Neuroimmunology
Autoantibodies: mechanism and testing
Dec. 20, 2024
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Optic neuritis (ON) …
- Updated 07.01.2024
- Released 01.24.1996
- Expires For CME 07.01.2027
Optic neuritis
Introduction
Overview
The author describes optic neuritis, which is 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.
Key points
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• Optic neuritis can occur alone or as a symptom of an underlying CNS autoimmune or demyelinating process like multiple sclerosis. Inflammation of the optic nerve can also arise from infection, granulomatous disease, and paraneoplastic and metabolic disorders. | |
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• Optic nerve inflammation causes subacute loss of vision, usually in one eye, and is usually associated with retro-orbital pain that is worsened with eye movement. | |
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• Clinical recovery and prognosis vary depending on the etiology. The prognosis of optic neuritis from multiple sclerosis is good with substantial or complete recovery 6 to 12 months after onset of symptoms. However, fundoscopy and ocular coherence tomography show residual thinning of the retinal nerve fiber layer in the affected eye and often reveal thinning in the normal fellow eye as well. Thus, bilateral damage is common, even if not apparent, and may be from sequential bouts. | |
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• High-dose glucocorticoid therapy speeds up recovery of the inflammation but has no long-term benefit. |
Historical note and terminology
Jean-Martin Charcot gave 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 two diseases (48). Sequin published the first American reports of "disseminated cerebrospinal sclerosis," including 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 (227). Adie, Denny-Brown, and McAlpine all stated that unilateral retrobulbar neuritis was a symptom of multiple sclerosis (132). 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 one of the many signs of definite multiple sclerosis. Severe optic neuritis could be from neuromyelitis optica/Devic disease, but the pathogenesis differs from multiple sclerosis-related idiopathic optic neuritis. This article focuses on optic neuritis as an isolated inflammatory demyelinating syndrome.
Clinical manifestations
Presentation and course
Optic neuritis typically begins with rapid, but not sudden, unilateral loss of vision. The dysfunction progresses over hours or days (86). It is associated with pain (92%) in or behind the eye (11). Pain may precede visual loss and lasts for days to weeks. An afferent pupillary defect is expected, unless the other eye is also concurrently involved or there is a history of optic neuritis in the other eye.
Visual loss is usually monocular, but 19% to 50% of adults (104; 09; 14) 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 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 (86). 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% (151).
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 lesions in the orbital optic nerve, but in only 30% of patients with lesions of intracranial pathways on MRI (62). 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 eye 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 (136). Severe, persistent pain beyond 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 (122).
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 (121; 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 (174). Clinically, complaints of bilateral visual field loss is noted with normal visual acuity, suggesting involvement of the posterior visual pathways. Transsynaptic degeneration can follow optic neuritis. The downstream optic tracts are thin from thalamus to pericalcarine and lateral occipital cortex in multiple sclerosis (81) and NMO/Devic disease (184). Altitudinal defects are characteristic of ischemic arterial disease, but they also appear in 6% to 20% of patients with optic neuritis (121).
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%) (28; 104). Papillitis is more common in children (65% to 70%) (122; 178; 87). With papillitis, inflammation of the anterior optic nerve causes disc swelling, and sometimes hemorrhages, cells in the vitreous, and deep retinal exudates, and 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 their 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 (75; 118). Six months after vision in the affected eye has recovered to 20/30 or better, there is residual 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. 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 (202). 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 (152) 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 (209). 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, vertical electric sensation triggered by neck flexion due to cervical cord lesions in multiple sclerosis (45), or a horizontal circular hug induced by a thoracic crunch movement due to cord lesions (Reder 2022, personal communication). The critical flicker fusion frequency is reduced. All of these symptoms are amplified by increased body temperature (Uhthoff sign) and by acidosis from exercise. 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 (191; 194). Impaired depth and motion perception could interfere with driving (72).
Less commonly recognized phenomena such as slit-like defects in the peripapillary nerve fiber layer, with or without a history of acute optic neuritis (78; 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 (143). 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 (139), 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, 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 one explanation for the huge range in incidence. In multiple sclerosis, it is associated with HLA-DR2. Seven percent with pars planitis will develop optic neuritis; 16% to 33% will develop multiple sclerosis (145; 172). The local target antigen 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 (170). 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 (122; 61; 87). In neuromyelitis optica spectrum disorders, optic neuritis is the first symptom in 80%; these are bilateral in 20% (148). Children with bilateral visual loss have a better prognosis than adults (161).
The risk of developing multiple sclerosis is discussed in the prognosis and complications section of this article.
Prognosis and complications
The clinical prognosis of optic neuritis associated with multiple sclerosis is surprisingly good. This data likely applies to isolated optic neuritis too. Of 457 patients, 91% to 95% had near-normal visual acuity of, at least 20/40, at one 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 (28). 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) (144), 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, severe attacks (OR=5.2), absence of pain, involvement of the intracanalicular optic nerve (52), obesity, 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 (82; 100). Visual impairment after six months was correlated with early markers of neuroaxonal injury in retina: retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness (188). Progressive visual worsening for more than 2 weeks, or no recovery after eight weeks, should prompt investigation into other causes of optic neuritis (119).
In children after a 2-year follow-up after optic neuritis, diagnoses were multiple sclerosis-associated optic neuritis (n = 90, 32.3%), single isolated optic neuritis (n = 86, 31), clinically isolated syndrome (n = 41, 14.7%), myelin oligodendrocyte glycoprotein antibody-associated optic neuritis (n = 22, 7.9%), and relapsing isolated optic neuritis (n = 18, 6.5%) (54). In those less than 10 years of age (prepubertal), the predominant diagnoses were MOG-associated optic neuritis and ADEM-associated optic neuritis; those greater than 10 years of age were more likely to develop multiple sclerosis. Recurrences were observed in 67 (24%) patients—28 with multiple sclerosis-associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with MOG-associated optic neuritis, eight with aquaporin-4 antibody related optic neuritis, and two with chronic relapsing inflammatory optic neuropathy. Recurrences were more common in females. The diagnosis of multiple sclerosis was more likely with onset at greater than or equal to 10 years (OR=1.24, p = 0.027), with cranial MRI lesions (OR=26.92, p< 0.001), and with oligoclonal bands (OR=9.7, p = 0.001).
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 (35). 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 seven 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 (151). Imaging with ocular coherence tomography can accurately define the loss. Visual evoked potential amplitude decay (indicative of axonal dysfunction) and visual acuity improve over four months, but visual evoked potential latency (indicative of demyelination) and motion perception remain impaired, interfering with walking and driving (176).
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 six had associated white matter lesions, evolved to multiple sclerosis in 40% over 1 to 5 years (120). Twenty-five percent to 75% of patients with optic neuritis have abnormal MRI scans. Seventy percent of optic neuritis patients with disseminated brain lesions on MRI have reduced attention and information processing speed (63), which is an indication of diffuse central nervous system dysfunction. Similarly, blood flow in the affected occipital cortex is reduced on functional MRI (213) and magnetization transfer (05), and activation of extra-occipital areas is increased (213). Conversely, 31% of army recruits with multiple sclerosis had optic signs (132).
In 39 studies before 1985, only one eighth to one third of patients with isolated idiopathic optic neuritis eventually developed clinical multiple sclerosis. Later studies had similar results. Low numbers in non-white European patients support a regional genetic variation in prognosis and lead to confusion with Devic disease. In 40 Italians older than 12 years of age, 25% developed multiple sclerosis (146), and 14% of 50 Swedish optic neuritis patients developed multiple sclerosis at one year (73). In the large, rigorous optic neuritis treatment trial, 17% of 126 placebo group patients in the United States developed multiple sclerosis over 2 years (in the placebo group) (10). At five years, 30% of the patients had developed multiple sclerosis (15); at 10 years, 38% of 388 patients, and at 15 years, 50% had multiple sclerosis independent of MRI lesions at baseline (160). Others find a higher rate of evolution to multiple sclerosis in Australia, Minnesota, and Europe, ranging from 40% to 60% (details in earlier versions of this chapter).
An isolated episode of optic neuritis without other signs of multiple sclerosis, NMO, or MOGAD (below) 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%) (49; 234), is associated with papillitis, and traditionally has a poor visual prognosis. However, a 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 (234). Optic neuritis, transverse myelitis, or cerebellitis are commonly present at the onset of multiple sclerosis in children (26).
Only 8% of 39 children developed a recurrence of optic neuritis and 15% developed multiple sclerosis after nine years (131). Other studies find multiple sclerosis in up to one third over 15 years. 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 (178). However, a larger study found that optic neuritis preceded by infections was less likely to lead to multiple sclerosis (142).
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 (28; 57; 178; 36). Multiple sclerosis is more likely to develop after optic neuritis in individuals aged 21 to 44 years (104; 179; 146), in women (179), and in patients with bilateral optic neuritis as adults (104) (though some reports disagree), rather than as children (161). Uhthoff symptom (192), retinal venous sheathing (139), 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 (15), as is onset of optic neuritis in January through March. Postvaccinal optic neuritis (178), a DR3 or DR2 background (70; 178), serum antibodies to proteasomes (22), potentially pathogenic (non-Leber) mitochondrial DNA variants (25), cerebrospinal fluid cells or oligoclonal bands (36; 85; 158), cerebrospinal fluid IgG (109), disseminated lesions on MRI (150; 189; 15), or abnormal evoked potentials also suggest that multiple sclerosis will develop (36). However, unless the lesions are concomitant, recurrent attacks of optic neuritis (either eye) do not increase the chance of developing multiple sclerosis (104; 70; 179), although one report disagrees (15). Visual function recovers less with successive episodes. A history of optic neuritis actually improves the long-term prognosis in multiple sclerosis patients compared to patients without optic neuritis (231).
Widespread MRI changes are more common when there is a history of optic neuritis in the fellow eye. However, when onset is bilateral, patients are not more likely to have MRI or clinical evidence of multiple sclerosis (09). Disseminated MRI lesions at the onset of optic neuritis increase the risk of developing multiple sclerosis. The MRI at baseline (disseminated lesions or not) is more often normal in optic neuritis than in other clinically isolated syndromes. With isolated idiopathic optic neuritis, 34% (150), 50% (107), 58% (15), 64% (154), to 70% (44) 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. With no baseline MRI lesions, a patient has a 25% chance of developing multiple sclerosis in 15 years (174). With one lesion, the cumulative probability is 60%. With three or more lesions, the likelihood is 78%. Spinal cord MRI determines dissemination in space in only 1% to 4% of optic neuritis patients who have normal brain MRIs (44).
CSF should be obtained when there is clinical uncertainty about diagnosis or prognosis. Oligoclonal bands predict future course, sometimes better than MRI. 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 (201). The combination of central nervous system MRI lesions plus oligoclonal bands augers a high risk for multiple sclerosis; 94% at four years (221). Patients with negative MRI yet positive bands are 10 times more likely to develop multiple sclerosis than those with negative MRI and no bands (42). A profile of negative MRI (specific) plus no oligoclonal bands (sensitive) strongly augurs against developing multiple sclerosis (0% at 2 years, 17% at 4 years) (221). In another series, the risk of developing multiple sclerosis was 66% at 4 years with three 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 (12). Recurrent optic neuritis is more common in patients who develop multiple sclerosis (48%) than in those who don’t (24%) (16). 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 (161). In children, 1 of 17 with recurrent optic neuritis developed multiple sclerosis.
Atypical features of optic neuritis, which include male gender, aged less than 18 years or greater than 50 years, absence of periocular pain, bilaterality, no light perception vision loss, vision loss that progresses past two weeks and that does not improve with steroids, or spontaneously, extensive optic nerve sheath enhancement including chiasm and optic tract, should prompt further workup of other conditions (01).
Glial autoantibodies (anti-MOG vs. oligodendrocytes or AQP4 IgG vs. astrocytes) are found in a third of all patients with recurrent optic neuritis (39). Antibodies to aquaporin 4 (NMO-IgG) have high sensitivity (73%) and specificity (91%) for NMOSD (135). 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. 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). Therapies sometimes differ from multiple sclerosis treatments. Effective therapies include antibodies to CD19, CD20, IL-6, and complement; and sometimes IVIG and plasmapheresis. Other disease-modifying therapies should be avoided, including interferon-beta, natalizumab, and S1P receptor modulators (112). The mechanism for adverse effects of interferon-beta in NMO is linked to the very high serum type I interferon levels compared to the subnormal levels in multiple sclerosis (65). Serum interferon levels have an odds ratio of 35 in discriminating between the two diseases.
Recurrent episodes of optic neuritis in multiple sclerosis often attack the previously affected nerve. However, in neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-positive recurrent optic neuritis, attacks are randomly distributed between the two optic nerves (141).
Chen and colleagues followed 87 patients with anti-myelin oligodendrocyte glycoprotein-associated optic neuritis and showed that 80% of patients had two or more attacks of optic neuritis with a median follow-up of 2.9 years (38). Thirty-seven percent of patients have bilateral simultaneous optic neuritis during one of their attacks. The prognosis of anti-aquaporin seronegative and myelin oligodendrocyte glycoprotein-associated optic neuritis 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%) (38; 115; 106). Antibodies to myelin oligodendrocyte glycoprotein are at high titers in children with recurrent optic neuritis (186).
Clinical vignette
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 in 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, and IgG; three 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 two weeks, her visual symptoms gradually improved. However, symptoms were worse after 10 minutes in the sauna at her health club for the next four weeks. After three 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.
Biological basis
Etiology and pathogenesis
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 (02). 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 (48). Idiopathic 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 not the cause of optic neuritis, but following an acute attack, antibodies to myelin basic protein appear in the serum. These antibodies become complexed to myelin basic protein within four months. The antibodies bind residues 61 to 106 of myelin basic protein (230). In a small subset of cases, antibodies recognize only proteolipid protein (229). Proteolipid protein induces experimental allergic optic neuritis in mice (171), 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 (77). 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 or from diverse inflammatory conditions, including multiple sclerosis, neuromyelitis optica spectrum disorders, myelin oligodendrocyte glycoprotein spectrum disorder, allogeneic bone marrow transplantation, granulomatous disease, anti-GFAP disease, anti-MOG disease postinfectious reactions (eg, following ehrlichiosis, tularemia, viral encephalitis, measles, mumps, chickenpox, hepatitis A and B, herpes zoster, HIV, HTLV-I, infectious mononucleosis, mumps, and some flaviviruses—Dengue and West Nile; these and other flaviviruses predominantly cause retinitis and vascular damage), contiguous inflammation (fungus, sarcoidosis, tuberculosis, Angiostrongylus cantonensis, brucellosis, chlamydia pneumoniae, or syphilis), or intraocular inflammation. With virus infections, the disease is often bilateral (61). When vaccination or virus infections are followed by optic neuritis in children, most have CSF oligoclonal bands and intrathecal antiviral antibody synthesis (178).
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. Yellow fever vaccination can cause optic neuritis. Many postvaccinal and postinfectious cases (9 of 21) subsequently develop multiple sclerosis within a year of the optic neuritis (178). The fever and inflammation from these infections may have exposed 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, Dqw1 (70), DR15, DQA-1B, DQB-1B (76), and a STAT4 allele in patients with optic neuritis. Compared to Caucasian patients, patients of African and Asian descent have worse visual acuity at onset and after one year (166), perhaps due to inclusion of neuromyelitis optica. Genetic influences may parallel the link of HLA-DRB/*1501 to Western, but not Asian, forms of multiple sclerosis (127). The Leber mutation may be a genetic risk factor for developing multiple sclerosis (225).
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 damage myelin or directly or indirectly 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 (03). Soluble ICAM, a product of activated white blood cells and endothelial cells, is increased in CSF at the first attack of optic neuritis (163). Serum interferon-gamma, interleukin-6 and interleukin-2 receptors, and CSF interleukin-2 are increased in patients with optic neuritis (47), 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 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 (126), as does endothelin-1 produced by activated astrocytes.
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 (204; 157), as is CXCL13 from myeloid cells, stromal cells, follicular B cells, and germinal center T cells – perhaps in meninges. However, cells secreting the anti-inflammatory cytokines, IL-10, IL-4, and TGF-beta are also more frequent, resulting in a complex mix of cytokines (a “cytokine storm”). The number of CSF cells producing inflammatory cytokines in optic neuritis did not correlate with MRI abnormalities or oligoclonal bands in an early study (128), but a later study showed that more IL-5, BDNF, and GDNF link to Gd+ MRI and oligoclonal bands (218). IL-8 in CSF correlates with acute and chronic visual loss in multiple sclerosis-associated optic neuritis (185). Markers of axonal injury and nitric oxide metabolites are increased in plasma.
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 (181). 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 (205). This oligoclonal response is often directed against multiple myelin basic protein epitopes, but more frequently against proteolipid protein (196). 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 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. In summary, immune changes in optic neuritis are similar to those in relapsing-remitting multiple sclerosis. There is no single target antigen and the response to myelin basic protein follows earlier immune activation of unknown cause.
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. Other mechanisms causing the B cell expansion should be considered.
Myeloid dendritic cells, which present antigens to T cells, are mature and activated in optic neuritis (219). They induce a Th1 bias and T cell proliferation. They are deactivated by simvastatin. However, statins increase disease activity when added to ongoing interferon treatment (24; 206) and block interferon signaling in vitro (53) and in vivo (64). Polymorphonuclear neutrophils are increased in the blood of patients with optic neuritis, compared to healthy controls.
Antioxidant enzymes suppress the demyelination in the optic nerves in experimental allergic optic neuritis, probably by interfering with the effects of inflammatory monokines (91). Uric acid, an antioxidant, is reduced in serum of patients with optic neuritis and 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 two years. Immune cells are also capable of secreting neurotrophic factors that induce repair.
Magnetic resonance spectroscopy of normal-appearing brain white matter after optic neuritis is often the same as in normal controls (214). 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 (232). After optic neuritis, there is trans-synaptic degeneration in the lateral geniculate nucleus. Fiber tracking with fast marching tractography, and with voxel-based analysis, shows dystrophy and lost connectivity in the optic radiations beyond the lateral geniculate (41; 80). Other studies find increased connectivity in the optic radiations, suggesting recruitment of activated neurons and dendrites to compensate for the damage (06).
Functional MRI shows that optic neuritis decreases afferent stimuli to the visual cortex, and reduces functional activation of the cortex (212). 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 three 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. In isolated optic neuritis, relatively more axons are usually destroyed along with the demyelination, although myelin loss still exceeds axonal loss. Ninety to 99% of patients with multiple sclerosis have lesions in the optic nerves at autopsy, with a high-low antero-posterior gradient of demyelination and axonal damage.
Epidemiology
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 in medium-risk areas for multiple sclerosis (Hawaii, Israel) (133). In Minnesota, the incidence is 5 per 100,000, and the prevalence is 115 per 100,000 (180). 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 (126). Risk of developing optic neuritis increases with female sex, obesity, smoking, white, and residence at high latitudes (29).
Episodes of optic neuritis are more common in the United States and Great Britain during spring and summer (211; 27; 104; 61), and in Sweden during the spring (114). In Poland optic neuritis appears in winter and spring (138). 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 and vitamin D (130).
The age in optic neuritis shows more patients at the young and old ends of the spectrum than in multiple sclerosis (132). 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) (132). In Japanese patients, compared to Caucasians, disc swelling is more common, but eye pain and periventricular plaques are less common (228). 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 (208). 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 diet. 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 (167). High serum vitamin D levels correlate 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).
Prevention
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 half as many patients treated with 1 gram of intravenous methylprednisolone per day than in groups treated with 60 mg/day of placebo or prednisone followed by a rapid taper (10). 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, patients with optic neuritis were treated for three days with 1 g of intravenous methylprednisolone and no taper (96). 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-long 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 (177).
Differential diagnosis
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 (86). Clinical differentiation from optic neuritis is sometimes difficult, but some patterns are characteristic.
Ischemic optic neuropathy (ION) (Nonarteritic ischemic optic neuritis, NAION). Here, loss of vision is usually acute and painless (in 90%), and it may not improve. Vision loss rarely progresses over several days with an unremitting course. 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. A visual field defect with a sharp border along the horizontal visual field meridian is more specific for ischemia (121; 84). 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%) (210). 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 was 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 with eye or temporal pain or tenderness and complete visual loss, 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 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 usually prevents 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, can compress 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.
Biotinidase deficiency. Biotinidase deficiency causes optic atrophy (biotin is vitamin B7).
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 (89).
Chemotherapy. Ara-C, cisplatin, 5-fluorouracil, and possibly tamoxifen.
Chronic relapsing inflammatory optic neuritis (CRION). Here, relapses occur after 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 relapses, and 38 were monophasic courses, of which MOG-IgG positivity was 0% and 29%, respectively. However, chronic relapsing inflammatory optic neuritis patients with MOG-IgG had more relapses than antibody negative cases (134).
Cogan syndrome. Cogan syndrome, with optic neuritis plus scleritis, episcleritis, and retinitis.
Compression. Compression is often 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. Optic nerve 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 (140).
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
Demyelinating diseases.
(a) Optic neuritis is often the first sign of multiple sclerosis, and the pathology of the optic nerve lesions can be similar or identical. Optic neuritis as defined here, however, is isolated to the optic nerves without dissemination in time and space, and CSF oligoclonal bands are less common in idiopathic optic neuritis. | |
(b) Devic disease, or neuromyelitis optica spectrum disorder (NMOSD), is a demyelinating, sometimes necrotic, inflammatory disease of the spinal cord and the optic nerves. This disease is more common in East Asian, Black, and South American than in European populations. Neuromyelitis optica spectrum disorder-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 in length and cross-section, more posterior, and can involve the chiasm--perhaps more than in idiopathic optic neuritis. The posterior location generates less pain. There is significant axonal and oligodendroglial loss and sometimes necrosis. Optical coherence tomography 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%). 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 strongly linked to other autoimmune diseases. Biotinidase deficiency can also mimic NMO. | |
(c) 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 disease. It partially overlaps with NMO, but only 40% are NMO-IgG positive (112). Neuromyelitis optica spectrum disorders and CNS Sjogren disease are treated with anti-B-cell therapy such as rituximab, as well as IVIG and plasmapheresis. Newer disease-modifying therapeutics are very effective in management of NMO and include eculizumab (anti-complement C5), inebilizumab (anti-CD19), and satralizumab (anti-IL-6). | |
(d) Myelin-oligodendrocyte-glycoprotein-IgG-associated (MOGAD) optic neuritis is defined by antibodies to myelin oligodendrocyte glycoprotein. Many have optic neuritis, often anterior and often bilateral. Optic disc swelling is common and pronounced. There is longitudinally extensive optic nerve and perineural sheath enhancement. It can also present with transverse myelitis with thoracolumbar and conus predominance and lesions in the deep gray nuclei. In the pediatric population, it commonly presents as acute disseminated encephalomyelitis or recurrent optic neuritis. Treatment options include azathioprine, mycophenolic acid, rituximab, IVIg, and corticosteroids. | |
(d) Optic neuritis 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; 17). | |
(e) Postvaccinal or postinfectious inflammatory demyelination can be 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 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 and rabies. 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 three 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, metronidazole, 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) (124). 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 three times per week) (155). This appears to be a direct effect of type I interferon, 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. 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-alpha (etanercept) and antibodies to tumor necrosis factor-alpha (adalimumab, certolizumab, infliximab) may trigger optic neuritis, as well as multiple sclerosis. There are several reports of optic neuritis with anti-CTLA-4 MAb (ipilizumab).
Immune-enhancing agents include anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies. Checkpoint inhibitor-associated optic neuritis differs from classical optic neuritis. It tends to be bilateral with painless visual decline, often with intact color vision. Visual function in most cases stabilized with drug cessation and systemic steroids (71; 226).
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) (233; 04). 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 neuropathy can be seen with sarcoidosis (below) and granulomatosis with polyangiitis.
Guillain-Barré syndrome. Guillain-Barre syndrome is associated with slowed visual evoked potentials in 16% (90).
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.
Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease [KFD]) with histiocytic optic lymph node inflammation is a rare self-limiting condition with a case report of bilateral optic neuritis.
Hysterical blindness.
Increased intracranial pressure (see pseudotumor).
Infarct (see acute ischemic optic neuropathy).
Infection and inflammation contiguous to the optic nerve. This can be associated with symptoms of optic neuritis (37). Direct damage is caused by sarcoidosis, mycoplasma pneumonia, toxoplasma gondii, tuberculosis (156); cysticercosis, parainfectious schistosomiasis, toxocariasis (Toxocara canis or possibly cati; older, less pain, and more disc swelling than in idiopathic optic neuritis); by 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 (137; 111), tularemia, typhoid (salmonella), or Whipple disease (Tropheryma whipplei), and also by fungus such as aspergillus, cryptococcus, histoplasmosis, and mucormycosis. 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).
Iritis.
Leber hereditary optic neuropathy (LHON). In men (90%), usually 15 to 25 years old, this mitochondrial syndrome causes sequential attacks of painless optic neuropathy associated with multiple sclerosis-like symptoms and diffuse MRI abnormalities (92). When diffuse white matter lesions are not present, the affected optic nerves show abnormalities on short-term inversion recovery MRI (123). 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.
Multiple sclerosis.
Neuroretinitis. This is a form of papillitis often seen with infections and characterized by associated deposits of lipids and protein. These deposits radiate from the macula 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 two 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 (162).
Nutritional neuropathy. This includes Jamaican and Tanzanian neuropathy and Cuban epidemic neuropathy as well as vitamin B12 and folate deficiency. It is often amplified by viral illness such as mumps.
Occipital lobe lesions.
Ocular pseudotumor.
Optic nerve glioma. "Benign" glioma of childhood or pilocytic astrocytoma; malignant glioblastoma is more common in adults.
Optic perineuritis associated with orbital pseudotumor.
Orbital cellulitis.
Papilledema. Papilledema is from increased intracranial pressure that interrupts axoplasmic flow, causing 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.
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 (168). 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 (164; 165).
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 (132) and often associated with optic pallor in multiple sclerosis (07). Pars planitis increases the risk of developing multiple sclerosis by 16%, and the risk of multiple sclerosis or optic neuritis by 20% (145). Fluorescein leakage on angiography also increases the risk for multiple sclerosis. Two percent of patients with intermediate, posterior, or panuveitis had optic neuritis in a medical database search, but only 0.6% with anterior uveitis. 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 retinal 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 white matter lesions in 12% and sometimes with multiple sclerosis (101). Causes of acute retinopathy include acute idiopathic maculopathy (AIM), acute retinal pigment epitheliitis (ARPE; Krill disease), acute macular neuroretinopathy (AMN), paracentral acute middle maculopathy (PAMM) seen on optical coherence tomography, acute zonal occult outer retinopathy (AAOR), acute idiopathic blind spot enlargement syndrome (AIBSE), and multiple evanescent white dot syndrome (MEWDS).
Sarcoidosis causing optic neuropathy (not optic neuritis) (46). Pallor is more frequent than disc edema. Granulomas in dura affect 5% of CNS sarcoid and are more frequent than is optic neuropathy with sarcoid. Uveitis is possible. Intraorbital inflammation, anterior uveitis, vitreitis, periphlebitis, and keratoconjunctivitis are common with sarcoidosis. Serum angiotensin converting enzyme (ACE) can be tested but has 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 (17). MRI lesions improve with glucocorticoids.
It sometimes causes elevated serum angiotensin converting enzyme (ACE), lysozyme, calcium, and liver function tests.
Sjögren syndrome. This involves the nervous system in 20% of cases; optic neuropathy is present in one fourth of cases with CNS involvement (50). 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.
Thyroid ophthalmopathy.
Tobacco-alcohol amblyopia.
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), and histiocytosis (non-Langerhans cell/orbital Rosai-Dorfman disease). 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 (165).
Venom from cobra or krait envenomation.
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 (inflammation can be bilateral), rubella; also chickenpox, chikungunya, coronavirus, coxsackie B5, cytomegalovirus, dengue fever (hemorrhagic), echovirus type 5, Epstein-Barr virus, hand-foot-and-mouth disease (coxsackie and enterovirus), hepatitis A and B, herpes zoster, human herpes virus-6B, HIV, HTLV-1, infectious mononucleosis, influenza A, parvovirus, varicella, and variola (61; 37). 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 with bilateral centrocecal scotomata (typical for nutritional/toxic damage) and optic atrophy (86; 193). 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.
Vitreoretinal traction.
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), cause patchy hair loss, and affect 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 (198).
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 two weeks, progressive loss over more than two weeks, and no recovery after three 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).
Diagnostic workup
The basic workup for optic neuritis consists of fundoscopy, visual acuity to document the degree of visual loss, a neurologic exam, MRI, and sometimes 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 two weeks, and recent sinusitis (37). 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 (11; 15).
In the past, some authors recommended essentially no investigation for optic neuritis (86). 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 tested 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%) (222). Visual evoked potentials help determine transmission along the optic nerve. A prolonged P100 will confirm optic neuropathy and demyelination. Visual evoked potentials and P100 slowing is worse with NMO than multiple sclerosis or idiopathic optic neuritis.
It was initially difficult to detect acute optic neuritis on MRI because of the small size of the nerve and surrounding 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 (149; 82). The normal prechiasmatic optic nerve is 15% brighter than the midorbital optic nerve, possibly confusing readings. In the asymptomatic eye, there is sometimes no slowing of visual evoked potentials, even when there are MRI lesions (102). 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). Diffusion tensor imaging (DTI) shows lesions undetectable with conventional MRI (Naismith 2008, personal communication). More radial diffusivity on DTI correlates with decline in vision.
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 poor 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. Anti-MOG-associated optic neuritis shows enhancement of more than half of the prechiasmatic optic nerve, 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 (38). 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 (175). The optic nerve involvement was longitudinal (not 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 can identify specific retinal and optic nerve pathology. In optic neuritis, it shows significant reduction of retinal nerve fiber layer (RNFL) thickness and macular volume (possible disappearance of retinal ganglion cells) (216). 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 (79). 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 (199). 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 (236). 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) and microvascular dropout. Microcytic macular edema was more prevalent in neuromyelitis optica spectrum disorder-associated optic neuritis and is linked to a higher frequency of clinical relapses (236).
Optical coherence tomography angiography can provide complementary information regarding the retinal blood vessels and aids in diagnosing the etiology of optic neuritis.
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 two years (94), but in 65%, latencies were prolonged and did not improve, even when vision had returned to normal. Low-contrast VEP can increase sensitivity. 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 (215). 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 (129). Neuromyelitis optica spectrum disorder patients have more severe multifocal visual evoked potentials amplitude reduction than in multiple sclerosis patients. In contrast, multifocal visual evoked potentials latency delay is more evident in multiple sclerosis. The disproportional amplitude to latency changes suggests that axonal loss is more significant than myelin loss in neuromyelitis optica spectrum disorder (199).
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 fusion frequency is reduced in 100% of affected eyes at onset, but returns to normal in over 90% of patients with recovery (235). Values are approximately 32 Hz in healthy eyes, but 20 Hz in optic neuritis. The digital flicker test is also sensitive. Critical flicker fusion 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% (74), or 48% (vs. 52% of multiple sclerosis) (203), free kappa-light chains (63%) (187), an elevated IgG index (20% to 36%) (74; 195), and oligoclonal bands (56% to 69%) (74; 195; 203). 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) 203). 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 two or three of 30 children with idiopathic optic neuritis had pleocytosis (122; 147), or elevated protein or gamma globulin (122). In contrast, frequent pleocytosis, excess IgG, oligoclonal bands, and antiviral antibodies appeared in 21 children with optic neuritis, but 16 of them had preceding bacterial or virus infections or vaccinations (178).
Management
In patients with Uhthoff sign, cooling the body by drinking ice water or taking a cold shower will often reverse the deficit (191). Some patients respond to 4-aminopyridine, a drug that increases the duration of the action potential in demyelinated axons by blocking potassium efflux (223). Red wine, possibly by reducing levels of endothelin-1 and thereby increasing ocular blood flow, temporarily increases visual acuity (93).
High-dose intravenous or oral (same absorption) glucocorticoids speed recovery, especially if started early in the course of neuritis. The typical dose is 1 g of intravenous methylprednisolone per day for three days. Inexpensive alternatives are oral dexamethasone, 98 mg twice a day for three 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 three 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 three weeks. High-dose steroids were initially claimed to reduce the risk of developing further attacks of optic neuritis (207; 11) and reduce progression to multiple sclerosis (10). 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. 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) (13). These differential effects vanished over five years, but oral steroids at this dose are no longer used to treat optic neuritis. Abrupt discontinuation of steroids may precipitate attacks of optic neuritis (56; 96; 61), suggesting that glucocorticoids should be tapered over three weeks (177). 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; 173). 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 are 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 (125; 169). This is also the case with MOG IgG-related optic neuritis, which is also steroid dependent for maintaining remission.
ACTH/repository corticotrophin improved low contrast visual acuity in the newly-symptomatic eye and also in the clinically uninvolved fellow eye (190). It also was less toxic and more beneficial than steroids in cases of Devic disease (18).
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 three months prior (220). Seventy-eight percent improved to near normal, compared to only 12% of untreated patients. Some of these may have been cases of neuromyelitis optica, as nearly half were Black, 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 six months following acute optic neuritis" (224). However, in two controlled trials, it had little benefit (159; 182). Patients with minimal recovery after corticosteroid therapy have a 12.8-fold chance of improvement in visual acuity with steroids plus IVIG; steroids plus plasmapheresis has an improvement odds ratio of 2.5 (83).
Plasma exchange may be effective in some steroid-refractory patients (183). 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 (153; 17).
Clemastine fumarate, a first generation antihistamine, improved nerve conduction velocity in optic nerves, years after optic neuritis (88). Effects were slight, but significant (VEP sped up slightly, from 128 to 126.3 msec, with very high error bars), and suggest enhanced myelination. Patients may complain that the drug is too sedating.
Opicinumab (anti-LINGO Mab) seemed to enhance remyelination, based on improvement in nerve conduction velocity (34). Benefit on vision was too minimal to submit to the FDA as a multiple sclerosis therapy.
CNM-Au8 is an investigational remyelination therapy using gold nanotechnology that is being studied in an ongoing phase 2 clinical trial (08). 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.
Lipoic acid, 1200 mg per day po, had no benefit.
Multiple sclerosis is often associated with optic neuritis. The exacerbation frequency in multiple sclerosis is reduced by interferon beta (200) 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 (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 (40). Relapses fell from 1.01 per year in the four years prior to therapy to 0.21 relapses per year in the three 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 five 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 ciliary neurotrophic factor, flupirtine (a Kv7 channel activator; 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.
Erythropoietin did not prevent retinal nerve fiber layer thinning in acute optic neuritis. Importantly, transition to multiple sclerosis was lower (36%) than with placebo (57%) (43).
Statins improved visual evoked potentials and latency in acute optic neuritis (217). However, significant mismatch in baseline function, despite randomization, makes the benefit questionable (116).
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 (51). In a correlational analysis of multiple sclerosis patients, optic neuritis attack severity was milder with higher serum vitamin D levels; recovery did not correlate (144).
Some drugs should be avoided. 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 (197).
Antitumor necrosis factor therapy (infliximab, adalimumab, etanercept) can occasionally trigger multiple sclerosis and optic neuritis. Ciprofloxin and its family members, levofloxacin, moxifloxacin, and others, increase inflammatory cytokines, and they can cause exacerbations of multiple sclerosis (Reder 1985, personal communication) (multiple cases were reported in Medlink; three journal editors asked for a controlled trial) and peripheral nerve inflammation (FDA-mandated black box in 2013 package insert).
Special considerations
Pregnancy
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.
Anesthesia
There is currently no literature available on the interactions of optic neuritis and anesthesia.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Anthony T Reder MD
Dr. Reder of the University of Chicago received honorariums from Biogen Idec, Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant as well as stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.
See Profile
Former Authors
- Rinu Abraham MD
Patient Profile
- Age range of presentation
-
- 2 to 65+ years
- Sex preponderance
-
- female>male, >2:1
- Heredity
-
- heredity may be a factor
- Population groups selectively affected
-
- Northern Europeans
- East Asians (Devic disease, NMO)
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Optic neuritis: H46
- ICD-11
-
- Optic neuritis: 9C40.1
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