Optic neuritis

Differential diagnosis
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There are 2 problems in the diagnosis of optic neuritis: ascertaining the cause of visual loss and determining whether there is demyelination outside the optic nerves. Acute or subacute visual loss is most commonly caused by optic neuritis, ischemic vascular disease, or increased intracranial pressure (Glaser 1990). Clinical differentiation from optic neuritis is sometimes impossible, but some patterns are characteristic.

Ischemic optic neuropathy.In ischemic optic neuropathy, the loss of vision is usually acute and painless (in 90%), and it may not improve. Vision loss occasionally progresses over several days with an unremitting course, but this is not typical. The optic nerve is swollen, and there is characteristically a unilateral inferior or superior attitudinal defect. Patients are older (40 to 80 years of age vs. 20 to 45 years of age). In optic neuritis, onset is over hours or days, rarely minutes, but not acute. Pain is much less common with ischemic optic neuropathy (12%) than with optic neuritis (92%) (Swartz et al 1995). The optic nerve is usually swollen in ischemic optic nerve disease, but only in one third of cases during optic neuritis. Severe disc edema, arterial attenuation, severe hemorrhages, or macular exudates argue against optic neuritis. The field defect is more specific for ischemia if there is a sharp border along the horizontal visual field meridian (Keltner et al 1993; Gerling et al 1998). In optic neuritis, the scotoma is centered on the fixation point and has a sloping border and poorly defined temporal and central margins. The pupillary light reaction is diminished on the side of the lesion. The amplitude of the pattern electroretinogram N95 peak is decreased in ischemic optic neuropathy, but not in optic neuritis. Severe and lasting visual loss is more common with ischemic disease, and cerebrospinal fluid is normal. This ischemic disorder has been mistakenly treated with interferon when “optic neuritis” was associated with brain lesions in the centrum semiovale (Horton 2002). Therapy with high-dose interferon-alpha has been linked to acute ischemic optic neuropathy, but interferon-beta has not.

 Vascular causes of visual loss include retinal artery occlusion, branch retinal artery occlusion (Susac), diabetic macular ischemia, and retinal vein occlusion

Neuromyelitis optica (Devic disease).This is a demyelinating disease of optic nerve and spinal cord. Seventy percent of patients have antibodies directed against the aquaporin-4 protein on the foot processes of astrocytes that regulates water flow at the blood-brain barrier. Optic nerve demyelination and destruction is often quite severe in this disorder, is often associated with cord lesions, and is associated with other autoimmune diseases. There is considerable overlap with CNS Sjögren syndrome (Javed et al 2008).

Temporal arteritis.Temporal arteritis should be suspected if eye or temporal pain or tenderness is present and visual loss is complete, especially in older patients. The disc is typically swollen, and edema may be segmental. Disc swelling, chalky white disc color, flame hemorrhages, and cotton-wool spots are more common than in optic neuritis.

Increased intracranial pressure.Increased intracranial pressure causes papilledema. Initially, there is transient visual obscuration or no visual loss at all. The blind spot may be enlarged. Eye pain is not usual, but headache, nausea, vomiting, and neurologic signs such as sixth nerve paresis may be present. There is bilateral elevation of the fundus and retinal hemorrhages, but reactions to light are normal. Decreasing the intracranial pressure can usually prevent visual loss.

Causes of visual loss that can mimic optic neuritis:

Acute ischemic optic neuropathy. (Above).

Aneurysm of intracranial blood vessels. Aneurysm of intracranial blood vessels, such as the ophthalmic artery, compressing the nerve.

Atopic optic neuritis. This is associated with atopic dermatitis and high IgE and possibly atopic myelitis.

Bee sting of the eye. Rarely, true optic neuritis will appear days to weeks after a bee or wasp sting.

Behçet disease. Optic neuropathy is relatively rare, and there is associated uveoretinitis and perivascular infiltrates (Kansu et al 1989). It responds to glucocorticoid therapy.

Carcinomatous optic neuropathy. It is typically associated with adenocarcinoma of breast and lung, lymphoma, and melanoma.

Central serous retinopathy. The disc is normal, but macular edema decreases visual acuity; this usually resolves spontaneously.

Cerebellar degeneration. Some hereditary forms and Kearns-Sayre syndrome exhibit visual symptoms. The ocular lesion is a pigmentary retinopathy; optic neuritis is rare (Gross et al 1992).

Chemotherapy. Ara-C, cisplatin, 5-fluorouracil, and possibly tamoxifen.

Chronic relapsing inflammatory optic neuritis (CRION). CRION is characterized by relapses that occur with rapid steroid withdrawal, suggesting this is a form of neuromyelitis optica and not the idiopathic form of optic neuritis (Kidd et al 2003; Plant 2008).

Compression. Compression is insidious, then discovered by patient, and then slowly progressive. From tumor (eg, meningioma, pituitary, lymphocytic leukemia, orbital lymphoma), cellulitis, eosinophilic granuloma, mucocele of the sphenoid sinus, osteopetrosis, tuberculoma, arachnoiditis, cavernous malformation of the optic nerve, or paraclinoid or fusiform aneurysm. Compression can reduce vision and decrease the amplitude and slow the latency of visual evoked potentials.

Connective tissue diseases. These are seldom linked to idiopathic optic neuritis (rare in systemic lupus erythematosus) (Drosos et al 1989). However, Sjögren syndrome and lupus spectrum disease are strongly linked to neuromyelitis optica/Devic disease (see below). The occasional coincidence of neuritis (“autoimmune optic neuropathy”) and connective tissue disease (Dutton et al 1982) may be from occlusive vasculopathy, especially with the presence of anticardiolipin antibodies, or from compression, as with Wegener granulomatosis. These cases often respond to glucocorticoid therapy, but require very slow oral steroid taper (Lin et al 2009).

Cranial arteritis, giant cell arteritis, temporal arteritis. This can affect the posterior optic nerve, without papilledema, in 70- to 80-year-old patients. Associated with devastating visual loss: temporal pain, fever, weight loss, headache, fever, elevated sedimentation rate, and polymyalgia rheumatica.

Crohn disease. This is rarely associated with optic neuritis

Demyelinating diseases.

(a) Optic neuritis is often the first sign of multiple sclerosis, and the pathology of the optic nerve lesions can be similar or identical. Optic neuritis as defined here, however, is isolated to the optic nerves without dissemination in time and space, and CSF oligoclonal bands are less common in optic neuritis.

(b) Devic disease, or neuromyelitis optica (NMO), is a demyelinating, sometimes necrotic, inflammatory disease of the spinal cord and the optic nerves. This disease is more common in East Asian and South American than in European populations. Compared to idiopathic optic neuritis, Devic disease is clinically more severe and rapid, pain is less common, and the damage in the optic nerves is more diffuse and often total, more posterior, and can involve the chiasm--perhaps more than in idiopathic neuromyelitis optica. It is more likely to recur, often quickly. There is significant axonal and oligodendroglial loss and sometimes necrosis. OCT shows marked loss of retinal nerve fiber layers. The first symptoms can be optic neuritis (76%), transverse myelitis (13%), or both (10%), but optic and cord symptoms often coexist within a month. Cerebrospinal fluid protein is high compared to multiple sclerosis and 75% have pleocytosis, but only 25% to 40% have oligoclonal bands. Serum IgG directed against the aquaporin 4 water channel (NMO-IgG) is a marker for NMO. There is significant overlap with connective tissue disease, including CNS Sjögren syndrome (Javed et al 2008). Devic disease may best be treated with IVIG and plasmapheresis.

(c) Postvaccinal or postinfectious reactions cause inflammatory demyelination that is localized (eg, transverse myelitis, optic neuritis) or diffuse (eg, encephalomyelitis, acute disseminated encephalomyelitis). The symptoms develop after upper respiratory tract infections (virus or mycoplasma) or vaccinations (eg, rabies). Other associations are based on case reports and may be spurious, but include optic neuritis after infection with hepatitis B and C, varicella, and variola (smallpox), CNS chlamydia pneumoniae, and after vaccination with BCG, meningococcus, Clostridium tetani, influenza, and variola (Fenichel 1982). There are rare reports of optic neuritis following vaccination for hepatitis A and B. Importantly, most studies show no association with vaccinations, including influenza and anthrax. Live virus vaccinations, however, activate different immune mechanisms. Yellow fever vaccinations, for instance, increase multiple sclerosis exacerbations 9-fold.

Diabetic papillopathy. Typically in young patients with mild visual loss and disc edema; usually resolves within 3 months.

Drugs and toxins. These can damage bilateral optic nerves or retinas and cause acute or insidious bilateral visual loss. These include antineoplastic agents (Ara-C, carboplatin, cisplatin, 5-fluorouracil, nitrosourea, paclitaxel, vincristine), amiodarone, carbon monoxide, chloramphenicol, chlorpropamide, cimetidine, clioquinol, cyanide (cassava roots), cyclosporine, dapsone, desferrioxamine, disulfiram, linezolid (oxazolidinone antibiotic), ethambutol, ethylene glycol (antifreeze), isoniazid, methanol, phenothiazines, possibly quinolone antibiotics, sildenafil (transient blue vision, but also anterior ischemic optic neuropathy), styrene vapor, tacrolimus (FK-506), trichloroethylene, and toluene (from glue sniffing, solvent abuse) (Kerrison 2004). One case was seen with imatinib, a tyrosine kinase inhibitor.

Interferon-alpha causes showing of visual evoked potentials over a 12-month period in patients with chronic viral hepatitis (3 million units subcutaneously 3 times per week) (Moschos et al 1998). This appears to be a direct effect of type I interferon in this patient population, but there could be additive dysfunction from virus-induced cytokines, products of damaged liver cells (possibly further damaged by interferon), or indirect effects of interferon such as temperature elevation. Also seen in this patient population, especially those with hypertension and diabetes, are retinal hemorrhages, cotton wool spots, and macular edema. These are not retinal nerve fiber layer infarcts. Routine screening is not recommended in this group, or in patients with multiple sclerosis.

Soluble tumor necrosis factor receptor-immunoglobulin fusion protein that captures tumor necrosis factor (etanercept) and antibodies to tumor necrosis factor (adalimumab, infliximab) may trigger optic neuritis, as well as multiple sclerosis.

Drusen of optic nerve. Autosomal dominant, hyaline bodies in optic nerves cause loss of peripheral vision.

Dysthyroid optic neuropathy. Secondary to compression of the optic nerve at the orbital apex by enlarged recti muscles.

Eales disease (primary perivasculitis of the retina, angiopathia retinae juvenilis, periphlebitis retinae). This is a syndrome of retinal perivasculitis and recurrent intraocular hemorrhages, is infrequently associated with neurologic abnormalities (7 of 17 patients) (White 1961; Atabay et al 1992). The highest prevalence is in India.

Glaucoma.Glaucoma can cause painful acute visual loss or chronic loss.

Glioma or pituitary tumors. These infiltrate the optic pathways or compress the optic nerve.

Granulomatous disease. Sarcoidosis or chronic relapsing inflammatory optic neuropathy can be very painful. MRI lesions resolve with glucocorticoids.

Guillain-Barré syndrome. Guillain-Barre syndrome is associated with slowed VEPs in 16% (Gungor et al 2011).

Hereditary causes. Dominant optic atrophy of Kjer; Leber hereditary optic neuropathy.

Herpes zoster ophthalmicus. MRI shows peripheral enhancement of the optic nerve sheath. Herpes simplex virus can cause acute retinal necrosis.

Hysterical blindness.

Increased intracranial pressure(see pseudotumor).

Infarct(see acute ischemic optic neuropathy).

Infection and inflammation contiguous to the optic nerve. This can be associated with symptoms of optic neuritis (Chan 2002). Direct damage can be caused by tuberculosis, sarcoidosis, fungus such as aspergillus, cryptococcus, mucor (mucormycosis), toxoplasma gondii; Lyme disease, Lyme disease (Borrelia burgdorferi), syphilis (Lesser et al 1990; Jacobson et al 1991), mycoplasma pneumonia (Nadkarni and Lisak 1993); cysticercosis, toxocariasis; anthrax, bartonellosis, borreliosis, brucellosis, cat-scratch disease (Bartonella henslae), Coxiella burnetii (Q fever), ehrlichiosis, familial Mediterranean fever, leprosy, malaria, meningococcal infection, purulent leptomeningitis, tularemia, typhoid, or Whipple disease (Tropheryma whipplei). Inflammation of the paranasal sinuses seldom causes optic nerve inflammation. These infections can cause relatively acute or progressive ocular symptoms (viruses below).

Infiltration by leukemia, lymphoma, or glioma (see tumor).

Inflammatory bowel disease(Ernst et al 1991).

Iritis.

Leber hereditary optic neuropathy. In men (90%), usually 15 to 25 years old, this mitochondrial syndrome causes sequential attacks of painless optic neuropathy that are associated with multiple sclerosis-like symptoms and diffuse MRI abnormalities (Harding et al 1992). In men, when diffuse white matter lesions are not present, the affected optic nerves show abnormalities on short-term inversion recovery MRI (Kermode et al 1989). The initial symptom is a central scotoma, often unilateral but eventually bilateral, within weeks. Visual loss is permanent and untreatable in this familial disorder.

Lyme disease. This is occasionally associated with unilateral or bilateral optic neuritis or ischemic optic neuropathy, in addition to retinal vasculitis. Visual evoked potentials can confirm CNS involvement. However, without proximate evidence of erythema chronicum migrans or a tick bite, even in endemic areas, Lyme titers are not justified (Jacobson 2003).

Lymphoma. This can be primary or secondary.

Maculopathy or macular degeneration(degenerative, hereditary, paraneoplastic, toxic). Distortions are detected with an Amsler grid, and central vision is reduced.

Metastasis. This is the most common intraocular malignant tumor.

Migraine. Auras evolve over minutes as spreading depression disturbs the function of occipital lobe neurons (“retinal migraines”). Complicated migraines can cause infarcts, including anterior ischemic optic neuropathy.

Multiple sclerosis.

Neuroretinitis. This is a form of papillitis often seen with infections and characterized by associated deposits of lipids and protein. These deposits radiate from the macula and form a stellate pattern at the macula or a half star between the macula and the disc. The "macular star" is formed as fluid from leaking disc capillaries accumulates within the Henle layer around the fovea. The macular star may take up to 2 weeks to form after the onset of papillitis. The symptoms are similar to those in typical optic neuritis, but neuroretinitis seldom progresses to multiple sclerosis (Parmley et al 1987).

Nutritional neuropathy. This includes Jamaican and Tanzanian neuropathy and Cuban epidemic neuropathy as well as vitamin B12 and folate deficiency. It often follows a viral illness such as mumps.

Occipital lobe lesions.

Ocular pseudotumor.

Optic nerve glioma. "Benign" glioma of childhood or pilocytic astrocytoma; malignant glioblastoma is more common in adults.

Optic perineuritis associated with orbital pseudotumor.

Orbital cellulitis.

Papilledema. Papilledema is from increased intracranial pressure, and it causes swelling of the peripapillary retinal nerve fiber layer. It is differentiated from papillitis, which is usually unilateral and causes rapid visual loss, afferent pupillary defect, pain, cells in the vitreous, disc swelling and loss of the central cup, and retinal exudates or a macular star. It is caused by interruption of axoplasmic flow.

Paraneoplastic. Visual disorders are linked to antibodies to CV2 protein or to optic neuritis collapsin response-mediator protein 5 (CRMP-5-IgG). The latter is associated with bilateral optic neuritis, vitreous inflammation with CD4 lymphocytes, CSF oligoclonal bands, and occasionally with extensive or patchy cord lesions (Pittock and Lucchinetti 2006). Seen with small cell lung, renal, thymic, or thyroid cancer. Neurologic findings with other paraneoplastic disorders are diverse.

Pars planitis (uveitis behind the iris) and perivenous sheathing. These are inflammatory changes of the retina, more common in multiple sclerosis than in normal controls (Kurtzke 1970) and often associated with optic pallor in multiple sclerosis (Bamford et al 1978). Pars planitis increases the risk of developing multiple sclerosis alone by 16%, and the risk of multiple sclerosis or optic neuritis by 20% (Malinowski et al 1993). Fluorescein leakage on angiography also increases the risk for multiple sclerosis. Other causes of uveitis include bacterial, viral, and toxoplasmosis infection. Uveomeningeal complaints are seen in Wegener granulomatosis, sarcoidosis, Behçet disease, Vogt-Koyanagi-Harada syndrome, and acute posterior multifocal placoid pigment epitheliopathy (Brazis et al 2004). Uveitis can be bilateral, and the eye with uveitis is usually the one affected by optic neuritis. Optic perineuritis is seen with Wegener granulomatosis.

Pseudotumor cerebri (idiopathic intracranial hypertension, benign intracranial hypertension). Causes bilateral disc swelling and an enlarged blind spot, versus the central scotoma seen in optic neuritis.

Radiation necrosis. This may be treated with corticosteroids and hyperbaric oxygen.

Retinal detachment. Retinal detachment and other retinal lesions can cause monocular metamorphopsia (wavy distorted images) and flashing lights or bursts of color.

Retinitis. Retinitis causes abnormal P50 and N95 electroretinogram potentials because of macular dysfunction. In optic neuritis, typically only the N95 is abnormal.

Retinopathy. Retinal disease can occasionally cause delayed visual evoked potentials, sometimes with normal amplitudes, and could be confused with optic neuritis. Vascular lesions, including diabetic macular ischemia, and retinal detachment, macular disease (central serous retinopathy, cystoid macular edema), paraneoplastic (cancer with anti-recoverin; melanoma with anti-rod bipolar cell antibodies), and disease of the outer retina (acute idiopathic blind spot enlargement, multiple evanescent white-dot syndrome). Acute zonal occult outer retinopathy, in young white women, is associated with multiple white matter lesions in 12% and sometimes with multiple sclerosis (Hintzen and van den Born 2006).

Sarcoidosis causing optic neuropathy(not optic neuritis) (DeBroff and Donahue 1993). Often responds to glucocorticoid therapy.

Sjögren syndrome. This involves the nervous system in 20% of cases; optic neuropathy is present in one fourth of cases with CNS involvement (Delalande 2004). It can also cause iridocyclitis. Patients older than 50 years of age with the onset of optic neuritis should be screened for Sjögren syndrome. There may be overlap with Devic disease, and the serum autoantibody marker, NMO-IgG, should be tested.

Subacute myelo-optic neuropathy. From halogenated hydroxyquinolines, including Entero-Vioform, diodoquin, and clioquinol. Patients with blindness are likely to have long lasting motor and sensory disruption.

Susac syndrome. This endotheliopathy causes occlusion of the brand retinal vessels, away from the optic disc.

Syphilis. Syphilis can causeoptic neuritis and perineuritisas well as keratitis, uveitis, vitreitis, and chorioretinitis.

Thyroid ophthalmopathy.

Tobacco-alcohol amblyopia.

Toxins (see drugs).

Trauma. This can be direct or after anterofrontal deceleration.

Tumor. Tumors include germinoma, glioblastoma, lymphoma, meningioma (may be bilateral in optic sheath). Others include carcinomatous meningitis, disseminated leukemia or lymphoma, and direct metastasis (breast, lung). Tumors can also generate oligoclonal bands (see infiltration).

Uremic optic neuropathy. Acute renal failure can cause bilateral disc edema and visual loss, sometimes reversed with dialysis and corticosteroids.

Uveitis. Intermediate uveitis, pan uveitis (see Clinical manifestations section).

Vaccination(see demyelination and postvaccinal encephalomyelitis).

Vasculitis. Temporal arteritis, cranial arteritis, Churg-Strauss syndrome(ciliary arteritis causing optic atrophy) is usually painful.

Viruses or viral encephalitis. There are case reports linking viruses to direct damage of the optic nerve. These include measles, mumps, rubella; chickenpox, chikungunya, coxsackie B5, cytomegalovirus, dengue fever (hemorrhagic), echovirus type 5, Epstein-Barr virus, hepatitis A and B, herpes zoster, human herpes virus-6B, HIV, HTLV-1, infectious mononucleosis, parvovirus, varicella, and variola (Farris and Pickard 1990; Chan 2002). West Nile virus can sometimes cause bilateral optic neuritis, but the predominant lesions are hemorrhage, vitreitis, chorioretinitis, uveitis, and occlusive retinal vasculitis. Some cases of optic neuritis follow the virus infection by a month, suggesting a postinfectious encephalomyelitis or virus-induced optic neuritis. Influenza infections are associated with optic neuritis in individual reports.

Vitamin B12 deficiency. This causes subacute combined degeneration, results in bilateral centrocecal scotomata (typical for nutritional/toxic damage) and optic atrophy (Glaser 1990; Sedwick 1991). A deficiency of B vitamins, plus a history of tobacco smoking, appears to cause bilateral optic neuropathy, as discovered in Cubans. A possibly related disorder affects 2% of young adults in Dar es Salaam, Tanzania. Biotinidase deficiency causes optic atrophy (biotin is vitamin B7).

Vitreoretinal traction.

Vogt-Koyanagi-Harada.Granulomatous disease can present with optic neuritis.

Wolfram syndrome. This is optic atrophy with familial juvenile-onset diabetes mellitus, diabetes insipidus, sensorineural deafness, and other neurodegenerative features. The gene mutation in WFS1 is on chromosome 4p16. MRI shows absence of the normal high signal of the posterior lobe of the pituitary, and atrophy of the optic nerves, chiasm, and tracts, plus atrophy of the cerebral cortex, cerebellum, hypothalamus, and brain stem. The brain shows severe degeneration of these areas and severe loss of neurons in the lateral geniculate, the paraventricular and supraoptic nuclei of the hypothalamus, and the basis pontis. In addition, there is widespread axonal dystrophy with axonal swellings in the pontocerebellar tracts, the optic radiations, the hippocampal fornices, and the deep cerebral white matter (Shannon et al 1999).

Warning signs or “red flags” that optic neuritis is not the correct diagnosis include optic atrophy with no history of demyelinating disease, severe disc edema with vitreous retraction, macular exudates, disc hemorrhage, history of cancer, rapid bilateral loss of vision, complete or painless loss of vision and light perception with no early recovery, atypical fundus exam (atrophic or swollen optic nerve head; retinal abnormalities), no pain, severe pain for more than 2 weeks, progressive loss over more than 2 weeks, and no recovery after 3 weeks of symptoms (Hickman et al 2002). The neuromyelitis optica spectrum is suggested with coincident myelitis, Afro-Caribbean ancestry with no early recovery, associated connective tissue disease such as Sjögren syndrome, and NMO-IgG in serum.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
References cited
Contributors
Web resources