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Evolving Management of Optic Neuritis and Multiple Sclerosis
PERSPECTIVE Evolving Management of Optic Neuritis and Multiple Sclerosis ANTHONY C. ARNOLD, MD
● PURPOSE:
To review the relation of optic neuritis to multiple sclerosis (MS) and the indications, modalities, and results of therapy for optic neuritis, for both visual and general neurologic function. ● DESIGN: Literature review and author’s experience. ● METHODS: Analysis of both laboratory and clinical evidence supporting the use of corticosteroids, immunomodulation agents, and other modalities in the treatment of optic neuritis and MS. ● RESULTS: Although treatment of optic neuritis with corticosteroids may hasten visual recovery to a minor degree, it has no long-term beneficial effect on visual outcome. Optic neuritis is frequently the initial manifestation of multiple sclerosis. The risk of later development of clinically definite MS (CDMS) correlates with white matter demyelinative lesions on magnetic resonance imaging (MRI). The role of corticosteroid therapy alone in reducing the risk of subsequent MS is unclear, but recent studies suggest that the combination of immunomodulation agents (IMAs) and corticosteroids significantly reduces the later development of MS. Current research indicates that, contrary to previous doctrine, axonal damage is an early finding in MS. ● CONCLUSIONS: The risk of MS after optic neuritis may be predicted. The use of corticosteroids and IMAs, particularly in those at substantial risk, reduces the frequency and severity of developing CDMS. Earlier, more aggressive therapy in optic neuritis may be proven to reduce permanent axonal injury and progressive disability in MS. (Am J Ophthalmol 2005;139:1101–1108. © 2005 by Elsevier Inc. All rights reserved.)
Accepted for publication Jan 20, 2005. From the Jules Stein Eye Institute, Los Angeles, California, USA. Inquiries to Anthony C. Arnold, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7005; Fax (310) 267-1918; e-mail: [email protected] 0002-9394/05/$30.00 doi:10.1016/j.ajo.2005.01.031
©
2005 BY
T
HE TREATMENT OF OPTIC NEURITIS IS CONTROVER-
sial. Although several specific forms of optic nerve inflammation require and respond to therapy (e.g., corticosteroids for sarcoid optic neuropathy, antibiotics for syphilitic optic neuropathy), management of typical demyelinative optic neuritis is not clear-cut. The use of corticosteroids, although a logical option for an inflammatory condition, has been of questionable benefit for visual recovery in this disorder in which there is a high spontaneous resolution rate. The relationship of optic neuritis to multiple sclerosis (MS) has also been unclear in the past, and the practical value of predicting the risk of MS after optic neuritis is limited because there was no proven intervention for reducing it. Corticosteroids have been the standard of therapy in documented MS to reduce morbidity of acute flare-ups and possibly reduce long-term morbidity from attacks. Interferons and other immunomodulation agents have been proved to reduce the risk of future attacks in established cases of relapsing-remitting MS (RR-MS). The beneficial effect of any of these agents to reduce the risk of developing MS and the effect on long-term visual outcome after an initial episode of isolated optic neuritis were unproven, however. Over the past decade, however, a large volume of new information has emerged regarding therapy for optic neuritis and MS. The data suggest that although treatment has only a minor effect on visual outcome, it may have a major effect on the course of neurologic disease. We have come to realize that not only can we substantially reduce later development of MS after an initial episode of optic neuritis, but that if we do not reduce this risk, we may substantially increase the long-term disability of affected patients. It must be emphasized that published data regarding idiopathic optic neuritis address only the typical, acute form. Infrequently, optic neuritis presents as an insidious, chronically progressive optic neuropathy, without discrete episode of pain, optic disk edema, or reversible visual loss. The optic neuropathy may be the presenting finding of MS
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or may occur in patients already diagnosed with the disease. In these patients, who typically demonstrate central visual loss and optic atrophy at presentation, corticosteroid therapy has not been shown to affect visual outcome, and, as with other progressive forms of MS, immunomodulation agents have not been shown to be effective in reducing visual or neurologic morbidity. In the management of typical idiopathic demyelinative optic neuritis, the ophthalmologist must consider many questions, a number of which remain unanswered. They may be divided into those regarding visual outcome (recovery of visual function, recurrence of optic neuritis) and those regarding neurologic outcome (incidence of MS, severity of neurologic dysfunction from MS). Questions regarding visual outcome: 1. What is the natural history of optic neuritis? 2. Does the severity of the initial visual loss affect the outcome? 3. Are recurrent attacks correlated with a worse visual prognosis? 4. Does corticosteroid therapy improve on the natural history? 5. Does route of administration or dose affect the outcome? 6. Is magnetic resonance imaging (MRI) of value for diagnosis or management of the visual aspects of optic neuritis? Questions regarding neurologic outcome: 1. What is the risk for development of MS after an initial attack of optic neuritis? 2. Are there clinical features of the optic neuritis that affect this risk? 3. Are there other predictors of risk? 4. Should every patient with optic neuritis undergo MRI of the brain? 5. How do we interpret MRI findings for management? 6. Is the MS that follows optic neuritis as the initial event more or less severe than that following other neurologic events? 7. Can we reduce the risk of development of MS after an initial attack of optic neuritis? 8. Should corticosteroids be administered in every case of optic neuritis? 9. Should immunomodulation agents be administered in every case of optic neuritis? 10. Is there evidence that reducing the frequency and severity of attacks in MS has a long-term effect on neurologic injury and disability? The Optic Neuritis Treatment Trial (ONTT) and the Longitudinal Optic Neuritis Study (the long-term follow-up study of the ONTT cohort) have provided a wealth of data regarding optic neuritis and its relationship to MS.1–5 Subsequent studies, including the Controlled HighRisk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS)6,7, have supplied information on the value of immunomodulation in reducing MS morbidity after optic 1102
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neuritis. Basic science studies have provided new insight into the pathophysiologic process of axonal injury in MS and how it may influence management.
VISUAL OUTCOME Natural History The typical clinical course for idiopathic optic neuritis is one of worsening visual function over days to weeks, followed by spontaneous recovery. Pain typically resolves over days, often as visual loss begins, and visual recovery usually begins within 2 to 3 weeks, stabilizing over months. In the ONTT, acuity began to improve within 3 weeks in 79% and within 5 weeks in 93% of patients.4 At 10 years, median visual acuity for affected eyes (these data include all treatment groups in the study, because there were no significant differences between treated and untreated eyes) was 20/16, with ⱖ20/20 in 74% and ⱖ20/40 in 92% (visual field data paralleled acuity; median field defect at 10 years was –1.25 dB).8 Only 3% were worse than 20/200, and even those with initially severe visual loss fared remarkably well; of those with visual acuity of counting fingers (CF) to no light perception, 76% were ⱖ20/40 at 10 years, and of those patients with NLP initially (14 cases), 57% had improved to ⱖ20/40 at 6 months.1 These figures also indicate, however, that not all cases of optic neuritis improve, and patients must be advised that recovery, although the rule, is not guaranteed. Optic neuritis not uncommonly recurs in either the same or the fellow eye. In the ONTT, 28% of patients developed recurrence within 5 years5 and 35% at 10 years.8 Recurrence was more frequent in patients who eventually developed MS (recurrent optic neuritis alone is not sufficient for the diagnosis of CDMS) and in those who received treatment with oral prednisone alone at standard doses (discussed later). A single recurrent attack was only rarely associated with substantial additional long-term visual loss (VA ⱕ20/200 in only one case at 5-year follow-up). Multiple recurrences, however, increased the frequency of severe long-term visual loss, with 6 of 26 cases (affected and fellow eyes combined) demonstrating VA ⱕ20/400 at 5 years.5 At 10-year follow-up, three patients demonstrated VA ⱕ20/200 in each eye; all had suffered recurrences.8 Corticosteroid Therapy The ONTT provided documentation of the effect of corticosteroid therapy on visual outcome in optic neuritis. First, intravenous methylprednisolone (IVMP) at a dose of 250 mg four times a day for 3 days, followed by 11 days of oral prednisone at 1 mg/kg/d resulted in increased rates of visual recovery during the first 15 days after vision loss. At successive follow-up examinations, however, this effect diminished; by 6 months, there was minimal difference between treated and placebo groups, and by 1 year and OF
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thereafter, there was no significant long-term benefit for visual function.1,8 With regard to visual function, therefore, this regimen is only considered for those patients requiring faster recovery, for example, monocular patients, those with severe bilateral visual loss, or those with vocational requirements for highest level of visual acuity or stereopsis (pilots, heavy machinery operators, commercial drivers). Although the ONTT protocol involved daily IVMP in divided doses, by common practice, pulse intravenous corticosteroid therapy is commonly administered as a single daily outpatient dose. The ONTT findings parallel those from multiple additional studies worldwide. Randomized, controlled studies of high-dose IVMP from England9 and Japan,10 and oral high-dose MP from Denmark11 revealed remarkably similar findings, with treatment speeding recovery of vision in the first few weeks after onset but providing no long-term beneficial effect. Second, the use of oral prednisone alone at the doses administered in the ONTT (1 mg/kg/d) produced no visual benefit, either for speeding recovery or for long-term visual function. Moreover, its use was associated with a significantly higher rate of recurrence in the affected or fellow eye (27% vs 13% in the IVMP and the placebo groups) at 6 months,1 an effect that was borne out through 10-year follow-up (44% vs 29% to 31%).8 This effect has not been confirmed in other studies and is debated. Oral corticosteroids at this dosage have been in common use for treatment of acute MS flare-ups, and the increased rate of recurrence has not previously been reported. Goodin12,13 reviewed statistical aspects of the ONTT and suggested that flaws in study design and data analysis negated this conclusion, particularly as recurrence rate was not a primary or secondary outcome in the original study design. ONTT investigators, conversely, emphasized the validity of the statistical methods used both in the planning and in the execution and data analysis for the ONTT.14 They postulated that these effects may have been the result of the relatively lower dose provided in the oral prednisone group, rather than the result of the oral route of administration itself.15 Such doses might have preferentially reduced suppressor/inducer CD4 ⫹ T-cell subsets responsible for suppressing the demyelinative process, whereas the higher-dose intravenous regimen achieved higher trough levels, with a greater effect on reducing helper/inducer CD8 ⫹ T-cell subsets active in the demyelinative process.16 Sellebjerg and associates11 reported the use of higher dose (500 mg/d) oral methylprednisolone for treatment of optic neuritis, without an increased recurrence rate at 1-year follow-up (although the authors indicated that the study had insufficient power to test this hypothesis adequately). A report of the Quality Standards Committee of the American Academy of Neurology in 200017 supported the use of high-dose corticosteroids, either by an oral or intravenous route, in cases requiring more rapid visual recovery. The continuing recommendaVOL. 139, NO. 6
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tion from the ONTT and the standard of practice in the U.S. neuro-ophthalmology community is not to treat idiopathic optic neuritis with oral prednisone at the relatively lower dosage of 1 mg/kg/d used in the ONTT. Value of MRI Although thin-section images through the orbits with the fat-suppression technique may provide documentation of the optic nerve inflammation in optic neuritis, the use of MRI for diagnosis is usually unnecessary. Only in cases with an atypical course (prolonged or severe pain, lack of visual recovery, atypical visual field loss, or evidence of orbital inflammation or infiltration) is such a detailed orbital study required to rule out other disease processes. Several investigators have studied the value of detailed optic nerve imaging to establish the specific location and extent of the inflammatory lesions and to identify patient subgroups with poor visual prognosis and those who may obtain more significant visual benefit from corticosteroid therapy. Miller and associates18 reported preliminary findings suggesting that optic nerve lesions of greater length and of location within the optic canal might have worse visual prognosis and might benefit more from therapy. These results were corroborated by those of Dunker and Wiegand,19 but neither Miller’s follow-up study nor a more recent study by Kupersmith and associates20 supported this initial impression. The value of MR imaging of the optic nerves for visual prognosis remains unclear.
DEVELOPMENT OF MS Risk of MS Approximately 15% to 20% of MS cases present as optic neuritis, and from 38% to 50% of MS cases develop it at some point. A large number of early studies have assessed the risk of development of MS after an isolated episode of optic neuritis, with figures ranging from 11.5% to 85%; such wide variation relates to differences in criteria for the diagnosis of both optic neuritis and MS and in length of follow-up. The series of Lessell and associates21,22 indicated a 35% risk of definite or probable MS at 7 years, increasing to 58% at 15 years. In the ONTT, the overall risk for development of CDMS after an initially isolated episode of idiopathic optic neuritis was 30% at 5-year2 and 38% at 10-year follow-up.8 The most valuable predictor for the development of subsequent CDMS is the presence of white matter abnormalities (demyelinating lesions) on brain MRIs. A substantial percentage (27% in the ONTT, up to 70% in other studies) of patients with isolated optic neuritis demonstrate initially abnormal MRI scans, as evidenced by two or more white matter lesions 3 mm in size on T2 images.23 Although the presence of such lesions is not sufficient to make the diagnosis of CDMS, it does provide evidence of multifocal brain involvement and, in the clinical scenario of optic neuritis, raises the risk signifiMULTIPLE SCLEROSIS
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cantly. In the ONTT, the 5-year risk for CDMS was 16% with a normal brain MRI scan (0 lesions), compared with 37% with one or two lesions and 51% with three or more lesions.2 At 10 years, the increased risk of CDMS with the presence of white matter lesions was borne out, but the only statistically significant difference was between no lesions (22% risk) and one or more lesions (56% risk); the gradually progressive risk with increasing volume load of lesions seen at 5 years was not continued at 10 years.24 Additional studies of this aspect provide similar data: Soderstrom and associates25 found a 36% overall risk (50% with abnormal MRI), and Ghezzi and associates26 found a 36% overall risk (52% with abnormal MRI); Druschky and associates27 found 54% with MS at 8-year follow-up. Other features that might increase the likelihood of later development of MS include younger age, female sex (Rizzo and Lessell22 reported 69% women vs 33% men at 15-year follow-up, whereas the ONTT found no difference28), Caucasian race (14% vs 5% for non-Caucasians in the ONTT),3 evidence of retinal periphlebitis29 (Lightman and associates30 found that of subjects with optic neuritis and periphlebitis, 57% developed MS at 3.5-year followup, compared with 16% of those with optic neuritis without it) and cerebrospinal fluid (CSF) and human leukocyte antigen (HLA) features. CSF studies in patients with isolated ON in the ONTT31 showed pleocytosis (36%), elevated myelin basic protein (MBP) levels (18%), increased immunoglobulin G synthesis (43%), and the presence of oligoclonal bands (50%). Only the presence of oligoclonal bands correlated with later development of CDMS, but in these patients MRI findings also predicted development of CDMS, and the additional value of CSF evaluation was unproved. Positive typing for CSF HLA BT101 has been reported to correlate with MS development,32 but although the presence of HLA DR2 is overrepresented in certain MS populations, its correlation with development of MS after optic neuritis is unclear.33 In general, studies of CSF and HLA type have not added essential information in cases of isolated optic neuritis. Several syndromes of optic nerve inflammation are associated with a low risk for MS. Bilateral simultaneous papillitis occurring in childhood is often viral or postviral in origin.34,35 Neuroretinitis, a syndrome of acute optic neuropathy with optic disk edema associated retinal edema, and lipid exudate in the papillomacular region, often in a macular “star” pattern, is also typically infectious, with Bartonella henselae (cat-scratch bacillus) a common etiologic organism.36 In the ONTT subgroup of patients without MRI white matter lesions at onset and no prior neurologic or optic neuritis events (“monofocal optic neuritis”), risk of MS was lower with male gender and the presence of optic disk edema. In this “monofocal” group with lack of pain (n ⫽ 19), severe optic disk edema (n ⫽ 21), peripapillary hemorrhage (n ⫽ 16), macular exudates (n ⫽ 8), or NLP vision (n ⫽ 6), none had developed MS at 5- or 10-year follow-up.2,24 It is critical for the clinician 1104
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to be aware of these patient subgroups that (1) are of low risk for MS and probably do not require immunomodulation therapy and (2) are more frequently infectious in origin and should be considered for specific etiologic tests.
BENEFITS OF THERAPY Corticosteroids At 2-year follow-up in the ONTT (in patients with two or more MRI white matter lesions3), the IVMP treatment group was found to show a significantly decreased risk for the development of MS (16% vs 36% in the placebo group and 32% in the oral prednisone group). In the patients with fewer MRI abnormalities, the lower risk for MS was not significantly affected by therapy. The beneficial effect was not maintained at 3 years, however; published data indicated a risk of 17% in the IVMP group compared with 21% in the placebo group and 25% in the oral prednisone group).37 The lack of a significant difference between the treatment groups was apparent regardless of the number of MRI abnormalities. This lack of benefit was borne out in subsequent 5- and 10-year follow-up studies.24 ONTT investigators postulated that early corticosteroid therapy might interfere with lymphokine release, thus decreasing the upregulation of antigen presentation that primes lymphocyte activity and could potentiate the recurring illness in MS.16 Like the finding of increased recurrence rate in the oral prednisone group, this finding has been controversial; IVMP has been in common use for other types of MS flare-ups, and this protective effect had not been previously documented. Moreover, in the CHAMPS,6,7 patients with optic neuritis who received IVMP alone (placebo group) went on to develop CDMS in 36/97 (37%) of cases at 25 months (compared with 16% in the IVMP treatment group and 36% in the placebo group of patients with two or more MRI lesions in the ONTT 2-year follow-up study). It is possible that differences in the patient cohorts and delay to onset of corticosteroid therapy between the ONTT and the CHAMPS account for the differences in rates of development of MS with IVMP use after optic neuritis. Moreover, this study was not designed to compare treatment with and without corticosteroids. The data do, however, suggest that the use of corticosteroids alone in the CHAMPS did not seem to lower the risk of subsequent MS over that seen in the untreated group with similar MRI findings in the ONTT. The value of this therapy alone for reducing long-term MS risk after initial optic neuritis is unproven. There is additional evidence, however, that high-dose IVMP therapy may decrease long-term morbidity in established RR-MS by reducing the brain atrophy that develops in chronic MS (discussed later). Trapp and associates38 documented early axonal transection in active demyelinating lesions, possibly caused by constituents in the inflammatory environment, including proteolytic enzymes, cytoOF
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kines, oxidative products, and free radicals produced by activated immune and glial cells. Thus aggressive highdose corticosteroid therapy might reduce axonal loss by counteracting this process. Zivadinov and associates39 reported a significant reduction in the volume of T1 “black holes,” whole brain atrophy, and disability progression with the use of pulsed IVMP every 4 to 6 months over a 5-year period; therapy did not significantly reduce relapse rate. Although this study was performed on a relatively small number of patients (88 total, 43 in the pulsed IVMP arm) and in a group with RR-MS rather than a monosymptomatic high-risk group, the effect of long-term pulsed IVMP on the MRI markers of permanent brain damage warrants further study. Immunomodulation Therapy During the past decade, three types of immunomodulation agents (IMAs) have become available for the treatment of RR-MS: interferon -1b (Betaseron; Berlex Laboratories, Montville, New Jersey), interferon beta 1a (Avonex; Biogen, Cambridge, Massachusetts; Rebif; Serono, Norwell, Massachusetts), and the synthetic copolymer glatiramer acetate (Copaxone; Teva Neuroscience, Kansas City, Missouri). Several largescale phase III multicenter clinical trials have established that the use of these agents has beneficial effects in reducing disability progression, acute demyelinative inflammation (active white matter lesions on T1-weighted MRI), total disease burden (cumulative white matter lesions on T2-weighted MRI), and brain atrophy (overall parenchymal volume and “black holes” of focal atrophy) in patients with established relapsing disease.40 – 43 In 1998, the National Multiple Sclerosis Society issued a consensus statement recommending that IMA therapy should be initiated immediately upon establishing a diagnosis of definite RR-MS.44 In recent years, investigators have addressed a related but different question: the effectiveness of the IMAs for reducing the risk of developing MS after a single demyelinating episode. Because optic neuritis is frequently the initial such episode in MS, the answer is of critical importance in ophthalmology. The CHAMPS was an industry-sponsored clinical trial designed to evaluate the effect of Avonex in lowering the rate of developing MS after a single demyelinating event.6 Of the 393 patients entered in this randomized, placebo-controlled trial, 192 (50%) had isolated optic neuritis as this initial event; the data on this optic neuritis subgroup was subsequently published separately.7 All subjects had two or more MR white matter lesions, and all received IVMP followed by oral corticosteroid therapy within 14 days of onset. They were then randomized to weekly injections of either 30-g IM Avonex or placebo. At the first interim analysis of study data, the study was terminated because a beneficial effect of therapy was determined: cumulative probability of MS development at 3 years was 35% in the treated group compared with 50% in the placebo group. Treatment also VOL. 139, NO. 6
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significantly reduced MR total disease burden and development of active lesions, confirming evidence of diminished disease activity. The Early Treatment of Multiple Sclerosis (ETOMS) study45 evaluated therapy with interferon beta 1a (Rebif) on 309 patients with a first neurologic episode consistent with MS, assessing the effect on lowering risk of subsequent CDMS. The study differed from the CHAMPS with regard to a number of features, including multifocal initial involvement (39%), delay to treatment of up to 3 months (vs 27 days), inconsistent use of corticosteroids, subcutaneous administration of the IMA, and lower incidence of optic neuritis as the initial event (35% vs 50%). Results, however, confirmed the findings of the CHAMPS, indicating that the risk of subsequent CDMS was reduced at 2-year follow-up from 45% with placebo to 34% with treatment. The implications of these studies for optic neuritis therapy are still debated. At minimum, however, all patients with idiopathic demyelinative optic neuritis must be advised of the therapeutic option of IMAs for reducing the risk of MS. We believe that all patients with this form of optic neuritis should be offered brain MRI, for two reasons: 1. It is the single best predictor of the risk for development of MS. 2. The available data on benefit of IMAs only applies to patients with at least two typical MRI white matter lesions; in those with lower risk based on MRI, the benefits of IMAs are unproved. An informed decision by patient and physician regarding the use of IMAs requires this baseline data. There are additional issues involved, including high cost of therapy (estimated $12,000/year), commitment to longterm (requirement for IMA therapy is presumed to be ongoing) weekly injections with side effects, and the possibility that therapy in any individual may be unnecessary (even at 10-year follow-up in the ONTT, some 44% were disease-free without therapy, and there is evidence that the clinical course of MS that develops after optic neuritis is less severe than other cases of MS46). There is not consensus on this issue at present; expert recommendations range from treatment in all cases, to treatment only in cases with at least two MRI lesions, to treatment only for those who, on repeat MRI (3 to 6 months), show newly active lesions, suggesting ongoing demyelinative activity. The decision to initiate IMA therapy after initially isolated optic neuritis requires a careful discussion of all aspects and consultation with a neurologist.
EARLY AXONAL DAMAGE MS HAS TRADITIONALLY BEEN CONSIDERED A DISEASE IN
which early primary inflammatory events injured myelin but spared axons; doctrine stated that only late in the disease do cumulative effects of multiple episodes produce axonal damage and permanent neurologic disability. An MULTIPLE SCLEROSIS
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increasing body of evidence from multiple sources now points to early axonal injury in MS. Immunocytochemical studies by Ferguson and associates47 have shown expression of amyloid precursor protein, a marker of axonal damage, in axons within acute MS lesions. Axonal transection, as evidenced by terminal axonal ovoids on confocal microscopy analysis of immunostained tissue, was common in acute lesions studied by Trapp and associates.38 Magnetic resonance spectroscopy studies confirmed early axonal loss in MS lesions.48 The development of focal hypointense lesions (“black holes”) on T1-weighted MRI and the development of whole brain atrophy have been found to be correlates of this permanent damage and have been used in clinical trials as markers for progressive neurologic injury.49 There is histopathologic evidence of axonal loss within the focal lesions.50 Such MRI findings have been documented early in the course of MS, before progressive neurologic disability has occurred. The use of IMAs was originally aimed in part at reducing late axonal injury in MS in chronic RR-MS. However, the concept that axonal loss is an early feature in demyelinating lesions and that subclinical permanent damage occurs early, gradually accumulating enough injury to result in clinical manifestations, forces us to rethink therapy. Whereas if early demyelinative episodes were not associated with axonal injury, early and aggressive therapy was only justified to reduce symptomatology during the flare-up, the finding of early axonal damage suggests that we do everything possible to reduce the number and severity of attacks, beginning with the first evidence of disease. Not only does this support the concept of aggressive IMA (and possibly IVMP) therapy after even a single attack, it prompts consideration of neuroprotective strategies. Agents such as memantine, currently under study for POAG, and brimonidine, which has shown effectiveness in the rat optic nerve crush model,51 might be considered for use in MS with and without optic neuritis, both for protection from future damage and reduction of damage in active attacks. Additionally, combinations of IMAs and agents with more selective mode of action may be of benefit. Natalizumab, a human monoclonal antibody with specific activity against ␣41 integrin, has recently been shown be effective in modifying the disease course in RR-MS.52 The statins, particularly simvastatin, have been shown to have immunomodulatory effects in addition to their cholesterol-lowering actions and have proved beneficial in trials of RR-MS.53 The potential long-term benefit of early interventional therapy with IMAs or other modalities remains untested.
play roles in decreasing the risk and severity of MS after optic neuritis. New concepts of MS pathogenesis, which indicate that axonal injury is an early feature of the disease, prompt consideration of more aggressive early intervention to reduce frequency and severity of inflammatory episodes, with the goal of reducing permanent axonal damage and long-term disability.
REFERENCES 1. Beck RW, Cleary PA, Anderson MM, Keltner JL, Shults WT, Kaufman DI, and the Optic Neuritis Study Group. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992;326:581– 588. 2. Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:1404 –1413. 3. Beck RW, Cleary PA, Trobe JD, Kaufman DI, Kupersmith MJ, Paty DW, and the Optic Neuritis Study Group. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 1993;329:1764 –1769. 4. Beck RW, Cleary PA, Backlund JC, and the Optic Neuritis Study Group. The course of recovery after optic neuritis. The experience of the Optic Neuritis Treatment Trial. Ophthalmology 1994;101:1771–1778. 5. The Optic Neuritis Study Group. Visual function 5 years after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1997;115:1545–1552. 6. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898 –904. 7. CHAMPS Study Group. Interferon -1a for optic neuritis patients at high risk for multiple sclerosis. Am J Ophthalmol 2001;132:463– 471. 8. Optic Neuritis Study Group. Visual function more than 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Am J Ophthalmol 2004;137:77– 83. 9. Kapoor R, Miller DH, Jones SJ, et al. Effects of intravenous methylprednisolone on outcome in MRI-based prognostic subgroups in acute optic neuritis. Neurology 1998;50:230 – 237. 10. Wakakura M, Mashimo K, Oono S, et al. Multicenter clinical trial for evaluating methylprednisolone pulse treatment of idiopathic optic neuritis in Japan. Japan J Ophthalmol 1999;43:133–138. 11. Sellebjerg F, Nielsen HS, Frederiksen JL, Olesen J. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 1999;52:1479 – 1484. 12. Goodin DS. Perils and pitfalls in the interpretation of clinical trials: a reflection on the recent experience in multiple sclerosis. Neuroepidemiology 1999;18:53– 63. 13. Goodin DS. Corticosteroids and optic neuritis [Letter to the Editor]. Neurology 1993;43:632– 633. 14. Beck RW. Corticosteroids and optic neuritis [Reply to Letter to the Editor]. Neurology 1993;43:633– 634.
CONCLUSIONS THE MAJOR TREATMENT STUDIES IN OPTIC NEURITIS AND
MS suggest that although therapy has no long-term effect on visual outcome, both corticosteroids and IMAs may 1106
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15. Corbett JJ, Cruse JM. Corticosteroids and optic neuritis [Reply to Letter to the Editor]. Neurology 1993;43:634. 16. Beck RW, Trobe JD, and the Optic Neuritis Study Group. The Optic Neuritis Treatment Trial. Putting the results in perspective. J Neuroophthalmol 1995;15:131–135. 17. Kaufman DI, Trobe JD, Eggenberger ER, Whitaker JN. Practice parameter: the role of corticosteroids in the management of acute monosymptomatic optic neuritis. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:2039 –2044. 18. Miller DH, Newton MR, van der Poel JC, Halliday AM, Kendall BE, Johnson G, et al. Magnetic resonance imaging of the optic nerve in optic neuritis. Neurology 1988;38:175–179. 19. Dunker S, Wiegand W. Prognostic value of magnetic resonance imaging in monosymptomatic optic neuritis. Ophthalmology 1996;103:1768 –1773. 20. Kupersmith MJ, Alban T, Zeiffer B, Lefton D. Contrastenhanced MRI in acute optic neuritis: relationship to visual performance. Brain 2002;125:812– 822. 21. Cohen MM, Lessell S, Wolf PA. A prospective study of the risk of developing multiple sclerosis in uncomplicated optic neuritis. Neurology 1979;29:208 –213. 22. Rizzo JF, Lessell S. Risk of developing multiple sclerosis after uncomplicated optic neuritis: a long-term prospective study. Neurology 1988;38:185–190. 23. Beck RW, Arrington J, Murtagh FR, Cleary PA, Kaufman DI. Brain magnetic resonance imaging in acute optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Neurol 1993;50:841– 846. 24. Optic Neuritis Study Group. High-and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis. Arch Ophthalmol 2003;121:944 –949. 25. Soderstrom M, Lindqvist M, Hillert J, Kall TB, Link H. Optic neuritis: findings on MRI, CSF examination, and HLA class II typing in 60 patients and results of a short-term follow-up. J Neurol 1994;241:391–397. 26. Ghezzi A, Martinelli V, Torri V, et al. Long-term follow-up of isolated optic neuritis: the risk of developing multiple sclerosis, its outcome, and the prognostic role of paraclinical tests. J Neurol 1999;246:770 –775. 27. Druschky A, Heckmann JG, Claus D, et al. Progression of optic neuritis to multiple sclerosis: an 8-year follow-up study. Clin Neurol Neurosurg 1999;101:189 –192. 28. Beck RW, Trobe JD, and the Optic Neuritis Study Group. What we have learned from the Optic Neuritis Treatment Trial. Ophthalmology 1995;102:1504 –1508. 29. Arnold AC, Pepose JS, Hepler RS, Foos RY. Retinal periphlebitis and retinitis in multiple sclerosis. Pathologic characteristics. Ophthalmology 1984;91:255–262. 30. Lightman S, McDonald WI, Bird AC, et al. Retinal venous sheathing in optic neuritis. Brain 1987;110:405– 414. 31. Rolak LA, Beck RW, Paty DW, Tourtellotte WW, Whitaker JN, Rudick RA. Cerebrospinal fluid in acute optic neuritis: experience of the Optic Neuritis Treatment Trial. Neurology 1996;46:368 –372. 32. Compston DA, Batchelor JR, Earl CJ, McDonald WI. Factors influencing the risk of multiple sclerosis developing in patients with optic neuritis. Brain 1978;101:495–511. 33. Francis DA, Compston DA, Batchelor JR, McDonald WI. A reassessment of the risk of multiple sclerosis developing in
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34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46. 47.
48.
49.
patients with optic neuritis after extended follow-up. J Neurol Neurosurg Psychiatry 1987;50:758 –765. Farris BK, Pickard DJ. Bilateral postinfectious optic neuritis and intravenous steroid therapy in children. Ophthalmology 1990;97:339 –345. Brady KM, Brar AS, Lee AG, Coats DK, Paysse EA, Steinkuller PG. Optic neuritis in children: clinical features and visual outcome. J AAPOS 1999;3:98 –103. Parmley VC, Schiffman JS, Maitland CG, Miller NR, Dreyer RF, Hoyt WF. Does neuroretinitis rule out multiple sclerosis? Arch Neurol 1987;44:1045–1048. Beck RW and the Optic Neuritis Study Group. The Optic Neuritis Treatment Trial: three year follow-up results. Arch Ophthalmol 1995;113:136 –137. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transaction in the lesions of multiple sclerosis. N Engl J Med 1998;338:278 –285. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylpredisolone on brain atrophy in relapsing-remitting MS. Neurology 2000;57:1239 –1247. IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995;45:1277–1285. PRISMS (Prevention of Relapses and Disability by Interferon -1a Subcutaneously in Multiple Sclerosis) Study Group, University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon -1a in relapsing MS. Neurology 2001;56:1628 –1636. Li DKB, Paty DW, and the UBC MS/MRI Analysis Research Group and the PRISMS Study Group. Magnetic imaging results of the PRISMS trial: a randomized doubleblind placebo-controlled study of interferon -1a in relapsing-remitting multiple sclerosis. Ann Neurol 1999;46: 197–206. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, and the Copolymer 1 Multiple Sclerosis Study Group. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 1995;45:1268 –1276. Galetta SL, Markowitz C, Lee AG. Immunomodulatory agents for the treatment of relapsing multiple sclerosis. Arch Intern Med 2002;162:2161–2169. Comi G, Filippi M, Wolinsky JS and the European/ Canadian Glatiramer Acetate Study Group. European/ Canadian multicenter, double-blind, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol 2001;49:290 –297. Optic Neuritis Study Group. Neurologic impairment 10 years after optic neuritis. Arch Neurol 2004;61:1386 –1389. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120: 393–399. De Stefano N, Narayanan S, Francis GS, et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 2001;58:65–70. Truyen L, van Waesberghe THTM, Barkof F, et al. Accumulation of hypointense lesions (“black holes”) on T1 spin
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nerve degeneration. Invest Ophthalmol Vis Sci 1999;40:65–73. 52. Miller DH, Khan OA, Shreemata WA, et al. A controlled clinical trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. 53. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004;363:1607–1608.
echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996;47:1469 –1476. 50. Van Walderveen MA, Kamphorst W, Scheltens P, et al. Histopathologic correlate of hypointense lesions on T1weighted spin-echo MRI in multiple sclerosis. Neurology 1998;50:1282–1288. 51. Yoles E, Wheeler LA, Schwartz M. Alpha-2 adrenoreceptor agonists are neuroprotective in a rat model of optic
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Biosketch Anthony C. Arnold, MD, is professor and chief, Division of Neuro-Ophthalmology, Jules Stein Eye Institute, UCLA Department of Ophthalmology, and director, UCLA Optic Neuropathy Center. He has a primary research interest in ischemic and inflammatory optic neuropathies.
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● PURPOSE:
To review the relation of optic neuritis to multiple sclerosis (MS) and the indications, modalities, and results of therapy for optic neuritis, for both visual and general neurologic function. ● DESIGN: Literature review and author’s experience. ● METHODS: Analysis of both laboratory and clinical evidence supporting the use of corticosteroids, immunomodulation agents, and other modalities in the treatment of optic neuritis and MS. ● RESULTS: Although treatment of optic neuritis with corticosteroids may hasten visual recovery to a minor degree, it has no long-term beneficial effect on visual outcome. Optic neuritis is frequently the initial manifestation of multiple sclerosis. The risk of later development of clinically definite MS (CDMS) correlates with white matter demyelinative lesions on magnetic resonance imaging (MRI). The role of corticosteroid therapy alone in reducing the risk of subsequent MS is unclear, but recent studies suggest that the combination of immunomodulation agents (IMAs) and corticosteroids significantly reduces the later development of MS. Current research indicates that, contrary to previous doctrine, axonal damage is an early finding in MS. ● CONCLUSIONS: The risk of MS after optic neuritis may be predicted. The use of corticosteroids and IMAs, particularly in those at substantial risk, reduces the frequency and severity of developing CDMS. Earlier, more aggressive therapy in optic neuritis may be proven to reduce permanent axonal injury and progressive disability in MS. (Am J Ophthalmol 2005;139:1101–1108. © 2005 by Elsevier Inc. All rights reserved.)
Accepted for publication Jan 20, 2005. From the Jules Stein Eye Institute, Los Angeles, California, USA. Inquiries to Anthony C. Arnold, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7005; Fax (310) 267-1918; e-mail: [email protected] 0002-9394/05/$30.00 doi:10.1016/j.ajo.2005.01.031
©
2005 BY
T
HE TREATMENT OF OPTIC NEURITIS IS CONTROVER-
sial. Although several specific forms of optic nerve inflammation require and respond to therapy (e.g., corticosteroids for sarcoid optic neuropathy, antibiotics for syphilitic optic neuropathy), management of typical demyelinative optic neuritis is not clear-cut. The use of corticosteroids, although a logical option for an inflammatory condition, has been of questionable benefit for visual recovery in this disorder in which there is a high spontaneous resolution rate. The relationship of optic neuritis to multiple sclerosis (MS) has also been unclear in the past, and the practical value of predicting the risk of MS after optic neuritis is limited because there was no proven intervention for reducing it. Corticosteroids have been the standard of therapy in documented MS to reduce morbidity of acute flare-ups and possibly reduce long-term morbidity from attacks. Interferons and other immunomodulation agents have been proved to reduce the risk of future attacks in established cases of relapsing-remitting MS (RR-MS). The beneficial effect of any of these agents to reduce the risk of developing MS and the effect on long-term visual outcome after an initial episode of isolated optic neuritis were unproven, however. Over the past decade, however, a large volume of new information has emerged regarding therapy for optic neuritis and MS. The data suggest that although treatment has only a minor effect on visual outcome, it may have a major effect on the course of neurologic disease. We have come to realize that not only can we substantially reduce later development of MS after an initial episode of optic neuritis, but that if we do not reduce this risk, we may substantially increase the long-term disability of affected patients. It must be emphasized that published data regarding idiopathic optic neuritis address only the typical, acute form. Infrequently, optic neuritis presents as an insidious, chronically progressive optic neuropathy, without discrete episode of pain, optic disk edema, or reversible visual loss. The optic neuropathy may be the presenting finding of MS
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or may occur in patients already diagnosed with the disease. In these patients, who typically demonstrate central visual loss and optic atrophy at presentation, corticosteroid therapy has not been shown to affect visual outcome, and, as with other progressive forms of MS, immunomodulation agents have not been shown to be effective in reducing visual or neurologic morbidity. In the management of typical idiopathic demyelinative optic neuritis, the ophthalmologist must consider many questions, a number of which remain unanswered. They may be divided into those regarding visual outcome (recovery of visual function, recurrence of optic neuritis) and those regarding neurologic outcome (incidence of MS, severity of neurologic dysfunction from MS). Questions regarding visual outcome: 1. What is the natural history of optic neuritis? 2. Does the severity of the initial visual loss affect the outcome? 3. Are recurrent attacks correlated with a worse visual prognosis? 4. Does corticosteroid therapy improve on the natural history? 5. Does route of administration or dose affect the outcome? 6. Is magnetic resonance imaging (MRI) of value for diagnosis or management of the visual aspects of optic neuritis? Questions regarding neurologic outcome: 1. What is the risk for development of MS after an initial attack of optic neuritis? 2. Are there clinical features of the optic neuritis that affect this risk? 3. Are there other predictors of risk? 4. Should every patient with optic neuritis undergo MRI of the brain? 5. How do we interpret MRI findings for management? 6. Is the MS that follows optic neuritis as the initial event more or less severe than that following other neurologic events? 7. Can we reduce the risk of development of MS after an initial attack of optic neuritis? 8. Should corticosteroids be administered in every case of optic neuritis? 9. Should immunomodulation agents be administered in every case of optic neuritis? 10. Is there evidence that reducing the frequency and severity of attacks in MS has a long-term effect on neurologic injury and disability? The Optic Neuritis Treatment Trial (ONTT) and the Longitudinal Optic Neuritis Study (the long-term follow-up study of the ONTT cohort) have provided a wealth of data regarding optic neuritis and its relationship to MS.1–5 Subsequent studies, including the Controlled HighRisk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS)6,7, have supplied information on the value of immunomodulation in reducing MS morbidity after optic 1102
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neuritis. Basic science studies have provided new insight into the pathophysiologic process of axonal injury in MS and how it may influence management.
VISUAL OUTCOME Natural History The typical clinical course for idiopathic optic neuritis is one of worsening visual function over days to weeks, followed by spontaneous recovery. Pain typically resolves over days, often as visual loss begins, and visual recovery usually begins within 2 to 3 weeks, stabilizing over months. In the ONTT, acuity began to improve within 3 weeks in 79% and within 5 weeks in 93% of patients.4 At 10 years, median visual acuity for affected eyes (these data include all treatment groups in the study, because there were no significant differences between treated and untreated eyes) was 20/16, with ⱖ20/20 in 74% and ⱖ20/40 in 92% (visual field data paralleled acuity; median field defect at 10 years was –1.25 dB).8 Only 3% were worse than 20/200, and even those with initially severe visual loss fared remarkably well; of those with visual acuity of counting fingers (CF) to no light perception, 76% were ⱖ20/40 at 10 years, and of those patients with NLP initially (14 cases), 57% had improved to ⱖ20/40 at 6 months.1 These figures also indicate, however, that not all cases of optic neuritis improve, and patients must be advised that recovery, although the rule, is not guaranteed. Optic neuritis not uncommonly recurs in either the same or the fellow eye. In the ONTT, 28% of patients developed recurrence within 5 years5 and 35% at 10 years.8 Recurrence was more frequent in patients who eventually developed MS (recurrent optic neuritis alone is not sufficient for the diagnosis of CDMS) and in those who received treatment with oral prednisone alone at standard doses (discussed later). A single recurrent attack was only rarely associated with substantial additional long-term visual loss (VA ⱕ20/200 in only one case at 5-year follow-up). Multiple recurrences, however, increased the frequency of severe long-term visual loss, with 6 of 26 cases (affected and fellow eyes combined) demonstrating VA ⱕ20/400 at 5 years.5 At 10-year follow-up, three patients demonstrated VA ⱕ20/200 in each eye; all had suffered recurrences.8 Corticosteroid Therapy The ONTT provided documentation of the effect of corticosteroid therapy on visual outcome in optic neuritis. First, intravenous methylprednisolone (IVMP) at a dose of 250 mg four times a day for 3 days, followed by 11 days of oral prednisone at 1 mg/kg/d resulted in increased rates of visual recovery during the first 15 days after vision loss. At successive follow-up examinations, however, this effect diminished; by 6 months, there was minimal difference between treated and placebo groups, and by 1 year and OF
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thereafter, there was no significant long-term benefit for visual function.1,8 With regard to visual function, therefore, this regimen is only considered for those patients requiring faster recovery, for example, monocular patients, those with severe bilateral visual loss, or those with vocational requirements for highest level of visual acuity or stereopsis (pilots, heavy machinery operators, commercial drivers). Although the ONTT protocol involved daily IVMP in divided doses, by common practice, pulse intravenous corticosteroid therapy is commonly administered as a single daily outpatient dose. The ONTT findings parallel those from multiple additional studies worldwide. Randomized, controlled studies of high-dose IVMP from England9 and Japan,10 and oral high-dose MP from Denmark11 revealed remarkably similar findings, with treatment speeding recovery of vision in the first few weeks after onset but providing no long-term beneficial effect. Second, the use of oral prednisone alone at the doses administered in the ONTT (1 mg/kg/d) produced no visual benefit, either for speeding recovery or for long-term visual function. Moreover, its use was associated with a significantly higher rate of recurrence in the affected or fellow eye (27% vs 13% in the IVMP and the placebo groups) at 6 months,1 an effect that was borne out through 10-year follow-up (44% vs 29% to 31%).8 This effect has not been confirmed in other studies and is debated. Oral corticosteroids at this dosage have been in common use for treatment of acute MS flare-ups, and the increased rate of recurrence has not previously been reported. Goodin12,13 reviewed statistical aspects of the ONTT and suggested that flaws in study design and data analysis negated this conclusion, particularly as recurrence rate was not a primary or secondary outcome in the original study design. ONTT investigators, conversely, emphasized the validity of the statistical methods used both in the planning and in the execution and data analysis for the ONTT.14 They postulated that these effects may have been the result of the relatively lower dose provided in the oral prednisone group, rather than the result of the oral route of administration itself.15 Such doses might have preferentially reduced suppressor/inducer CD4 ⫹ T-cell subsets responsible for suppressing the demyelinative process, whereas the higher-dose intravenous regimen achieved higher trough levels, with a greater effect on reducing helper/inducer CD8 ⫹ T-cell subsets active in the demyelinative process.16 Sellebjerg and associates11 reported the use of higher dose (500 mg/d) oral methylprednisolone for treatment of optic neuritis, without an increased recurrence rate at 1-year follow-up (although the authors indicated that the study had insufficient power to test this hypothesis adequately). A report of the Quality Standards Committee of the American Academy of Neurology in 200017 supported the use of high-dose corticosteroids, either by an oral or intravenous route, in cases requiring more rapid visual recovery. The continuing recommendaVOL. 139, NO. 6
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tion from the ONTT and the standard of practice in the U.S. neuro-ophthalmology community is not to treat idiopathic optic neuritis with oral prednisone at the relatively lower dosage of 1 mg/kg/d used in the ONTT. Value of MRI Although thin-section images through the orbits with the fat-suppression technique may provide documentation of the optic nerve inflammation in optic neuritis, the use of MRI for diagnosis is usually unnecessary. Only in cases with an atypical course (prolonged or severe pain, lack of visual recovery, atypical visual field loss, or evidence of orbital inflammation or infiltration) is such a detailed orbital study required to rule out other disease processes. Several investigators have studied the value of detailed optic nerve imaging to establish the specific location and extent of the inflammatory lesions and to identify patient subgroups with poor visual prognosis and those who may obtain more significant visual benefit from corticosteroid therapy. Miller and associates18 reported preliminary findings suggesting that optic nerve lesions of greater length and of location within the optic canal might have worse visual prognosis and might benefit more from therapy. These results were corroborated by those of Dunker and Wiegand,19 but neither Miller’s follow-up study nor a more recent study by Kupersmith and associates20 supported this initial impression. The value of MR imaging of the optic nerves for visual prognosis remains unclear.
DEVELOPMENT OF MS Risk of MS Approximately 15% to 20% of MS cases present as optic neuritis, and from 38% to 50% of MS cases develop it at some point. A large number of early studies have assessed the risk of development of MS after an isolated episode of optic neuritis, with figures ranging from 11.5% to 85%; such wide variation relates to differences in criteria for the diagnosis of both optic neuritis and MS and in length of follow-up. The series of Lessell and associates21,22 indicated a 35% risk of definite or probable MS at 7 years, increasing to 58% at 15 years. In the ONTT, the overall risk for development of CDMS after an initially isolated episode of idiopathic optic neuritis was 30% at 5-year2 and 38% at 10-year follow-up.8 The most valuable predictor for the development of subsequent CDMS is the presence of white matter abnormalities (demyelinating lesions) on brain MRIs. A substantial percentage (27% in the ONTT, up to 70% in other studies) of patients with isolated optic neuritis demonstrate initially abnormal MRI scans, as evidenced by two or more white matter lesions 3 mm in size on T2 images.23 Although the presence of such lesions is not sufficient to make the diagnosis of CDMS, it does provide evidence of multifocal brain involvement and, in the clinical scenario of optic neuritis, raises the risk signifiMULTIPLE SCLEROSIS
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cantly. In the ONTT, the 5-year risk for CDMS was 16% with a normal brain MRI scan (0 lesions), compared with 37% with one or two lesions and 51% with three or more lesions.2 At 10 years, the increased risk of CDMS with the presence of white matter lesions was borne out, but the only statistically significant difference was between no lesions (22% risk) and one or more lesions (56% risk); the gradually progressive risk with increasing volume load of lesions seen at 5 years was not continued at 10 years.24 Additional studies of this aspect provide similar data: Soderstrom and associates25 found a 36% overall risk (50% with abnormal MRI), and Ghezzi and associates26 found a 36% overall risk (52% with abnormal MRI); Druschky and associates27 found 54% with MS at 8-year follow-up. Other features that might increase the likelihood of later development of MS include younger age, female sex (Rizzo and Lessell22 reported 69% women vs 33% men at 15-year follow-up, whereas the ONTT found no difference28), Caucasian race (14% vs 5% for non-Caucasians in the ONTT),3 evidence of retinal periphlebitis29 (Lightman and associates30 found that of subjects with optic neuritis and periphlebitis, 57% developed MS at 3.5-year followup, compared with 16% of those with optic neuritis without it) and cerebrospinal fluid (CSF) and human leukocyte antigen (HLA) features. CSF studies in patients with isolated ON in the ONTT31 showed pleocytosis (36%), elevated myelin basic protein (MBP) levels (18%), increased immunoglobulin G synthesis (43%), and the presence of oligoclonal bands (50%). Only the presence of oligoclonal bands correlated with later development of CDMS, but in these patients MRI findings also predicted development of CDMS, and the additional value of CSF evaluation was unproved. Positive typing for CSF HLA BT101 has been reported to correlate with MS development,32 but although the presence of HLA DR2 is overrepresented in certain MS populations, its correlation with development of MS after optic neuritis is unclear.33 In general, studies of CSF and HLA type have not added essential information in cases of isolated optic neuritis. Several syndromes of optic nerve inflammation are associated with a low risk for MS. Bilateral simultaneous papillitis occurring in childhood is often viral or postviral in origin.34,35 Neuroretinitis, a syndrome of acute optic neuropathy with optic disk edema associated retinal edema, and lipid exudate in the papillomacular region, often in a macular “star” pattern, is also typically infectious, with Bartonella henselae (cat-scratch bacillus) a common etiologic organism.36 In the ONTT subgroup of patients without MRI white matter lesions at onset and no prior neurologic or optic neuritis events (“monofocal optic neuritis”), risk of MS was lower with male gender and the presence of optic disk edema. In this “monofocal” group with lack of pain (n ⫽ 19), severe optic disk edema (n ⫽ 21), peripapillary hemorrhage (n ⫽ 16), macular exudates (n ⫽ 8), or NLP vision (n ⫽ 6), none had developed MS at 5- or 10-year follow-up.2,24 It is critical for the clinician 1104
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to be aware of these patient subgroups that (1) are of low risk for MS and probably do not require immunomodulation therapy and (2) are more frequently infectious in origin and should be considered for specific etiologic tests.
BENEFITS OF THERAPY Corticosteroids At 2-year follow-up in the ONTT (in patients with two or more MRI white matter lesions3), the IVMP treatment group was found to show a significantly decreased risk for the development of MS (16% vs 36% in the placebo group and 32% in the oral prednisone group). In the patients with fewer MRI abnormalities, the lower risk for MS was not significantly affected by therapy. The beneficial effect was not maintained at 3 years, however; published data indicated a risk of 17% in the IVMP group compared with 21% in the placebo group and 25% in the oral prednisone group).37 The lack of a significant difference between the treatment groups was apparent regardless of the number of MRI abnormalities. This lack of benefit was borne out in subsequent 5- and 10-year follow-up studies.24 ONTT investigators postulated that early corticosteroid therapy might interfere with lymphokine release, thus decreasing the upregulation of antigen presentation that primes lymphocyte activity and could potentiate the recurring illness in MS.16 Like the finding of increased recurrence rate in the oral prednisone group, this finding has been controversial; IVMP has been in common use for other types of MS flare-ups, and this protective effect had not been previously documented. Moreover, in the CHAMPS,6,7 patients with optic neuritis who received IVMP alone (placebo group) went on to develop CDMS in 36/97 (37%) of cases at 25 months (compared with 16% in the IVMP treatment group and 36% in the placebo group of patients with two or more MRI lesions in the ONTT 2-year follow-up study). It is possible that differences in the patient cohorts and delay to onset of corticosteroid therapy between the ONTT and the CHAMPS account for the differences in rates of development of MS with IVMP use after optic neuritis. Moreover, this study was not designed to compare treatment with and without corticosteroids. The data do, however, suggest that the use of corticosteroids alone in the CHAMPS did not seem to lower the risk of subsequent MS over that seen in the untreated group with similar MRI findings in the ONTT. The value of this therapy alone for reducing long-term MS risk after initial optic neuritis is unproven. There is additional evidence, however, that high-dose IVMP therapy may decrease long-term morbidity in established RR-MS by reducing the brain atrophy that develops in chronic MS (discussed later). Trapp and associates38 documented early axonal transection in active demyelinating lesions, possibly caused by constituents in the inflammatory environment, including proteolytic enzymes, cytoOF
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kines, oxidative products, and free radicals produced by activated immune and glial cells. Thus aggressive highdose corticosteroid therapy might reduce axonal loss by counteracting this process. Zivadinov and associates39 reported a significant reduction in the volume of T1 “black holes,” whole brain atrophy, and disability progression with the use of pulsed IVMP every 4 to 6 months over a 5-year period; therapy did not significantly reduce relapse rate. Although this study was performed on a relatively small number of patients (88 total, 43 in the pulsed IVMP arm) and in a group with RR-MS rather than a monosymptomatic high-risk group, the effect of long-term pulsed IVMP on the MRI markers of permanent brain damage warrants further study. Immunomodulation Therapy During the past decade, three types of immunomodulation agents (IMAs) have become available for the treatment of RR-MS: interferon -1b (Betaseron; Berlex Laboratories, Montville, New Jersey), interferon beta 1a (Avonex; Biogen, Cambridge, Massachusetts; Rebif; Serono, Norwell, Massachusetts), and the synthetic copolymer glatiramer acetate (Copaxone; Teva Neuroscience, Kansas City, Missouri). Several largescale phase III multicenter clinical trials have established that the use of these agents has beneficial effects in reducing disability progression, acute demyelinative inflammation (active white matter lesions on T1-weighted MRI), total disease burden (cumulative white matter lesions on T2-weighted MRI), and brain atrophy (overall parenchymal volume and “black holes” of focal atrophy) in patients with established relapsing disease.40 – 43 In 1998, the National Multiple Sclerosis Society issued a consensus statement recommending that IMA therapy should be initiated immediately upon establishing a diagnosis of definite RR-MS.44 In recent years, investigators have addressed a related but different question: the effectiveness of the IMAs for reducing the risk of developing MS after a single demyelinating episode. Because optic neuritis is frequently the initial such episode in MS, the answer is of critical importance in ophthalmology. The CHAMPS was an industry-sponsored clinical trial designed to evaluate the effect of Avonex in lowering the rate of developing MS after a single demyelinating event.6 Of the 393 patients entered in this randomized, placebo-controlled trial, 192 (50%) had isolated optic neuritis as this initial event; the data on this optic neuritis subgroup was subsequently published separately.7 All subjects had two or more MR white matter lesions, and all received IVMP followed by oral corticosteroid therapy within 14 days of onset. They were then randomized to weekly injections of either 30-g IM Avonex or placebo. At the first interim analysis of study data, the study was terminated because a beneficial effect of therapy was determined: cumulative probability of MS development at 3 years was 35% in the treated group compared with 50% in the placebo group. Treatment also VOL. 139, NO. 6
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significantly reduced MR total disease burden and development of active lesions, confirming evidence of diminished disease activity. The Early Treatment of Multiple Sclerosis (ETOMS) study45 evaluated therapy with interferon beta 1a (Rebif) on 309 patients with a first neurologic episode consistent with MS, assessing the effect on lowering risk of subsequent CDMS. The study differed from the CHAMPS with regard to a number of features, including multifocal initial involvement (39%), delay to treatment of up to 3 months (vs 27 days), inconsistent use of corticosteroids, subcutaneous administration of the IMA, and lower incidence of optic neuritis as the initial event (35% vs 50%). Results, however, confirmed the findings of the CHAMPS, indicating that the risk of subsequent CDMS was reduced at 2-year follow-up from 45% with placebo to 34% with treatment. The implications of these studies for optic neuritis therapy are still debated. At minimum, however, all patients with idiopathic demyelinative optic neuritis must be advised of the therapeutic option of IMAs for reducing the risk of MS. We believe that all patients with this form of optic neuritis should be offered brain MRI, for two reasons: 1. It is the single best predictor of the risk for development of MS. 2. The available data on benefit of IMAs only applies to patients with at least two typical MRI white matter lesions; in those with lower risk based on MRI, the benefits of IMAs are unproved. An informed decision by patient and physician regarding the use of IMAs requires this baseline data. There are additional issues involved, including high cost of therapy (estimated $12,000/year), commitment to longterm (requirement for IMA therapy is presumed to be ongoing) weekly injections with side effects, and the possibility that therapy in any individual may be unnecessary (even at 10-year follow-up in the ONTT, some 44% were disease-free without therapy, and there is evidence that the clinical course of MS that develops after optic neuritis is less severe than other cases of MS46). There is not consensus on this issue at present; expert recommendations range from treatment in all cases, to treatment only in cases with at least two MRI lesions, to treatment only for those who, on repeat MRI (3 to 6 months), show newly active lesions, suggesting ongoing demyelinative activity. The decision to initiate IMA therapy after initially isolated optic neuritis requires a careful discussion of all aspects and consultation with a neurologist.
EARLY AXONAL DAMAGE MS HAS TRADITIONALLY BEEN CONSIDERED A DISEASE IN
which early primary inflammatory events injured myelin but spared axons; doctrine stated that only late in the disease do cumulative effects of multiple episodes produce axonal damage and permanent neurologic disability. An MULTIPLE SCLEROSIS
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increasing body of evidence from multiple sources now points to early axonal injury in MS. Immunocytochemical studies by Ferguson and associates47 have shown expression of amyloid precursor protein, a marker of axonal damage, in axons within acute MS lesions. Axonal transection, as evidenced by terminal axonal ovoids on confocal microscopy analysis of immunostained tissue, was common in acute lesions studied by Trapp and associates.38 Magnetic resonance spectroscopy studies confirmed early axonal loss in MS lesions.48 The development of focal hypointense lesions (“black holes”) on T1-weighted MRI and the development of whole brain atrophy have been found to be correlates of this permanent damage and have been used in clinical trials as markers for progressive neurologic injury.49 There is histopathologic evidence of axonal loss within the focal lesions.50 Such MRI findings have been documented early in the course of MS, before progressive neurologic disability has occurred. The use of IMAs was originally aimed in part at reducing late axonal injury in MS in chronic RR-MS. However, the concept that axonal loss is an early feature in demyelinating lesions and that subclinical permanent damage occurs early, gradually accumulating enough injury to result in clinical manifestations, forces us to rethink therapy. Whereas if early demyelinative episodes were not associated with axonal injury, early and aggressive therapy was only justified to reduce symptomatology during the flare-up, the finding of early axonal damage suggests that we do everything possible to reduce the number and severity of attacks, beginning with the first evidence of disease. Not only does this support the concept of aggressive IMA (and possibly IVMP) therapy after even a single attack, it prompts consideration of neuroprotective strategies. Agents such as memantine, currently under study for POAG, and brimonidine, which has shown effectiveness in the rat optic nerve crush model,51 might be considered for use in MS with and without optic neuritis, both for protection from future damage and reduction of damage in active attacks. Additionally, combinations of IMAs and agents with more selective mode of action may be of benefit. Natalizumab, a human monoclonal antibody with specific activity against ␣41 integrin, has recently been shown be effective in modifying the disease course in RR-MS.52 The statins, particularly simvastatin, have been shown to have immunomodulatory effects in addition to their cholesterol-lowering actions and have proved beneficial in trials of RR-MS.53 The potential long-term benefit of early interventional therapy with IMAs or other modalities remains untested.
play roles in decreasing the risk and severity of MS after optic neuritis. New concepts of MS pathogenesis, which indicate that axonal injury is an early feature of the disease, prompt consideration of more aggressive early intervention to reduce frequency and severity of inflammatory episodes, with the goal of reducing permanent axonal damage and long-term disability.
REFERENCES 1. Beck RW, Cleary PA, Anderson MM, Keltner JL, Shults WT, Kaufman DI, and the Optic Neuritis Study Group. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992;326:581– 588. 2. Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:1404 –1413. 3. Beck RW, Cleary PA, Trobe JD, Kaufman DI, Kupersmith MJ, Paty DW, and the Optic Neuritis Study Group. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 1993;329:1764 –1769. 4. Beck RW, Cleary PA, Backlund JC, and the Optic Neuritis Study Group. The course of recovery after optic neuritis. The experience of the Optic Neuritis Treatment Trial. Ophthalmology 1994;101:1771–1778. 5. The Optic Neuritis Study Group. Visual function 5 years after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1997;115:1545–1552. 6. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898 –904. 7. CHAMPS Study Group. Interferon -1a for optic neuritis patients at high risk for multiple sclerosis. Am J Ophthalmol 2001;132:463– 471. 8. Optic Neuritis Study Group. Visual function more than 10 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Am J Ophthalmol 2004;137:77– 83. 9. Kapoor R, Miller DH, Jones SJ, et al. Effects of intravenous methylprednisolone on outcome in MRI-based prognostic subgroups in acute optic neuritis. Neurology 1998;50:230 – 237. 10. Wakakura M, Mashimo K, Oono S, et al. Multicenter clinical trial for evaluating methylprednisolone pulse treatment of idiopathic optic neuritis in Japan. Japan J Ophthalmol 1999;43:133–138. 11. Sellebjerg F, Nielsen HS, Frederiksen JL, Olesen J. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 1999;52:1479 – 1484. 12. Goodin DS. Perils and pitfalls in the interpretation of clinical trials: a reflection on the recent experience in multiple sclerosis. Neuroepidemiology 1999;18:53– 63. 13. Goodin DS. Corticosteroids and optic neuritis [Letter to the Editor]. Neurology 1993;43:632– 633. 14. Beck RW. Corticosteroids and optic neuritis [Reply to Letter to the Editor]. Neurology 1993;43:633– 634.
CONCLUSIONS THE MAJOR TREATMENT STUDIES IN OPTIC NEURITIS AND
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15. Corbett JJ, Cruse JM. Corticosteroids and optic neuritis [Reply to Letter to the Editor]. Neurology 1993;43:634. 16. Beck RW, Trobe JD, and the Optic Neuritis Study Group. The Optic Neuritis Treatment Trial. Putting the results in perspective. J Neuroophthalmol 1995;15:131–135. 17. Kaufman DI, Trobe JD, Eggenberger ER, Whitaker JN. Practice parameter: the role of corticosteroids in the management of acute monosymptomatic optic neuritis. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:2039 –2044. 18. Miller DH, Newton MR, van der Poel JC, Halliday AM, Kendall BE, Johnson G, et al. Magnetic resonance imaging of the optic nerve in optic neuritis. Neurology 1988;38:175–179. 19. Dunker S, Wiegand W. Prognostic value of magnetic resonance imaging in monosymptomatic optic neuritis. Ophthalmology 1996;103:1768 –1773. 20. Kupersmith MJ, Alban T, Zeiffer B, Lefton D. Contrastenhanced MRI in acute optic neuritis: relationship to visual performance. Brain 2002;125:812– 822. 21. Cohen MM, Lessell S, Wolf PA. A prospective study of the risk of developing multiple sclerosis in uncomplicated optic neuritis. Neurology 1979;29:208 –213. 22. Rizzo JF, Lessell S. Risk of developing multiple sclerosis after uncomplicated optic neuritis: a long-term prospective study. Neurology 1988;38:185–190. 23. Beck RW, Arrington J, Murtagh FR, Cleary PA, Kaufman DI. Brain magnetic resonance imaging in acute optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Neurol 1993;50:841– 846. 24. Optic Neuritis Study Group. High-and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis. Arch Ophthalmol 2003;121:944 –949. 25. Soderstrom M, Lindqvist M, Hillert J, Kall TB, Link H. Optic neuritis: findings on MRI, CSF examination, and HLA class II typing in 60 patients and results of a short-term follow-up. J Neurol 1994;241:391–397. 26. Ghezzi A, Martinelli V, Torri V, et al. Long-term follow-up of isolated optic neuritis: the risk of developing multiple sclerosis, its outcome, and the prognostic role of paraclinical tests. J Neurol 1999;246:770 –775. 27. Druschky A, Heckmann JG, Claus D, et al. Progression of optic neuritis to multiple sclerosis: an 8-year follow-up study. Clin Neurol Neurosurg 1999;101:189 –192. 28. Beck RW, Trobe JD, and the Optic Neuritis Study Group. What we have learned from the Optic Neuritis Treatment Trial. Ophthalmology 1995;102:1504 –1508. 29. Arnold AC, Pepose JS, Hepler RS, Foos RY. Retinal periphlebitis and retinitis in multiple sclerosis. Pathologic characteristics. Ophthalmology 1984;91:255–262. 30. Lightman S, McDonald WI, Bird AC, et al. Retinal venous sheathing in optic neuritis. Brain 1987;110:405– 414. 31. Rolak LA, Beck RW, Paty DW, Tourtellotte WW, Whitaker JN, Rudick RA. Cerebrospinal fluid in acute optic neuritis: experience of the Optic Neuritis Treatment Trial. Neurology 1996;46:368 –372. 32. Compston DA, Batchelor JR, Earl CJ, McDonald WI. Factors influencing the risk of multiple sclerosis developing in patients with optic neuritis. Brain 1978;101:495–511. 33. Francis DA, Compston DA, Batchelor JR, McDonald WI. A reassessment of the risk of multiple sclerosis developing in
VOL. 139, NO. 6
OPTIC NEURITIS
AND
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46. 47.
48.
49.
patients with optic neuritis after extended follow-up. J Neurol Neurosurg Psychiatry 1987;50:758 –765. Farris BK, Pickard DJ. Bilateral postinfectious optic neuritis and intravenous steroid therapy in children. Ophthalmology 1990;97:339 –345. Brady KM, Brar AS, Lee AG, Coats DK, Paysse EA, Steinkuller PG. Optic neuritis in children: clinical features and visual outcome. J AAPOS 1999;3:98 –103. Parmley VC, Schiffman JS, Maitland CG, Miller NR, Dreyer RF, Hoyt WF. Does neuroretinitis rule out multiple sclerosis? Arch Neurol 1987;44:1045–1048. Beck RW and the Optic Neuritis Study Group. The Optic Neuritis Treatment Trial: three year follow-up results. Arch Ophthalmol 1995;113:136 –137. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transaction in the lesions of multiple sclerosis. N Engl J Med 1998;338:278 –285. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylpredisolone on brain atrophy in relapsing-remitting MS. Neurology 2000;57:1239 –1247. IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995;45:1277–1285. PRISMS (Prevention of Relapses and Disability by Interferon -1a Subcutaneously in Multiple Sclerosis) Study Group, University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon -1a in relapsing MS. Neurology 2001;56:1628 –1636. Li DKB, Paty DW, and the UBC MS/MRI Analysis Research Group and the PRISMS Study Group. Magnetic imaging results of the PRISMS trial: a randomized doubleblind placebo-controlled study of interferon -1a in relapsing-remitting multiple sclerosis. Ann Neurol 1999;46: 197–206. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, and the Copolymer 1 Multiple Sclerosis Study Group. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 1995;45:1268 –1276. Galetta SL, Markowitz C, Lee AG. Immunomodulatory agents for the treatment of relapsing multiple sclerosis. Arch Intern Med 2002;162:2161–2169. Comi G, Filippi M, Wolinsky JS and the European/ Canadian Glatiramer Acetate Study Group. European/ Canadian multicenter, double-blind, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol 2001;49:290 –297. Optic Neuritis Study Group. Neurologic impairment 10 years after optic neuritis. Arch Neurol 2004;61:1386 –1389. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120: 393–399. De Stefano N, Narayanan S, Francis GS, et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 2001;58:65–70. Truyen L, van Waesberghe THTM, Barkof F, et al. Accumulation of hypointense lesions (“black holes”) on T1 spin
MULTIPLE SCLEROSIS
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nerve degeneration. Invest Ophthalmol Vis Sci 1999;40:65–73. 52. Miller DH, Khan OA, Shreemata WA, et al. A controlled clinical trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. 53. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004;363:1607–1608.
echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996;47:1469 –1476. 50. Van Walderveen MA, Kamphorst W, Scheltens P, et al. Histopathologic correlate of hypointense lesions on T1weighted spin-echo MRI in multiple sclerosis. Neurology 1998;50:1282–1288. 51. Yoles E, Wheeler LA, Schwartz M. Alpha-2 adrenoreceptor agonists are neuroprotective in a rat model of optic
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Biosketch Anthony C. Arnold, MD, is professor and chief, Division of Neuro-Ophthalmology, Jules Stein Eye Institute, UCLA Department of Ophthalmology, and director, UCLA Optic Neuropathy Center. He has a primary research interest in ischemic and inflammatory optic neuropathies.
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