Optic neuropathies

INTRODUCTION — The optic nerve carries the greater than one million axons that derive from the retinal ganglion cells and project to eight visual nuclei. Actually an extension or tract of the central nervous system, not a true peripheral nerve, the conventional designation of the optic nerve applies to that portion of this tract that extends from the eye to the optic chiasm.

This topic will review functional anatomy of the optic nerve and the differential diagnosis of optic nerve pathologies. Specific disorders are discussed in detail separately. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis" and "Nonarteritic anterior ischemic optic neuropathy: Clinical features and diagnosis".)

ANATOMY — The optic nerve has four anatomic segments: the intraocular, intraorbital, intracanalicular, and intracranial sections [1,2].

●The intraocular portion, or the optic disc, consists of the unmyelinated retinal ganglion cell axons and astrocytes. As the nerve exits the globe, crossing the collagenous lamina cribrosa, it increases in diameter as it becomes myelinated by oligodendrocytes.

●The intraorbital segment of the optic nerve is approximately 25 to 30 mm. Within the orbital apex, the optic nerve is surrounded by dura, arachnoid, and pia mater. The subarachnoid space contains cerebrospinal fluid (CSF) continuous with that of the brain and spinal cord. The dural covering fuses with the sclera around the optic nerve and more posteriorly with the periosteum of the optic canal. The nerve courses through the annulus of Zinn, which contains the connective tissue origins of the superior, medial, lateral, and inferior rectus muscles.

●The nerve then passes through the optic foramen into the bony optic canal, which lies posteromedially in the lesser wing of the sphenoid bone, and is approximately 4 to 10 mm in length. The ophthalmic artery and ocular sympathetic nerve fibers also travel through the optic canal.

●Intracranially, the optic nerve courses medially and rises at an angle of 45 degrees toward the chiasm. This segment of the optic nerve is approximately 16 mm in length and lies superior to the cavernous sinus and inferior to the frontal lobe and anterior cerebral and anterior communicating arteries.

The blood supply of the optic disc and nerve is distinct from that of the retina, which is supplied by the central retinal artery. The disc is supplied by anastomosing arterioles supplied by the posterior ciliary arteries, the pial arteriole plexus, and the peripapillary choroid. The intraorbital segment receives blood from perforating branches of the ophthalmic artery, while the intracanalicular and intracranial portions are supplied by pial branches of the ophthalmic, internal carotid, anterior cerebral, and anterior communicating arteries.

CLINICAL FEATURES — Optic nerve lesions usually produce monocular visual loss. Pain is a variable feature that, when present, suggests optic nerve disease. Other features common to optic neuropathy include:

●Afferent pupillary defect if the lesion is unilateral or asymmetric

●Central vision loss (scotoma) on visual field testing

●Dyschromatopsia often out of proportion to acuity loss

●Papillitis on funduscopic examination if the optic disc is involved (picture 1 and picture 2)

●Eventual optic atrophy

The clinical presentation varies with etiology. Many are acute, but some etiologies are associated with a more subacute or even a chronic progressive course. Ophthalmologic examination and magnetic resonance imaging (MRI) of the brain and orbits are often essential to the diagnosis. In other cases, lumbar puncture with spinal fluid examination and other tests are required.

ETIOLOGIES — Optic neuritis is the most common cause of optic nerve disease in younger adults, while ischemic optic neuropathy is the most common etiology in older patients. The clinical features of the more common optic neuropathies are summarized in the tables (table 1 and table 2).

Ischemic optic neuropathy — Ischemic optic neuropathy is more common in patients over age 50. Ischemic optic neuropathy is generally categorized as anterior (affecting the optic disc) versus posterior (retrobulbar) and as arteritic versus nonarteritic. Anterior involvement is usual with both arteritic and nonarteritic ischemic optic neuropathy (AION and NAION). Posterior ischemic optic neuropathy (PION) can also be due to either arteritic or nonarteritic etiologies, but should raise the suspicion of arteritis [3,4]. Nonconventional etiologies, such as acute volume loss, hypotension, and associated surgical procedures (cardiac or spinal surgery) are more common in PION [4-6].

Nonarteritic ischemic optic neuropathy — NAION is the most common form of ischemic optic neuropathy. It is an idiopathic, ischemic insult of the optic nerve head characterized by acute, monocular, painless visual loss with optic disc swelling (picture 3) [7]. Visual loss occurs due to poor perfusion in the circulation of the posterior ciliary artery, which supplies the optic nerve head [8]. Patients are usually older than 50 years and often have hypertension, diabetes mellitus, and other vascular risk factors.

Patients frequently notice the vision loss first upon waking up in the morning [9]. There is usually decreased visual acuity and an altitudinal visual field defect. The disc appears swollen and may have splinter hemorrhages (picture 3). The cup of the involved disc is typically small. If the fellow eye also has a small cup, it is considered to be at risk for future ischemic events. Magnetic resonance imaging (MRI) usually does not show enhancement or signal abnormality in the optic nerve. This is in contrast to optic neuritis, which almost always produces an MRI abnormality [10].

The prognosis for visual recovery is relatively poor (in contrast to optic neuritis). There is no effective treatment; optic nerve decompression is not effective [11,12]. Recurrent events in the same eye are very rare. The cumulative risk of vision loss in the opposite eye is 14.7 percent over the next five years [13]. There is usually an interval of several months or years between these events. Involvement of both eyes in rapid succession strongly suggests arteritis. There is no evidence that antiplatelet therapy reduces the risk of contralateral involvement; however, most patients are treated with antiplatelet therapy on the basis of their underlying vascular risk factors.

NAION is discussed in detail separately. (See "Nonarteritic anterior ischemic optic neuropathy: Epidemiology, pathogenesis, and etiologies" and "Nonarteritic anterior ischemic optic neuropathy: Clinical features and diagnosis" and "Nonarteritic anterior ischemic optic neuropathy: Prognosis and treatment" and "Posterior ischemic optic neuropathy".)

Arteritic ischemic optic neuropathy — Arteritic anterior ischemic optic neuropathy occurs primarily in patients older than 70 years and is usually due to giant cell arteritis (GCA). GCA has a significant association with polymyalgia rheumatica, a constellation of symptoms that includes jaw claudication, proximal myalgias and arthralgias, scalp tenderness, headache, and fatigue along with a significantly elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Funduscopic examination demonstrates a pale, swollen disc, peripapillary hemorrhages, branch or central retinal artery occlusions, or cotton wool spots. Temporal artery biopsy is the gold standard for diagnosis, but treatment with corticosteroids should not be delayed pending biopsy or results [8]. Thrombocytosis has been associated with a higher risk of permanent vision loss in patients with GCA [14]. Binocular involvement occurs in a third of cases, often within the first day.

This topic is discussed separately. (See "Clinical manifestations of giant cell arteritis" and "Pathogenesis of giant cell arteritis" and "Diagnosis of giant cell arteritis" and "Treatment of giant cell arteritis".)

Optic neuritis — Optic neuritis is an inflammatory, demyelinating condition that is highly associated with multiple sclerosis (MS), occurring in 50 percent of individuals at some course of their illness [15-17].

Patients typically present with acute, often painful visual loss, which is usually monocular. Individuals are typically between the ages of 18 and 40 years [15]. Symptoms develop over a few to several days, reaching maximum severity within two weeks [18]. Most cases (two-thirds) are retrobulbar with a normal fundus appearance (picture 1), while one-third have papillitis on presentation (picture 2). Gadolinium-enhanced MRI demonstrates optic nerve inflammation in 95 percent of patients (picture 2) [19]. Visual recovery is common and often complete; most patients achieve better than 20/40 vision at one year [18]. Visual recovery is less likely, but still common in those with more severe visual loss at presentation. The clinical features and diagnosis of optic neuritis are discussed separately. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis".)

Final visual outcomes are not influenced by treatment, but recovery can be hastened by intravenous methylprednisolone [20]. Oral prednisone therapy is not recommended, because of increased risk of recurrent optic neuritis seen in one treatment trial. Patients at high risk for MS, assessed on the basis of MRI, may benefit from immunomodulatory therapy. The prognosis and treatment of optic neuritis is discussed separately. (See "Optic neuritis: Prognosis and treatment".)

Infections — Optic neuritis may complicate meningitis or encephalitis of any cause either as a direct effect of the infectious organism or from a secondary vasculitis [21]. West Nile virus in particular has been reported to produce optic neuritis in association with meningitis [22,23]. Typically, in these conditions, other symptoms and signs of underlying infection, as well as MRI and cerebrospinal fluid (CSF) findings, point to the underlying cause. When the meningitis is more indolent, as with some cases of tuberculosis and cryptococcus, optic nerve involvement may be a primary manifestation [24-26].

Acute viral infections, as well as cat scratch disease and toxoplasmosis and others, can cause an isolated infection of the eye. These typically produce inflammation of the retina along with the optic disc, so-called neuroretinitis [27-31]. Funduscopic examination usually reveals macular edema, in addition to optic disk swelling. Macular exudates form within days, often in a star-shaped pattern, "macular star." This finding helps to distinguish neuroretinitis from optic neuritis. Systemic antibiotics when appropriate and corticosteroids have been reported to produce improvement. (See "Treatment of cat scratch disease" and "Toxoplasmosis: Ocular disease".)

Syphilitic optic neuritis may be monocular or binocular and is associated with vitreal inflammation, a feature that helps to distinguish this from optic neuritis [31,32]. Antibiotic therapy is associated with recovery, but patients may relapse (see "Neurosyphilis"). Lyme disease is an uncertain cause of retrobulbar optic neuritis but may cause papillitis [33,34].

Inflammatory optic neuropathies — Inflammatory optic neuropathies may be due to parainfectious causes, systemic connective tissue disease, and other local or systemic inflammatory conditions.

Parainfectious — Postviral optic neuritis has been associated with measles, mumps, chickenpox, influenza, and Epstein-Barr virus, typically following the clinical infection by one to three weeks [35]. More common in children than adults and more frequently bilateral than optic neuritis, an immune-mediated process is likely. Papillitis, frequently with retinitis, is common, and there may also be a meningoencephalitis with typical MRI and CSF changes. Visual recovery is usually excellent, even with no treatment. Corticosteroids may or may not hasten recovery, but this treatment is reasonable to consider, particularly in cases of bilateral, severe visual loss. Some consider this a forme fruste of acute disseminated encephalomyelitis. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

While there are many case reports of optic neuritis occurring as a postvaccination phenomenon, case-control studies have not confirmed an association between vaccines and optic neuritis or other demyelinating diseases in adults [36].

Bilateral optic neuritis can also occur in the Guillain-Barré syndrome [37]. Papillitis is common in this setting. Published case reports frequently report an antecedent infection with mycoplasma pneumoniae and recovery with treatment of Guillain-Barré syndrome [38,39]. (See "Guillain-Barré syndrome in adults: Treatment and prognosis".)

Sarcoidosis — Optic neuropathy occurs in approximately 5 percent of patients with sarcoidosis and may be the initial manifestation [10,40]. Clinical features are similar to optic neuritis. Bilateral involvement has been reported in 24 to 64 percent [40,41]. The optic disc may have a nodular appearance, representing the granulomatous infiltration. MRI can demonstrate signal abnormality and nerve thickening with gadolinium enhancement that may be generalized, nodular, or meningeal. Other cerebral parenchymal lesions and more widespread meningitis may also be seen on MRI. Visual recovery often follows corticosteroid treatment, but some patients have permanent vision loss [40]. Relapsing vision loss following a short course of corticosteroids for presumed optic neuritis is a clue to this disorder. (See "Neurologic sarcoidosis".)

Chronic relapsing inflammatory optic neuropathy — Chronic relapsing inflammatory optic neuropathy (CRION) is a rare, relapsing autoimmune optic neuritis in which no other known systemic disease can be found; these patients do not have sarcoidosis, lupus, MS, neuromyelitis optica (NMO), or other cause [42,43]. On first presentation, the clinical features are those of optic neuritis, including enhancement of the optic nerve on MRI. In contrast to patients with optic neuritis, tapering glucocorticoid therapy leads to a clinical relapse. In order to stay in remission, patients with CRION require chronic immunosuppression with steroid-sparing agents such azathioprine, methotrexate, cyclophosphamide, or intravenous immune globulin (IVIG). Diagnostic work-up should exclude other systemic, metabolic, toxic, or paraneoplastic causes of optic neuropathy, including serum myelin oligodendrocyte glycoprotein (MOG) and aquaporin 4 (AQP4) immunoglobulin G (IgG) antibody tests.

Systemic autoimmune disease — Optic neuritis is a rare manifestation of other systemic inflammatory or connective tissue disease and usually occurs in the setting of an established diagnosis [44]. The mechanisms and therefore presentations of optic nerve involvement vary with the disorder. In some cases, optic neuritis may represent shared coincidence of autoimmune diseases, rather than a primary manifestation of the systemic disease.

●Systemic lupus erythematosus (SLE). Optic nerve involvement occurs in approximately 1 percent of patients with SLE and may be due to vasculitis or to thrombosis secondary to antiphospholipid antibody syndrome [44-46].

●Sjögren's disease (SjD). Optic neuritis may be the presenting symptom of this disorder [44,47]. In one eight-year, retrospective review of 82 patients with SjD, 16 percent had optic neuritis [48].

●Granulomatosis with polyangiitis. Extension of inflammation in the sinus and parasinus areas can produce optic neuritis, usually with other orbital signs [49].

●Behçet syndrome. Despite producing severe meningitis and uveitis, optic neuritis is a rare complication in this disorder [44,50].

●Inflammatory bowel disease. The higher than expected incidence of optic neuritis in these disorders may reflect coincidence of autoimmune diseases [51,52].

Paraneoplastic disease — Paraneoplastic optic neuritis has been described in a few reports, usually in association with paraneoplastic encephalomyelitis or retinitis and small cell lung cancer [53-55].

Compressive optic neuropathies — In this category of disorders, gradual vision loss is the more usual presentation, as expected with slowly growing lesions; however, the presentation can be acute. Pain is variable. MRI of the brain and orbits will confirm or rule out diagnoses associated with compressive optic neuropathy. Corticosteroid therapy may produce early visual improvement due to reduction in edema, and therefore may be misleading as to the underlying etiology.

Neoplasia — A variety of tumors can produce optic nerve compression. Sellar and parasellar masses (craniopharyngioma, meningioma, or pituitary adenoma), optic nerve sheath meningiomas, and metastatic lesions are included in the differential diagnosis.

Tumors, particularly optic nerve gliomas associated with neurofibromatosis, but also lymphoma and other hematologic malignancies, can also infiltrate rather than compress the optic nerve [56,57].

Others — The optic nerve can be compressed by other, non-neoplastic processes within the orbit or subarachnoid space. These include:

●Dysthyroid ophthalmopathy (see "Clinical features and diagnosis of thyroid eye disease")

●Carotid-ophthalmic artery aneurysms

●Abscess

Idiopathic intracranial hypertension or pseudotumor cerebri can lead to a bilateral optic neuropathy. Patients usually present with headache sometimes accompanied by horizontal diplopia. Vision loss may be slowly progressive or may appear abruptly. Funduscopic examination reveals papilledema. Visual field defects are characterized by enlarged blind spot and/or generalized constriction. If untreated, patients may become blind. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis".)

Genetic causes — Two of the more common of the genetic causes of optic neuropathy are Leber hereditary optic neuropathy and Kjer's disease.

Leber hereditary optic neuropathy — In this disorder, vision loss is subacute and painless, with sequential involvement of both eyes over a period of weeks to months.

This disorder affects young males predominantly (80 to 90 percent of patients) and is inherited through a mitochondrial DNA mutation. Three mutations at positions 11,778, 3460, and 14,484 are responsible for greater than 90 percent of all cases of Leber [58]. These genes are involved in complex I of the mitochondrial respiratory chain [59].

Funduscopic examination usually shows circumpapillary telangiectasia, but up to one-third of patients can have a normal appearing disc. Nerve fiber layer swelling around the disc can be seen, although fluorescein angiography does not show leakage from the disc or papillary area [60]. Central vision is affected more severely. MRI can show signal abnormality in the optic nerves, but enhancement usually does not occur [10,61,62]. Prognosis for recovery varies depending on the mutation [58].

This topic is discussed in more detail separately. (See "Neuropathies associated with hereditary disorders", section on 'Leber hereditary optic neuropathy'.)

Kjer-type autosomal dominant optic atrophy — This entity primarily affects children in the first decade of life with slowly progressive, bilateral loss of vision. As with other optic neuropathies, there is pallor of the optic disc, cecocentral scotoma, and color vision loss. The OPA1 gene located on chromosome 3q28 has been implicated in the majority of patients with dominant optic atrophy [63,64].

Toxic and metabolic causes — Toxic metabolic causes of optic neuropathy include an extensive list of possible agents. Typically, involvement is bilateral; onset may be abrupt or slowly progressive.

Drugs and toxins — A number of toxins and drugs have been associated with optic neuropathy (table 3). In many cases of toxin exposure, the visual loss is severe and permanent [65].

Patients experiencing vision loss as an adverse effect of medications can have limited impairment if the vision loss is detected early and the drug discontinued [65]. Most of these medications are believed to have direct toxic effects on the optic nerve [66]. Of these, the risks associated with ethambutol are perhaps best characterized [67]. (See "Ethambutol: An overview", section on 'Visual changes'.)

Other medications are believed to affect the optic nerve indirectly through other mechanisms:

●Infliximab is believed to cause an autoimmune optic neuritis [68,69]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

●Several cases of severe optic neuropathy in patients treated with bevacizumab for glioblastoma were summarized in a 2009 report [70]. The mechanism is uncertain; however, vascular etiologies, drug-induced sensitivity to radiation, and direct toxic effects are possible.

●Sildenafil and other drugs prescribed for erectile dysfunction have been reported to produce a NAION [71,72]. An association is not proven; however, the close temporal proximity of drug administration and symptoms in these cases suggests cause and effect. (See 'Ischemic optic neuropathy' above.)

●Amiodarone's association with optic neuropathy remains somewhat controversial [73,74]. Some cases appear indistinguishable from NAION. Other reported cases of a more insidious onset with slow progression and simultaneous bilateral involvement suggest a more direct toxic effect. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Optic neuropathy'.)

●Several cases of optic neuritis have been reported to be associated with immune checkpoint inhibitors. This class of medications is used in oncology for the treatment of a variety of cancers. Because of the mechanism of action of these drugs, it is presumed that the optic neuritis triggered by these medications is autoimmune in nature and possibly responsive to treatment with steroids [75].

Nutritional deficiencies — Nutritional deficiencies are presumed to have played a role in endemic optic neuropathy reported under conditions of deprivation, such as in prisoners of war (eg, Cuba in the 1990s, southeast Asia during World War II) [76-78]. An endemic optic neuropathy in Tanzania described in several reports from 1988 through 2013 has also been attributed to nutritional deficiencies [79-82].

Specific deficiencies of vitamins B12, B1, and folate have been implicated. Most nutritional optic neuropathies appear to be exacerbated by tobacco and possibly alcoholism (tobacco-alcohol amblyopia) [83]. Vision loss may be unilateral or bilateral, and can have an acute, subacute, or slowly progressive presentation [78]. MRI is typically normal [10,84]. Early vitamin supplementation and/or smoking cessation have been anecdotally associated with visual recovery, but this is not guaranteed.

Radiation — Radiation-induced damage of the optic nerves and/or chiasm can occur 6 to 24 months after radiation therapy, usually for nasal carcinoma. In one series of 219 patients who received radiotherapy for carcinomas of the nasal or paranasal region, retinopathy occurred in seven, optic neuropathy with blindness in eight, and chiasm damage with bilateral visual impairment in one [85]. These complications are rare with doses of radiation less than 50 Gy. The vision loss is usually slowly progressive, and there is no treatment proven to be effective. MRI may show signal abnormality with enhancement in the optic nerve. (See "Delayed complications of cranial irradiation", section on 'Optic neuropathy'.)

Trauma — Closed head injury may damage the optic nerve, usually affecting the intraorbital or intracanalicular segments. The mechanism may be contusion or hemorrhage; rarely, the optic nerve is transected or avulsed [86,87]. In the latter case, vision does not improve. Otherwise, the prognosis depends upon the extent of the injury; approximately half of patients recover. Imaging studies and an ophthalmologic consult are indicated to evaluate for pathologies (optic nerve sheath hematoma, orbital hemorrhage) that require surgery. Surgical decompression and high-dose corticosteroids are sometimes used but are not of proven benefit [88-90].

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●Basics topic (see "Patient education: Optic neuritis (The Basics)")

SUMMARY

●An optic nerve lesion produces visual loss, usually monocular. Other clinical features can include dyschromatopsia, pain (especially with eye movement), and papillitis, depending on the etiology. (See 'Clinical features' above.)

●The potential causes of optic neuropathy are diverse (table 1). (See 'Etiologies' above.)

●Optic neuritis is the most common cause of optic nerve disease in younger adults, while ischemic optic neuropathy is the most common etiology in older patients. (See 'Ischemic optic neuropathy' above and 'Optic neuritis' above.)

●Associated demographic and clinical features, including age and gender; the presence of pain, papillitis, or bilateral involvement; and the acuity of presentation, are useful to identify the most likely etiology (table 2).

●Giant cell arteritis (GCA) should always be considered in the differential diagnosis of optic neuropathy in individuals over 50 years because of its potential for permanent vision loss, which can be prevented by prompt intervention. (See 'Arteritic ischemic optic neuropathy' above.)