Optic neuritis: a review.
Acute demyelinating optic neuritis (ON) is the initial presentation
in approximately 20% of cases of multiple sclerosis (MS) and is
characterized by unilateral, subacute, painful visual loss without
systemic or neurological symptoms. The Optic Neuritis Treatment Trial
(ONTT) has provided valuable insights into both the natural history and
clinical course of demyelinating ON with respect to treatment. Visual
function improves spontaneously over weeks and within 12 months 93% have
recovered to a visual acuity of at least 20/40. Treatment with high-dose
corticosteroids may accelerate visual recovery, but has little impact on
long-term visual outcome. In the ONTT the 10-year risk of recurrence of
demyelinating ON was 35%. The presence of white matter lesions on the
initial magnetic resonance image of the brain has been identified as the
strongest predictor for the development of MS. The 15-year risk of
developing MS in the ONTT was 25% with no lesions, but 75% with one or
more lesions. Since there is evidence of early axonal damage in acute
demyelinating ON, disease-modifying drugs should be considered in
patients at high risk of developing MS in the future as prophylaxis
against permanent neurological impairment.
KEY WORDS: OPTIC NEURITIS; MULTIPLE SCLEROSIS; OPTIC NEURITIS TREATMENT TRIAL; DEMYELINATING OPTIC NEUROPATHY; CORTICOSTEROIDS; DISEASE-MODIFYING DRUGS
(Dosage and administration)
Corticosteroids (Complications and side effects)
Optic neuritis (Complications and side effects)
Optic neuritis (Diagnosis)
Optic neuritis (Development and progression)
Optic neuritis (Demographic aspects)
Optic neuritis (Statistics)
Optic neuritis (Drug therapy)
Multiple sclerosis (Risk factors)
|Publication:||Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 PAREXEL MMS Europe Ltd. ISSN: 1352-8963|
|Issue:||Date: Nov, 2009 Source Volume: 16 Source Issue: 3|
|Topic:||Event Code: 680 Labor Distribution by Employer|
|Product:||Product Code: 2831136 Intravenous Immune Globulins NAICS Code: 325414 Biological Product (except Diagnostic) Manufacturing SIC Code: 2836 Biological products exc. diagnostic|
|Geographic:||Geographic Scope: United Kingdom Geographic Code: 4EUUK United Kingdom|
In most parts of the world acute demyelinating optic neuritis (ON) is the most common cause of unilateral painful visual loss in a young adult. In those regions where multiple sclerosis (MS) is common, most cases of ON are related to that disorder, although the diagnosis is not made until a second symptomatic episode (relapse) when the disorder can be referred to as MS-associated ON (MSAON). Typical cases can be referred to as demyelinating ON until a diagnosis of MS is made. Since ON can herald a more diffuse demyelinating disease, care should be taken in making an accurate diagnosis, and careful consideration given to treatment options, particularly as other causes of ON not related to MS require quite different management. The diagnosis of demyelinating ON is usually made clinically, although imaging of the optic nerves, preferably by magnetic resonance imaging (MRI), is mandatory for atypical cases. MRI of the brain can also yield prognostic information in terms of the patient's future risk of a second, MS-defining, episode. Much information has been gleaned from the ON Treatment Trial (ONTT) (1) where 377 patients with acute ON were prospectively assessed with respect to visual function, recurrence of optic neuritis and development of MS over 15 years. (2) The design of the ONTT was to measure visual field and contrast sensitivity as the primary endpoints of the trial and visual acuity and colour vision identified as secondary endpoints. (3) This article reviews adult demyelinating ON as a primary demyelinating inflammation of the nerve occurring either in isolation or in association with MS. ON in childhood, bilateral ON (both excluded from the ONTT) and non-MS-associated ON are important conditions that involve a different set of clinical phenotypes. We refer the reader to recent reviews on the differential diagnosis of ON. (4-6)
The clinical course of demyelinating ON initially involves an episode of demyelination followed, in the majority of cases, by near-full recovery; recurrent attacks are also compatible with good visual function. (7) However a small group of patients will have a poor visual outcome after a single attack and progressive visual loss is seen in MS. The pathogenesis of demyelinating ON is thought to involve an inflammatory process that leads to activation of peripheral T-lymphocytes which cross the blood-brain barrier and cause a delayed type hypersensitivity reaction culminating in axonal loss. Clinical recovery reflects the combined effects of demyelination with conduction block and axonal injury on the one hand, remyelination with compensatory neuronal recruitment on the other.
However, irreversible axonal damage occurs early in the disease process. A study using ocular coherence tomography (OCT) demonstrated that axonal injury is common in ON8 and observed retinal nerve fibre layer (RNFL) thinning in 74% of individuals within 3 months of acute ON. In this and another cross-sectional study of MS patients with ON, (9) RNFL was significantly reduced in the affected eye when compared with fellow eyes or disease-free controls. These and other studies (10) have correlated RNFL thinning with impaired visual function. OCT can be employed to monitor such progressive axonal loss in both primary and secondary progressive MS. (11)
For reasons that are not well understood, the incidence of MSAON is highest in populations located at higher latitudes, in northern USA, northern Europe and Australasia and falls significantly closer to the equator. (12) In the USA, studies have estimated the annual incidence of ON is five per 100 000, with a prevalence of 115 per 100 000; (13) these demographics closely follow those of MS. In addition, it is seen more commonly in Caucasians, and quite rarely in black populations. (14) Whites of northern European descent develop ON eight times more frequently than blacks and Asians. Studies have shown that individuals who migrate before puberty take on the incidence of MS in the area to which they migrate. (15,16) Therefore, an interaction exists between ethnic origin and the latitude at which the person grows up.
Clinical Features and Diagnosis
Typically, patients with first presentation of acute demyelinating ON are otherwise healthy young adults. A history of preceding viral illness may be present. There is a female preponderance by a ratio of approximately 3:1, (17) with most patients presenting between 20 and 45 years of age. Demyelinating ON is rare in children and is then often related to a post or para-infectious demyelination. In contrast to adults, demyelinating ON in children presents with bilateral involvement, in 60-70% of cases, and profound visual loss at presentation is more common. (18-21)
The classic triad of inflammatory ON consists of loss of vision, periocular pain and dyschromatopsia, and is unilateral in 70% of adults. The typical clinical course, outlined in Table 1, is that of retro-orbital pain usually exacerbated by eye movement, and loss of central vision. Visual loss varies from mild reduction to no perception of light and progresses over 7-10 days before reaching a nadir.
Periocular pain occurs in more than 90% of cases, may precede or coincide with the visual symptoms and usually resolves over days. All patients show reduced contrast sensitivity and dyschromatopsia, which are often out of proportion to the visual acuity deficit. Most persons show mixed red-green and blue-yellow colour defects, one type or the other predominating. (22) Any type of visual field defect is possible although the ONTT suggested that altitudinal field defects, arcuate defects and nasal steps were more common.
The amplitude of the pupillary light reflex is decreased in the affected eye which is clinically detected as a relative afferent pupillary defect (RAPD), an objective, but non-specific sign of optic neuropathy. In bilateral cases, or in cases with a preexisting optic neuropathy in the fellow eye, an RAPD may not be apparent. Two-thirds of cases of acute demyelinating ON are retrobulbar and the optic nerve appears normal. The disc swelling of demyelinating ON is diffuse and the presence of segmental changes, altitudinal swelling, pallor, arterial attenuation, and splinter haemorrhages should bring its diagnosis into question.
Additional associated clinical findings include: a reduction in vision in bright light; Uhthoff's phenomenon, exercise- or heat-induced exacerbation of visual symptoms described in 50% of patients with isolated ON; (23) and the Pulfrich phenomenon, in which anomalous perception of the direction of movement of an object occurs due to asymmetry of conduction velocity in the optic nerves.
Misdiagnosis of ON is not uncommon. (24,25) Although demyelination is its most common identifiable cause, many other causes of optic neuropathy may resemble ON (see Table 2). The reader is referred to a recent publication for a more detailed discussion of the differential diagnoses of ON. (26)
Neuromyelitis optica (NMO), also known as Devic's disease, is a rare cause of ON associated with myelitis. When recurrent, this disease has in the past often been misclassified as MS, but it is a separate entity that is distinguished from MS by its severity, by disease location (it affects the optic nerves and extensive segments of the spinal cord, largely sparing the brain) and by cerebrospinal fluid (CSF) analysis (polymorphonuclear pleocytosis and absence of oligoclonal banding). Serum NMO-immunoglobulin G is a specific autoantibody marker for NMO, targeting the water channel aquaporin-4 and is found in 70% of cases, suggesting that NMO may be a novel autoimmune channelopathy.
Investigations should be guided by the clinical presentation. A thorough list of differential diagnoses including their clinical features and further management strategy can be found in other reviews on this topic. (4,5,27,28)
The diagnosis of ON is usually made on clinical grounds. Neuro-ophthalmic assessments can improve diagnostic accuracy, and early review is essential to ensure visual recovery has begun and the diagnosis reconsidered if it has not. In a typical case of demyelinating ON as outlined in Table 1, without any clinical signs and symptoms of a systemic disease, the yield from diagnostic tests is extremely low and is of no value in typical cases. (29) However, if there are atypical features, as outlined in Table 3, suggestive of an alternative diagnosis, a comprehensive assessment should be undertaken.
The real value of MRI in typical demyelinating ON is not to image the optic nerves, but to image the brain as a prognostic indicator for the future development of MS. Orbital MRI should be reserved for those suspected of visual loss secondary to disease processes other than demyelinating ON. Visual evoked potentials (VEPs) are not helpful in differentiating between different causes of optic neuropathy in the acute phase. Subclinical cases may be confirmed electrophysiologically by VEPs if dyschromatopsia and optic disc pallor are discovered. Cerebrospinal fluid analysis is usually not necessary in patients with typical demyelinating ON.30 In the ONTT only the presence of oligoclonal bands correlated with later development of MS; even so, these patients also had an abnormal baseline MRI which predicted their higher risk of MS, rendering CSF analysis unnecessary. (31) In general, CSF analysis should be reserved for patients with atypical ON, especially in children, bilateral cases or when systemic or infectious diseases are suspected.
Low-contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli-Robson chart) have been found to show a high correlation with structural biomarkers, such as brain MRI (32) and RNFL thickness, (9) as measured by OCT, linking visual function with structural derangements within the anterior visual system. These simple and reproducible bedside examinations have been able to distinguished MS patients from disease-free control subjects (33,34) and are a sensitive clinical measure of visual dysfunction in both established MS and subclinical disease.
Recovery of visual loss occurs spontaneously starting within 2-3 weeks in 80%,7 stabilizing over months and continuing to improve for up to 1 year. (35) In the ONTT 79% and 93% of patients started to show signs of improvement within 3 and 5 weeks of onset respectively. (35) In the same study, 1 year following the initial attack of ON, 93% and 69% had a visual acuity better than 20/40 and 20/20 in the affected eye respectively. (36) At 15-year follow-up 72%2 (>92%) of patients had a visual acuity of 20/20 (>20/40) or better in the affected eye respectively and only 1% were worse than 20/200 in both eyes. (2,7) On average, visual function was worse in patients eventually diagnosed with MS than in those without MS. The severity of initial visual loss does appear to affect final visual outcome (37) and in the ONTT the best predictor of visual recovery was the baseline acuity at enrolment. (24) A recent analysis of the ONTT database evaluated predictors of abnormal 6-month vision, and reported that recovery is not as good with poor baseline visual acuity, but even with [less than or equal to]20/200 at baseline, recovery to [greater than or equal to]20/40 occurs in 85%.38 It is possible that other types of testing, such as measuring contrast sensitivity, OCT of the peripapillary RNFL, VEPs or MRI of the optic nerve could better discriminate between patients likely and unlikely to have permanent deficits in visual function after ON.
Temporal optic disc pallor develops within 4-6 weeks from the onset of ON and the RAPD may disappear when visual recovery is full.
Acute Therapeutic Options for ON
A meta-analysis of 12 randomized, controlled trials of corticosteroid treatment in both patients with ON and MS confirmed that although high-dose intravenous corticosteroids were effective in improving short-term visual recovery, there was no statistically significant benefit in long-term outcome, (39) even in those presenting with severe visual loss. Corticosteroids do cause side-effects, both minor, such as insomnia, weight gain and mood alterations, and major, including psychotic depression, pancreatitis and osteonecrosis. (27)
Although routine treatment of typical demyelinating ON with corticosteroids is not advised due to lack of long-term benefit and the potential for side-effects, there are specific situations where corticosteroids may be offered to shorten the period of functional impairment. Corticosteroids, therefore, are considered for patients who require faster recovery, such as monocular patients, patients with severe bilateral visual loss, or those with occupations requiring normal visual acuity. The recommended regimen is 1 g of intravenous methylprednisolone sodium succinate per day for three days, based on the ONTT. (25) An oral taper, however, is not normally necessary as this short treatment is unlikely to suppress the hypothalamic-pituitary axis. (40) Review within 1 month is recommended to ensure that vision does not deteriorate after cessation of treatment. Appropriate consent should be taken prior to commencing corticosteroids.
Intravenous immunoglobulin (IVIG) treatment in acute ON has been shown to have no beneficial effect. (41,42) There are no randomized prospective studies evaluating the role of plasma exchange in demyelinating ON and small studies of its use do not conclusively demonstrate a visual improvement beyond that expected from its natural history. (43) However, this would not be surprising if, as suggested, more severe cases such as NMO were included in the series.
At present, there is no treatment that can reverse established poor visual outcome after typical demyelinating ON.
Risk of Recurrence of ON
Optic neuritis can recur either in the same or the contralateral eye. The ONTT has shown that 28% (44) and 35% (7) of patients developed recurrence of ON within 5 and 10 years, respectively. Not surprisingly, recurrence was more common in patients who were subsequently diagnosed with MS. In the ONTT the risk of recurrence of ON at 5 years was found to be higher in the oral prednisolone (1 mg/kg) group (41%) when compared with those who received intravenous methylprednisolone or placebo (25%). (45)
At 10 years this higher risk between the prednisolone-treated (44%) and intravenous group (29%) had persisted, (7) but was no longer statistically significant (P=0.07). It is unclear whether this result should lead to a cessation in the use of oral prednisolone in acute ON as the effect has not been confirmed in other studies and was only statistically significant at an early time-point in the ONTT. Furthermore, this outcome measure was not one of the planned primary or secondary measures of the ONTT, (46) has no definitive biological explanation and should be viewed critically as a likely chance finding. It is also unclear whether the use of high-dose oral corticosteroids would also increase the risk of recurrent ON.47 A small prospective controlled clinical trial of oral methylprednisolone (500 mg/day for five days) showed no increase in the rate of demyelinating attacks. (48)
Risk of Developing MS
Multiple sclerosis is a clinical diagnosis based on the dissemination of typical lesions of the CNS in time and space. The ONTT reported that the risk of development of MS after an episode of isolated unilateral ON is 38% at 10 years (1) and 50% at 15 years. (49) Another study reported that 54% of patients with ON go on to develop MS after 30 years. (13) Up to 75% of female patients and 35% of male patients initially presenting with ON ultimately develop MS.50 In children the risk of MS following an episode of demyelinating ON is much lower than in adults and estimated to be 26% after 40 years. (21)
The most significant contribution of imaging in the setting of demyelinating ON is in imaging the brain. This is due to the fact that the most valuable predictor for the development of subsequent MS is the presence of white matter abnormalities. In a patient with demyelinating ON, the presence of even a single, 3 mm-diameter, T2-signal lesion seen on MRI increases the probability that additional neurological manifestations sufficient for a diagnosis of MS will develop. (51)
In the ONTT, the 5-year risk of developing MS was 16% in patients with normal brain MRI findings, 37% with 1-2 lesions and 51% with three or more lesions. At 10 years, the only statistically significant difference was between no lesions (22% risk) and one or more lesions (56% risk), (1,7,44) which at 15 years had risen to 25% and 75% respectively. (49,52) The mean time to diagnosis in patients who subsequently developed MS was 3 years. However, among patients with brain lesions seen on MRI, the 10- and 15-year probability of remaining free of MS was 44% and 25% respectively. Conversely, even in the absence of brain lesions the risk of developing MS was 22% and 25% at 10 and 15 years respectively.
In a similar study which looked at the predictive role of MRI lesions, but with fewer patients and lower follow-up rate, after 10 years MS was present in 83% of those with MRI lesions at enrolment and in 11% of those without. (53,54)
Other than lack of MRI findings, being male, having papillitis, vision of no light perception, lack of pain, retinal exudates and peripapillary haemorrhages are associated with a lower risk of developing MS. (1,7,44)
In the ONTT at 2-year follow-up of patients with acute ON and two or more lesions on MRI, the intravenous-methylprednisolone therapy group (versus placebo and oral prednisone groups) showed a significantly decreased risk of developing MS. However, this benefit was not maintained at 3 years (29,55,56) and is of doubtful significance.
Moreover, as mentioned above, this outcome measure was not one of the planned primary or secondary measures of the ONTT.
Magnetic resonance imaging evidence of dissemination of lesions of the CNS in time and space is sufficient for the diagnosis of MS even before clinical dissemination has occurred according to the McDonald diagnostic criteria. (57) When MRI was repeated at 3 months in patients presenting with a clinically isolated syndrome (CIS), the McDonald criteria were found to have a specificity of 93% and a positive predictive value of 83% for the development of clinically definite MS (CDMS) at 3 years. (58)
Pathological and MRI studies suggest that axonal damage occurs early on during the course of MS which will result in permanent neurological impairment. (59-61) This issue is at the centre of the debate over whether early intervention with DMDs in CIS, especially those with high-risk features for developing MS, can delay progression to CDMS. (62)
To date, there are three randomized, double-blind, placebo-controlled trials using interferon beta 1-a and 1-b in patients with CIS, such as ON, who have at least two or more white matter lesions on brain MRI. All three studies: the Controlled High-Risk Avonex[R] MS Study (CHAMPS), (63-65) the Early Treatment of MS (ETOMS) study (66) and the Betaferon[R] in Newly Emerging MS For Initial Treatment (BENEFIT) study, (67) demonstrated that interferon beta increases the time interval to a second MS-defining relapse in high-risk patients at 1-5 years. Patients in the interferon group also had significantly fewer lesions on brain MRI than did those in the placebo group. This effect is identical to the known effect of these treatments in relapsing-remitting MS, where the number of relapses is reduced by one-third, although here expressed as the time interval between the first and second relapses. In deciding whether or not to recommend such treatment after a first episode of demyelinating ON it should be remembered that over 40% of patients with abnormal MRI scans at baseline will not go on to have a second, MS-defining, episode at 10 years; also, these treatments are only partially effective: the patient needs to be treated for about 6 years in order to prevent one relapse (68) and finally, the long-term visual prognosis is favourable even if MS develops. (2)
Practical Help and Advice
Despite the fact that many patients presenting with ON for the first time will not develop MS, patients should be made aware of this association by the clinician. A fully informed discussion with the patient about their individual risk of developing MS, together with the availability of DMDs, can facilitate a decision about whether to organize a brain MRI. It is also crucial to emphasize that the patient may never develop MS.
Despite evidence that the majority of patients recover good vision based on objective parameters, many patients commonly complain of residual deficits in vision, (69) colour vision, (70) contrast sensitivity and difficulty with depth and motion perception, the latter due to the Pulfrich phenomenon. Symptomatic relief can be afforded by spectacles with one tinted lens in front of the unaffected eye to balance the delay in conduction from the other side. (71) Patients can alleviate Uhthoff's phenomenon by remaining indoors on hot and humid days and drinking plenty of cool fluids, but principally they need to be reassured that Uhthoff's symptoms are entirely reversible and not damaging to vision.
For patients who experience permanent visual impairment following ON a wide range of low-vision aids are available and formal psychological and emotional support are offered for people coming to terms with visual problems.
A thorough history-targeted ophthalmic and neurological examination of a patient presenting with painful unilateral visual loss should help to clinically identify those with typical demyelinating ON. Conditions which mimic demyelinating ON should be considered and atypical features promptly investigated. Specific neuroimaging and other laboratory studies must be directed by the clinical history and examination. When rapid visual recovery is desirable, intravenous methylprednisolone can be considered after discussion of possible side-effects and with the patient bearing in mind that treatment does not alter the final visual outcome.
The presence of any number of white matter lesions on brain MRI at first presentation in acute demyelinating ON can identify those at high risk of developing MS in the future; it may be appropriate to offer these individuals DMDs as prophylaxis, according to local protocols and following full discussion with the patient. Other high-risk clinical characteristics and natural-history information can aid in estimating a patient's individual 10-year risk for MS being the final diagnosis, bearing in mind that even when MRI lesions are present 40% will not develop CDMS within 10 years.
Conflicts of Interest
No conflicts of interest were declared in relation to this article.
* Acute demyelinating ON is the most common cause of unilateral painful visual loss in a young adult
* The diagnosis of ON is made clinically and consists of a classic triad of visual loss, periocular pain and dyschromatopsia
* Recovery of visual loss occurs spontaneously starting within 2-3 weeks and stabilizing over months
* MRI of the brain can yield prognostic information in terms of the patient's future risk of a second MS-defining episode
* The decision to treat with disease-modifying therapies (DMDs) should be individualized and the patient fully involved in the decision making process
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PN Shams [1,2], GT Plant [1,2,3]
 The National Hospital for Neurology & Neurosurgery, London, UK;  Moorfields Eye Hospital, London, UK;  St Thomas' Hospital, London, UK
Address for Correspondence
Gordon T Plant, Box 93, The National Hospital for Neurology & Neurosurgery, London WC1N 3BG, UK
Received: 26 May 2008
Accepted: 5 December 2008
Table 1: Features of typical demyelinating ON in adults * Acute to subacute onset--progressive over a few days to 2 weeks * Young adult patient, typically less than 45 years of age, but may be of any age * Periocular pain (90%), especially with eye movement--preceding or coinciding with visual loss * Unilateral loss of visual acuity--variable severity * Reduced contrast and colour vision--out of proportion to loss of visual acuity * Exacerbation of symptoms with increased body temperature (Uhthoff's phenomenon) * Ipsilateral relative afferent pupillary defect * Normal (65%) or swollen (35%) optic nerve head * Mild periphlebitis (venous sheathing) * Visual field defect--almost any type * Spontaneous visual improvement in >90% starting within 2-3 weeks regardless of treatment * No deterioration in vision when corticosteroids are withdrawn * Pallor of the optic disc is seen within 4-6 weeks from onset of visual loss * Overall, 50% of clinically isolated cases of ON go on to develop a second MS-defining episode by 15 years. The risk of developing MS is 25% when baseline MRI is normal and 75% when MRI has one or more brain lesions typical for MS (49,52) * Ancillary investigations suggestive of MS Table 2: Differential diagnosis of ON Corticosteroid-responsive optic neuropathies Sarcoidosis, systemic lupus erythematosus, Behcet syndrome, autoimmune ON, NMO, chronic relapsing inflammatory optic neuropathy Other inflammatory conditions Post-infection, post-vaccination, neuroretinitis, acute disseminated encephalomyelitis Compressive optic neuropathies Primary tumours, gliomas, meningioma, pituitary tumours--particularly craniopharyngioma in children, metastases, sinus mucocoeles, arterial aneurysms Ischaemic optic neuropathies Anterior and posterior ischaemic optic neuropathy, giant cell arteritis, diabetic papillopathy Infective conditions Tuberculosis, syphilis, Lyme disease, viral ON, toxocariasis or helminthitis (usually visible retinal/optic head lesion) Toxic and nutritional optic neuropathy Vitamin B12 deficiency, tobacco-ethanol amblyopia, methanol intoxication, ethambutol toxicity Inherited conditions Leber hereditary optic neuropathy Ocular causes Posterior scleritis, maculopathy, retinopathy, big blind spot syndrome Periorbital infection Cellulitis, severe suppurative sinusitis Factitious visual loss Intentional or 'hysterical' Table 3: Features of atypical ON in adults * Age <50 or >12 years * Bilateral simultaneous or rapidly sequential ON and chiasmitis * Severe visual loss--no light perception * Progressive visual loss for >2 weeks from onset * Painless visual loss * Pain following onset of visual loss or persistent pain for >2 weeks from onset * Severe pain that restricts eye movements or wakes patient from sleep * Unusual ocular findings: ** Marked anterior and/or posterior segment inflammation ** Marked periphlebitis (venous sheathing) ** Markedly swollen optic nerve head ** Marked optic disc haemorrhages ** Macular star * Lack of any visual recovery within 5 weeks or continued deterioration in visual function * Symptoms or signs of a systemic disorder other than MS * African or Asian race * Family history * Corticosteroid-dependent optic neuropathy/ deterioration in vision when corticosteroids are withdrawn * Previous history of neoplasia * Ancillary investigations suggestive of a diagnosis other than MS (NMO, sarcoidosis, Behcet syndrome)
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