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Optic Neuritis
Laura J. Balcer, M.D., M.S.C.E.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors clinical recommendations.

A 25-year-old woman presents with a one-week history of blurred vision in the left eye. One day before the onset of visual loss, she noted a dull ache in the left periorbital region accompanied by pain on eye movement. Her symptoms progressed for three days but have not worsened since. The patient has no history of other visual or neurologic symptoms. Examination reveals visual acuity of 20/40 in the left eye when tested with a Snellen chart, reduced color perception, and a left afferent pupillary defect (i.e., a poor response of the left pupil to light stimulation as compared with the right pupil, on a swinging flashlight test). There is no visible swelling of the optic disk or pallor of the optic nerve, and a neurologic examination is normal. How should she be evaluated and treated?

The Cl inic a l Probl e m

Optic neuritis is a condition involving primary inflammation of the optic nerve. It may be associated with a variety of systemic autoimmune disorders, but the most common form, acute demyelinating optic neuritis, is best known for its association with multiple sclerosis.1-4 Acute demyelinating optic neuritis is the presenting feature (i.e., the first clinical demyelinating event) in 15 to 20 percent of patients with multiple sclerosis, and it occurs at some time during the course of the disease in 50 percent of patients.5-8 During a 10-year follow-up, multiple sclerosis was diagnosed in 38 percent of patients with a first episode of optic neuritis who were enrolled in the Optic Neuritis Treatment Trial (ONTT), a multicenter study of the effects of high-dose corticosteroid treatment on visual outcome.4 The risk was greatest among patients who had one or more demyelinating lesions on magnetic resonance imaging (MRI) of the brain at baseline but was not influenced over the long term by corticosteroid treatment.4,9 Additional data from natural-history studies indicate an even higher rate of multiple sclerosis among patients during a longer follow-up period after the first demyelinating events.10 Recurrences of optic neuritis after a single isolated episode are not uncommon. Among patients in the placebo group of the ONTT, the risk of at least one recurrence was 31 percent during the 10-year follow-up period and was greatest among those in whom multiple sclerosis had developed (48 percent in patients with multiple sclerosis vs. 24 percent in patients without multiple sclerosis).11 The high risk of multiple sclerosis associated with optic neuritis, combined with data from clinical trials demonstrating a reduction in this risk with early therapy among selected patients, underscores the importance of accurate diagnosis and management.12-15
From the Division of Neuro-ophthalmology, Departments of Neurology and Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia. Address reprint requests to Dr. Balcer at the Department of Neurology, 3 East Gates, 3400 Spruce St., Philadelphia, PA 19104, or at lbalcer@mail.med.upenn.edu. N Engl J Med 2006;354:1273-80.
Copyright 2006 Massachusetts Medical Society.

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S t r ategie s a nd E v idence
Diagnosis

History and Physical Examination

Acute demyelinating optic neuritis is a clinical diagnosis that is made on the basis of the history and clinical features (Table 1). Patients report subacute visual loss and difficulty perceiving colors; objects, particularly red ones, appear washed out. Pain on eye movement is common and was reported by 92 percent of the participants in the ONTT.1,21 Visual loss is usually monocular but may involve both eyes, particularly in children, and typically progresses to its nadir over a period of hours to days. In the placebo group of the ONTT, median visual acuity in affected eyes was 20/60 at baseline but improved to 20/25 by day 15 and to 20/20 by one month of follow-up.22,23

Worsening beyond one week or failure of recovery to begin within four weeks is considered suspicious for other diagnoses (Table 1).5-8,16,17 Although the majority of patients recover their visual acuity, subtle symptoms may persist. Even patients whose visual acuity recovers to 20/20 or better may report that their vision seems blurred, washed out, or not right.24 Examination of patients with acute demyelinating optic neuritis reveals evidence of optic neuropathy (e.g., impaired visual acuity and color vision, visual-field loss, and afferent pupillary defect).21 The visual acuity in affected eyes ranges from 20/20 or better to no light perception. An afferent pupillary defect is almost always present in the affected eye and is assessed by stimulating each pupil with a bright light in an alternating pattern; even mild dysfunction of the optic nerve

Table 1. Clinical Features and Differential Diagnosis of Acute Demyelinating Optic Neuritis. Characteristic Age (yr) Male sex (%) Pain Acute Demyelinating Optic Neuritis* 20 to 50 33 Present in >90% of patients; exacerbated by eye movement; resolves within 1 wk Anterior Ischemic Optic Neuropathy >50 50 Present in <10% of patients; accompanied by headache in patients with temporal arteritis Lebers Hereditary Optic Neuropathy 26 to 37 80 to 90 Not usually present; occasionally accompanied by headache

Visual loss

Progresses over a period of hours to days Sudden onset, often noted by patients Progresses over a period of weeks (maximum of 10 days); unilateral in on awakening; unilateral in adult pato months; involves both eyes adult patients; signs of optic neuropathy tients; signs of optic neuropathy (e.g., sequentially; signs of optic (e.g., visual-field loss and impaired visual visual-field loss and impaired visual neuropathy (e.g., visual-field acuity and color vision) acuity and color vision) loss and impaired visual acuity and color vision) Swelling present in one third of patients; hemorrhages and retinal exudates rare Swelling present; sectoral involvement May be pale or hyperemic; often of optic-nerve head and hemorrhages telangiectatic vessels present possible; optic disk in the fellow eye is crowded with a small or no cup Caused by central or cecocentral scotomas

Optic disk

Visual-field loss

Typically central but may be arcuate (radiat- Typically altitudinal (involving area ing from physiological blind spot), cecoabove or below horizontal) central (involving central vision and physiologic blind spot), hemianopic (involving area to right or left of vertical)

Recovery of Begins within 2 to 4 weeks and generally visual acuity reaches 20/20 or better in 75% of patients with normal vision at baseline

Improves by 3 or more lines on a Snellen Occurs to some degree in approxchart over a period of months in apimately 33% of patients proximately 40% of patients

* Absence of these typical features should suggest other causes of inflammatory optic neuropathy or alternative diagnoses (e.g., sarcoidosis, systemic lupus and other vasculitides, paraneoplastic disease, syphilis, Lyme disease, Bartonella henselae infection [associated with cat scratch neuroretinitis], ischemic optic neuropathy, or Lebers hereditary optic neuropathy).5-8,11,16,17 The time course of symptom onset distinguishes demyelinating optic neuritis from other inflammatory or compressive optic neuropathies in which visual function may worsen relentlessly over a period of weeks to months (e.g., sarcoid neuropathy, meningioma, or pituitary adenoma). Optic neuritis is more frequently bilateral in children than in adults and is more commonly associated with optic-disk swelling in children than in adults.18-20 These ophthalmoscopic findings were associated with an extremely low risk or no risk of multiple sclerosis within 10 years of follow-up among patients in the Optic Neuritis Treatment Trial.4 Data are from the Ischemic Optic Neuropathy Decompression Trial.16

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results in reduced constriction of the affected and contralateral pupils in reaction to light when the affected eye is stimulated during the swinging flashlight test. Absence of this finding in patients with acute visual loss suggests retinal disease (e.g., central serous retinopathy) or coincident optic-nerve dysfunction in the other eye.5-8 Visual-field loss is typical of acute demyelinating optic neuritis.21,25-27 Central scotomas are classic, but a more broad spectrum of patterns typically occurs, including diffuse defects (i.e., generalized depression of the entire central 30 degrees of the visual field) and focal defects.26,27 Altitudinal defects (visual-field loss above or below the horizontal meridian) are less common and should prompt consideration of a diagnosis of anterior ischemic optic neuropathy (Table 1). In addition to assessing visual acuity and the visual field, low-contrast letter acuity (perception of light gray letters of progressively smaller size on a white background) and contrast sensitivity (minimum contrast level or shade of gray at which patients can perceive letters of a single large size) are methods used to detect visual dysfunction in patients with acute optic neuritis and multiple sclerosis.28-30 Although these tests are not routinely performed in clinical practice, reductions in the scores for these measures have been demonstrated even in patients with visual acuities of 20/20 or better according to a Snellen chart. The optic disk appears normal in two thirds of patients with optic neuritis; these patients are said to have retrobulbar optic neuritis (Fig. 1A).21 When swelling (papillitis) is present in patients with optic neuritis (Fig. 1B), hemorrhages are uncommon. The presence of hemorrhages with swelling suggests alternative diagnoses, such as
Figure 1. The Optic Disk in Acute Demyelinating Optic Neuritis. In two thirds of cases, the optic disk appears normal (Panel A) and the patients are said to have retrobulbar optic neuritis. When optic-disk swelling (papillitis) is present (Panel B), it is mild and diffuse; there are no peripapillary hemorrhages, cotton-wool spots, or retinal exudates (lipid deposits) in this setting. Peripapillary hemorrhages, such as those seen in anterior ischemic optic neuropathy (Panel C, arrows), are associated with an extremely low risk or no risk of multiple sclerosis in patients with optic neuritis as a first demyelinating event and normal MRI of the brain.4 (Courtesy of Dr. Nicholas J. Volpe, Department of Ophthalmology, University of Pennsylvania School of Medicine, Scheie Eye Institute, Philadelphia.)

anterior ischemic optic neuropathy (Table 1 and Fig. 1C).4 Lipid deposits, called retinal exudates, that result from optic-disk edema are rare and suggest a diagnosis of neuroretinitis. After weeks of follow-up, clinically observable atrophy of the optic-nerve head and thinning of the nerve-fiber layer of the surrounding retina may develop despite recovery of visual acuity.30
A

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Several features of the history and examination are predictive of the risk of multiple sclerosis. Among patients in the ONTT who had optic neuritis as their first clinical demyelinating event and no white-matter lesions on MRI of the brain, the features associated with no risk or an extremely low risk of the development of multiple sclerosis within the 10-year follow-up period included hemorrhage of the optic disk or surrounding retina and the absence of pain. Severe disk swelling, no light perception, and retinal exudates were also associated with a low risk of multiple sclerosis; patients with these findings may have had alternative diagnoses.4
MRI

MRI of the brain should be performed routinely, preferably within two weeks after the onset of symptoms.9 Gadolinium-enhanced MRI (with fat saturation) of the orbits shows enhancement and enlargement of the optic nerve (Fig. 2A). More important is determining whether there are lesions indicating a high risk of multiple sclerosis. Characteristic demyelinating lesions in patients at risk for multiple sclerosis are 3 mm or larger in diameter, are ovoid, are located in periventricular areas of the white matter, and radiate toward the ventricular spaces (Fig. 2B).12-15 In the ONTT, the risk of multiple sclerosis within 10 years after the first episode of optic neuritis was 56 percent among patients with one or more characteristic white-matter lesions at baseline, as compared with 22 percent among patients with no lesions.4
Other Methods of Diagnosis

Oligoclonal banding of proteins in the cerebrospinal fluid is a useful predictor of the risk of multiple sclerosis. This is true particularly among patients with normal findings on brain MRI31 but also among patients with abnormal findings that are not classic for demyelination (e.g., small, punctate lesions that are not periventricular or ovoid). Tests of visual evoked potentials may be helpful in patients in whom the diagnosis of acute demyelinating optic neuritis is in question. Abnormal findings (e.g., increased latencies and reduced amplitudes of waveform) are consistent with demyelination in the afferent visual pathways and are observed in more than 65 percent

Figure 2. MRI of Brain and Orbits in a Patient with Acute Demyelinating Optic Neuritis. A T1-weighted gadolinium-enhanced axial image of the orbits with fat-saturation techniques (Panel A) shows diffuse enhancement of the left optic nerve (arrows). In patients with optic neuritis as a first demyelinating event, T2 -weighted and T1-weighted gadoliniumenhanced MRI of the brain are also recommended to identify white-matter lesions, which would indicate a high risk of multiple sclerosis. Characteristic demyelinating lesions have been defined in clinical trials as 3 mm or larger in diameter, with at least one periventricular or ovoid lesion (Panel B, arrows). 4,12-15 The T2 -weighted axial MRI in Panel B shows multiple areas of increased signal intensity in the periventricular white matter of the cerebral hemispheres. In the ONTT, the presence of one characteristic lesion at the time of acute visual loss more than doubled the risk of multiple sclerosis, as compared with the risk among patients with a normal MRI scan of the brain.4

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prednisone and 16.7 percent among those receiving placebo. Among patients with two or more white-matter lesions, the rate of multiple sclerosis at two years was 16.2 percent in the group receiving intravenous methylprednisolone, 32.4 percent in the group receiving prednisone, and 35.9 percent in the placebo group.24 However, the benefits of methylprednisolone did not persist on assessments beyond two years. Oral prednisone alone was associated with a significantly increased risk of recurrent optic neuritis among patients in the first 2 years (30 percent, vs. 13 percent for patients receiving intravenous methylprednisolone and 16 percent for those receiving placebo); the risk of recurrent disease continued to appear higher in the oral prednisone group at 10 years of follow-up, although the differences between groups were no longer significant.24 Similarly, a randomized trial in Japan showed quicker recovery of visual acuity among patients receiving intravenous methylShort-Term Treatment prednisolone as compared with those receiving a Intravenous methylprednisolone hastens recovery control drug (methylcobalamin) but no long-term of visual function but does not affect long-term effect on visual outcome.36 visual outcome.1,5-8,11 In the ONTT, patients were randomly assigned within 8 days after the onset Long-Term Therapy of symptoms to receive oral prednisone (1 mg per Interferon beta-1a and interferon beta-1b have kilogram of body weight per day for 14 days, with been shown to reduce the development of multisubsequent tapering over a period of 4 days), intra- ple sclerosis in patients with acute demyelinating venous methylprednisolone (250 mg every 6 hours optic neuritis and two or more characteristic defor 3 days) followed by oral prednisone (1 mg per myelinating lesions on MRI of the brain. Three kilogram per day for 11 days, with subsequent randomized trials have suggested a role for early tapering over a period of 4 days), or oral placebo.1 treatment in the setting of a first clinical demyeTreatment with intravenous methylprednisolone linating event.12-15 resulted in more rapid recovery of visual function The Controlled High-Risk Subjects Avonex to normal, particularly for visual fields (P<0.001 Multiple Sclerosis Prevention Study (CHAMPS) for the comparison with both of the other groups) included 383 patients with acute optic neuritis or and contrast sensitivity (P = 0.02 for the compari- other first demyelinating events who were at high son with both of the other groups).1 Differences risk for multiple sclerosis according to MRI eviwere greatest 4 and 15 days after the first episode dence (two or more white-matter lesions).12 All of optic neuritis and remained significant at the patients received 1 g per day of intravenous meth6-month follow-up for contrast sensitivity and ylprednisolone for 3 days; 193 patients were rancolor vision. At one year of follow-up and beyond, domly assigned within 27 days to receive weekly visual outcomes did not differ significantly be- intramuscular injections of 30 g of interferon tween groups.11,22,23 beta-1a (Avonex) and 190 were randomly assigned The rate of multiple sclerosis at two years of to weekly injections of placebo. Patients treated follow-up among patients who received intrave- with interferon beta-1a had a reduced three-year nous methylprednisolone was 7.5 percent, as com- cumulative probability of multiple sclerosis as pared with 14.7 percent among patients receiving compared with those receiving placebo (35 perof patients with optic neuritis.32,33 However, such testing is not routinely indicated, and abnormal findings may also occur with other conditions, such as optic-nerve compression, infiltration, and nondemyelinating inflammation. Multifocal visual evoked potentials can be a more sensitive and specific tool for detecting demyelinating optic neuritis, although the technique is not widely available for routine use.33 Optical coherence tomography is a noninvasive technique that uses near-infrared light to determine the thickness of retinal tissues. In research studies, it has been used to demonstrate thinning of the nerve-fiber layer of the retina in patients with a history of acute demyelinating optic neuritis, as well as in patients with multiple sclerosis who have no known history of optic neuritis.34,35 This technique currently is not used routinely in practice to assess patients with optic neuritis.

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cent vs. 50 percent); they also had a lower rate of new lesions on MRI. Results were similar in the subgroup of patients who presented with optic neuritis.13 An extension study (Controlled HighRisk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance, known as CHAMPIONS) showed that patients randomly assigned initially to interferon beta-1a still had a lower probability of multiple sclerosis at five years of follow-up (21 percent) as compared with patients who initially had received placebo but had begun to receive active treatment at two to three years of follow-up (35 percent).37 In the Early Treatment of Multiple Sclerosis study, 308 patients with first clinical demyelinating events (98 of whom had acute optic neuritis) were randomly assigned to receive either 22 g weekly of interferon beta-1a (Rebif) subcutaneously or placebo.14 Treatment was initiated within three months; 39 percent of patients had evidence of two or more central nervous system lesions at presentation. Seventy percent of patients received corticosteroids (variable dose and route of administration) before interferon beta-1a. During a twoyear period, multiple sclerosis was found to be significantly less likely to develop in patients in the interferon beta-1a group than in patients in the placebo group (34 percent vs. 45 percent), and significantly fewer new lesions on T2-weighted MRI developed in patients in the interferon beta-1a group. Preliminary results from the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial, involving 487 patients with a first clinical demyelinating event (80 patients with optic neuritis), suggest that 250 g of interferon beta-1b (Betaseron) subcutaneously every other day delays the development of multiple sclerosis.15 Consistent with other studies, multiple sclerosis was significantly less likely to be diagnosed in the interferon group within two years of follow-up as compared with the placebo group (28 percent vs. 45 percent). Patients in the interferon group also had significantly fewer lesions on brain MRI than did patients in the placebo group.

associated with an increased risk of recurrence, suggesting that this therapy be avoided.1,11 A study of patients who received higher doses of oral methylprednisolone (500 mg per day for 5 days, followed by a 10-day period of tapering) showed that recovery from visual symptoms, as assessed with the use of a visual-analogue scale, was hastened, but the study did not provide sufficient data regarding the risk of recurrent optic neuritis.38
Interferon Therapy

Interferon therapy has been investigated only in patients with acute demyelinating optic neuritis as a first clinical demyelinating event and two or more white-matter lesions on MRI of the brain.12-15 However, in longitudinal studies, the presence of one demyelinating lesion was associated with a risk of multiple sclerosis similar to the risk associated with multiple lesions.10 Evidence is lacking regarding the benefits of long-term treatment of patients with one lesion on MRI, but early therapy, continued surveillance with MRI at intervals of three to six months, or both seem reasonable in this setting.6
Intravenous Immunoglobulin

A small pilot study suggested that intravenous immunoglobulin may have some benefit in patients with resolved optic neuritis and substantial residual visual deficits. However, subsequent randomized trials in which the outcome measure was either visual acuity or contrast sensitivity failed to demonstrate a significant benefit.39,40
Pediatric Optic Neuritis

Acute optic neuritis in children differs from the typical adult form.18-20 Optic-disk swelling and bilateral disease are more common in children, as is severe loss of visual acuity (20/200 or worse in 84 percent of eyes in one series).19 Recovery of visual acuity is to 20/40 or better in 76 percent of patients. As in adults, the condition is predictive of the subsequent risk of multiple sclerosis, although estimates of risk vary among studies. In one longitudinal study, multiple sclerosis developed in 13 percent of children within 10 years after the first episode of optic neuritis, and in 19 percent within 20 years.18 A r e a s of Uncer ta in t y Effects of corticosteroid treatment and other High-Dose Oral Corticosteroids therapies on the recovery of visual function and Treatment of optic neuritis with oral prednisone on the risk of multiple sclerosis in children have at a dose of 1 mg per kilogram per day has been not been established by randomized trials, but

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Table 2. Treatment Options for Acute Demyelinating Optic Neuritis in Patients at High Risk for Multiple Sclerosis.* Treatment Short-term Intravenous methylprednisolone 1 g daily for 3 days plus 1 mg/kg of body Contraindications: systemic infection, immunodeficiency, severe hypertension weight of oral prednisone daily for 11 Potential side effects: sleep disturbances, days followed by 4 days of tapering mild mood changes, stomach upset, (day 1, 20 mg; days 2 and 4, 10 mg) weight gain, hyperglycemia, worsening hypertension Standard Dosage Contraindications and Potential Side Effects

Long-term Interferon beta-1a (Avonex) 30 g intramuscularly once weekly Interferon beta-1a (Rebif) 22 g subcutaneously once weekly 250 g subcutaneously every other day Interferon beta-1b (Betaseron) Contraindications: pregnancy, hypersensitivity to interferon beta or human albumin Potential side effects: influenza-like symptoms (e.g., fever, chills, and myalgias, which may be treated symptomatically), depression, anemia, hepatic dysfunction, inflammation at the injection site of subcutaneous preparations Monitoring: complete blood counts, liver function tests

* Characteristic demyelinating lesions in patients at risk for multiple sclerosis (indicating high risk in first episodes of acute optic neuritis) are 3 mm or larger in diameter, are ovoid, are located in periventricular areas of the white matter, and radiate toward the ventricular spaces.12-15

on the basis of data in adults, treatment with intravenous methylprednisolone is generally recommended if visual loss is unilateral and severe or is bilateral.20 Interferon therapy is considered in children with abnormal MRI scans of the brain, but data regarding the efficacy of therapy to prevent multiple sclerosis are lacking in this population.

Guidel ine s
Practice parameters published by the Quality Standards Subcommittee of the American Academy of Neurology note that intravenous methylprednisolone may hasten recovery of visual function but that no evidence of long-term benefit exists.41 This practice guideline antedated the publication of the clinical trials of interferon.

Sum m a r y a nd R ec om mendat ions

The patient described in the vignette has signs and symptoms typical of acute monosymptomatic demyelinating optic neuritis. Such patients should undergo evaluation with gadoliniumenhanced MRI of the brain to determine the risk

of the development of multiple sclerosis. If there are two or more white-matter lesions that are 3 mm or more in diameter, ovoid, and periventricular in location, which suggest a high risk of multiple sclerosis, treatment to reduce this risk should be strongly considered. I recommend intravenous methylprednisolone (1 g per day for 3 days) followed by oral prednisone (1 mg per kilogram per day for 11 days, with subsequent tapering over a period of 4 days). This therapy is based on data suggesting that it is likely to hasten recovery of visual function by two to three weeks and may reduce the risk of multiple sclerosis within two years after the first episode of optic neuritis. Treatment with interferon beta-1a or interferon beta-1b should be strongly considered after methylprednisolone treatment (Table 2), with the aim of further reducing or delaying development of multiple sclerosis during the long term. Oral prednisone alone may increase the risk for recurrent optic neuritis and should be avoided.
Dr. Balcer reports having received research fees from Biogen, Berlex, Centocor, and Serono. No other potential conflict of interest relevant to this article was reported. I am indebted to Steven Galetta for helpful comments regarding the manuscript.

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