor with mass effect or edema, obstructive hydrocephalus, meningitis, certain medications (e.g., “cyclines” such as tetracycline, doxycycline, and minocycline, lithium, vitamin A, retinoic acid, isotretinoin, and prednisone), 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 ). 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, three surgical options exist: optic nerve sheath fenestration, cerebral venous sinus stenting, 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, autofluorescence, 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; however, patients are not usually aware of the field deficit because it is usually a long-standing process. Optic nerve drusen can give the appearance of papilledema and is one of the causes of pseudopapilledema.

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. Optic nerve hypoplasia, which is a congenitally smaller optic nerve, can be isolated or be part of a syndrome. Septo-optic dysplasia combines bilateral optic nerve hypoplasia with dysgenesis of midline brain structures, often with pituitary dysfunction. Children of mothers who are type 1 diabetics and up to a quarter of patients with fetal alcohol syndrome will have disk hypoplasia with associated inferior visual field loss, among other ocular manifestations. Superior segmental optic nerve hypoplasia is segmental thinning of the superior part of the optic nerve, and there is a corresponding field defect inferiorly. This is not associated with septo-optic dysplasia. 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 but 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, ganglion cell layer, and total macular thickness. These measurements can help to define subtle cases of disk edema or atrophy and changes in disk appearance over time, along with evaluation of the macula.

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. 5.6 ). Examination may also demonstrate loss of central acuity, contrast sensitivity, and color perception in the affected eye.

Initially, funduscopic appearance of the affected disk is normal, 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 disease or neuromyelitis optica (NMO), once considered a more aggressive form of MS, defined by episodes of optic neuritis and transverse myelitis. The immunopathogenesis and treatment is distinct from MS, and patients with vision loss from NMO must be treated aggressively because this does affect their final visual outcome. Initial treatment recommendations for vision loss are parenteral corticosteroids, plasmapheresis, and/or intravenous immunoglobulin (IVIg), with long-term immunosuppressive agents, such as azathioprine and rituximab, used to prevent relapses. The presence of a hallmark serum immunoglobulin (NMO-IgG directed against the aquaporin-4 protein [AQP4]) is central to diagnosis. A minority of patients seronegative for AQP4 have antibodies against myelin oligodendrocyte glycoprotein (MOG) and have an overlapping clinical syndrome with NMO.

Optic neuritis can occasionally be idiopathic, with prolonged surveillance never leading to a diagnosis of MS. This is called clinically isolated syndrome. 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 changes 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 these clinical settings: as bilateral visual loss after major surgery (cardiac or spine); and as unilateral visual loss, either as a complication of TA or of peripheral vascular disease. It can also occur in the setting of shock or hypotension. 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 on 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.

Genetic, nutritional, 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, genetic 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 typically 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. The most common mutations are: 11778 (which has the worst visual prognosis), 3460, 15257, and 15812. 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 B ₁₂ , which, if deficient, can precipitate LHON. Several studies have also discussed the effectiveness of idebenone. LHON is an attractive candidate for gene therapy; there are now clinical trials evaluating the effectiveness of this 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 is also caused by defective mitochondrial metabolism, but the four known mutations are inherited in an autosomal dominant manner. Additional, related mutations can cause optic atrophies with X-linked and recessive inheritance.

Hypovitaminosis, especially thiamine (B ₁ ), folic acid, and cyanocobalamin (B ₁₂ ), can produce a progressive bilateral nutritional optic neuropathy. Hypovitaminosis is seen in smokers and from alcoholism with poor nutrition (there is an additive risk from the toxicity of smoking and alcohol). It is also seen from poor nutrition with 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 and color vision testing are recommended for patients taking ethambutol or isoniazid. 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 collapsin response-mediator protein 5 (CRMP-5). Treatment is centered on identifying and treating the underlying cancer.

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 may be reversible when compression is relieved before pallor develops. Additional findings of proptosis and limitation of extraocular movements suggest 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, optic nerve sheath meningioma, and optic nerve glioma. Cavernous hemangiomas are typically treated conservatively by observation unless there is vision loss. Optic nerve meningioma when causing vision loss can be removed surgically. Fractionated stereotactic external beam radiation can limit tumor growth. Glioma of the optic nerve cannot be easily resected without potentially compromising the optic nerve. Therefore 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. Given the possibility of rare, aggressive gliomas requiring early excision, frequent reimaging is indicated 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 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, diplopia, periorbital edema, and, if untreated, loss of sight. 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. Pain is out of proportion to expected findings on exam, and 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, remains 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 previously, 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, such 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.