Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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The author describes optic neuritis, which can be a part of a spectrum of demyelinating diseases that includes multiple sclerosis. This update includes information on the diagnosis of optic neuritis, how optical coherence tomography and MRI lesions affect prognosis, and the overlap of optic neuritis with neuromyelitis optica spectrum disorders and antimyelin oligodendrocyte glycoprotein associated encephalomyelitis among other etiologies.
• Optic neuritis can occur alone or in many cases as a symptom of an underlying CNS autoimmune or demyelinating process like multiple sclerosis. It can also be associated with other causes like infection, granulomatous disease, and paraneoplastic and metabolic disorders.
• Optic nerve inflammation causes subacute loss of vision, usually in 1 eye, and usually associated with retro-orbital pain that is worsened with eye movement.
• Clinical recovery and prognosis will vary depending on the etiology. The prognosis of optic neuritis from multiple sclerosis is good with substantial or complete recovery at 6 months to 1 year after onset of symptoms, but ocular coherence tomography shows residual thinning of the retinal nerve fiber layer in the affected eye and often reveals thinning in the normal fellow eye as well. Thus, bilateral optic neuritis is common, even if not apparent.
• High-dose glucocorticoid therapy speeds up recovery of the inflammation, but has no long-term benefit.
Jean-Martin Charcot recorded the best early descriptions of optic neuritis. He reported an account of a woman with multiple sclerosis and feebleness of vision in 1835, illustrating a link between the 2 diseases (49). Sequin published the first American reports of "disseminated cerebrospinal sclerosis," including cases of optic neuritis with subacute transverse myelitis. A more detailed historical description, starting with Arabic texts in the ninth century that began to distinguish between eye paralysis and abnormal perception, is detailed by Volpe (231). Adie, Denny-Brown, and McAlpine all stated that unilateral retrobulbar neuritis was a symptom of multiple sclerosis (133). However, many patients with optic neuritis do not develop multiple sclerosis. This suggests there is a spectrum from a sole demyelinating episode, to a forme fruste of multiple sclerosis, to 1 of the many signs of definite multiple sclerosis. Severe optic neuritis could be from neuromyelitis optica/Devic disease, but the pathogenesis is different from the multiple sclerosis-related idiopathic optic neuritis. This article focuses on optic neuritis as an isolated inflammatory demyelinating syndrome.
Optic neuritis typically begins with rapid, but not sudden, loss of vision and is usually unilateral. The onset of visual loss is subacute, and dysfunction progresses over hours or days (84). It is associated with pain (92%) in or behind the eye (12). Pain may precede visual loss and lasts for days to weeks. An afferent pupillary defect is expected, unless the other eye is also involved concurrently or there is a history of optic neuritis in the other eye.
Visual loss is usually monocular, but 19% to 50% of adults (104; 10; 15) and 60% of children have bilateral loss. Even with unilateral optic neuritis, the “normal” fellow eye has decreased visual acuity in 70%, but this resolves quickly (69). Visual function is worst at 7 to 10 days after onset of symptoms. It usually begins to improve rapidly after 2 weeks, and resolution continues over several months. Complete recovery of visual acuity is common, even after near blindness at the peak of symptoms (84). Some patients may complain of visual "blurring" yet have normal visual acuity on testing. The reason for this is that visual acuity can be normal even with significant axonal loss; 20/20 vision requires only 44% of normal foveal axons; 20/70 vision requires only 5% (154).
Retro-orbital pain is common (80% to 90%) and may precede visual loss (104; 69). The sheath of the optic nerve is pain-sensitive, unlike most of the deep cerebral areas that are demyelinated in multiple sclerosis. Pain is felt in the eye or ophthalmic division of the trigeminal nerve in more than 90% of patients with MRI lesions in the orbital optic nerve, but in only 30% of patients with lesions of intracranial pathways (63). Pain and disc swelling is most likely when there is gadolinium enhancement of the anterior orbital optic nerve (100). Pain can be present at rest, with pressure on the globe, and with voluntary movement. The pain in the globe or brow is worse with eye movement because of traction of the superior and medial recti on the optic nerve sheath at the orbital apex (139). Severe, persistent pain outside the expected several weeks could suggest another underlying etiology such as posterior scleritis, infection, sarcoidosis, or granulomatous optic neuropathy. Headache is present in nearly one third of children with optic neuritis (123).
Deficit in the central field of vision is commonly mentioned by the patients and detectable in 97%; however, on formal testing, central vision is preferentially diminished in only 10%. The central scotoma is described as blurring or a dark patch, and visual acuity is not improved when looking through a pinhole. Diffuse loss is more common and is seen in 50% of affected eyes (122; 69). Paracentral or peripheral field defects are less common. Chiasmal neuritis is a variant of optic neuritis, which is similar in clinical course except that visual field defects are bitemporal or junctional, and pain is less prevalent (178). Clinically, when bilateral visual field loss is noted with normal visual acuity, it suggests involvement of the posterior visual pathways. Altitudinal defects are characteristic of ischemic arterial disease, but they also appear in 6% to 20% of patients with optic neuritis (122).
The fundus is normal in 60% of patients, especially when the inflammation is retrobulbar (104). The fundus sometimes appears blurred, possibly from prior optic neuritis, or shows papillitis with swelling of the optic nerve head and peripheral hemorrhages (17% to 40%; severe in 5%) (29; 104). Papillitis is more common in children (65% to 70%) (123; 182; 85). With papillitis, inflammation of the anterior optic nerve causes disc swelling, and sometimes hemorrhages, cells in the vitreous, and deep retinal exudates. It can cause loss of normal spontaneous venous pulsations. Swelling is from inflammation and edema, obstruction of axonal transport, and venous congestion.
After the neuritis resolves, the disc is often pale (optic pallor), most commonly in the temporal aspect.
Optic pallor appears when axons drop out and the transparent nerve fiber bundles are no longer able to conduct light. This light normally would pass into the disc and pass through capillaries. Instead, it is reflected from glial cells and appears white instead of pink, usually in the temporal area.
Low-contrast testing is more sensitive than regular contrast, and this is abnormal in nearly 90% of patients with normal visual acuity (69). Colors are often drab, even in the 30% of patients whose visual acuity is normal. Red desaturation is traditionally expected, but loss of blue hues may be as common as loss of red (74; 118). Six months after vision in the affected eye has recovered to 20/30 or better, there remains abnormal color vision (dyschromatopsia) (57%), contrast sensitivity (72%), perimetry (26%), stereo acuity (80%), light brightness (89%), pupillary reaction (89%), and optic disc appearance (77%) (68). The non-affected eye (acuity = 20/20) sometimes has problems with color vision (21%), visual contrast (33%), and disc appearance (5%). Improvement in visual acuity and visual fields is correlated with the physical length of nerve enhancement on MRI (shorter is better) (100).
Apparent light intensity is reduced in the affected eye, and this corresponds to a Marcus Gunn pupillary response (ie, relative afferent pupillary defect, APD) in the swinging flashlight test. Quicker redilation indicates a subtle afferent pupillary defect. Retinal disease, bilateral optic neuritis, or history of optic neuritis in the other eye can negate the test. A neutral density filter can amplify the defect from optic neuritis (eg, the normal eye at 20/20 is reduced to 20/40 with the filter. In the affected eye, however, 20/40 drops to 20/100). The filter can help differentiate optic neuritis from ischemic optic neuropathy, retinal disease, and functional defects where changes with the filter are minimal or absent.
Depth perception is impaired in 80% of patients with a history of optic neuritis. The damage alters the trajectory of moving objects (Pulfrich phenomenon, in which a swinging pendulum seems to bend toward the eye that has the slower conduction velocity). Even in multiple sclerosis patients with 20/20 vision and no history of optic neuritis, Randot stereoacuity testing shows binocular depth perception defects in 74% of patients (205). The horizontal disparity that gives rise to depth perception (binocular integration) requires input from both optic nerve and the inferior temporal cortex. Depth perception can be easily tested at the patient’s bedside with a swinging black pen (155) or formally with stereopsis grids. Impaired depth and motion perception could interfere with driving.
Bright lights cause glare disability and a prolonged afterimage; for example, lights of an oncoming car at night cause a lingering phantasm of headlights. This "flight of colors" is as common as slowed visual evoked potentials (213). Visual fading (Troxler effect) occurs after prolonged fixation, and small objects disappear. This interferes with seeing computer and cell phone screens, but eye movements away and back from the object will improve visualization.
Eye movements sometimes cause fleeting flashes of light (movement phosphenes); the mechanism corresponds to that of Lhermitte sign from cervical cord lesions in multiple sclerosis (46). The critical flicker fusion frequency is reduced. All of these symptoms are amplified by increased body temperature (Uhthoff sign) and by acidosis from exercise, sometimes without a rise in body temperature. Visual evoked potentials are slowed in healthy, normal optic nerves by a rise in temperature of 1.6°C. In eyes with prior optic neuritis, even minimal heat or exercise can diminish visual acuity, sometimes within minutes (194; 197). Impaired depth and motion perception could interfere with driving (71).
Less commonly recognized phenomena such as slit-like defects in the peripapillary nerve fiber layer are described in patients with multiple sclerosis, with or without a history of acute optic neuritis (77; 58). With red-free light, retinal nerve fiber layer defects and an abnormally small neuroretinal rim are often visible, and are sometimes present when visual evoked potentials are normal (146). These defects are due to axonal pathology and suggest optic nerve damage.
Periphlebitis retinae (perivenous sheathing) and pars planitis are more common during active multiple sclerosis than in optic neuritis. Twelve percent of patients with optic neuritis have retinal venous sheathing. These patients are more likely to develop multiple sclerosis (142), but the sheathing does not predict clinical disease course. Periphlebitis retinae consist of glistening cuffs of immune cells around segments of retinal veins. After infiltration of the walls of veins by lymphocytes and plasma cells, thick hyaline material in concentric lamellae replaces the normal lacy periventricular connective tissue. The residual fine lines of scarring and venous sheathing around veins are easily seen with an ophthalmoscope (59). There is leakage on fluorescein angiography. Because there is no myelin in the retina, some vascular changes may be independent of demyelination.
Between 1% and 50% of patients with pars planitis have multiple sclerosis. This form of uveitis is restricted to the area behind the iris, the pars plana of the ciliary body. It is not an anterior uveitis (in the anterior chamber or iris) or a posterior uveitis (in vitreous, choroid, retina, or optic nerve). An angled lens or slit lamp helps visualize protein and cells that have settled to the bottom of the vitreous and formed “snowballs” from an inflammatory attack against the highly vascular uvea (iris, ciliary body, and retinal pigment epithelium). Pars planitis is difficult to detect; this difficulty is 1 explanation for the huge range in incidence. In those with multiple sclerosis, it is associated with HLA-DR2. Seven percent will develop optic neuritis; 16% to 33% will develop multiple sclerosis (148; 176). The local antigen that is a target of the immune attack remains unknown, but similar inflammation is seen with bacterial, viral, and protozoal infections, and with autoimmune diseases (30).
Bilateral vision loss is associated with infections and acute disseminated encephalomyelitis and is more common in people of Korean (105) and black South African descent (174). These authors may have been describing Devic disease, formally known as neuromyelitis optica spectrum disorder. Typical infections that cause bilateral visual loss include but are not limited to chickenpox and human herpes virus-6B; vaccination is another etiology (123; 62; 85). In neuromyelitis optica spectrum disorders, optic neuritis is the first symptom in 80%; these are bilateral in 20% (151). Children with bilateral visual loss have a better prognosis than adults (164).
The risk of developing multiple sclerosis is discussed in the prognosis and complications section of this article.
The clinical prognosis of optic neuritis is surprisingly good, in general. Of 457 patients, 91% to 95% had a visual acuity of at least 20/40 at 1 year after the ictus and 92% at 10 and 15 years (Beck and Clearly 1993). In an earlier study, 68% recovered to 20/30 or better vision and 87% were above 20/180 (104). Another study found good recovery in 86% of patients (29). Better recovery is associated with pediatric age versus adult, female sex (odds ratio = 0.44), high vitamin D (odds ratio = 0.47 for a 10 mg/dl increase in serum vitamin D), severe attacks (OR=5.2) (147), a short stretch of involved optic nerve on gadolinium-enhanced MRI, high visual evoked potential amplitudes, and an early, rapid rate of improvement in vision (100). Poor prognostic factors for visual recovery include initial low visual acuity, absence of pain, involvement of the intracanalicular optic nerve (53), and decreased axial diffusivity on diffusion tensor imaging MRI. Long lesions seen on MRI in the posterior intracanalicular segment of the nerve cause slow and incomplete recovery (80; 100). Visual impairment after 6 months was correlated with early markers of neuroaxonal injury in retina: retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness (191). Progressive visual worsening for more than 2 weeks, or no recovery after 8 weeks, should caution one to look into other causes of optic neuritis (119).
Almost all patients with a moderate defect recover completely or to near normal within a year; 40% of those with total or severe blindness at onset recover to normal (36). Improvement in visual acuity and visual fields is correlated with the physical length of nerve enhancement on MRI (shorter is better) (100). Evoked potentials and contrast sensitivity improve over 2 years (in some studies but not others), likely from resolution of inflammation, ion channel reorganization, and remyelination. With time, however, the insidious effects of mild but continual low-grade demyelination and axonal degeneration usually become more evident as optic atrophy evolves over several years (32). However, more often than not, reduced contrast sensitivity and stereopsis often persist, even when acuity has returned to normal.
Atrophy of the disc and retina is seen over time, especially with lesions that cause poor visual acuity and slowed evoked potentials. Distal axons degenerate completely with 7 days, but the cell body and proximal axon appear normal for 3 to 4 weeks. These then degenerate rapidly, and by 6 to 8 weeks there are no more viable cells among the affected retinal ganglion cells (154). Imaging with ocular coherence tomography can accurately define the loss. Visual evoked potential amplitude dropout (indicative of axonal dysfunction) and visual acuity improve over 4 months, but visual evoked potential latency (indicative of demyelination) and motion perception remain impaired, interfering with walking and driving (180).
The risk of developing multiple sclerosis after isolated optic neuritis is controversial. (The 1983 Poser criteria did not consider recurrence of optic neuritis, even in the fellow eye, as multiple sclerosis—unless it occurs more than 15 days from the initial episode.) Optic neuritis can be the first sign of multiple sclerosis.
Lesions are often disseminated beyond the eye. Idiopathic chiasmal lesions in 20 patients, in whom 6 had associated white matter lesions, evolved to multiple sclerosis in 40% over 1 to 5 years (120). Between 25% and 75% of patients with optic neuritis have abnormal MRI scans. In 70% of optic neuritis patients with disseminated brain lesions on MRI, attention and information processing speed are reduced (64), an indication of diffuse central nervous system dysfunction. Similarly, blood flow in the affected occipital cortex is reduced on functional MRI (218) and magnetization transfer (06), and activation of extra-occipital areas is increased (218). Conversely, 31% of army recruits with multiple sclerosis had optic signs (133).
In 39 studies before 1985, only one eighth to one third of patients with isolated idiopathic optic neuritis eventually developed clinical multiple sclerosis. Other studies had similar results; 12% of 110 Mexicans developed multiple sclerosis at 2 years (44). Four percent of 23 Chileans monitored developed multiple sclerosis within 10 years after optic neuritis (02). Of 88 Brazilians studied, 11% developed multiple sclerosis within 5 years, but the median time to multiple sclerosis was 1 year and lesions were frequently spinal (136). In Pakistan, 15% developed multiple sclerosis at 5 years and 24% at 10 years (121). The low numbers in these 4 studies suggest a regional variation in prognosis and perhaps may be confused with Devic disease. In 40 Italians older than 12 years of age, 25% developed multiple sclerosis (149), and 14% of 50 Swedish optic neuritis patients developed multiple sclerosis at 1 year (72). In the large optic neuritis treatment trial, 17% of 126 patients in the United States developed multiple sclerosis over 2 years (in the placebo group) (11). At 5 years, 30% of the patients had developed multiple sclerosis (16); at 10 years, 38% of 388 patients (some had been treated with steroids) had multiple sclerosis (some, maybe 5%, had prior neuritis in fellow eye), and at 15 years, 50% had multiple sclerosis independent of MRI lesions at baseline (163).
Others find a higher rate of evolution to multiple sclerosis. Thirty-two percent of 82 Australians developed multiple sclerosis over 5 years (94) and 40% at 15 years. Thirty-nine percent of Minnesotans developed the disease at 10 years, but 60% of those developed multiple sclerosis by 40 years of age. Perivenous sheathing and recurrent optic neuritis increased the risk (184). In a related series of Minnesotans, 30% developed multiple sclerosis after 10 years, 13% developed neuromyelitis optica, and these had more severe and more rapid onset. Early recurrence of optic neuritis increased the risk of multiple sclerosis (171). There was a nonsignificant trend for intravenous steroids to prevent conversion to multiple sclerosis (171). Other studies showed a higher incidence of progression to multiple sclerosis; 26% of 86 Swedes at 5 years, 34% at 10 years, and 38% over 13 years (161), 42% of Italians at 10 years and 52% at 15 years, 42% of 36 Norwegian patients within 2 years (Gronning et al 1989), 48% of Londoners at 5 years, with more disability with enhancing or infratentorial MRI lesions (212), 57% of 30 Danes within 6 years (03), 58% of 60 New Englanders over 15 years (183), and 60% of 48 Dutch over 2 years (193). The risk was 57% in 101 British patients followed for 11.6 years, although 45 of the original 146 were not included in the follow-up.
An isolated episode of optic neuritis without other signs of multiple sclerosis should not be treated with disease-modifying therapy. However, if there are associated MRI lesions and CSF oligoclonal bands, the risk of multiple sclerosis is high, and a disease-modifying therapy is usually appropriate.
In children compared to adults, optic neuritis more often follows a virus infection, is more often bilateral (42% vs. 6%) (50; 238), is associated with papillitis, and traditionally has a poor visual prognosis. However, another study of 36 children with optic neuritis showed full recovery in 83% of eyes, even though one half had brain MRI lesions at presentation and one third developed multiple sclerosis over a 2.4-year follow-up (238). Optic neuritis, transverse myelitis, or cerebellitis are commonly present at the onset of multiple sclerosis in children (27).
Only 8% of 39 children developed a recurrence of optic neuritis and 15% developed multiple sclerosis after 9 years (132). In 94 children at the Mayo Clinic with optic neuritis, only 13% had progressed to multiple sclerosis at 10 years, and only 26% by 40 years (145). In Philadelphia, Pennsylvania, 18 children with optic neuritis were followed for more than 2 years, and 3 of the 18 developed multiple sclerosis (25). All 3 children had positive brain MRI at onset, but 11 children with negative MRI did not develop multiple sclerosis. In Brazil, 10 of 27 children with optic neuritis had bilateral problems, but only 1 out of 27 developed multiple sclerosis over 13 months (135). In Turkey, 8 of 31 children developed multiple sclerosis after 2.2 years and were more likely to be older girls with unilateral optic neuritis (35). One study found that optic neuritis is likely to evolve into multiple sclerosis in children when it is associated with cerebrospinal fluid inflammation and bacterial or virus infections or vaccinations (182). However, a larger study found that optic neuritis preceded by infections was less likely to lead to multiple sclerosis (145).
Predictions of the risk of developing multiple sclerosis should not be based on linear models. Onset of multiple sclerosis is most frequent in the first 1 to 5 years after optic neuritis than at later times (29; 57; 182; 37). Multiple sclerosis is more likely to develop after optic neuritis in individuals aged 21 to 44 years (104; 183; 149), in women (183), and in patients with bilateral optic neuritis as adults (104) (though some reports disagree), rather than as children (164). Uhthoff symptom (195), retinal venous sheathing (142), pain, no optic disc swelling, severe visual acuity loss, prior optic neuritis in the fellow eye, and prior nonspecific neurologic symptoms are also predictors of multiple sclerosis (16), as is onset of optic neuritis in January through March. Postvaccinal optic neuritis (182), a DR3 or DR2 background (70; 182), serum antibodies to proteasomes (22), potentially pathogenic (non-Leber) mitochondrial DNA variants (26), cerebrospinal fluid cells or oligoclonal bands (37; 83; 161), cerebrospinal fluid IgG (109), disseminated lesions on MRI (153; 192; 16), or abnormal evoked potentials also suggest that multiple sclerosis will develop (37). Unless the lesions are concomitant, recurrent attacks of optic neuritis (either eye) do not increase the chance of developing multiple sclerosis (104; 70; 183), although 1 report disagrees (16). Visual function is less likely to recover with successive episodes. A history of optic neuritis in a multiple sclerosis patient actually improves the long-term prognosis compared to patients without optic neuritis (235).
Widespread MRI changes are more common when there is a history of optic neuritis in the fellow eye. However, when the fellow eye is involved at onset, patients are not more likely to have MRI or clinical evidence of multiple sclerosis (10). Disseminated MRI lesions at the onset of optic neuritis increase the risk of developing multiple sclerosis, but the lesion burden does not correlate perfectly. The MRI at baseline (disseminated lesions or not) is more often normal in optic neuritis than in other clinically isolated syndromes. The MRI may be the most important predictor of developing multiple sclerosis (216). With isolated idiopathic optic neuritis, 34% (153), 50% (107), 58% (16), 64% (157), to 70% (45) of patients have disseminated lesions on MRI that are similar to the lesions seen in multiple sclerosis. Single non-enhanced MRIs are unable to definitively show dissemination over time, but lesions of different intensities do suggest temporal dispersion. One year after optic neuritis, 12 of 34 (35%) patients with disseminated MRI lesions at onset developed clinical signs of multiple sclerosis (153). Of 19 patients without MRI lesions, none developed clinical multiple sclerosis, although 3 had new MRI lesions. In a second study with a 5.6-year follow-up of 74 patients with optic neuritis, 22% developed clinical multiple sclerosis (109); 76% of these had abnormal MRIs initially. Of note, half of the patients who did not develop clinical multiple sclerosis also had abnormal MRIs at onset. In a third study, optic neuritis with no MRI lesions led to multiple sclerosis at 5 years in 16%, versus 51% of patients with 3 or more MRI lesions (16). The 10-year data for this study show multiple sclerosis in 22% without MRI lesions, and in 56% in those with 1 or more MRI lesions. The amount of disability was unrelated to baseline lesion load. In a fourth study, optic neuritis with no MRI lesions led to multiple sclerosis at 5.5 years in 6% of 44 optic neuritis patients, versus 82% of patients with an abnormal MRI (157). With no baseline MRI lesions, a patient has a 25% chance of developing multiple sclerosis in 15 years (178). With 1 lesion, the cumulative probability is 60%. With 3 or more lesions, the likelihood is 78%. Optic nerve enhancement itself does not count as a lesion. In a fifth study of 102 Italian patients, optic neuritis with no MRI lesions did not lead to multiple sclerosis at 8 years, whereas 57% of patients with an abnormal MRI did develop the disease (82). Despite the correlation between MRI lesions and development of multiple sclerosis, 19 to 31 years after the first episode of optic neuritis, 20 out of 30 patients had brain MRI lesions, yet had no clinical manifestations (161). Spinal cord MRI helps determine dissemination in space in only 1% to 4% of optic neuritis patients who have normal brain MRIs (45).
Oligoclonal bands add to prediction of future course, and are a better predictor than MRI in some studies. CSF should be obtained when there is clinical uncertainty about prognosis. Oligoclonal bands as a predictor of multiple sclerosis after monosymptomatic optic neuritis have 90% sensitivity, 60% specificity, and an odds ratio of 34, but there is heterogeneity between 10 studies (204). The combination of central nervous system MRI lesions plus oligoclonal bands augers a high risk for multiple sclerosis; 94% at 4 years (226). Patients with negative MRI yet positive bands are 10 times more likely to develop multiple sclerosis than those with negative MRI and no bands (43). A profile of negative MRI (specific) plus no oligoclonal bands (sensitive) is a strong predictor of not developing multiple sclerosis (0% at 2 years, 17% at 4 years) (226). In another series, the risk of developing multiple sclerosis was 66% at 4 years with 3 or more brain MRI lesions plus oligoclonal bands, but only 9% with neither (113). Neurofilament light chain CSF levels do not predict development of multiple sclerosis, but do correlate with more residual damage in the eye.
Development of multiple sclerosis is more likely with prior optic neuritis, other neurologic symptoms, white race, and a family history of multiple sclerosis. Patients with optic neuritis and HLA-DR3, especially in combination with DR2, are more likely to develop multiple sclerosis (70). A multiple sclerosis-associated retrovirus has been associated with development of multiple sclerosis after an attack of optic neuritis. Prognostic factors against developing multiple sclerosis are male gender, simultaneous bilateral onset, and atypical features for optic neuritis that suggest another etiology for visual loss, such as poor vision, severe disc swelling, hemorrhages, and lack of pain.
Optic neuritis recurs in either eye in 35% of patients at 10 years (13). Recurrent optic neuritis is more common in patients who develop multiple sclerosis (48%) than in those who don’t (24%) (17). Bilateral simultaneous optic neuritis led to multiple sclerosis in only 1 of 11 adults after an interval of up to 30 years. Sequential optic neuritis, however, led to diagnosis of multiple sclerosis in 8 of 20 (164). In children, 1 of 17 with recurrent optic neuritis developed multiple sclerosis.
Glial autoantibodies (MOG or AQP4 IgG) are found in a third of all patients with recurrent optic neuritis (40). The antibody aquaporin 4 (NMO-IgG) has high sensitivity (73%) and specificity (91%) for NMO (138). NMO-IgG was positive in many cases of the Asian type of multiple sclerosis (optic nerve and spinal cord predominance), but not in classic Western-type multiple sclerosis. Discovery of this antibody has caused reevaluation of what was once considered optico-spinal multiple sclerosis. Now, neuromyelitis optica spectrum disorders are considered an entirely different disease separate from multiple sclerosis, with a more devastating prognosis, different disease associations (systemic autoimmune comorbidities with NMO), and different therapies (IVIG and plasmapheresis, and avoidance of interferon-beta in NMO) (112).
Recurrent episodes of optic neuritis in multiple sclerosis attack the previously affected nerve more often than when compared to neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-positive recurrent optic neuritis, where it seems to be randomly distributed between the 2 optic nerves (144). Antibodies to myelin oligodendrocyte glycoprotein are at high titers in children with recurrent optic neuritis (189).
Chen and colleagues followed 87 patients with anti-myelin oligodendrocyte glycoprotein-associated optic neuritis and showed that 80% of patients had 2 or more attacks of optic neuritis with a median follow-up of 2.9 years (39). Thirty-seven percent of patients have bilateral simultaneous optic neuritis during one of their attacks. The prognosis of seronegative optic neuritis and myelin oligodendrocyte glycoprotein-associated optic neuritis 6 months after the onset of symptoms was favorable compared to neuromyelitis optica. MOG IgG is associated with a greater relapse rate but better visual outcomes; a final visual acuity of less than 20/200 is uncommon (< 6%) (39; 115). A similar study from Japan of 531 cases of unilateral or bilateral noninfectious optic neuritis also concluded that anti-aquaporin-4 antibody-positive optic neuritis had poor visual outcomes. In contrast, MOG-Ab positive cases would manifest with severe clinical findings of optic neuritis before treatment, but few showed concurrent lesions in sites other than the optic nerve and generally showed good treatment response, with favorable visual outcome (106).
A previously healthy, 28-year-old former gymnast noticed that she was having difficulty seeing fine lines with her left eye. The symptoms progressed over the next day, and she began to have difficulty discriminating between letters in newspaper headlines. Pain within the depths of the orbit was minor at first, but soon became moderate in severity and was worse with eye movement or pressure on the globe.
On examination, her vision was 20/200 in the left eye and 20/40 in the right eye. There was a central scotoma, and red and blue colors were less intense in the left eye. There was an afferent pupillary defect on the left. The rest of her neurologic exam was normal. A spinal tap showed normal glucose, protein, IgG, 3 white blood cells per mm3, and no oligoclonal bands. Visual evoked potentials were delayed on the left eye at 120 msec and slightly delayed at 112 msec in the right. MRI was normal.
She was not treated, but after 2 weeks, her visual symptoms gradually improved. However, symptoms were worse after 10 minutes in the sauna at her health club for the next 4 weeks. After 3 months, her vision was 20/20 in both eyes, and the central scotoma was gone. Red perception remained slightly reduced on the left. Visual evoked potentials were 115 msec on the left and 110 msec on the right.
Allbutt believed that optic atrophy in multiple sclerosis, tabes dorsalis, and cerebellar diseases were caused by traveling degeneration that propagated rostrally from a primary lesion in the spinal cord (01). Other putative causes of optic neuritis and multiple sclerosis have included antecedent illnesses, cold temperatures, grief, dysplastic glia, myelinotoxic factors, heavy metals, spirochetes, viruses, venular thrombosis, and vasospasm (49). Current belief is that optic neuritis is immune-mediated, although the specific mechanism and target antigen are unclear unlike in neuromyelitis optica spectrum disorders and MOG-associated optic neuritis.
Antibodies to brain antigens are neither the cause nor the consequence of optic neuritis. During an acute attack of optic neuritis, antibodies to myelin basic protein appear in the serum. These antibodies become complexed to myelin basic protein within 4 months. The antibodies bind residues 61 to 106 of myelin basic protein (234). In a small subset of cases, antibodies recognize only proteolipid protein (233). Proteolipid protein induces experimental allergic optic neuritis in mice (175), indicating that this antigen can induce region-specific immune responses. Cell-mediated cytotoxicity against lymphocytes coated with myelin basic protein, cerebrosides, and gangliosides also correlates with disease activity (76). However, in optic neuritis, the target of the activated T cells and monocytes is unknown.
Optic neuritis can be a primary idiopathic inflammation of the optic nerve. It can also be a result of diverse inflammatory conditions, including multiple sclerosis, neuromyelitis optica spectrum disorders, myelin oligodendrocyte glycoprotein spectrum disorder, allogeneic bone marrow transplantation, granulomatous disease, anti-GFAP disease, postvaccinal or postinfectious reactions (eg, following ehrlichiosis, tularemia, viral encephalitis, measles, mumps, chickenpox, hepatitis A and B, herpes zoster, HIV, HTLV-I, infectious mononucleosis, mumps, West Nile virus), contiguous inflammation (fungus, sarcoidosis, tuberculosis, Angiostrongylus cantonensis, brucellosis, chlamydia pneumoniae, or syphilis), or intraocular inflammation. After virus infections, the disease is often bilateral (62). When vaccination or virus infections are followed by optic neuritis in children, most have CSF oligoclonal bands and intrathecal antiviral antibody synthesis (182). Despite multiple case reports of linkage to vaccination, well-controlled epidemiologic studies show no increase in optic neuritis after vaccination for hepatitis B, influenza, measles, mumps, rubella, or tetanus. Many postvaccinal and postinfectious cases (9 of 21) subsequently develop multiple sclerosis within a year of the optic neuritis (182). The fever and inflammation from these infections may expose preexisting subclinical optic neuritis or multiple sclerosis. Patients with virus-specific oligoclonal IgG antibodies in CSF are more likely to develop multiple sclerosis. These epidemiologic data raise the question of whether optic neuritis and infectious antigens are connected, or whether optic neuritis is a nonspecific response to immune activation.
There is some genetic influence in susceptibility to multiple sclerosis. Optic neuritis is frequently associated with multiple sclerosis, and by implication, there is an increased risk (undefined) for family members. There is an increased frequency of HLA-DR2, DR3, and Dqw1 (70), and DR15, DQA-1B, and DQB-1B (75) in patients with optic neuritis. Compared to Caucasian patients, patients of African and Asian descent have worse visual acuity at onset and after 1 year (169). The neuromyelitis optica form of multiple sclerosis is more common in those of African ancestry. This suggests genetic influences that parallel the link of HLA-DRB/*1501 to Western, but not Asian (neuromyelitis optica), forms of multiple sclerosis (128). The Leber mutation may be a genetic risk factor for developing multiple sclerosis (230).
During an attack of optic neuritis, lymphocytes and monocytes infiltrate the optic nerve, an extension of the central nervous system containing a million myelinated fibers. Immune cells directly damage myelin or indirectly cause dysfunction by secreting proteases, nitric oxide, and cytokines that interfere with neuronal function (“conduction block”). Experimental injection of lymphokines into the posterior eye causes an inflammatory response and slowing of visual evoked potentials within hours (04). Soluble ICAM, a product of activated white blood cells and endothelial cells, is increased in CSF at the first attack of optic neuritis (166). Serum interferon-gamma, interleukin-6 and interleukin-2 receptors, and CSF interleukin-2 are increased in patients with optic neuritis (48), indicating that T cells are activated and are secreting cytokines in both compartments. These inflammatory cytokines also induce major histocompatibility complex antigens that could provoke chronic inflammation. In 6 patients who had optic neuritis 10 years earlier, mononuclear cells expressed more major histocompatibility complex class II protein than cells from healthy controls, suggesting they were activated (127).
Myelin basic protein-reactive and proteolipid protein-reactive T cells that produce interferon-gamma, tumor necrosis factor, or lymphotoxin are increased in the CSF in optic neuritis and multiple sclerosis (207; 160). However, cells secreting the antiinflammatory cytokines, IL-10, IL-4, and TGF-beta are also more frequent, resulting in a complex mix of cytokines (a “cytokine storm,” H link). The number of CSF cells producing inflammatory cytokines in optic neuritis did not correlate with MRI abnormalities or oligoclonal bands in an early study (129), but a later study showed that more IL-5, BDNF, and GDNF link to Gd+ MRI and oligoclonal bands (223). IL-8 in CSF correlates with acute and chronic visual loss in multiple sclerosis-associated optic neuritis (188).
The inflammation is reversible. Surprisingly, high expression of the activation markers, HLA-DR and CD45RO, on T cells correlates with fewer oligoclonal bands in the CSF and with better visual recovery (185). Activation may mark beneficial regulatory T cells, or it may make activated helper cells more susceptible to apoptosis. The vitreous is highly immunosuppressive, so local factors may inhibit inflammation and even enhance repair.
B cells that recognize myelin basic protein are at normal levels in the periphery but are increased 100-fold in the cerebrospinal fluid in both multiple sclerosis and optic neuritis, compared to normal controls (208). In individual patients, this oligoclonal response is often directed against multiple myelin basic protein epitopes, but more frequently against proteolipid protein (199). In mice transgenic for T cell receptors that recognize myelin oligodendrocyte glycoprotein, 30% spontaneously develop optic neuritis without any signs of experimental allergic encephalomyelitis (21). Immunization with oligodendrocyte-specific protein induces an intense optic neuritis. Optic neuritis has appeared in several cases of anti-GQ1b antibody-positive Miller-Fisher syndrome (ophthalmoplegia, ataxia, and areflexia in Guillain-Barré syndrome), suggesting there is a reaction to this ganglioside that amplifies or causes the neuritis. In multiple sclerosis, anti-myelin basic protein responses are more common than anti-proteolipid protein responses. The antigen-specific response may change over time in demyelinating disease. This suggests there is no single target antigen and that the response to myelin basic protein follows earlier immune activation of unknown cause. In summary, immune changes in optic neuritis are similar to those in relapsing-remitting multiple sclerosis.
Oligoclonal bands are from expanded B cell clones that all produce the same type of immunoglobulin. This suggests there is an antigen, but a specific optic neuritis or multiple sclerosis antigen has not been defined, and other mechanisms from the B cell expansion should be considered.
Myeloid dendritic cells, which present antigens to T cells, are mature and activated in optic neuritis (224). They induce a Th1 bias and T cell proliferation. They are deactivated by simvastatin, but caution must be exercised in the use of statins in conjunction with interferons in demyelinating diseases. Statins increase disease activity when added to ongoing interferon treatment (24; 209) and block interferon signaling in vitro (54) and in vivo (65). Polymorphonuclear neutrophils are increased in the blood of patients with optic neuritis, compared to healthy controls.
Markers of axonal injury and nitric oxide metabolites are increased in plasma. Antioxidant enzymes suppress the demyelination in the optic nerves in experimental allergic optic neuritis, probably by interfering with the effects of inflammatory monokines (90). Uric acid, an antioxidant, is reduced in serum of patients with optic neuritis, a phenomenon also seen in multiple sclerosis. Functional recovery follows resolution of inflammation and of conduction block, expression of new sodium channels on demyelinated axons, and cord remyelination that can continue for up to 2 years. Additionally, immune cells are also capable of secreting neurotrophic factors that induce repair.
Magnetic resonance spectroscopy of normal-appearing white matter after optic neuritis is often the same as in normal controls, unless there are visible MRI lesions outside the optic nerve (219). In other cases, MRI lesions are present in multiple areas of the CNS, suggesting an overlap between the 2 demyelinating diseases. During recovery of the affected nerve, functional MRI shows extreme activation of areas other than the occipital cortex (extra-striate) including insula, claustrum, thalamus, as well as lateral temporal and posterior parietal cortex (236). After optic neuritis, there is trans-synaptic degeneration in the lateral geniculate nucleus. Fiber tracking with fast marching tractography, and with fixel-based analysis, shows dystrophy and lost connectivity in the optic radiations beyond the lateral geniculate (42; 79). Other studies do not find loss of integrity in the optic radiations, but do find increased connectivity in them, suggesting recruitment of activated neurons and dendrites to compensate for the damage (07).
Functional MRI shows that optic neuritis decreases afferent stimuli to the visual cortex, and reduces functional activation of the cortex (217). Disruption of the ventral visual stream from the V1 cortical area and the posterior parietal cortex interferes with construction, recognition, and identification of the visual world. At 3 months, visual activation reverses. There is more activity in the occipital and lateral temporal cortices and the hippocampus, suggesting visual processing is less efficient.
Histologically, in the scattered plaques of multiple sclerosis, axons are usually preserved (although some subtypes of multiple sclerosis differ). In isolated optic neuritis, relatively more axons are usually destroyed along with the demyelination, although myelin loss does exceed axonal loss. Ninety-five percent to 99% of patients with multiple sclerosis have lesions in the optic nerves at autopsy.
In a critical review of all epidemiological studies of optic neuritis before 1985, the incidence was approximately 3 in 100,000 people in northern latitudes where multiple sclerosis is common (northern United States, Western Europe), and fell to 1 in 100,000 people in medium-risk areas for multiple sclerosis (Hawaii, Israel) (134). In Minnesota, the incidence is 5 per 100,000, and the prevalence is 115 per 100,000 (184). A south-to-north gradient exists in Australia. Optic neuritis is 2.5 times more common in women than in men. Certain major histocompatibility complex class II antigens are over-represented in optic neuritis, suggesting a genetic predisposition for specific immune responses (127).
Episodes of optic neuritis are more common in the United States and Great Britain during spring and summer (215; 28; 104; 62), and in Sweden during the spring (114). In Poland optic neuritis appears in winter and spring (141). The maximum frequency of monosymptomatic optic neuritis is twice as high in the spring as in the fall, possibly an influence of virus infections or loss of sun exposure (131).
The age distribution is slightly different from that of multiple sclerosis; there are more patients at the young and old ends of the spectrum (133). Optic neuritis is proportionately more frequent than multiple sclerosis in Asia, where it presents as an isolated symptom or as part of Devic disease (neuromyelitis optica) (133). In Japanese patients, compared to Caucasians, disc swelling is more common, but eye pain and periventricular plaques are less common (232). In an area of high multiple sclerosis frequency, asymptomatic brain lesions appear in 73% of MRI scans done at the first episode of optic neuritis; in areas with lower multiple sclerosis frequency, patients are less likely to have brain lesions (211). In these early studies, a higher prevalence of the “oriental” (Devic-like) form of multiple sclerosis or Devic disease itself in Japan and China would also reduce the apparent frequency of brain lesions on MRI at the time of diagnosis with optic neuritis.
Vitamin D in serum is controlled by sun exposure and dietary intake. Low vitamin D levels increase risk for developing multiple sclerosis and increase the number of exacerbations and speed of progression in patients with known multiple sclerosis. Vitamin D levels are lower in new onset optic neuritis (48 nmol/L; 19 ng/ml) than in known multiple sclerosis (64 nmol/L; 25 ng/ml), perhaps because multiple sclerosis patients were supplementing their diets with vitamin D (170). High serum vitamin D levels correlated with low IgG index and low white cell count in CSF, and with acute retinal nerve fiber layer swelling and chronic ganglion cell layer thinning on ocular coherence tomography (33).
If upper respiratory tract infections could be avoided, episodes of optic neuritis following virus infections would be prevented. High doses of glucocorticoids may modify the course of optic neuritis and multiple sclerosis, sometimes adversely. In the first analysis of the 1992 multicenter optic neuritis study, multiple sclerosis developed in fewer patients treated with high-dose methylprednisolone than in groups treated with 60 mg/day of placebo or prednisone followed by a rapid taper (11). However, after refining the diagnostic criteria for multiple sclerosis, the same group found no effect of steroids on development of multiple sclerosis. In another study, the mode of steroid administration and steroid discontinuation profoundly altered the probability of future attacks of optic neuritis (96). Patients with optic neuritis were treated for 3 days with 1 g of intravenous methylprednisolone and no taper. Sixty-six percent had recurrent bouts of optic neuritis, and 83% of the patients developed multiple sclerosis within 18 months. In contrast, recurrent optic neuritis developed in only 14% of untreated patients, and in only 33% of patients treated with 60 mg of oral prednisone for 10 days followed by a month taper. No untreated patients, and 7% of patients treated with prednisone, developed multiple sclerosis during a 6-year follow-up. These studies, and similar provocative effects after sudden steroid withdrawal in experimental autoimmune encephalitis, suggest that rapid discontinuation of steroid therapy may be dangerous (181).
The diagnosis of optic neuritis requires 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 ischemic vascular disease, optic neuritis, or increased intracranial pressure (84). Clinical differentiation from optic neuritis is sometimes impossible, but some patterns are characteristic.
Ischemic optic neuropathy (ION) (Nonarteritic ischemic optic neuritis, NAION). 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. In optic neuritis, onset is over hours or days, rarely minutes, but not acute. 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 (122; 81). There is characteristically a unilateral inferior or superior attitudinal defect. In optic neuritis, the scotoma is centered on the fixation point and has a sloping border and poorly defined temporal and central margins. With ischemia, patients are older (40 to 80 years of age vs. 20 to 45 years of age), and more likely to be men. Pain is much less common with ischemic optic neuropathy (12%) than with optic neuritis (92%) (214). 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 MRI lesions in the centrum semiovale (103). Therapy with high-dose interferon-alpha has been linked to acute ischemic optic neuropathy, but interferon-beta has not.
Other vascular causes of visual loss include retinal artery occlusion, branch retinal artery occlusion (Susac), diabetic macular ischemia, and retinal vein occlusion
Neuromyelitis optica spectrum disorders (Devic disease). This is a demyelinating disease of optic nerve and spinal cord, which is discussed below with demyelinating disease.
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. It can be bilateral, and there is associated uveoretinitis and perivascular infiltrates (117). It responds to glucocorticoid therapy.
Carcinomatous optic neuropathy. It is typically associated with adenocarcinoma of breast and lung, lymphoma, and melanoma.
Central retinal vain occlusion. Disc edema and peripapillary hemorrhages.
Central serous retinopathy or chorioretinopathy. The disc is normal, but macular edema decreases visual acuity; this is painless and usually resolves spontaneously. It may worsen with glucocorticoid therapy.
Cerebellar degeneration. Some hereditary forms and Kearns-Sayre syndrome exhibit visual symptoms. The ocular lesion is a pigmentary retinopathy; optic neuritis is rare (88).
Chemotherapy. Ara-C, cisplatin, 5-fluorouracil, and possibly tamoxifen.
Chronic relapsing inflammatory optic neuritis (CRION). In chronic relapsing inflammatory optic neuritis, relapses occur on rapid steroid withdrawal. “Normal-appearing” white matter of visual pathways may show widespread abnormalities on MRI diffusion tensor imaging. A nonprogressive form, relapsing optic neuritis, is twice as common as chronic relapsing inflammatory optic neuritis, is less severe, and is less steroid-dependent (10% vs. 42%) (19). In a retrospective analysis, 64 patients with inflammatory optic neuritis did not meet criteria for multiple sclerosis, acute disseminated encephalomyelitis, or neuromyelitis optica. Twelve of these patients fulfilled criteria for chronic relapsing inflammatory optic neuritis, and 11 were positive for MOG-IgG. Among the other 52 iON patients not meeting the criteria for chronic relapsing inflammatory optic neuritis, 14 had relapsing disease courses, and 38 had monophasic courses, of which MOG-IgG positivity was 0% and 29%, respectively. Chronic relapsing inflammatory optic neuritis patients with MOG-IgG had more relapses than antibody negative cases (137).
Compression. Compression is insidious, then discovered by patient, and then slowly progressive. From tumor (eg, meningioma, pituitary, lymphocytic leukemia, orbital lymphoma), cellulitis, eosinophilic granuloma, hypertrophic pachymeningitis, infection of paranasal sinuses, 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) (55). However, Sjögren syndrome and lupus spectrum disease are strongly linked to neuromyelitis optica/Devic disease (see below). The occasional coincidence of optic neuritis (“autoimmune optic neuropathy”) and connective tissue disease (56) may be from occlusive vasculopathy, especially with the presence of anticardiolipin antibodies, or from compression, as with Wegener granulomatosis. Bilateral optic neuritis is reported in ankylosing spondylitis and CIDP. These cases often respond to glucocorticoid therapy, but require very slow oral steroid taper (143).
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 and tenderness over the artery, fever, weight loss, headache, fever, elevated sedimentation rate, and polymyalgia rheumatica.
CRION—see Chronic relapsing inflammatory optic neuritis
Crohn disease. This is rarely associated with optic neuritis
(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 idiopathic optic neuritis.
(b) Devic disease, or neuromyelitis optica spectrum disorders, 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, neuromyelitis optica spectrum disorders-associated optic neuritis is clinically more severe and rapid, often bilateral, 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 optic neuritis. There is significant axonal and oligodendroglial loss and sometimes necrosis. OCT shows marked loss of retinal nerve fiber layers and is more severe than in multiple sclerosis (20). The first symptoms can be optic neuritis (76%), transverse myelitis (13%), or both (10%), but optic and cord symptoms often coexist within a month. Posterior fossa, periaqueductal gray, and hypothalamic lesions may also be seen. Cerebrospinal fluid protein is high compared to multiple sclerosis and 75% have pleocytosis, but only 25% to 40% have oligoclonal bands. Seventy percent of patients have antibodies “IgG NMO” directed against the aquaporin-4 water channel protein on the foot processes of astrocytes that regulates water flow at the blood-brain barrier. Optic nerve demyelination and destruction is often severe in this disorder, is often associated with cord lesions, and is associated with other autoimmune diseases.
There is significant overlap with connective tissue disease, including CNS Sjögren syndrome. This predominantly affects young women of color, and all have inflammation on minor salivary gland biopsy, indicating Sjogren syndrome. It partially overlaps with NMO, but only 40% are NMO-IgG positive (112). Neuromyelitis optica spectrum disorders and CNS Sjogren disease may best be treated with anti-B-cell therapy such as rituximab, as well as IVIG and plasmapheresis. Biotinidase deficiency can also mimic NMO.
(c) Myelin-oligodendrocyte-glycoprotein-IgG-associated optic neuritis is defined by antibodies to myelin oligodendrocyte glycoprotein. Many have optic neuritis, often bilateral; longitudinally extensive optic nerve and perineural sheath enhancement can be seen. It can also present with transverse myelitis with thoracolumbar and conus predominance and lesions in the deep gray nuclei. In the pediatric population, this commonly presents as acute disseminated encephalomyelitis or recurrent optic neuritis.
(d) Optic neuritis associated with glial fibrillary acidic protein (GFAP) autoantibodies usually presents with bilateral, symmetric optic disc swelling in the absence of elevated intracranial pressure. Sometimes seen is inflammatory papillitis, ie, venular leakage on fluorescein angiography. Clinical presentation can include meningo-encephalomyelitis. So far, there are no reported cases with retrobulbar optic nerve involvement. MRI shows characteristic radial perivascular enhancement. Serum and CSF GFAP should be tested (67; 18).
(e) 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, below), CNS chlamydia pneumoniae, and after vaccination with BCG, meningococcus, Clostridium tetani, influenza, and variola (66). 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) (125). 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) (158). 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 (and possibly further hepatotoxicity from 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. There are several reports of optic neuritis with anti-CTLA-4 MAb (ipilizumab).
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) (237; 05). The highest prevalence is in India.
Glaucoma. Glaucoma can cause painful acute visual loss or chronic loss, with sparing of central vision, unlike optic neuritis.
Glioma or pituitary tumors. These infiltrate the optic pathways or compress the optic nerve.
Granulomatous disease. Optic neuritis can be seen with granulomatous diseases like sarcoidosis and granulomatosis with polyangiitis. Optic neuropathy associated with sarcoidosis is described below.
Guillain-Barré syndrome. Guillain-Barre syndrome is associated with slowed VEPs in 16% (89).
Hereditary causes. Dominant optic atrophy of Kjer; Leber hereditary optic neuropathy (below), and dominantly inherited optic atrophy from OPA1 mutation. Biotinidase deficiency, with low biotin levels, is linked to optic neuritis and transverse myelitis.
Herpes zoster ophthalmicus. MRI shows peripheral enhancement of the optic nerve sheath. Herpes simplex virus can cause acute retinal necrosis.
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 (38). Direct damage can be caused by tuberculosis, sarcoidosis, fungus such as aspergillus, cryptococcus, histoplasmosis, mucormycosis, toxoplasma gondii; mycoplasma pneumonia (159); cysticercosis, parainfectious schistosomiasis, toxocariasis (Toxocara canis or possibly cati; older, less pain, and more disk swelling than in idiopathic optic neuritis); bacterial infections such as anthrax, bartonellosis (cat scratch disease with neuroretinitis, disc edema, macular star), Lyme disease (borreliosis; Borrelia burgdorferi), brucellosis, cat-scratch disease (Bartonella henselae), Coxiella burnetii (Q fever), ehrlichiosis, familial Mediterranean fever, leprosy, malaria, meningococcal infection, purulent leptomeningitis, syphilis (140; 111), tularemia, typhoid (salmonella), 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 such as Cohn disease (60).
Leber hereditary optic neuropathy (LHON). 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 (91). In men, when diffuse white matter lesions are not present, the affected optic nerves show abnormalities on short-term inversion recovery MRI (124). The initial symptom is a central scotoma, often unilateral but eventually bilateral, within weeks. There is often pseudoedema of the retinal nerve fiber layer, plus hyperemia and swelling of the optic disc. There is no leakage on fluorescein angiogram, but there may be telangiectatic and tortuous peripapillary vessels. Visual loss is permanent and untreatable in this familial disorder. In multiple sclerosis with optic neuritis, LHON mutations are not increased in frequency.
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 (110). Treatment with doxycycline or ceftriaxone is recommended.
Lymphoma. This can be primary or secondary.
Maculopathy or macular degeneration (degenerative, hereditary, paraneoplastic, toxic—including macular edema from fingolimod therapy). Distortions are detected with an Amsler grid, and central vision is reduced.
Metastasis. This is the most common intraocular malignant tumor.
Migraine. Auras, often with shimmering, jagged borders, evolve and expand over minutes as spreading depression disturbs the function of occipital lobe neurons. “Retinal migraines” can occur without headache. Complicated migraines can cause infarcts, including anterior ischemic optic neuropathy.
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 to 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 (165).
Nutritional neuropathy. This includes Jamaican and Tanzanian neuropathy and Cuban epidemic neuropathy as well as vitamin B12 and folate deficiency. It often is amplified by viral illness such as mumps.
Occipital lobe lesions.
Optic nerve glioma. "Benign" glioma of childhood or pilocytic astrocytoma; malignant glioblastoma is more common in adults.
Optic perineuritis associated with orbital pseudotumor.
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. Often bilateral, but can be asymmetric. There is variable visual field loss. Visual disorders are linked to antibodies to CV2 protein or to 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 (172). Seen with small cell lung, renal, thymic, or thyroid cancer. Neurologic findings with other paraneoplastic disorders are diverse. Antibodies to Hu, Yo, Ma, Ri, Tr, and voltage-gated Ca++ channels are linked to optic neuritis. Melanoma-associated retinopathy syndrome causes night blindness (nyctalopia) and photopsia with a shimmering border; associated antibodies stain the bipolar layer of the retina (167; 168).
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 (133) and often associated with optic pallor in multiple sclerosis (08). Pars planitis increases the risk of developing multiple sclerosis alone by 16%, and the risk of multiple sclerosis or optic neuritis by 20% (148). 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 (30). 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 ameliorated 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 is occasionally associated with delayed visual evoked potentials, sometimes with normal amplitudes, and could be confused with optic neuritis. Vascular lesions can arise from diabetic macular ischemia. Other causes of retinopathy are retinal detachment, macular disease (central serous retinopathy, cystoid macular edema), paraneoplastic disease (cancer with anti-recoverin; melanoma with anti-rod bipolar cell antibodies), and diseases 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 (101).
Sarcoidosis causing optic neuropathy (not optic neuritis) (47). Pallor is more frequent than disc edema. Granulomas in dura are more frequent than is optic neuritis with sarcoid, and affect 5% of CNS sarcoid. Uveitis is possible. Intraorbital inflammation, anterior uveitis, vitreitis, periphlebitis, and keratoconjunctivitis are common with sarcoidosis. Serum angiotensin converting enzyme can be tested, although it has a low sensitivity and specificity of 66% to 67% (31). CSF sometimes shows elevated protein and lymphocytic pleocytosis. There is a lack of clear or defining characteristics with most clinical presentations in sarcoidosis, which is also known as the “great-mimicker.” If there is suspicion for sarcoidosis, then chest CT, FDG-PET scan, or tissue biopsy need to be performed (18). MRI lesions improve with glucocorticoids.
It sometimes causes elevated serum angiotensin converting enzyme (ACE), lysozyme, calcium, and liver function tests and sometimes 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 (51). 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 neuromyelitis optica spectrum disorders (112), 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 branch retinal arteries, away from the optic disc, and it is associated with corpus callosum lesions on MRI and cochlear microangiopathy, which reduces ability to hear.
Syphilis. Syphilis can cause optic neuritis and perineuritis as well as keratitis, uveitis, vitreitis, and chorioretinitis.
Toxins (see drugs).
Trauma. This can be direct or after anterofrontal deceleration.
Tumor. Tumors include germinoma, glioblastoma, leukemic infiltration, lymphoma, meningioma (may be bilateral in optic sheath). Others include carcinomatous meningitis, 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 (168).
Viruses or viral encephalitis. There are case reports linking viruses to direct damage of the optic nerve and sometimes describe lesions as vasculitis. Symptoms are often bilateral. Etiologies include measles, mumps, rubella; also chickenpox, chikungunya, coronavirus, 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, influenza A, parvovirus, varicella, and variola (62; 38). 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 and results in bilateral centrocecal scotomata (typical for nutritional/toxic damage) and optic atrophy (84; 196). 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).
Vogt-Koyanagi-Harada disease. (Uveomeningitis syndrome, uveomeningoencephalitic syndrome) affects pigmented melanin-containing tissues. Bilateral, diffuse uveitis is characteristic; it may also affect the inner ear (hearing loss and tinnitus), patchy hair loss, and CNS meninges with headaches and photophobia. It rarely can present with optic neuritis. It may be linked to excessive IL-17.
Wolfram syndrome. This is optic atrophy with familial juvenile-onset diabetes mellitus, diabetes insipidus, sensorineural deafness, and other neurodegenerative features. The gene mutation in wolframin WFS1 ion channel 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. There is widespread axonal dystrophy with axonal swellings in the pontocerebellar tracts, the optic radiations, the hippocampal fornices, and the deep cerebral white matter (201).
Warning signs or “red flags” that optic neuritis is not idiopathic and that an underlying inflammatory condition is the cause include rapid bilateral loss of vision, no pain or severe pain for more than 2 weeks, progressive loss over more than 2 weeks, and no recovery after 3 weeks of symptoms, complete or painless loss of vision and light perception with no early recovery, history of cancer, atypical fundus exam (atrophic or swollen optic nerve head; retinal abnormalities), optic atrophy with no history of demyelinating disease, severe disc edema with vitreous retraction, macular exudates, disc hemorrhage, and no response to corticosteroids or relapse upon stopping steroids (97).
The basic workup for optic neuritis should consist of fundoscopy, visual acuity to document the degree of visual loss, a neurologic exam, MRI, and lumbar puncture to rule out associated diseases, especially multiple sclerosis. Orbital MRI with fat suppression is important in atypical optic neuritis—patients older than 45 years of age, bilateral onset, no pain, vertical hemianopsia, swollen optic nerves, retinal exudates, progression over more than 2 weeks, and recent sinusitis (38). An ophthalmologic exam detects associated ocular abnormalities in approximately 20% of patients. When there are relevant clues, sedimentation rate, antinuclear antibodies, angiotensin converting enzyme levels, and tests for Lyme disease and syphilis are needed but are of little value in typical cases (12; Beck et al 1997).
In the past, some authors recommended essentially no investigation for optic neuritis (84). However, the presence of multiple sclerosis should be documented because it can be ameliorated by therapy. Serum NMO-IgG and anti-MOG IgG should be evaluated in patients with a history of severe bilateral or recurrent optic neuritis, as therapy differs between multiple sclerosis, neuromyelitis optica, and MOG-associated disease. CNS Sjögren disease, most common in young black women, overlaps with neuromyelitis optica spectrum disorder (112). A combination of visual tests to assess severity and predict prognosis could be used as a “visual disability severity scale,” including low-contrast visual acuity, ocular coherence tomography retinal nerve fiber layer thickness, optic nerve diameter, multifocal visual evoked potentials, low-contrast multifocal visual evoked potentials, and diffusion tensor MRI (Pula 2009, personal communication).
Some patients with multiple sclerosis have no history of optic neuritis and have normal visual acuity. In these patients, subclinical optic tract lesions are detected with visual evoked potentials (82%), contrast sensitivity tests (73%), pupillary light reflex (52%), flight of colors tests (36%), and color vision tests (Ishihara plates) (32%) (227). Visual evoked potentials help determine transmission along the optic nerve. A prolonged P100 will confirm optic neuropathy and demyelination. Optical coherence tomography can identify specific retinal and optic nerve pathology. Optical coherence tomography angiography can provide complementary information regarding the retinal blood vessels and aids in diagnosing the etiology of optic neuritis.
It was initially difficult to detect acute optic neuritis on MRI because of the small size of the nerve and because it is surrounded by fat that interferes with conventional T1 and T2 MRI. Short tau inversion recovery (STIR) MRI is more sensitive and reveals high-signal lesions in 85% of affected nerves and 20% of unaffected nerves (152; 80). In the asymptomatic eye, there is sometimes no slowing of visual evoked potentials, even when there are MRI lesions (102). Diffusion tensor imaging (DTI) shows lesions undetectable with conventional MRI (Naismith 2008, personal communication). More radial diffusivity on DTI correlates with decline in vision. Fast spin echo (FSE) and fluid attenuated inversion recovery (FLAIR) with fat suppression further improve imaging. Fat-suppressed T2 MRI (STIR) shows swelling of the nerve and dilatation of the anterior subarachnoid space. Fat-suppressed T1 shows enhancement of the optic nerve sheath (99).
Enhancement with dye indicates optic nerve inflammation or demyelination and is not seen with ischemic lesions. Lesion length correlates with defects in visual fields and with slowing of visual evoked potentials. The mean duration of enhancement is 63 days (range, 0 to 113). Optic nerve atrophy on MRI correlates with low visual acuity and color vision, retinal nerve fiber thinning, and reduced visual evoked potential amplitude, but not delayed latency—an effect of demyelination.
On MRI, certain characteristics to the optic nerve lesion can aid in determining if there is an underlying process like neuromyelitis optica or myelin oligodendrocyte glycoprotein. The radiologic appearance of anti-MOG-associated optic neuritis has distinguishing features such as enhancement of more than half of the prechiasmatic optic nerve, which is found in 80% of patients. Perineural enhancement with or without orbital fat stranding appears in over 50% of patients and is not typical with multiple sclerosis or neuromyelitis optica spectrum disorder-associated optic neuritis (39). In another retrospective study, 64% of AQP4-positive patients had chiasmal involvement compared to only 5% in anti-MOG disease and 15% in multiple sclerosis (179). The optic nerve involvement was longitudinal (compared to focal) in 95% of anti-MOG patients, 100% of AQP4 patients, but only 54% of multiple sclerosis patients.
Optical coherence tomography (OCT) with near-infrared light shows significant reduction of retinal nerve fiber layer (RNFL) thickness and macular volume (possible disappearance of retinal ganglion cells) (221). Six months after idiopathic or multiple sclerosis-related optic neuritis, the peripapillary nerve fiber layer is decreased by 45.3 um and macular thickness by 17.3 um (78). Two thirds of the macular atrophy is from loss of ganglion cells and inner plexiform layer cells, and a decrease at 1 month predicts later loss of color and low-contrast visual acuity and visual fields. The morphologic and functional loss seems more homogenously distributed over the macula in multiple sclerosis and more localized to the foveal and parafoveal area in neuromyelitis optica spectrum disorder (202). Patients with optic neuritis secondary to neuromyelitis optica spectrum disorder have more pronounced retinal nerve fiber layer thinning and visual function impairment than the idiopathic optic neuritis group (240). Severity of retinal nerve fiber layer loss from different etiologies is as follows: neuromyelitis optica (NMO) > optic neuritis > normal fellow eye in multiple sclerosis > normal fellow eye in ADEM > normal eyes. Damage is worse in men than women. Retinal nerve fiber layer degeneration and axonal loss is more likely when there are prolonged visual evoked potentials, impaired color vision, and poor low-contrast visual acuity (95). Microcytic macular edema was more prevalent in neuromyelitis optica spectrum disorder-associated optic neuritis and is linked to a higher frequency of clinical relapses (240).
Visual evoked potentials (VEP), triggered by a pattern reversal checkerboard, are often, or always, slowed in the affected eye. Thirty-five percent of 47 patients with optic neuritis returned to normal within 2 years (93), but latencies in the other patients were prolonged and did not improve, even when vision had returned to normal. Evoked amplitudes are normal or only mildly reduced in optic neuritis. Three-dimensional visual evoked potentials are moderately more sensitive than conventional visual evoked potentials for detecting post-chiasmal lesions (220). Multifocal visual evoked potentials (mfVEP) can potentially isolate and follow small sectors of an affected optic nerve but take longer to administer than the conventional evoked potentials. Visual evoked potentials correlate well with optical coherence tomography measures of the retinal nerve fiber layer (r=0.8) and are possibly more sensitive (130). Neuromyelitis optica spectrum disorder patients have more severe multifocal visual evoked potentials amplitude reduction compared with multiple sclerosis patients. In contrast, multifocal visual evoked potentials latency delay is more evident in multiple sclerosis patients. The disproportional amplitude to latency changes suggests that axonal loss was more significant than myelin loss in neuromyelitis optica spectrum disorder (202).
Electroretinogram detects outer retinal lesions. It typically shows abnormal P50 (early, A) and N95 (late, B) waves in retinal disorders, but only an abnormal N95 component in optic nerve disorders. However, the P50 can be abnormal in active optic neuritis. It does not correlate with visual evoked potentials.
Critical flicker frequency is reduced in 100% of affected eyes at onset, but returns to normal in over 90% of patients with recovery (239). Critical flicker frequency is lower in optic neuritis than in nonarteritic acute ischemic optic neuropathy. Elevated body temperature amplifies abnormalities in tests of function; normal eyes are much less sensitive to temperature increases.
The spinal fluid in optic neuritis sometimes contains elevated protein, mild lymphocytosis, 35% (104), 38% (73), or 48% (vs. 52% of multiple sclerosis) (206), free kappa-light chains (63%) (190), an elevated IgG index (20% to 36%) (73; 198), and oligoclonal bands (56% to 69%) (73; 198; 206). The presence of oligoclonal bands correlates with MRI lesions, and the presence or absence of bands tends to remain constant over time (Tourtellotte 1975, personal communication) 206). Myelin basic protein levels are usually normal. In Devic disease, bands are less common (27%) and tend to disappear.
In children, cerebrospinal fluid changes are variable. Only 2 or 3 of 30 children with idiopathic optic neuritis had pleocytosis (123; 150), or elevated protein or gamma globulin (123). In contrast, another study showed frequent pleocytosis, excess IgG, oligoclonal bands, and antiviral antibodies in 21 children with optic neuritis, but 16 of the children had preceding bacterial or virus infections or vaccinations (182).
In patients with Uhthoff sign, cooling the body by drinking ice water or taking a cold shower will often reverse the deficit (194). Some patients respond to 4-aminopyridine, a drug that increases the duration of the action potential in demyelinated axons by blocking potassium efflux (228). Red wine, possibly by reducing levels of endothelin-1 and thereby increasing ocular blood flow, temporarily increases visual acuity (92).
High-dose intravenous glucocorticoids speed recovery, especially if started early in the course of neuritis. This did not change functional outcomes in the optic neuritis treatment trial. The typical dose is 1 g of intravenous methylprednisolone per day for 3 days. Inexpensive alternatives are oral dexamethasone, 98 mg twice a day for 3 days, prednisone ten 50 mg tablets twice a day, or drinking a 1 g vial of methylprednisolone mixed into an iced fruit drink once a day for 3 days. Oral absorption of steroids is equivalent or nearly equivalent to IV absorption. Glucocorticoid boluses are sometimes followed by oral prednisone, tapered from 60 to 5 mg over 3 weeks. High-dose steroids were initially claimed to reduce the risk of developing further attacks of optic neuritis (210; 12) and reduce progression to multiple sclerosis (11). However, later studies showed that steroids did not lead to long-term improvement (97; 98) and did not prevent optic nerve atrophy, a position taken by the American Academy of Neurology in 2000. Nonetheless, neurologists (87%) are more likely than ophthalmologists (48%) to use the high-dose steroid bolus as therapy for optic neuritis (23).
Oral steroids at moderate doses of approximately 60 mg/day, with a relatively abrupt taper, actually seemed to provoke twice as many attacks of multiple sclerosis compared to high-dose intravenous steroids or placebo in the optic neuritis treatment trial (ONTT) (14). These differential effects vanished over 5 years, but oral steroids at this dose are no longer used to treat optic neuritis. An abrupt discontinuation of steroids may precipitate attacks of optic neuritis (56; 96; 62), suggesting that glucocorticoids should be tapered over 3 weeks (181). Nonetheless, 17% of ophthalmologists and neurologists treat acute optic neuritis with oral steroids and a short taper; this group is less likely to know the results of the ONTT (23; 177). ACTH is another potential therapy for acute optic neuritis if steroid therapy fails or is contraindicated.
Some of the information on responses to steroid therapy in optic neuritis may be biased from admixing idiopathic optic neuritis with neuromyelitis optica. The latter has features of antibody-mediated connective tissue disease, and abrupt steroid discontinuations may be more dangerous in this variant. In chronic relapsing inflammatory optic neuritis (CRION), relapses occur with rapid steroid withdrawal, suggesting this is a NMO-IgG seronegative form of neuromyelitis optica and not the idiopathic form of optic neuritis (126; 173). This is also the case with MOG IgG-related optic neuritis, which is also steroid dependent for maintaining remission. The same holds true for optic neuropathy related to granulomatous disease such as sarcoidosis.
Intravenous immunoglobulin was effective in relapsing-remitting multiple sclerosis patients with severe optic neuritis (vision worse than 20/400) who had failed high-dose intravenous methylprednisolone 3 months prior (225). Seventy-eight percent improved to near normal, compared to only 12% of untreated patients. Note that some of these may have been cases of neuromyelitis optica, as nearly half were African American, and this study predated the use of testing for the neuromyelitis optica antibody. In earlier studies, intravenous immunoglobulin improved vision in patients whose "visual acuity failed to recover after 6 months following acute optic neuritis" (229). However, in 2 controlled trials, it had little benefit (162; 186).
Plasma exchange may be effective in some steroid-refractory patients (187). However, spontaneous recovery may explain putative efficacy (119). There have been a few retrospective studies comparing intravenous methylprednisolone to plasma exchange. Improvement noted in visual acuity and visual fields with plasma exchange and a shorter interval to treatment from onset of symptoms seemed to improve outcomes (156; 18).
Clemastine fumarate, a first generation antihistamine, improved nerve conduction velocity in optic nerves, years after optic neuritis (86). Effects were slight, but significant (VEP sped up from 128 to 126.3 msec, with very high error bars), and suggest enhanced myelination.
Atacicept, which binds to the TACI receptor and thus eliminates B cells, tended to reduce RNFL loss, but increased transition to multiple sclerosis after optic neuritis (200). Opicinumab (anti-LINGO Mab) seemed to enhance remyelination, based on improvement in nerve conduction velocity (34).
CNM-Au8 is an investigational remyelination therapy using gold nanotechnology that is being studied in an ongoing phase 2 clinical trial (09). This therapy may aid in eliminating toxic free radicals and will thereby enhance ability to remyelinate. Early data are promising with notable trends in improved vision.
Multiple sclerosis is often associated with optic neuritis. The exacerbation frequency in multiple sclerosis is reduced by interferon beta (203) and now 12 additional drugs. These therapies are most effective if started early. If optic neuritis is a forme fruste of multiple sclerosis or shares a similar etiology, treatment with these agents seems reasonable. Interferon beta-1a therapy of acute monosymptomatic optic neuritis with multiple sclerosis-like MRI abnormalities reduced the chance of developing multiple sclerosis (108). In clinically isolated syndromes and optic neuritis, the chance of developing multiple sclerosis is reduced by approximately 50% with subcutaneous weekly IFN beta-1a and with every-other-day IFN beta-1b in multiple studies (119). The latter is approved for treatment of clinically isolated syndrome when there is a confirmatory MRI with multi-aged lesions. In Taiwan, 44 μg of interferon beta-1a thrice weekly reduced the chance of relapses of optic neuritis in patients with multiple sclerosis (41). Relapses fell from 1.01 per year in the 4 years prior to therapy to 0.21 relapses per year in the 3 years after therapy. There was no paired placebo group, but in this group of Asian patients, interferon did not cause exacerbations.
“High risk” patients with optic neuritis plus concomitant MRI lesions have a two thirds chance of developing multiple sclerosis within 5 years, yet some will not. Conversely, only 10% of patients with optic neuritis and a normal brain MRI will develop multiple sclerosis. An intensive history and examination, as well as MRI, spinal fluid, and patient psychology must be integrated into the decision to start long-term, expensive therapy.
Future treatments include neuroprotective agents such as erythropoietin, which prevents retinal nerve fiber layer thinning—but failed to prevent transition to multiple sclerosis in a small trial, ciliary neurotrophic factor, flupirtine (a Kv7 channel activator; in contrast, 4-aminopyridine is a K channel blocker), memantine (high-concentration-NMDA blocker), and sirtuin/SIRT1 activators (histone deacetylases). Three- to six-month pulses of interferon or other nonsteroidal multiple sclerosis drugs have not been tested. Inflammation in the eye can induce trophic factors from Muller cells.
Vitamin D3 supplementation (50,000 U/week x 1 year) reduced MRI lesions and conversion to clinically definite multiple sclerosis in a small, blinded, randomized study (52). In a correlational analysis of multiple sclerosis patients, optic neuritis attack severity was milder with higher serum vitamin D levels; recovery did not correlate (147).
Statins improved visual evoked potentials and latency in acute optic neuritis (222). However, significant mismatch in baseline function, despite randomization, makes the benefit questionable (116).
Antitumor necrosis factor therapy (infliximab, adalimumab, etanercept) can occasionally trigger multiple sclerosis and optic neuritis.
No epidemiologic studies have been done. As in multiple sclerosis, the normal immunosuppression of pregnancy probably makes optic neuritis less likely during pregnancy, but more likely for a few months after delivery.
There is currently no literature available on the interactions of optic neuritis and anesthesia.
Rinu Abraham MD
Dr. Abraham of the University of Chicago has no relevant financial relationships to disclose.See Profile
Anthony T Reder MD
Dr. Reder of the University of Chicago received honorariums from Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Mallinckrodt, Serono, and Teva-Marion for service on advisory boards and as a consultant and stock options from NKMax America for advisory work.See Profile
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Jan. 18, 2022
Movement disorders are prominent in the clinical presentation of many autoimmune disorders. These abnormal motor phenomena include faciobrachial dystonic seizures, neuromyotonia, chorea, myorhythmia, stereotypies, dystonia, tremor, parkinsonism, ataxia, and stiff-person-like phenomena. Each type of autoimmune encephalitis presents with a different profile of abnormal movements, and a therapeutic response to immunomodulatory therapy suggests that these motor phenomena also have an autoimmune pathogenesis.
Dec. 30, 2021
Acquired sensory neuronopathies depend on a primary involvement of sensory neurons in dorsal root ganglia leading eventually to a definitive and irreversible degeneration of the cell body. They include toxic, infectious, and dysimmune mechanisms, although an important proportion remains idiopathic after an extensive workup. The loss of large sensory neurons results in ataxia that usually predominates in the lower limbs, resulting in ataxic gate and Romberg sign.
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Neuro-Ophthalmology & Neuro-Otology
Toxic or nutritional optic neuropathy is classically characterized by gradual painless progressive vision loss, bilateral central or cecocentral scotomas, marked dyschromatopsia, loss of high spatial frequency contrast sensitivity, temporal pallor, and loss of papillomacular bundle. A thorough history of medication use, toxic exposure, substance abuse, dietary deficiency, past surgeries, family history, and peripheral neurologic symptoms should be documented. Early recognition, removal of toxic agents, and supplementation of nutritional deficiencies may lead to protracted visual recovery.
Dec. 02, 2021
Neuro-Ophthalmology & Neuro-Otology
Isolated fourth nerve palsy is a typically benign condition that causes ipsilateral hypertropia in primary gaze that increases on contralateral gaze and ipsilateral head tilt. The most frequent etiologies for isolated fourth nerve palsy are decompensation of a congenital weakness, head or surgical trauma, extra-axial nerve ischemia, nerve inflammation, and local compression by tumor.
Nov. 16, 2021
Hashimoto encephalopathy is a poorly understood syndrome of reversible cognitive impairment in the setting of antithyroid autoantibodies. There are no validated criteria for the diagnosis of the disease, but proposed diagnostic criteria include: (1) encephalopathy with seizures, myoclonus, or stroke-like episodes; (2) subclinical or mild overt thyroid disease; (3) normal or nonspecific abnormalities on brain MRI; (4) positive serum anti-TPO or anti-TG antibodies; (5) absence of well-characterized neuronal antibodies in CSF and serum; (6) reasonable exclusion of alternative causes.
Oct. 28, 2021
Clinically isolated syndrome is a first symptomatic episode of central nervous system dysfunction due to inflammatory demyelination, which may indicate the onset of multiple sclerosis, or may be an isolated incident. Patients may show accelerated brain atrophy and mild cognitive impairments.
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General Child Neurology
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