E. .. ~ f..¢nbw.~¥r. 1.... e x. n‘ . fi‘.‘§, ”dug ‘ . 52!. y. . fix .. T 3X :V: v‘WE. fl. ‘ . r. In. 7.14 pit, us, wig u. .4 by ,.m; .nn ‘~ ‘ .. «aw... in: v... on ‘ v . . . twp.” «1. .\. 3w: JP}... .1 ha" furnam3wufivu‘ .,.. :a...‘ . rp ... .4, t in. 1R. \I«. 3.“ nu. .31.}. .‘ s) LIBRARY 203‘? Michigan State University This is to certify that the thesis entitled THE OPTIC NERVE AND NEURO-OPHTHALMOLOGY AS A STUDY MODEL FOR MULTIPLE SCLEROSIS presented by ERIC R. EGGENBERGER has been accepted towards fulfillment of the requirements for the MS. degree in Epidemiology A“! dam Major Professor’s Signature 7, M1 100 7- / . I Date MSU is an Affirmative Action/Equal Opportunity Institution PLACE IN RETURN BOX to remove this checkout from your record. To AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE 6/07 p:ICIRC/DateDue.indd-p.1 THE OPTIC NERVE AND NEURO-OPHTHALMOLOGY AS A STUDY MODEL FOR MULTIPLE SCLEROSIS By Eric R. Eggenberger A THESIS Submitted to Michigan State University In partial fulfillment of the requirements for a degree of MASTERS OF SCIENCE Department of Epidemiology 2007 ABSTRACT THE OPTIC NERVE AND NEURO-OPHTHALMOLOGY AS A STUDY MODEL FOR MULTIPLE SCLEROSIS By Eric R. Eggenberger, DO The optic nerve and neuro-ophthalmology in general serve as useful study models for several central nervous system diseases, including multiple sclerosis. The Optic Neuritis Treatment Trial and Longitudinal Optic Neuritis Study substantiated the relative value of steroid therapy for optic neuritis and the risk of progression to MS based on MRI findings. The CHAMPS trial demonstrated the benefit of early interferon therapy in patients at high risk for MS. Combination therapy trials such as SENTINEL reminded us of the complexity and our incomplete understanding of the immune system in MS. Optical coherence tomography affords us a simple and non-invasive means to quantify the visual axonal status in MS. Our clinic continues to focus on refining therapy, enhancing our understanding of the natural history, and developing imaging tools for MS utilizing quantifiable neuro-ophthalmic endpoints. This Masters of Science thesis summarizes the epidemiology of multiple sclerosis and several optic nerve disease processes pertaining to multiple sclerosis, and provides details on the just-mentioned clinical epidemiology. ACKOWLEDGMENTS I wish to thank Carolyn, Cody and Tristan for their unwavering support. TABLE OF CONTENTS List of tables. List of Figures Chapter 1 Specific aims of the thesis project ...................................................... 1 Chapter 2 Background and significance ............................................................. 2 Chapter 3 Longitudinal Optic Neuritis Study (LONS) ............................................ 17 Chapter 4 CHAMPS study data ....................................................................... 71 Chapter 5 Combination trials in MS .................................................................. 100 Chapter 6 Optical coherence tomography studies in MS ...................................... 134 Chapter 7 Conclusions ................................................................................. 144 References ................................................................................... 147 iv LIST OF TABLES Table 1. McDonald MS diagnostic criteria .................................... Pg 4 Table 2. The Kurtzke Expanded Disability Status Scale (EDSS) ...... Pg 6 LIST OF FIGURES Figure 1. Annualized relapse rate by trimester of pregnancy; a decreased relapse risk is noted in trimester 3, while a rise in the relapse rate occurs in the 3 months post-partum (modified from Confavreux et al.1998) ........... Pg 11 Figure 2. Left image is T2 weighted MRI demonstrating typical T2 hyperintensities; right image is corresponding T1-weighted sequence demonstrating T1 “black holes” .......................................................... Pg 13 Figure 3. OCT printout of a patient several years status post optic neuritis right eye demonstrates nerve fiber layer loss preferentially affecting the temporal aspect of the nerve. The top figure is a linear tracing of the nerve fiber layer thickness demonstrating decline below age and gender-matched controls in the temporal portion; the bottom circular depiction demonstrates the nerve as it appears per fundus view with the temporal section labeled “T” measuring 42- micron thickness ............................................................................ Pg 142 vi KEY TO ABBREVIATIONS ACT — Avonex Combination Trial (Avonex, IVMP, methotrexate) CDMS — clinically definite multiple sclerosis CHAMPS - Controlled, High-risk patient Avonex Multiple sclerosis Prevention Study CHAMPIONS - Controlled, High-risk patient Avonex Multiple sclerosis Prevention In On-going Neurologic Surveillance CIS — clinically isolated syndrome. Combin — Combination in MS trial (interferon, glatiramer) LONS - Longitudinal Optic Neuritis Study IVMP — intravenous methylprednisolone MRI — magnetic resonance imaging MS - multiple sclerosis NEI — National Eye Institute NIH - National Institutes of Health OCT — optical coherence tomography ONTT - Optic Neuritis Treatment Trial SENTINEL - Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis vii Chapter 1: Specific Aims of the Thesis Project Neuro-ophthalmology provides a quantifiable avenue of study that is applicable to many generalized central nervous system diseases, and commonly employs magnetic resonance (MRI) or other imaging techniques in this endeavor. Multiple sclerosis is a common inflammatory-degenerative disease of the central nervous system that usually produces ocular symptoms. Neuro- ophthalmological inquiries help quantify some of the functional nervous system changes that result from multiple sclerosis (MS). Specific questions bearing relevance to this course of research within neurology and neuro-ophthalmology include: 1. 2. What is the long term visual prognosis of optic neuritis? What is the Iong-terrn relationship between optic neuritis and MS? What are the long term MRI features of optic neuritis? What is the value of early interferon therapy in monosymptomatic patients at high risk for MS? What is the value of combination therapy in MS? What are the optical coherence tomography (OCT) correlates of optic neuritis? How does the OCT nerve fiber layer thickness correlate with EDSS and MRI features? Chapter 2: Background and Epidemiology of MS Multiple sclerosis (MS) is one of the most common causes of neurological disability in younger patients [Hirtz D et al, 2007]. The most prevalent form of MS, relapsing remitting MS, is characterized by “attacks” or exacerbations, which cause neurologic dysfunction within a discrete part of the central nervous system. The average age at onset of MS is in the early 30s. Exact incidence and prevalence figures are extremely hard to obtain, in part because of the lack of a specific diagnostic test, the continued advances in diagnostic testing, and changing diagnostic criteria. Increased awareness of the disease and the greater use of MRI scans in the US have helped increase the reported prevalence over time, also. The National Multiple Sclerosis Society estimates that approximately 400,000 patients in the US (and approximately 1,000,000 worldwide) currently have MS [National MS Society]. MS has a distinct region- specific incidence and prevalence character, generally increasing in prevalence in northern regions; the highest MS prevalence in the US is found in the upper midwest (158/100,000), whereas lower prevalence is found in the south (77/100,000) and southwest (74/100,000) [Minden et al, 1993]. It is unclear if this reflects environmental factors, genetic factors, or a combination of these [Bulman and Ebers, 1992; Eggenberger 1996]. The diagnosis of MS is based on clinical grounds, meaning there is no gold standard lab or scan to definitively establish the diagnosis. MS was diagnosed in accord with the Poser criteria (1983) until the McDonald criteria (published 2001, and revised 2005) became the standard. The Poser criteria are: . Clinically definite MS 0 2 attacks and cliniCal evidence of 2 separate lesions 0 2 attacks, clinical evidence of one and paraclinical evidence of another separate lesion Laboratory supported Definite MS . 2 attacks, either clinical or paraclinical evidence of 1 lesion, and cerebrospinal fluid (CSF) immunologic abnormalities 0 1 attack, clinical evidence of 2 separate lesions & CSF abnormalities 0 1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, and CSF abnormalities Clinically probable MS 0 2 attacks and clinical evidence of 1 lesion 0 1 attack and clinical evidence of 2 separate lesions . 1 attack, clinical evidence of 1 lesion, and paraclinical evidence of another separate lesion Laboratory supported probable MS . 2 attacks and CSF abnormalities [Poser et al, 1983] Both these criteria incorporate the idea of separation of neurologic symptoms and signs in time and space (thus the “multiple” of MS); this requires distinct areas of central nervous system dysfunction occurring separately in time (at least 1 month between distinct exacerbations). The McDonald criterion incorporates MRI as a technique to demonstrate separation of these lesions in time and space (see below) [McDonald et al, 2001]. The McDonald criteria are organized in accord with the requirements to satisfy the diagnosis of MS under specific clinical presentations: Table 1. McDonald MS criteria. Clinical Presentation Additional Data Needed ___ f ' . 2 or more attacks JNone; clinical evidence will suffice (relapses) (additional evidence desirable; must be . 2 or more objective ,consistent with MS) clinical lesions 7 l . 2 or more attacks Dissemination in space, demonstrated by: . 1 objective clinical lesion , . MRI ' . or a positive CSF and 2 or more MRI lesions consistent with MS . or further clinical attack involving different site Dissemination in time, demonstrated by: V . 1 attack . 2 or more objective .1 . MRI clinical lesions , . or second clinical attack . 1 attack IDissemination in space by demonstrated by: . . . 1 objective clinical lesion - MRI (monosymptomatic i . or positive CSF and 2 or more MRI presentation) ? lesions consistent with MS - land lDissemination in time demonstrated by: l . MRI . or second clinical attack Insidious neurological Positive CSF progression suggestive of MS and :(primary progressive MS) Dissemination in space demonstrated by: 0 MRI evidence of 9 or more T2 brain lesions or 2 or more spinal cord lesions or 4-8 brain and 1 spinal cord lesion or positive VEP with 4-8 MRI lesions or positive VEP with <4 brain lesions plus 1 spinal cord lesion and Dissemination in time demonstrated by: 0 MRI . or continued progression for 1 year WED—anew" et al,2_001] The early phases of the disease appear to be mediated by an inflammatory pathophysiologic process. Clinically, this phase is marked by attacks, during which the patient experiences a novel symptom or worsening of an old symptom. This inflammation may affect nearly any portion of the nervous system, but has a predilection for the white matter tracks involving vision (both optic nerve mediated loss of vision, and brainstem tracks producing double vision), motor, sensory, coordination, bowel and bladder-invested fibers. Over 50% of patients with MS have evidence of optic neuropathy on exam, and optic neuritis is the second most common initial MS symptom, whereas the much less-specific sensory change is the most common presenting event. Although many standard textbooks describe MS as a demyelinating disease, there is axonal loss, which occurs early in the disease and accounts for significant disability [Rovaris et al, 2005]. Exacerbations produce symptoms that tend to persist for weeks to months, and then often improve spontaneously, and may even resolve entirely in the early phases. Exacerbations are often treated with a short course of high dose steroids to shorten the duration of symptoms. Prior to the Optic Neuritis Treatment Trial (ONTT) and its follow up study, the Longitudinal Optic Neuritis Study (LONS), the relative risks and benefits of the various steroid regiments used in practice were unknown. Over time, exacerbations typically produce a degree of residual disability that tends to accumulate over time, and is often graded clinically with the Expanded Disability Status Scale (EDSS). The EDSS is scored 0 — 10 with a heavy emphasis on ambulation; 4 (severe disability but unassisted ambulation, and 6 (needs assistance to ambulate) are common EDSS milestones used in clinical trials [Optic Neuritis Study Group, 1997, 2003, 2004]. Table 2. The Kurtzke Expanded Disability Status Scale (EDSS).* Kurtzke Expanded Disability Status Scale 0.0 Normal neurological examination 1.0 No disability, minimal signs in one FS 1.5 No disability, minimal skits in more than one FS 2.0 Minimal disability in one FS 2.5 Mild disability in one FS or minimal disability in two FS 3.0 Moderate disability in one FS, or mild disability in three or four FS. Fully ambulatory 3.5 Fully ambulatory but moderate disability in 1 FS and > minimal disability in several others 4.0 Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability; able to walk without aid or rest some 500 meters 4.5 Fully ambulatory without aid, able to work full day, some limitation of full activity or require min assistance; relatively severe disability; able to walk without aid or rest 300 meters. 5.0 Ambulatory without aid or rest for about 200 meters; disability severe enough to impair full daily activities (work a full day without special provisions) 5.5 Ambulatory without aid or rest for 100 meters; disability severe enough to preclude full daily activities 6.0 Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk about 100 meters with or without resting 6.5 Constant bilateral assist (canes, crutches, braces) to walk about 20 meters without resting 7.0 Unable to walk beyond 5 meters even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up in wheelchair some 12 hours a day 7.5 Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but not in standard wheelchair a full day; May require motorized wheelchair 8.0 Essentially restricted to bed or chair or perambulated in wheelchair; may be out of bed much of the day; retains many self-care functions; generally has effective use of arms 8.5 Essentially restricted to bed much of day; has some effective use of arms retains some self care functions 9.0 Confined to bed; can still communicate and eat. 9.5 Totally helpless bed patient; unable to communicate effectively or eat/swallow 10.0 Death due to MS *http://www.mult-sclerosis.org/expandeddisabilitystatusscale.html (last accessed 3112/07). Although the EDSS has become embedded as a central outcome measure in MS study, it has several drawbacks including non-ordinal character, inter-rater variability, and emphasis on ambulation status in deference to other neurologic function. Several attempts to supplement this scale have been forwarded, the most recent of which is the MS Functional Composite (MSFC). The MSFC includes a timed 25-foot walk, 9-hole peg test to assess upper extremity dexterity, and the Paced Auditory Serial Addition Test (PASAT) to measure cognition status. The MSFC has been adopted to the extent that it is often incorporated into MS trials, but has not been accepted as a sole clinical outcome measure by the USF DA. In addition, a binocular contrast sensitivity- based measure of visual acuity may be added to the MSFC to provide a visually based measure of function [Balcer et al, 2003]. The cause of death of patients with MS has been investigated by several groups, but perhaps the Danish MS Registry has contributed the most evidence on this question. This registry was established in 1956 and encompasses all Danish patients with MS. Analysis of 6068 subjects in this registry who died between 1951 and 1993 was performed by Koch-Henriksen and colleagues [Koch-Henriksen et al, 1998]. MS was on the death certificate as the underlying cause in 55.4%. Cardiovascular (17.6%), cancer (8.6%), respiratory or infectious causes (5.1%), other natural causes (9.5%), and accident or suicide (3.8%) were noted in descending order. Among 8142 incident cases who had onset of multiple sclerosis between 1951—93 the standardized mortality ratios for causes of death other than MS were highest for infectious or pulmonary diseases: 2.46 (95% confidence interval (95% CI) 2.04-2.94); suicide: 1.62 (95% CI 1.29—2.01); cardiac or vascular diseases: 1.34 (95% CI 1.22-1.48); accidents 1.34 (95% CI 1.02-1.71); and cancers: 0.79 (95% CI 0.70—0.90). The authors concluded that more than half of patients with MS die from the disease or complications from MS; the increased risk of death from suicide and accidents can be indirectly attributed to multiple sclerosis. Among non-MS causes, patients with MS have an increased death risk from cardiovascular diseases but a reduced cancer death risk; the authors acknowledge that the diminished risk of dying from cancer may be a result of incomplete ascertainment of cancers in disabled patients with MS. This database was also used to investigate trends in survival and death rates in a 2004 publication. This study utilized all patients with onset between 1949 - 1996 (9881 patients, of whom 4254 had died before end of follow-up). The median survival time from onset was approximately 10 years shorter for MS patients than for the age-matched general population, and MS was associated with a 3-fold increase in the risk for death. The probability for survival improved significantly during the observation period such that the 10-year excess mortality was almost halved in comparison with that in the mid-1900s [Bn‘mnum-Hansen et al, 2004]. One of the essential questions in MS research is the role of genetics and environmental factors (e.g., race vs. place, nature vs. nurture). Research has focused on genetic regions involved in the immune system such as the major histocompatibility complex (MHC); however, no MHC component has been shown to be both necessary and sufficient for MS development. The exact role of genetics is not likely to be fully revealed in the near future due to several confounding factors. Genetic loci may contribute unevenly to MS risk. Genetics may interact at different steps in the autoimmune initiation process and resistance alleles may also play a role. Without definite location of susceptibility alleles, the entire body of geographic and latitude-based evidence is difficult to interpret [Poser CM, 1994]. Nonetheless, a genetic influence is widely accepted [Sadovnick, 1994]. Additional evidence for the strong genetic influence includes the rarity of the disease among African Blacks, the Japanese or the Chinese. MS has never been reported in ethnically pure lnuits, North and South American Indians, Australian aborigines, New Zealand Maoris, Pacific Islanders or Lapps. In the past, a central construct in MS epidemiology was the theory that incidence increased with distance from the equator. The latitude theory has been largely tempered by a realization of the importance of genetics (although not to the exclusion of environmental factors). In a general way, the disease is more frequent in areas settled by and currently inhabited by individuals of Scandinavian descent (Norway, Sweden, Denmark, Iceland, North America, the British Isles, Ireland, Australia, and New Zealand). Therefore, the geographic prevalence data concerning MS may reflect genetics in addition to environment [Davenport, 1922; Jersild et al, 1972; Kurtzke, 1993; Poser, 1994; Sadovnick, 1994]. There is some evidence that persons emigrating from a country of high MS frequency to a region of low MS frequency bring with them a higher risk of the disease if they emigrate after puberty. Those who immigrate before puberty seem to acquire the lower MS risk of the country of destination. Several problems exist with these studies, however; for example, migrants likely 10 represent a select, but heterogeneous population, and are likely to be healthier than non-immigrants [Alter et al, 1966]. The familial rate for MS approaches 20% (combined prevalence rate for first, second, and third degree relatives of index patients) [Ebers et al, 2000]. Concordance rates for MS in monozygotic twins are approximately 25%, compared to only 2.4% for dizygotic sets (close to the non-twin sibling rate). The lifetime prevalence of MS in the children of a parent with MS is approximately 2-3% [Poser CM, 1994; Sadovnick et al, 1993; Sadovnick, 1994]. Figure 1. Trimester of Study Figure 1. Annualized relapse rate by trimester of pregnancy; a decreased relapse risk is noted in trimester 3, while a rise in the relapse rate occurs in the 3 months post-partum (modified from Confavreux et al, 1998). Pregnancy and viral infections are two known natural influences on the course of MS. \firal infection and the immediate postpartum period predispose to 11 relapse, while the third trimester of pregnancy is one of relative protection [Confavreux et al, 1998]. There is no known influence on the course of MS from factors such as trauma and vaccines. The development of clinical MS appears to be based on genetics plus environment. The ‘MS trait’ concept is a theory to understand the genetics and environmental factors that influence MS [Poser, 1994]. This MS trait is a systemic, non-pathological condition (a “disease waiting to happen”) that includes several common features: - Vigorous response to many viral antigens o CSF oligoclonal bands 0 CNS perivascular lymphocytic infiltration» blood brain barrier breakdown 0 Similar lymphocyte responses to blast transformation tests Magnetic resonance imaging (MRI) has aided the discovery of the inflammatory component of the disease, especially T2 hyperintensities in addition to the relatively frequent appearance of enhancing lesions after the administration of gadolinium. This T2 hyperintense inflammatory component of the MRI in MS is often very dynamic, with lesions appearing and evolving ten times more frequently than the standard clinical examination rate of change. Surprisingly, this easily visualized inflammatory component does not correlate very well with disability [Li et al, 2006]. The axonal component is more difficult to visualize on MRI, but is thought to underlie MRI-demonstrable atrophy and black holes on 12 T1-weighted sequences; these features correlate better with disability than the more readily apparent T2 inflammatory changes. Figure 2. Figure 2: left image is T2-weighted MRI demonstrating typical T2 hyperintensities; right image is the corresponding T1-weighted sequence demonstrating T1 “black holes”. Treatment of MS can be divided according to symptomatic, acute and chronic forms. Symptomatic treatments aim to decrease disability associated with ongoing neurologic dysfunction, such as medication used to improve bladder control or spasticity. Acute treatment most often takes the form of high dose corticosteroids to shorter the duration of an exacerbation. USFDA-approved chronic therapies include interferon beta, and glatiramer acetate for remitting- relapsing MS, while mitoxantrone is indicated for secondary progressive MS. Treatment with interferon or glatiramer acetate is associated with decreased frequency and severity of exacerbations and decreased accumulation of MS- related MRI changes over time. The therapies for relapsing MS (interferon beta and glatiramer acetate) share several features: they are all parenteral (either intramuscular or subcutaneous injections); they decrease exacerbation rates by approximately 1/3; and are very expensive (approximately $1000/month). With respect to the natural history and clinical course, MS evolves in a highly individual, unpredictable manner in patients, although after 25 - 30 years, most patients enter a secondary progressive phase of the disease. During this phase, disability accumulates in a slower, steady fashion without exacerbations over time. This phase of the disease appears be degenerative in origin in contrast to the initial inflammatory-driven relapses, and is much more difficult to treat. The MRI scans in secondary progressive disease tend to show fewer enhancing lesions and a less dynamic picture of T2 lesion evolution compared to the remitting-relapsing form of MS [Wolinsky, 2002; Arnold and Matthews, 2002; Barkof et al, 2005]. MS typically begins as a “clinically isolated syndrome” (CIS) suggestive of demyelination. CIS may take the form of numbness, optic neuritis, weakness or diplopia in descending order of occurrence frequency. Because there is no diagnostic test for MS, the disease cannot be definitively diagnosed in a patient with CIS until either a new clinical event occurs, or sufficient MRI changes over time are demonstrable. The time between the first and second attack is highly variable and ranges from weeks to years [Tintoré et al, 2006; Jacobs et al, 2000]. Prior to the CHAMPS study, the effect of traditional MS therapies like interferon added after a CIS was not known. 14 A continuous line of research involving neuro-ophthalmology and imaging techniques as they have been applied to MS will be outlined in this thesis. This line of research began with the author’s involvement in the National Eye Institute (NED-sponsored LongitUdinaI Optic Neuritis Study (LONS), the follow up study to the Optic Neuritis Treatment Trial (ONTT). The LONS published 5- year results in 1997, 10-year results in 2003, and is currently collecting 15-year data. This research was followed by the CHAMPS (Controlled High-risk patient Avonex Multiple sclerosis Prevention Study) trial that first published results in 2000, and the follow up study, CHAMPIONS (Controlled High-risk patient Avonex Multiple sclerosis Prevention Study In Ongoing Neurologic Surveillance). Current studies include the ACT (Avonex Combination Trial), the NIH-sponsored Combin trial, and the LONS 15-year follow up study with the MSU-directed optical coherence tomography (OCT) sub-study. Future research directions will continue along this evolving path. The remainder of this thesis report is organized in relation to publications related to four research endeavors, and a conclusions chapter. The author has served as the principal investigator for each of these trials in addition to service on the writing committees for the dissemination of this research. Chapter 3 is entitled “Longitudinal Optic Neuritis Study (LONS)” and discusses 5- and 10- year follow up findings related to the specific aims 1, 2, and 3 of the project. Chapter 4 is entitled “CHAMPS study data” and relates to specific aim 4 of the project. Chapter 5 is entitled “Combination trials in MS” and relates to specific aim 5 of the project. Chapter 6 is entitled “Optical coherence tomography 15 studies in MS” and relates to specific aims 6 and 7 of the project. Chapter 7 is entitled “Conclusions”, and will summarize the most salient features of the research and outline future directions. 16 Chapter 3 THE OPTIC NEURITIS STUDY GROUP. Visual Function More Than 10 Years After Optic Neuritis: Experience of the Optic Neuritis Treatment Trial. Am J Ophthalmol 2004; 1 37:77—83. (A summary overview of this article will be found on page 68 of this thesis.) Optic Neuritis Study Group. High- and Low-risk Profiles for the Development of Multiple Sclerosis Within 10 Years after Optic Neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 2003; 121 :944-949. (A summary overview of this article will be found on page 69 of this thesis.) Optic Neuritis Study Group. Long-term Brain Magnetic Resonance Imaging Changes After Optic Neuritis in Patients Without Clinically Definite Multiple Sclerosis. Arch Neurol. 2004;61:1538-1541 (A summary overview of this article will be found on page 69 of this thesis.) 17 Visual Function More Than 10 Years After Optic Neuritis: Experience of the Optic Neuritis Treatment Trial THE OPTIC NEURITIS STUDY GROUP* PURPOSE: To assess visual function more than 10 years after an episode of optic neuritis in patients enrolled in the Optic Neuritis Treatment Trial. DESIGN: Longitudinal follow-up of a randomized clinical trial. METHODS: Vision testing included measures of visual acuity, contrast sensitivity, and visual field. Quality of life was assessed with the National Eye Institute Visual Function Questionnaire. RESULTS: Examinations were completed on 319 patients. In most patients, visual function test results in the eyes that experienced optic neuritis at study entry (“affected eyes”) were normal or only slightly abnormal after 9.9 to 13.7 years. Visual acuity in the affected eyes was >20/20 in 74%, 20l25 to 20/40 in 18%, <20/40 to 20/200 in 5%, and <20/200 in 3%. On average, visual function was worse in patients with multiple sclerosis (MS) than in those without MS. Recurrent optic neuritis in either eye occurred in 35% of patients. Such attacks were more frequent in patients with MS (P < .001). The National Eye Institute Visual Function Questionnaire scores were lower when visual acuity was abnormal and when MS was present. CONCLUSIONS: Most patients retained good to excellent vision more than 10 years after an attack of optic neuritis. Recurrences were more frequent in 18 patients with MS [tables and figures appear in the original article]. (Am J Ophthalmol 2004;137:77—83. © 2004 by Elsevier Inc. All rights reserved.) Accepted for publication July 15,2003. lntemet Advance publication at ajo.com July 16, 2003. *The writing committee, investigators, and coordinators who participated in the study are listed in the Appendix. This study was supported by a Cooperative Agreement (U10 EY09435) from the National Eye Institute, National Institutes of Health. Inquiries to Robin L. Gal, MSPH, Optic Neuritis Study Group Coordinating Center, Jaeb Center for Health Research, 15310 Amberly Dr, Suite 350, Tampa, FL 33647; fax: (813) 975-8761; e-mail: ontt@jaeb.org 0002-9394/04l$30.00 © 2004 BY ELSEVIER INC.ALL RIGHTS RESERVED. doi: 10.1 016/80002-9394(03)00862-6 THE OPTIC NEURITIS TREATMENT TRIAL (ONTT) Assessed the efficacy of corticosteroids in the treatment of acute optic neuritis. Through continued support of the National Eye Institute, longitudinal follow-up of the cohort has provided an opportunity to develop an understanding of the course after optic neuritis including the visual function, recurrences and development of multiple sclerosis (MS). Herein, we report the visual function, quality of life, and frequency of recurrent optic neuritis 9.9 to 13.7 years after entry into the ONTT. 19 In a separate publication, we report the results of the neurologic follow-up of the canon} METHODS BETWEEN JUNE 1988 AND JULY 1991, 454 PATIENTS WITH optic neuritis were enrolled into the ONTT and completed the baseline testing (one enrolled patient withdrew before completing the baseline testing, and two patients were found to have a compressive optic nerve lesion rather than optic neuritis). Patients provided written informed consent for each follow-up phase. After the conclusion of the treatment trial in 1992, 410 patients consented to continued follow-up, and in 1997, 387 patients again consented to continue in follow-up. The investigational review board at each participating institution approved the protocol. The design of the ONTT has been described previously in detail?6 Important features are summarized here. The criteria for entry into the ONTT included a diagnosis of acute unilateral optic neuritis with visual symptoms for 8 days or less, age between 18 and 46 years, no previous history of optic neuritis or ophthalmoscopic signs of optic atrophy in the affected eye, and no evidence of a systemic disease other than MS that might be associated with the optic neuritis. Patients who experienced prior episodes of optic neuritis in the other (fellow) eye or prior demyelinative attacks of MS were eligible only if corticosteroids had not been prescribed. This minimized the number of patients enrolled who had a prior diagnosis of MS, and those diagnosed as having MS 20 at the time of enrollment had minimal or no neurologic disability. At study entry, patients were randomly assigned to receive a short course of oral prednisone, oral placebo, or intravenous methylprednisolone sodium succinate followed by oral prednisone. Patients were examined at eight follow-up visits within the first year and then at yearly intervals until 1997. From 2001 to 2002, the consenting patients were recalled for an examination. Visual acuity was measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) testing protocol, contrast sensitivity with the PelIi-Robson chart, and visual field with the Humphrey Field Analyzer 30-2 program. Quality of life was assessed by completion of the National Eye Institute Visual Function Questionnaire (NEI-VFQ). A structured neurologic examination was performed and an assessment was made as to whether the patient met criteria for clinically definite MS (referred to subsequently as “MS”).7 Categorical variables were compared with the Fisher exact test. Differences in visual acuity, contrast sensitivity, and visual field testing were compared with the Wilcoxon rank-sum test. Differences in mean age between patients who did vs did not have continued follow-up were compared with an independent samples ttest. The questionnaire subscale scores were compared between ONTT patients and a reference group from Mangione and associates8 with an independent samples ttest. An increasing association between the response on the quality 21 of life questionnaire with better visual acuity in both eyes and with increasing disability level was evaluated with simple linear regression. All reported P values are two-tailed. Analyses were conducted using SAS version 8.2 statistical software (SAS Institute, Cary, North Carolina, USA). RESULTS AN EXAMINATION WAS COMPLETED FOR 319 (82%) OF THE 387 patients who consented to continue in follow-up beyond 1997. The time from entry into the ONTT until the examination ranged from 9.9 to 13.7 years. For 272 patients (85%), the examination was completed at one of the original ONTT clinical centers. The remaining 47 patients (15%) completed the examination with a non-study ophthalmologist, because returning to an ONTT clinical center was not feasible. Among the 454 patients in the original ONTT cohort, the 319 patients who completed the examination were similar to the 135 patients who'did not complete the examination in mean age at entry into the ONTT (32 years vs 31 years, P=.15), proportion of females (78% vs 73%, P = .27), proportion with abnormal baseline brain magnetic resonance imaging (MRI) scan (53% vs 47%, P = .24), and proportion with MS at baseline (8% vs 8%, P> .99). Patients not completing the examination were more likely to be African American (21% vs 9%, P = .002), however, and on average had slightly worse acuity in the 22 affected eye at baseline (median baseline logarithm of the minimal angle of resolution (LogMAR) acuity 0.64 vs 0.48, P=:I .02). For the 135 original ONTT patients not completing the 10—year examination, 23 (17%) completed less than 1 year of follow-up, 35 (26%) completed 1 to 4 years of follow-up, and 77 (57%) completed 5 or more years of follow-up. Among these patients, visual acuity was 20/20 or better in both eyes at the last completed visit in 82 (61%). Visual acuity in the affected eye was 20/40 or better in 120 (89%) and in the fellow eye was better than 20l40 in 127 (94%). Five patients had acuity worse than 20/40 in each eye, with three of these patients having acuity worse than 20/200 in each eye at their last visit. Two of the three patients with acuity worse than 20I200 in each eye died; the death of one patient was related to MS. Visual function test results in most patients were normal or only slightly abnormal both in the affected eyes (eyes with optic neuritis at the time of study entry) and in the fellow eyes (Tables 1 and 2). In the affected eyes, the probability of having 20/20 or better acuity after 10 years was lower when the baseline acuity was more severely affected (P < .001 ). This was particularly true when the baseline acuity was counting fingers or worse (Table 3). Most patients showed little change in vision from the time of the 5-year examination until the current examination (Figure 1). For 251 (81%) of the 31.0 patients with both a 5-year and a current examination, the current examination 23 of visual acuity in the affected eye was within 1 line of the 5-year acuity. For 14 eyes (5%), the current examination acuity was more than 1 line better and for 45 (15%) it was more than 1 line worse. Among these 45 eyes, visual acuity remained 20/40 or better in 27 (60%). Although most patients retained excellent visual function, 28 patients (9% of the 319 patients with a current examination) had a visual acuity that was worse than 20/40 in the affected eye and 11 patients (3%) had a visual acuity that was worse than 20/40 in the fellow eye. Six patients (2%) had visual acuity worse than 20/40 in both eyes (Table 2). In three of these patients, visual acuity was worse than 20/200 in both eyes. All three patients experienced at least one recurrence of optic neuritis; one patient had a recurrence in only the affected eye, one patient had a new attack of optic neuritis in the fellow eye, and one had a recurrent attack of optic neuritis in one eye and a new attack of optic neuritis in the fellow eye. Two of the three patients had MS. Patients with MS were more likely to have abnormal visual function than were patients without MS in both the affected and fellow eyes (Table 4). As reported after 1 and 5 years, there were no significant differences in visual function comparing the three ONTT treatment groups (data not shown). Among the 319 patients completing the examination, 112 (35%) had a documented recurrence of optic neuritis in the previously affected eye, at least one attack of optic neuritis in the fellow eye, or both after entry into the ONTT. 24 At least one new episode of optic neuritis occurred in the affected eye only in 45 patients (14%), in the fellow eye only in 39 patients (12%), and in each eye in 28 patients (9%; Table 5). An additional 13 patients reported symptoms consistent with a recurrence that Was not confirmed on examination (six in the affected eye and seven in the fellow eye). The proportion of patients who had experienced a recurrence in either eye was twofold greater (48%) in patients who had a diagnosis of MS at the current examination (including those diagnosed as MS at baseline) compared with patients who did not have MS (24%; P < .001; Table 5). As previously reported, the proportion of patients with a recurrence in either eye was higher in the prednisone treatment group (44%) than in the intravenous group (29%, P = .3) or in the placebo group (31%, P = .07). The absolute difference between the placebo and prednisone groups (13%) has remained essentially unchanged since our report of this difference after the first 6 months of follow-up.2 The NEI-VFQ scores were lower (worse) in all subscales in the study patients than in the reference group8 used for comparison (Table 6). Scores were highest in patients with acuity of 20/20 or better in each eye, intermediate in patients with one eye with 20/20 or better and one eye worse, and lowest in patients with both eyes worse than 2020. Similarly, scores were highest in patients without MS, intermediate in patients with MS but no more than mild disability, and lowest in patients with MS and moderate or severe disability. 25 DISCUSSION CONTINUED FOLLOW-UP OF THE COHORT OF PATIENTS who were enrolled into the ON'I'l' has provided a unique opportunity to assess the long- terrn course of vision after an epiSode of acute optic neuritis. We found that in most patients, once visual acuity stabilized after the initial episode of optic neuritis (as determined from the acuity measurement 1 year after the episode), it remained remarkably stable for more than 10 years. After 10 years, 69% of patients had acuity of 20/20 or better in each eye, whereas 1% were worse than 20/200 in both eyes. As we reported after 5 years of follow-up, visual function was worse in those patients with MS than in those without MS. Further attacks of optic neuritis in either eye occurred in 35% of all patients, and were twofold more common among patients diagnosed with MS at baseline or who developed MS during the follow-up period. As a group, the patients in our cohort had lower (worse) quality of life scores as measured on the NEI-VFQ when compared with a reference group. A reduction in NEI-VFQ scores was strongly related to a measured reduction in visual acuity and to the presence of MS. Among patients with acuity in each eye of 20/20 or better and among patients who did not have MS, the scores were similar to the reference group. There are few long-term follow-up data available in the literature for comparison with our results. Our finding that after more than 10 years of follow-up, 86% of the affected eyes had visual acuity of 320/25 and 91% had acuity 320/40 is comparable with that of Bradley and Whitty,9who reported that 86% of 66 patients were 320/25 (mean follow-up after episode of optic neuritis 10.2 years 26 [range, 6 months to 20 years]) and that of Cohen and associates,1°who reported that 82% of 60 patients had visual acuity 320/40 (mean follow-up 7.1 years [range, 5—12 years] after optic neuritis). The 10—year ONTT recurrence rate of 35% is similar to that reported by Cohen and coworkers10 (42%) but higher than that reported in other studies with extended follow-up such as those by Bradley and Whitty9 (18%), Hutchinson11 (24%), and Rodriguez and col- leagues12 (16%). Over time, some attrition of the original ONTT cohort has occurred. This attrition has more impact on the vision assessment than it does on the neurologic assessment since for the latter we were able in many cases to determine whether MS had developed through either phone contact with the patient or medical records, whereas the former requires the completion of specific visual function tests. Patients who were no longer being followed up in the cohort had slightly worse acuity in the affected eye both at baseline and at the time of the last completed visit. Thus, our reported vision results for the patients completing the examination are likely to be slightly biased toward those with better vision. Our results can be used by clinicians to advise patients that the long-term visual prognosis is good after an episode of optic neuritis. Follow-up of this cohort will continue with the support of the National Eye Institute, and patients will be examined again in 2006. 27 REFERENCES Optic Neuritis Study Group. High and low risk profiles for the development of multiple sclerosis within ten years after optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 2003;121:944 -949. Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992;326:581—588. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 1993;329: 1764—1769. Cleary PA, Beck RW, Anderson MM Jr, et al. Design, methods, and conduct of the Optic Neuritis Treatment Trial. Control Clin Trials 1993;14:123-142. Optic Neuritis Study Group. The clinical profile of acute optic neuritis. Experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1991 ;109:1673—1678. Optic Neuritis Study Group. Visual function five years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1997;115:1545-1552. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227—231. Mangione CM, Lee PP, Gutierrez P, et al. Development of the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Arch Ophthal 2001;119:1050 -1058. 28 Bradley WG, Whitty CWM. Acute optic neuritis: prognosis for development of multiple sclerosis. J Neurol Neurosurg Psychiatry 1968;31 :10 —18. Cohen M, Lessell S, Wolf P. A prospective study of the risk of developing multiple sclerosis in uncomplicated optic neuritis. Neurology 1979;29:208 -213. Hutchinson WM. Acute optic neuritis and the prognosis for multiple sclerosis. J Neurol Neurosurg Psychiatry 1976;39: 283-289. Rodriguez M, Siva A, Cross SA, O’Brien PC, Kurland LT. Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurology 1995;45:244— 250. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983;33:1444—1452. APPENDIX WRITING COMMITTEE, CLINICAL CENTERS, INVESTIGATORS, AND COORDINATORS WRITING COMMITTEE: Lead authors: Roy W. Beck, MD, PhD, Robin L. Gal, MSPH. Contributing authors: M. Tariq Bhatti, MD, Michael C. Brodsky, MD, Edward G. Buckley, MD, Georgia A. Chrousos, MD, James Corbett, MD, Eric Eggenberger, DO, James A. Goodwin, MD, Barrett Katz, MD, David I. Kaufman, DO, John L. Keltner, MD, Mark J. Kupersmith, MD, Neil R. Miller, MD, Pamela S. Moke, MSPH, Sarkis Nazarian, MD, Silvia Orengo-Nania, MD, Peter J. Savino, MD, William T. Shults, MD, Craig H. Smith, MD, Jonathan D. Trobe, MD, Michael Wall, MD, and Dongyuan Xing, MPH 29 Listed below are the investigators and clinical center staff active in the current phase of the study (I = investigator, C = coordinator, and T = technician). CLINICAL CENTERS: University of Arkansas, Little Rock, Arkansas: Michael Brodsky, MD (I), Sarkis Nazarian, MD (I), Shirley Hankins (C). Baylor College of Medicine, Houston, Texas: Silvia Orengo-Nania (l), George J. Hutton, MD (I), Ronald L. Gross, MD (I), Benita Slight (C), Pamela Frady (T). Duke University, Durham, North Carolina: Edward G. Buckley, MD (I), E. Wayne Massey, MD (I), Malcolm M. Anderson (C), Lois B. Duncan (T). University of Florida, Gainesville, Florida: M. Tariq Bhatti, MD (I), John Guy, MD (I), Melvin Greer, MD (I), Revonda Burke (C), Renae Preston (T). Georgetown University, Washington, DC: Georgia A. Chrousos, MD (I), Pamela Young Blake, MD (I), Sharlene Smith (C), Pat Kryzminski (T). University of Illinois, Chicago, Illinois: James Goodwin, MD (I), Andrew Cross (C), Jessie Garcia (T). University of Iowa, Iowa City, Iowa: Michael Wall, MD (I), Carmen Musser (C), Kim Woodward (T). Wills Eye Hospital, Philadelphia, Pennsylvania: Peter J. Savino, MD (I), Thomas Leist, MD (I), Diane Branciforte (C), Reginald Edwards (T). Johns Hopkins University, Baltimore, Maryland: Neil Miller, MD (I), David Irani, MD (I), Justin McArthur, MD (I), Stephen Reich, MD (I), Marianne Medura (C), Lula West (T). University of Michigan, Ann Arbor, Michigan: Jonathan D. Trobe, MD (I), Wayne Comblath, MD (I), Sharon Boyk (C), Cheryl Terpening (T). Michigan State 30 University, East Lansing, Michigan: David I. Kaufman, DO (I), Eric Eggenberger, DO (I), Sandra Holliday (C). Beth Israel Medical Center, New York, New York: Mark J. Kupersmith, MD (I), Gary Mandel (C, T). Devers Eye Institute, Portland, Oregon: William T. Shults, MD (I), Leslie McAIIister, MD (I), Reed Wilson, MD (I), Sue Swinford (C), Mary Dierkes (T), Joanne Fraser (T). Swedish Medical Center, Seattle, Washington: Craig H. Smith, MD (I), Dennis Kuder (C), Elizabeth Tran (T). COORDINATING CENTER: Jaeb Center for Health Research, Tampa, Florida: Pamela S. Moke, MSPH (Director), Roy W. Beck, MD, PhD, Robin L. Gal, MSPH, Craig Kollman, PhD, Raymond T. Kraker, MSPH, Dongyuan Xing, MPH, Julie Arends (Technician Certification, Devers Eye Institute, Portland, Oregon). VISUAL FIELD READING CENTER: University of California, Davis: John L. Keltner, MD (Director), Chris A. Johnson, PhD (Discoveries in Sight, Devers Eye Institute, Portland, Oregon), Kimberly E. Cello, Shannan E. Bandermann, MA, Daniel E. Redline. MRI READING CENTER: University Diagnostic Reading Institute, Tampa, Florida: John A. Arrington, MD, F. Reed Murtagh, MD. NATIONAL INSTITUTES OF HEALTH: National Eye Institute, Bethesda, Maryland: Donald Everett, MA. ADDITIONAL PHYSICIANS WHO CONDUCTED STUDY EXAMINATIONS: James Bates, MD, Swaraj Bose, MD, William Burchfield, MD, Vern Campbell, MD, Woody Davis, MD, Eldi Deschamps, MD, John Donavan, MD, Jonathan Frantz, MD, Benjamin Frishberg, MD, Grant Geske, DO, Harry Grossman, MD, N. Patrick Hale, MD, Warren Hamilton, MD, Robert Hanna, MD, Richard Henry, 31 MD, Richard lmes, MD, George Joseph, MD, Steven Katz, MD, Barbara Kimbrough, MD, Lanning Kline, MD, Christine Langerhorst, MD, Paul Leep, MD, Wallace Marsh, MD, John McCrary, MD, Michael Morgan, MD, Nancy Newman, MD, Brad Oren, MD, lfeanyi Orizu, MD, Victoria Pelak, MD, Ronald Pinkenburg, MD, Judith Piros, MD, Alfredo Sadun, MD, Ruta Skrinska, MD, James Swartley, MD, Kenneth Talbert, MD, James Tammaro, MD, Dilip Thomas, MD, David Waitzman, MD, Thomas Whittaker, MD, Jon Yokubaitis, MD. 32 High- and Low-Risk Profiles for the Development of Multiple Sclerosis within 10 Years after Optic Neuritis Experience of the Optic Neuritis Treatment Trial Optic Neuritis Study Group* Objective: To identify factors associated with a high and low risk of developing multiple sclerosis after an initial episode of optic neuritis. Methods: Three hundred eighty-eight patients who experienced acute optic neuritis between July 1, 1988, and June 30, 1991, were followed up prospectively for the development of multiple sclerosis. Consenting patients were reassessed after 10 to 13 years. Results: The 10-year risk of multiple sclerosis was 38% (95% confidence interval, 33%—43%). Patients (160) who had 1 or more typical lesions on the baseline magnetic resonance imaging (MRI) scan of the brain had a 56% risk; those with no lesions (191) had a 22% risk (P .001, log rank test). Among the patients who had no lesions on MRI, male gender and optic disc swelling were associated with a lower risk of multiple sclerosis, as was the presence of the following atypical features for optic neuritis: no light perception vision; absence of pain; and ophthalmoscopic findings of severe optic disc edema, peripapillary hemorrhages, or retinal exudates. 33 Conclusions: The 10-year risk of multiple sclerosis following an initial episode of acute optic neuritis is significantly higher if there is a single brain MRI lesion; higher numbers of lesions do not appreciably increase that risk. However, even when brain lesions are seen on MRI, more than 40% of the patients will not develop clinical multiple sclerosis after 10 years. In the absence of MRI lesions, certain demographic and clinical features seem to predict a very low likelihood of developing multiple sclerosis. This natural history information is a critical input for estimating a patient’s 10-year multiple sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of optic neuritis or other initial demyelinating events in the central nervous system [see original text for figures and tables]. Arch Ophthalmol. 2003;121 :944-949 OPTIC NEURITIS, an acute inflammatory disorder of the optic nerve, is a common initial manifestation of multiple sclerosis.1 It typically manifests as sudden monocular visual loss accompanied by eye pain in young adults, with women more commonly affected than men. Even when optic neuritis occurs without other clinical signs of multiple sclerosis, magnetic resonance imaging (MRI) of the brain often demonstrates white matter T2-signal abnormalities (referred to subsequently as “lesions”).2 In a patient with optic neuritis, the presence of brain T2-signal lesions seen on MRI increases the probability that additional neurological manifestations sufficient for a diagnosis of multiple sclerosis will develop.3 We have previously reported the 5 -year risk of developing multiple sclerosis after an initial episode of optic neuritis, based on 388 patients enrolled in the Optic Neuritis Treatment Trial.4 Herein we report the 10-year risk of developing multiple sclerosis, including high- and low-risk profiles, based on further follow-up of the Optic Neuritis Treatment Trial cohort. The study protocol5 was approved by the institutional review board at each of 15 clinical centers. Patients provided written informed consent for participation in the original treatment trial (ie, the Optic Neuritis Treatment Trial). Patients provided written informed consent for continuation in the follow-up study after the first 2 years and again after the first 5 years. The study protocol has been detailed in prior publications and is summarized below.“‘8 Between July 1, 1988, and June 30, 1991, we enrolled 388 patients with acute optic neuritis who did not already have clinically definite multiple sclerosis9 at study enrollment. The major eligibility criteria were as follows: (1) a diagnosis of acute unilateral optic neuritis with visual symptoms of 8 days or less, (2) aged between 18 and 46 years, (3) no evidence of a systemic disease other than multiple sclerosis that might be associated with optic neuritis, and (4) no previous treatment for multiple sclerosis. Patients were randomized to receive a single course of either intravenous methylprednisolone sodium succinate followed by oral prednisone, oral prednisone alone, or oral placebo. For 351 of the 388 patients, unenhanced MRIs of the brain, performed at study enrollment, were 35 graded at a central reading center by a standardized protocol that included a count of the number of T2 white matter lesions at least 3 mm in diameter.2 Standardized neurological examinations were performed at study enrollment, after 6 and 12 months, and then annually through 1997. Thereafter, semiannual telephone contact was made with the patients until the period of 2001-2002, when willing patients underwent another standardized neurological examination. For living patients who were unwilling to undergo a neurological examination, an attempt was made to obtain information from a telephone interview and from medical records. DIAGNOSTIC CRITERIA FOR MULTIPLE SCLEROSIS Patients were defined as having multiple sclerosis if a clinical examination documented a new neurological deficit consistent with a patient report of neurological symptoms of at least 24 hours’ duration and separated by at least 4 weeks from the initial optic neuritis event.9 The deficit had to be attributable to demyelination in the central nervous system but not in the optic nerves. STATISTICAL ANALYSIS Cumulative probabilities (referred to subsequently as “risk”) of developing multiple sclerosis were calculated with use of the Kaplan-Meier method and, where indicated, compared with the log rank test. Data for patients not developing multiple sclerosis were censored on the later of either the date of the most 36 recent neurological examination or the date of the last telephone assessment at which the patient reported no history consistent with the diagnosis of multiple sclerosis. Unadjusted and adjusted hazard ratios for the development of multiple sclerosis were determined from a Cox proportional hazards regression model.10 Predictive factors for multiple sclerosis were assessed separately for patients with and without brain lesions seen on MRI. These factors were identified prior to the study and are the same factors that were evaluated after 5 years of follow-up.4 The baseline characteristics of the “noncompleters” (patients without multiple sclerosis who had I-10 years of follow-up data) and “completers” (patients with multiple sclerosis or at least 10 years of follow-up data) were compared using the Fisher exact test for categorical variables and a Wilcoxon rank sumtest for continuous variables. All reported P values are 2-tailed. STATUS OF THE COHORT The mean age of the 388 patients at the time of study enrollment was 31.7 years; 77% were female. The cohort was 85%white, 13% African American, 2% Hispanic, and 0.5% Asian. Data were considered complete (diagnosis of multiple sclerosis or follow-up of at least 10 years) for 36,(87%) of the 388 patients. Among the 243 patients who did not develop multiple sclerosis, the median follow-up time was 11.5 years (interquartile range, 10.4-12.2 years), with at least 10 years of follow-up data available for 191 (79%) of the patients (162 patients by neurological examination and 29 patients by telephone assessment). Three patients died prior to 10 years after study enrollment from causes unrelated to multiple sclerosis. 37 The age and sex of the 336 completers and the 52 noncompleters were similar (mean age, 31.9 vs 30.3 years, P = .13; female sex, 79% vs 67%, P = .08), but the completers were more likely to be White (87% vs 73%, P = .02). One or more baseline brain lesions seen on MRI were present in 144 (48%) of the 302 completers with baseline brain MRI and in 16 (33%) of the 49 noncompleters with baseline MRI (P = .06). DEVELOPMENT OF MULTIPLE SCLEROSIS The 10-year risk of multiple sclerosis was 38% (95% confidence interval [CI], 33%- 43%) and the 12-year risk was 40%(95% Cl, 35%-45%). Among the 145 patients who developed multiple sclerosis, the median time to diagnosis was 3.0 years. In 34% of patients, the diagnosis was made within the first 2 years after study enrollment, and in 72%, it was made within 5 years. The 10-year risk of multiple sclerosis was similar in the 3 original Optic Neuritis Treatment Trial groups (P = .49). The development of multiple sclerosis was strongly associated with the presence of1 or more lesions on the baseline MRI of the brain (P <.001; Table 1 and the Figure). The 10-year risk of multiple sclerosis was 56% in the 160 patients with 1 or more brain lesions seen on MRI and 22% in the 191 patients with no lesions. However, among those with brain lesions seen on MRI, the risk with multiple lesions was not significantly higher than it was with a single lesion (58% vs 38 51%; P = .22, log rank test). Among patients who had not developed multiple sclerosis at 5 years after study enrollment, the probability of being diagnosed as having multiple sclerosis between 5 and 10 years was 7% in the 142 patients with no brain lesions seen on MRI and 27% in the 89 patients with 1 or more lesions. In the presence of 1 or more brain lesions seen on MRI, a history of nonspecific neurological symptoms (usually transient numbness) or prior optic neuritis in the fellow eye further increased the 10-year risk of multiple sclerosis (70% vs 50%, P = .005). However, among these 160 patients with 1 or more brain lesions seen on MRI, no demographic or clinical features of the optic neuritis were predictive of developing multiple sclerosis (Table 2). In contrast, among the 191 patients without brain lesions seen on MRI, certain features did alter the risk of multiple sclerosis. The risk of multiple sclerosis was lower in male patients than in female patients (hazard ratio, 0.35; 95%Cl, 0.12- 0.98) and was lower when the optic disc was swollen (anterior optic neuritis, papillitis) than when it was not swollen (retrobulbar neuritis; hazard ratio, 0.41; 95% CI, 0.20-0.84) (Table 2). Among female patients, the risk of multiple sclerosis was halved when optic disc swelling was present. Among male patients, only 1 of 24 patients with cptic disc swelling developed multiple sclerosis (Table 3). One hundred seventy-nine of the 191 patients with no brain lesions seen on MRI had no history of neurological symptoms or optic neuritis in the fellow eye and would be considered to have monofocal optic neuritis; their 10-year risk of multiple 39 sclerosis was 20%. In patients of both genders without brain lesions seen on MRI, multiple sclerosis did not develop in any patients Whose visual loss was painless (18 patients) or total (no light perception, 6 patients), or in those who had ophthalmoscopic findings of severe disc swelling (22 patients), hemorrhage of the optic disc or surrounding retina (16 patients), or retinal exudates (8 patients). When the criteria for multiple sclerosis were expanded to include the occurrence of optic neuritis in the fellow eye, the 10-year risk of multiple sclerosis was 45%: 31% in patients with no baseline brain lesions seen on MRI and 60% in patients with 1 or more lesions. COMMENT Within our cohort of 388 patients followed up from the onset of an acute episode of optic neuritis, the 10-year risk of development of multiple sclerosis, based strictly on conventional clinical criteria, was 38%, compared with a 5-year risk of 30%.4 Thus, although our patients continued to develop multiple sclerosis with each passing year, most did so within the first 5 years after the initial episode of acute optic neuritis. Our results have applicability not only to optic neuritis but also to patients seen with an initial demyelinating event of the brainstem or spinal cord because the 3 presentations share a common pathogenesis and have been reported to have similar risks for multiple sclerosis.11 4O Our finding of a 38% 10-year risk of multiple sclerosis after acute optic neuritis is similar to that of several prior reports‘z'.14 and lower than that of other reports,”17 all of which had smaller sample sizes. Differences in risk estimates across studies can also be attribUted to differences in patient inclusion criteria, retention rates, and diagnostic criteria for multiple sclerosis. The most potent predictor of multiple sclerosis in our study was the presence of white matter lesions on the baseline MRI scan of the brain. The presence of 1 such lesion at least 3 mm in diameter more than doubled the 10-year risk of multiple sclerosis (from 22% to 56%). However, the presence of 1 or more lesions did not signify that the patient was destined to develop multiple sclerosis. Among patients with brain lesions seen on MRI, the 10-year probability of remaining free of multiple sclerosis was 44%. Conversely, the absence of brain lesions seen on MRI did not eliminate the risk of developing multiple sclerosis; in the absence of any lesions, the 10-year probability of multiple sclerosis was 22%. Among patients with 1 or more brain lesions seen on MRI, no demographic characteristics or clinical features of acute optic neuritis were useful in further defining the risk. But among patients without brain MRI lesions, the risk was 3 times lower in male patients than in female patients, consistent with the well-documented lower prevalence of multiple sclerosis in male patients than in female patients and consistent with findings from studies conducted prior to the availability of MRI of the brain.”14 The risk was also lower when the optic 41 neuritis was associated with a swollen rather than a normal optic disc. Among female patients with no brain MRI lesions, those with optic disc edema had a risk of multiple sclerosis that was half as great as those without optic disc edema. The risk of multiple sclerosis when no“ baseline brain lesions were present on MRI was 0 among the small group of patients who had any one of the following findings: no light perception vision in the affected eye, optic fundus findings including severe optic disc edema, peripapillary hemorrhages, retinal exudates, or the absence of periocular pain. Thus, when there are no brain MRI lesions, the presence of any of these clinical features seems to predict a very low risk of multiple sclerosis. In patients who bear these atypical features, the optic neuritis may not be part of a multifocal demyelinating central nervous system illness. The difference in the risk profile between patients with and without brain MRI lesions is not surprising. Patients with MRI lesions already have imaging evidence of disseminated disease, the pathogenesis of which is almost certainly related to multiple sclerosis. Therefore, there is no reason to expect to be able to identify true risk factors for future development of multiple sclerosis. However, the group of patients with optic neuritis and a normal brain MRI likely includes a subgroup destined to have multiple sclerosis and another subgroup not destined to have multiple sclerosis. Regarding the predictive role of MRI lesions, the only comparable study”15 enrolled 131 patients with an acute demyelinating event in which optic neuritis 42 constituted half of the cohort. Ten-year follow-up was achieved in 81 patients (62%) and 12- to 16-year follow-up in 72 patients (55%). After 10 years, multiple sclerosis was present in 83% of those with enrollment MRI lesions and in 11% of those without enrollment MRI lesions. Differences between these results and ours may be related to that study’s smaller sample size and lower follow-up rate. That study found, as we did, that once there is at least 1 MRI lesion, an increasing number of lesions does not appreciably amplify the long-term risk of multiple sclerosis. The eligibility criteria of our study were sufficiently broad that our results should be applicable to most patients seen with optic neuritis as an initial demyelinating event. Having incomplete data for 13% of the original cohort is unlikely to be a source of appreciable bias. However, because the patients with incomplete follow-up had a lower prevalence of MRI scans of the brain with 1 or more lesions than did the patients with complete follow-up, our computed 10-year risk of multiple sclerosis could be a slight overestimate. Our results are important to the clinician in several respects. First, they reaffirm the prognostic value of an MRI scan of the brain performed at the time of an initial episode of acute optic neuritis. The presence of a single at least 3-mm-diameter brain MRI white matter lesion markedly increases the risk of developing multiple sclerosis; higher numbers of lesions do not appreciably increase that risk. Second, they establish that even when MRI lesions are present, clinically defined 43 multiple sclerosis does not develop within 10 years in more than 40% of patients. Third, the results highlight the importanceof an ophthalmologic examination for patients whose MRI of the brain is normal because ophthalmoscopy can identify features (severe optic disc swelling, hemorrhages, and exudates) associated with a very low risk of developing multiple sclerosis. This natural history information is a critical input for estimating a patient’s 10-year multiple sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of acute optic neuritis or other initial demyelinating events in the central nervous system. Submitted for publication March 18, 2003; final revision received April 23, 2003; accepted May 1, 2003. This study was supported by cooperative agreement U10 EY09435 from the National Eye Institute, National Institutes of Health, Bethesda, Md. Corresponding author and reprints: Roy W. Beck, MD, PhD, Optic Neuritis Study Group Coordinating Center, Jaeb Center for Health Research, 15310 Amberly Dr, Suite 350, Tampa, FL 33647 (e-mail: ontt@jaeb.org). Writing Committee: Lead authors: Roy W. Beck, MD; Jonathan D. Trobe, MD; Pamela S. Moke, MSPH; Robin L. Gal, MSPH; Dongyuan Xing, MPH. Contributing authors: M. Tariq Bhatti, MD; Michael C. Brodsky, MD; Edward G. Buckley, MD; Georgia A. Chrousos, MD; James Corbett, MD; Eric Eggenberger, DO; James A. Goodwin, MD; Barrett Katz, MD; David I. Kaufman, DO; John L. Keltner, MD; Mark J. Kupersmith, MD; Neil R. Miller, MD; Sarkis Nazarian, MD; Silvia Orengo- Nania, MD; Peter J. Savino, MD; William T. Shults, MD; Craig H. Smith, MD; 44 Michael Wall, MD. Listed below are the investigators and clinical center staff active in the current phase of the study (I indicates inVestigator; C, coordinator; and T, technician). Clinical Centers University of Arkansas, Little Rock: Michael C. Brodsky, MD (I); Sarkis Nazarian, MD (I); Shirley Hankins (C). Baylor College of Medicine, Houston, Tex: Silvia Orengo-Nania, MD (I); George J. Hutton, MD (I); Ronald L. Gross, MD (I); Benita Slight (C); Pamela Frady (T). Duke University, Durham, NC: Edward G. Buckley, MD (I); E. Wayne Massey, MD (I); Malcom M. Anderson (C); Lois B. Duncan (T). University of Florida, Gainesville: M. Tariq Bhatti, MD (I); John Guy, MD (I); Melvin Greer, MD (I); Revonda Burke (C); Renae Preston (T). Georgetown University, Washington, DC: Georgia A. Chrousos, MD (I); Pamela Young Blake, MD (I); Sharlene Smith (C); Pat Kryzminski (T). University of Illinois, Chicago: James Goodwin, MD (I); Andrew Cross (C); Jessie Garcia (T). University of Iowa, Iowa City: Michael Wall, MD (I); Carmen Musser (C); Kim Woodward (T). Wills Eye Hospital, Philadelphia, Pa: Peter J. Savino, MD (I); Thomas Leist, MD (I); Diane Branciforte (C); Reginald Edwards (T). Johns Hopkins University, Baltimore, Md: Neil Miller, MD (I); David Irani, MD (I); Justin McArthur, MD (I); Stephen Reich, MD (I); Marianne Medura (C); Lula West (T). University of Michigan, Ann Arbor: Jonathan D. Trobe, MD (I); Wayne Comblath, MD (I); Sharon Boyk (C); Cheryl Terpening (T). Michigan State University, East Lansing: 45 David I. Kaufman, DO (I); Eric Eggenberger, DO (I); Sandra Holliday (C). Beth Israel Medical Center, New York, NY: Mark J. Kupersmith, MD (I); Gary Mandel (C, T). Devers Eye Institute, Portland, Ore: William T. Shults, MD (I); Leslie McAIIister, MD (I); Reed Wilson, MD (I); Sue Swinford (C); Mary Dierkes (T); Joanne Fraser (T). Swedish Medical Center, Seattle, Wash: Craig H. Smith, MD (I); Dennis Kuder (C); Elizabeth Tran (T). Coordinating Center Jaeb Center for Health Research, Inc, Tampa, Fla: Pamela S. Moke, MSPH (Director); Roy W. Beck, MD, PhD; Robin L. Gal, MSPH; Craig Kollman, PhD; Raymond T. Kraker, MSPH; Dongyuan Xing, MPH; Julie Arends (Technician certification Devers Eye Institute). Visual Field Reading Center University of California, Davis: John L. Keltner, MD (Director); Chris A. Johnson, PhD (Discoveries in Sight, Devers Eye Institute); Kimberly E. Cello; Shannan Bandermann, MA; Daniel E. Redline. MRI Reading Center University Diagnostic Institute, Tampa: John A. Arrington, MD; F. Reed Murtagh, MD. National Institutes of Health National Eye Institute, Bethesda, Md: Donald Everett, 46 MA. Additional Physicians Who Conducted Study Examinations George Aita, MD; Robert Annstrbng, MD; Donald Barone, MD; James Bates, MD; W. W. Blessing, MB, PhD; Swaraj Bose, MD; Robert Burger, MD; Joanna Cooper, MD; Dennis Dewey, MD; Christina Diaz, MD; Philip Ente, MD; Edward Fox, MD; Benjamin Frishberg, MD; Jerry Gage, DO; Deborah Gelinas, MD; Allen Han, MD; Robert Hemdon, MD; Mary Kerber, MD; Donald Kitt, MD; Lanning Kline, MD; John Livingstone, MD; Martha Lusser, MD; Sharon Lynch, MD; Joanne Lynn, MD; Julia Mikell, MD; Shanan Munoz, MD; Muhammad Nayer, MD; Nancy Newman, MD; Brad Oren, MD; Victoria Pelak, MD; Diana Reed, MD; David Richman, MD; Emily Riser, MD; Donald Roth, MD; Alfredo Sadun, MD; Antoine Samman, MD; Alan Sconzert, MD; Christopher Sheppard, MD; Dilip Thomas, MD; David Waitzman, MD; Thomas Whittaker, MD; Allen Zechowy, MD; Steven Zuckerman, MD. REFERENCES 1. Ebers GC. Optic neuritis and multiple sclerosis. Arch Neurol. 1985;42:702-704. 2. Beck RW, Arrington J, Murtagh FR, Cleary PA, Kaufman DI, for the Optic Neu ritls Study Group. Brain magnetic resonance imaging in acute optic neuritis: experience of the Optic Neuritis Study Group. Arch Neurol. 1993;50:841-846. 3. Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presen tation to predict conversion to clinically definite multiple sclerosis. Brain. 1997;120:2059-2069. 47 —-_I 4. Optic Neuritis Study Group. The 5-year risk of MS alter optic neuritis: experience of the Optic Neuritis Treatment Trial. Neurology. 1997;49:1404-1413. 5. Cleary PA, Beck RW, Anderson MM Jr, Kenny DJ, Backlund JY, Gilbert PR. Design, methods, and conduct of the Optic Neuritis Treatment Trial. Control Clin Trials. 1993;14:123-142. 6. Optic Neuritis Study Group. The clinical profile of acute optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1991;109:1673-1678. 7. Optic Neuritis Study Group. Visual function five years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1997;115:1545-1552. 8. Beck RW, Cleary PA, Anderson MM, Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992:3262 581-588. 9. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13:227-231. 10. Cox DR. Regression models and life-tables. J R Stat Soc. 1972;34:187-220. 11. Brex PA, Ciccarelli O, O’Riordan Jl, Sailer M, Thompson AJ, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346:158-164. 12. Rizzo JF Ill, Lessell S. Risk of developing multiple sclerosis after uncomplicated optic neuritis: a long-term prospective study. Neurology. 1988;38:185-190. 13. Rodriguez M, Siva A, Cross SA, O’Brien PC, Kuriand LT. Optic neuritis: a population- based study in Olmsted County, Minnesota. Neurology. 1995;45:244-250. 14. Sandberg—Wollheim M, Bynke H, Cronqvist S, Holtas S, Platz P, Ryder LP. A longterm prospective study of optic neuritis: evaluation of risk factors. Ann Neurol. 1990;27:386- 48 393. 15. O’Riordan Jl, Thompson AJ, Kingsley DP, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS: a 10-year follow-up. Brain. 1998; 121:495-503. 16. Hutchinson WM. Acute optic neUritis and the prognosis for multiple sclerosis. J Neurol Neurosurg Psychiatry. 1976;39:283-289. 17. Francis DA, Compston DA, Batchelor JR, McDonald WI. A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up. J Neurol Neurosurg Psychiatry. 1987;50:758-765. 49 ORIGINAL CONTRIBUTION: Long-term Brain Magnetic Resonance Imaging Changes After Optic Neuritis in Patients Without Clinically Definite Multiple Sclerosis Optic Neuritis Study Group Background: Long-term follow-up of the Optic Neuritis Treatment Trial (ONTT) cohort to evaluate brain magnetic resonance imaging (MRI) in patients who have not developed clinically definite multiple sclerosis. Objective: To detemilne the proportion of patients with monosymptomatic optic neuritis who manifest new brain MRI lesions without having developed clinically definite multiple sclerosis 10 to 14 years after enrollment in the ONTT. Design: Observational study. Setting: Fourteen clinical centers. Participants: One hundred eight ONTT patients who had not developed clinically definite multiple sclerosis 10 to 14 years after study enrollment. Main Outcome Measure: Development of new T2 lesions on follow-up brain MRI. 50 Results: At least 1 T2 lesion 3 mm or larger was observed on follow-up MRIs in 27 (44%) of 61 patients with normal baseline MRIs. Additional lesions ( 3 mm) were present on follow-up MRIs in 26 (74%) of 35 patients with abnormal baseline MRIs. Conclusions: A subset of patients with monosymptomatic optic neuritis manifest neither clinical signs nor MRI evidence of demyelination after more than 10 years of follow-up. In other cases followed up for this length of time, MRI signal abnormalities may accumulate without causing new clinical manifestations of multiple sclerosis. This information is useful in counseling patients who develop first-episode optic neuritis [tables and figures appear in the original article]. Arch Neurol . 2004;61:1538-1541 Authors: The authors for the Optic Neuritis Study Group are the Writing Committee listed in the box on page 1540. Group Information: A listing has been published of the clinical centers and their investigators and clinical center staff who participated in the current phase of the study (Arch Ophthalmol. 2003;121:948). The Coordinating Center is located at the Jaeb Center for Health Research, Tampa, Fla. Financial Interest: None. AT THE TIME OF monosymptomatic optic neuritis, magnetic resonance imaging (MRI) of the brain often demonstrates white matter T2 signal abnormalities.1-6 51 The presence of such lesions increases the probability that the patient will develop additional neurological manifestations sufficient for a diagnosis of clinically definite multiple sclerosis (CDMS).7 Although longitudinal changes on MRI in patients who have CDMS have been well studied,8 there are limited data on long-term MRI changes in patients who do not develop CDMS. Continued follow up of the cohort of participants enrolled in the Optic Neuritis Treatment Trial (ONTT) has provided the opportunity to evaluate brain MRIs 10 to 14 years after the onset of optic neuritis in patients who have not developed CDMS. The objective of this study was to determine the proportion of such patients who manifest new brain MRI lesions on follow-up MRIs. METHODS Between July 1, 1988, and June 30, 1991, 457 patients with acute optic neuritis were enrolled in the Optic Neuritis Treatment Trial. The study protocol, including the informed consent process, has been reported in detail in previous publications.9-14 At study enrollment (1988-1991), brain MRIs were performed using a standardized protocol and graded at a central reading center.15 Between March 23, 2001, and November 7, 2002, patients still in follow-up were asked to consent to have a follow-up MRI if they had a gradable baseline MRI and had not developed CDMS. A follow-up MRI was performed for 108 (71%) of the 153 patients who met these criteria. The frequency of baseline MRIs showing 1 or 52 more lesions did not differ significantly between the 45 eligible patients who did not have a follow-up MRI and those who did have a follow-up MRI (31% vs 32%). At baseline , most imaging was performed on a 1.5-T MRI machine with 5-mm- thick T2-weighted axial segments with a 2.5-mm gap. At follow-up, the MRI protocol included 3 -mm -thick segments with no gap . A fluid attenuated inversion recovery sequence was used in the follow-up but not in the baseline MRIs. The follow-up MRIs were independently read by the same 2 neuroradiologists (J.A. and F .R.M.), who graded the baseline MRIs using similar methods.15 The classification system, consisting of 5 grades, was identical to that used for baseline MRIs. Grade 0 indicated a normal MRI; grade 1, changes not specific for demyelinative disease; and grades 2 through 4, changes suggestive of demyelination, with the severity increasing with higher grades. Subclasses were established within grades 1 through 4. To be considered a lesion, the signal abnormality had to be at least 3 mm. Smaller lesions were called “punctate.” A direct comparison was made with the baseline MRIs to determine if new lesions were present on the follow-up MRI that were absent on the baseline MRI. Analyses were conducted using SAS version 8.2 statistical software (SAS Institute Inc, Cary, NC). For comparisons of patients with and without new or additional lesions, categorical 53 variables were compared with the Fisher exact test, and continuous variables with an independent samples t test. The association between the number of baseline lesions and the presence of new lesions in patients with baseline lesions ( 3 mm) was assessed by logistic regression. All reported P values are 2- tailed. RESULTS The 108 patients (22% male, 78% female) had a mean age of 32.7 years at the time of the baseline MRI (age range, 18.2-46.0 years) and 44.8 years at the time of the follow-up MRI (age range, 30.9-59.4 years). The mean time between the baseline and follow-up MRIs was 12.2 years (range, 10.2-14.5 years). At baseline, 61 (56%) of the 108 patients had a normal MRI, 35 patients (32%) had at least 1 lesion (3 mm), and 12 (11%) patients had 1 or more punctate lesions but no lesions 3 mm or larger. PATIENTS WITH NO LESIONS ON BASELINE MRI On the follow-up MRI, at least 1 new lesion (3 mm) was seen in 27 (44%) of the 61 patients who had no baseline lesions (Table 1). Among patients who had no baseline lesions, the 34 patients who remained lesion free (no lesions 3 mm) were similar to the 27 patients who developed lesions in sex (female, 76% vs 74%; P = .99) and race/ethnicity (white, 88% vs 78%; P = .31) but tended to be younger (mean age at randomization, 30.8 vs 34.2 years; P = .07). The presence of at least 1 lesion ( 3 mm) on the follow-up MRI was not associated with whether 54 the optic disc was swollen or normal during the optic neuritis episode at baseline (40% vs 48%, P = .61). PATIENTS WITH AT LEAST 1 LESION (3 mm) ON BASELINE MRI On the follow-up MRI, at least 1 new lesion (3 mm) was seen in 26 (74%) of the 35 patients with 1 or more lesions at baseline (Table 2). The number of baseline lesions did not predict whether new lesions were present on the follow-up MRI (P = .69). The frequency of a new lesion was 74% when 1 or 2 lesions were present on the baseline MRI and 75% when more than 2 lesions were present on the baseline MRI. There were no demographic or clinical characteristics of the 9 patients who did not develop new lesions that distinguished them from the majority who developed new lesions. 55 Table 1. Magnetic Resonance Imaging (MRI) Grade on Follow-up for 61 Patients with No Lesions on Baseline MRI [No. (%)] MRI Grade of Patients Grade 0 - No lesions: 33 (54) Grade 1 4 Nonovoid, nonperiventricular lesions: 4 (7) 3 Nonovoid, nonperiventricular lesions: 2 (3) 2 Nonovoid, nonperiventricular lesions: 4 (7) 1 Nonovoid, nonperiventricular lesion: 1 (2) 1 Nonovoid, nonperiventricular lesion + 1 (3-mm) punctate lesions: 1 (2) 2 Punctate ( 3-mm) lesions only: 0 1 Punctate ( 3-mm) lesion: 1 (2) Grade 2 2 Lesions, 1 periventricular: 0 1 Periventricular lesion: 3 (5) 1 Ovoid, nonperiventricular lesion: 1 (2) 1 Ovoid, periventricular lesion: 1 (2) Grade 3 3 Lesions only, 1 periventricular: 0 56 2 Lesions only, both periventricular: 1 (2) 2 Lesions only, neither periventricular, both ovoid: 0 2 Lesions only, neither periventricular, 1 ovoid: 0 2 Lesions only, 1 periventricular and ovoid: 0 2 Lesions only, 1 periventricular and 1 ovoid: 0 Grade 4 4 Lesions, 1 periventricular: 6 (10) 3 Lesions only, 2 periventricular: 2 (3) 3 Lesions, none periventricular, 2 ovoid: 1 (2) 2 Lesions only, 1 periventricular and 1 large brain stem: 0 3 Lesions, 1 periventricular and 1 ovoid: 0 3 Lesions, 1 ovoid: 0 3 Lesions, 1 periventricular and 1 ovoid: 0 PATIENTS WITH PUNCTATE LESIONS ONLY ON BASELINE MRI Twelve patients had punctate lesions ( 3 mm)as the only abnormalities on the baseline MRI; 7 patients had 1 punctate lesion, and 5 patients had 2 or more. Nine of these 12 patients were found to have at least 1 lesion that was 3 mm or larger on the follow-up MRI: 4 had 3 or more nonovoid-nonperiventricular lesions and 5 had 3 or more lesions at least 1 of which was periventricular. 57 COMMENT Magnetic resonance imaging has taken on an increasingly important role in the diagnosis and monitoring of patients with multiple sclerosis (MS).16 Current MS diagnostic criteria following a monosymptomatic presentation incorporate changes in serial MRI findings as documentation of dissemination in time.17 Accordingly, the long-term MRI characteristics of patients with mono- symptomatic optic neuritis who do not develop MS on clinical grounds are of great interest. Among 61 patients with a normal baseline MRI who had not developed clinical evidence of MS after 10 years, 27 (44%) exhibited at least 1 new 3-mm or greater lesion on follow-up brain MRIs. Subclinical demyelination is the most logical explanation for the new MRI findings within this relatively young population although, for some of the patients, it is possible that the lesions were present at the time of the initial MRI but were undetected owing to the MRI technique used. however, the fact that 34 patients (56%) did not develop clinical signs or MRI evidence of demyelination after 10 years suggests that there are many cases of optic neuritis that may be unrelated to MS. Among the 35 patients whose baseline MRI showed at least 1 T2-weighted lesion 3 mm or larger, 26 patients (74%) developed at least 1 new lesion 3 mm or larger on follow-up MRI in the absence of a clinical diagnosis of MS. This phenomenon merely underscores the well-known dissociation between MRI 58 findings and clinical expression of MS. The fact that an abnormal baseline MRI was more likely to show additional lesions than a normal baseline MRI emphasizes the predictive value of the initial MRI. The presence of even a single lesion predicted the development of further lesions. However, the development of new lesions does not necessarily indicate that the patient will develop clinical signs of MS even after 10 years. Among the 12 patients with only punctate T2-weighted hyperintensities on baseline MRI, 9 patients (75%) exhibited changes on long-term MRI, a frequency similar to that in the patients with at least 1 lesion 3 mm or larger on baseline MRI. This finding suggests that a focal signal abnormality of any size may predict that additional signal abnormalities will occur in this population] These data have several limitations. Magnetic resonance imaging technology continues to advance, and multicenter, serial MRI studies are often forced to compare MRIs obtained with different magnets, field strengths, and protocols. Repositioning errors on serial imaging is also a source of potential difference between baseline and follow-up MRIs. The use of higher-fieId-strength magnets and smaller-slice-thickness MRIs at follow-up may have overestimated MRI changes over time. However, changes in these parameters appear to affect the assessment of lesion volume more than lesion numbers.18-20 In 1 series of patients with monosymptomatic demyelinating syndromes, 27% exhibited asymptomatic spinal cord lesions on MRI.21 Imaging confined to the brain would 59 likely produce an underestimation of the total burden of T2-weighted changes over time. It is possible that not all T2-weighted MRI changes over time were the result of demyelination. Vasculopathic risk factors such as advanced age, diabetes mellitus, and hypertension may contribute to T2-weighted MRI lesions, but this seems unlikely to explain a significant portion of the change observed in this relatively young cohort. Despite the limitations on interpretation of the results imposed by the differences in MRI technique from the baseline to the follow-up MRIs. these differences influence only the incidence of new lesions and not our observed proportion of patients who have remained lesion free after 10 years. CONCLUSIONS These data are unique in reporting the long-term MRI changes following monosymptomatic optic neuritis in the absence of the development of clinical signs of MS. The results support the notion that not all cases of monosymptomatic optic neuritis are necessarily related to MS since a subset of patients manifest neither clinical signs nor MRI evidence of demyelination after more than 10 years of follow-up. In addition, the results indicate that MRI signal abnormalities may accumulate without causing any clinical manifestations of MS even when the patient is followed up for more than a decade. This information is useful in counseling patients who develop first-episode optic neuritis. 60 Optic Neuritis Study Group Members Writing Committee: Lead authors: Eric R. Eggenberger, DO; Roy W. Beck, MD, PhD; Robin L. Gal, MSPH; Dongyuan Xing, MPH; Jonathan D. Trobe, MD; John Arrington, MD; F. Reed Murtagh, MD. Contributing authors: M. Tariq Bhatti, MD; Michael C. Brodsky, MD; Edward G. Buckley, MD; Georgia A. Chrousos, MD; James J. Corbett, MD; James A. Goodwin, MD; Barrett Katz, MD; David I. Kaufman, DO; John L. Keltner, MD; Mark J. Kupersmith, MD; Neil R. Miller, MD; Pamela S. Moke, MSPH; Silvia Orengo-Nania, MD; Sarkis Nazarian, MD; Peter J. Savino, MD; William T. Shults, MD; Craig H. Smith, MD; Michael Wall, MD. Accepted for Publication: March 24, 2004. Correspondence: Robin L. Gal, MSPH, Jaeb Center for Health Research, 15310 Amberly Dr, Suite 350, Tampa, FL 33647 (rgal@jaeb.org). Author Contributions: Study concept and design: Beck, Trobe, Kaufman, Savino, and Smith. Acquisition of data: Beck, Gal, Trobe, Arrington, Bhatti, Brodsky, Buckley, Chrousos, Corbett, Goodwin, Kaufman, Keltner, Kupersmith, Miller, Moke, Orengo-Nania, Nazarian, Shults, and Smith. Analysis and interpretation of data: Eggenberger, Beck, Gal, Xing, Trobe, Arrington, Murtagh, Brodsky, Katz, Kupersmith, Miller, Smith, and Wall. Drafting of the manuscript: Eggenberger, Beck, Gal, Xing, Trobe, Moke, and Smith. Critical revision of the manuscript for important intellectual content: Beck, Gal, Trobe, Arrington, Murtagh, Bhatti, Brodsky, Buckley, Chrousos, Corbett, Goodwin, Katz, Kaufman, Keltner, 61 Kupersmith, Miller, Orengo-Nania, Nazarian, Savino, Shults, Smith, and Wall. Statistical expertise: Beck and Xing. Obtained funding: Beck and Brodsky. Administrative, technical, and material support: Eggenberger, Beck, Gal, Arrington, Murtagh, Bhatti, Kaufman, Keltner, Kupersmith, Miller, Moke, and Smith. Study supervision: Beck, Gal, Trobe, Brodsky, Chrousos, Katz, Kaufman, Miller, Orengo-Nania, and Smith. Ongoing collection of data from participants: Savino. Funding/Support: This study was supported by cooperative agreement U10 EY09435 from the National Eye Institute, National Institutes of Health, Bethesda, Md. REFERENCES 1. Jacobs L, Kinkel PR, Kinkel WR. Silent brain lesions in patients with isolated idiopathic optic neuritis: a clinical and nuclear magnetic resonance imaging study. Arch Neurol. 1986;43:452-455. 2. On'nerod IEC, McDonald WI, du Boulay GH, et al. Disseminated lesions at presentation in patients with optic neuritis. J Neurol Neurosurg Psychiatry. 1986;49:124-127. 3. Johns K, Lavin P, Elliot JH, Partain CL. Magnetic resonance imaging of the brain in isolated optic neuritis. Arch Ophthalmol. 1986;104:1486-1488. 4. Miller DH, Orrnerod IEC, McDonald WI, et al. The early risk of multiple sclerosis after optic neuritis. J Neurol Neurosurg Psychiatry. 1988;51:1569-1571. 5. Frederiksen JL, Larsson HB, Henriksen O, Olesen J. Magnetic resonance 62 imaging of the brain in patients with acute monosymptomatic optic neuritis. Acta Neu rol Scand. 1989;80:512-517. 6. Jacobs L, Munschauer FE, Kaba SE. Clinical and magnetic resonance imaging in optic neuritis. Neurology. '1991 ;41 115-19. 7. Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain. 1997; 120:2059-2069. 8. Brex PA, Ciccarelli O, O’Riordan Jl, Sailer M, Thompson AJ, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346:158-164. 9. Cleary PA, Beck RW, Anderson MM Jr, et al. Design, methods, and conduct of the Optic Neuritis Treatment Trial. Control Clin Trials. 1993;14:123-142. 10. Optic Neuritis Study Group. The clinical profile of acute optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1991;109:1673-1678. 11. Optic Neuritis Study Group. Visual function five years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 1997;115:1545-1552. 12. 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. 13. Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992; 326:581-588. 63 14. Beck RW, Trobe JD, Moke PS, et al. High- and low-risk profiles for the development of multiple sclerosis within ten years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol. 2003;121:944-949. 15. Beck RW, Arrington J, Murtagh FR, Cleary PA, Kaufman DI; Optic Neuritis Study Group. Brain magnetic resonance imaging in acute optic neuritis: experience of the Optic Neuritis Study Group. Arch Neurol. 1993;50:841- 846. 16. Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61:602-611. 17. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the lntemational Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50:121-127. 18. Molyneux PD, Tubridy N, Parker GJ, et al. The effect of section thickness on MR lesion detection and quantification in multiple sclerosis. AJNR Am J Neuroradiol. 1998;19:1715-1720. 19. Filippi M, van Waesberghe JH, Horsfield MA, et al. Interscanner variation in brain MRI lesion load measurements in MS: implications for clinical trials. Neurology. 1997;49:371-377. 20. Lee DH, Vellet AD, Eliasziw M, et al. MR imaging field strength: prospective evaluation of the diagnostic accuracy of MR for diagnosis of multiple sclerosis at 0.5 and 1.5 T. Radiology. 1995;194:257-262. 21. O’Riordan JI, Thompson AJ, Kingsley DP, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS: a 10-year follow-up. Brain. 1998; 121:495-503. 65 Chapter 3: Longitudinal Optic Neuritis Study (LONS) The National Eye Institute-sponsored ONTT (Optic Neuritis Treatment Trial) studied the effects of treatment on optic neuritis, and the relationship between optic neuritis and MS. The ONTT study began recruitment in 1988, enrolling subjects with optic neuritis of less than 8 days duration, and without a prior history of steroid therapy. The subjects were randomized to one of three groups: 1. oral placebo; 2. oral prednisone in 1 mg/kg/day dose for 11 days, or; 3. intravenous methylprednisolone 1 gm daily for three days, then prednisone 1 mg/kg/day for 11 days. The trial enrolled 455 subjects with acute optic neuritis. The baseline lab tests, including ANA, CBC, and RPR were of no value in the evaluation of clinically typical acute optic neuritis, and one conclusion of the trial was that these labs are unnecessary in the management of this condition [Optic Neuritis Study Group, 1991]. The practice standard for optic neuritis therapy at the time the ONTT began generally consisted of a course of oral prednisone in 1 mg/kg/day dose. The ONTT investigated the effects this oral prednisone dose compared to high-dose intravenous methylprednisolone, or placebo on visual function, neurological status, and the development of MS. Despite being the “standard” therapy for optic neuritis, the oral prednisone alone treatment was no better than placebo concerning visual recovery, and was associated with twice the recurrence rate of optic neuritis compared to placebo. This increased recurrence rate of optic neuritis in the oral prednisone group was noted not only early, but also at 5- and 66 10-year follow-up. This finding in large measure led to one of the conclusions of the American Academy of Neurology Practice Parameter paper on the management of optic neuritis; the AAN “practice standard” states that oral prednisone in 1 mg/kg dose is contraindicated for optic neuritis [Kaufman et al, 2000i The visual effect of intravenous methylprednisolone (IVMP) in acute optic neuritis was quantified in this cohort over long term follow up. IVMP was associated with improved speed of visual recovery, but no long term visual function benefit compared to placebo or oral prednisone; at 6 months follow up, there was no difference in visual acuity, color, or visual fields between the groups. This and other lines of research contributed to another of the AAN Practice Parameter statements on optic neuritis, a “practice option” concerning the consideration of high doses steroids [Kaufi'nan et al, 2000]. This research documented the strong association between optic neuritis and MS, and quantified the risk of developing MS after a first isolated episode of optic neuritis based on MRI data and the initial clinical neuro-ophthalmic features. The initial “baseline” MRI was abnormal in approximately half of the ONTT cohort at trial entrance, and this proved to be a strong predictor of the subsequent development of MS in the subcohort of patients without definite or probable MS at study entrance (n=388). If the baseline MRI had at least three T2 lesions, the 5-year rate of MS was 51%, whereas if the baseline MRI was entirely normal, 67 then the 5-year MS risk was 16%. In the face of an abnormal baseline MRI, a 2- 3-year partial protective effect in the IV methylprednisolone group was noted, during which fewer further demyelinating episodes occurred compared to the placebo or oral prednisone alone groups; at 5-years, this effect had disappeared [LONS Study Group, 1997]. The LONS study group was reassembled for 10-year clinical and MRI follow up. Patients presenting for 10-year LONS follow up underwent vision testing to include measures of visual acuity, contrast sensitivity, and visual field. Quality of life was assessed with the National Eye Institute Visual Function Questionnaire. Examinations were completed on 319 patients. In most patients, visual function test results in the eyes that experienced optic neuritis at study entry (“affected eyes”) were normal or only slightly abnormal after 9.9 to 13.7 years. Visual acuity in the affected eye was >20/20 in 74%, 20/25 to 20/40 in 18%, <20/40 to 20/200 in 5%, and <20/200 in 3%. On average, visual function was worse in patients with multiple sclerosis (MS) than in those without MS. Recurrent optic neuritis in either eye occurred in 35% of patients. Such attacks were more frequent in patients with MS (p < .001). The National Eye Institute Visual Function Questionnaire scores were lower when visual acuity was abnormal and when MS was present. At 10-year follow up, visual acuity generally remained excellent; there were no differences in visual function testing among the treatment groups. The visually-related conclusions from the 10-year data was that most patients retained good to excellent vision more than 10 years after an 68 attack of optic neuritis, and that recurrent optic neuritis was more frequent in patients with MS. [Beck et al, 2004; Cole et al, 2000] One of the key 10-year results related to the risk of MS development in the LONS group. The LONS 10-year data included 388 patients entering the study without a diagnosis of clinically definite or probable MS. The overall 10-year risk of MS in this group was 38% (95% Cl 33 — 43%). Patients with one or more typical MRI T2 lesions at baseline had a 56% risk of developing MS, while those with no lesions on their baseline MRI had a 22% risk of MS at 10 years (p<0.001, log rank test). Among patients with a normal baseline MRI, male gender and optic disc swelling were features associated with a lower MS risk, and no patient with “atypical” features developed MS at 10 years (atypical features include: no light perception vision, n=6; painless onset, n=18; severe disc edema, n=22; peripapillary hemorrhages, n=16; or retinal exudate, n=8).- The baseline MRI was predictive of the development of MS over 10 years, although the number of lesions did not appreciably increase the risk [Optic Neuritis Study Group, 2003]. MRI scans were also performed on patients in the LONS cohort who had not been diagnosed with clinically definite or probable MS at 10-year follow up. The objective of this observational sub-study performed at 14 clinical centers was to determine the proportion of patients with monosymptomatic optic neuritis who manifest new brain MRI lesions without having developed clinically definite multiple sclerosis 10-years after enrollment in the ONTT. The participants 69 included 108 ONTT patients who had not developed clinically definite multiple sclerosis 10- to 14-years after study enrollment, and the main outcome measure was the development of new T2 lesions on follow-up brain MRI. This sub-cohort was similar to the whole group, with 78% female gender and mean age 32.7 years at the time of baseline MRI. At least one T2 lesion 3 mm or larger was observed on follow-up MRI in 27 (44%) of 61 patients with a normal baseline MRI. Additional lesions (33 mm) were present on the follow-up MRI in 26 (74%) of 35 patients with an abnormal baseline MRI. We concluded that a subset of patients with monosymptomatic optic neuritis manifest neither clinical signs nor MRI evidence of demyelination after more than 10-years of follow-up. In other cases followed for this length of time, MRI signal abnormalities may accumulate without causing new overt, clinical manifestations of multiple sclerosis. This information is useful in counseling patients who develop first-episode optic neuritis [LONS Study Group, 2004]. 70 Chapter 4 Jacobs LD, Beck RW, Simon JH, et al. Intramuscular Interferon Beta-1a Therapy Initiated During a First Demyelinating Event in Multiple Sclerosis. New England Journal of Medicine 2000;343(13):898-904 (A summary overview of this article will be found on page 95 of this thesis.) 71 INTRAMUSCULAR INTERFERON BETA-1a THERAPY INITIATED DURING A FIRST DEMYELINATING EVENT IN MULTIPLE SCLEROSIS LAWRENCE D. JACOBS, M.D., ROY W. BECK, M.D., PH.D., JACK H. SIMON, M.D., PH.D., R. PHILLIP KINKEL, M.D., CAROL M. BROWNSCHEIDLE, PH.D., THOMAS J. MURRAY, M.D., NANCY A. SIMONIAN, M.D., PETER J. SLASOR, SC.D., ALFRED W. SANDROCK, M.D., PH.D., AND THE CHAMPS STUDY GROUP* 72 ABSTRACT Background: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value. Methods: We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical demyelinating event (optic neuritis, incomplete transverse myelitis, or a brain-stem or cerebellar syndrome) and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain. After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 pg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo. The study end points were the development of clinically definite multiple sclerosis and changes in findings on MRI of the brain. The trial was stopped after a preplanned interim efficacy analysis. Results: During three years of follow-up, the cumulative probability of the development of clinically definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002). As compared with the patients in the placebo group, patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer gadolinium-enhancing lesions (P<0.001) at 18 months. Conclusions: Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that 73 indicate a high risk of clinically definite multiple sclerosis. (N Engl J Med 2000;343:898-904.) @2000, Massachusetts Medical Society. From the Department of Neurology, State University of New York School of Medicine at Buffalo and Buffalo General Hospital, Buffalo (L.D.J., C.M.B.); the Jaeb Center for Health Research, Tampa, Fla. (R.W.B.); the Department of Radiology—MRI, University of Colorado Health Sciences Center, Denver (J.H.S.); the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland (R.P.K.); the Multiple Sclerosis Research Unit, Centre for Clinical Research, Victoria General Hospital, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada (T.J.M.); and Blogen, Cambridge, Mass. (N.A.S., P.J.S., A.W.S.). Address reprint requests to Dr. Jacobs at the Department of Neurology, Buffalo General Hospital, 100 High St., Buffalo, NY 14203, or at ljacobs@kaleidahealth.org. *Other participants in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) are listed in the Appendix. MULTIPLE sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system that most commonly affects women, with an onset typically between 20 and 40 years of age. A diagnosis of clinically definite multiple sclerosis requires the occurrence of at least two neurologic events consistent with demyelination that are separated both anatomically in the central 74 nervous system and temporally.1 Magnetic resonance imaging (MRI) of the brain, by identifying lesions consistent with the occurrence of demyelination, can add certainty to the diagnosis.2,3 The presence of such MRI-identified lesions in a patient with an isolated syndrome of the optic nerve (optic neuritis), spinal cord (incomplete transverse myelitis), or brain stem or cerebellum of recent onset is associated with a high risk of clinically definite multiple sclerosis.4-8 When the cause is demyelination, all three syndromes are presumed to have a common pathogenesis. Interferon-beta has demonstrated benefits in the treatment of patients with established multiple sclerosis, including slowing the progression of physical disability,9,10 reducing the rate of clinical relapses,9-11 and reducing the development of brain lesions, as assessed by MRI,9-12 and brain atrophy.13 However, it is not known whether treatment of patients earlier in the course of multiple sclerosis is of value. Therefore, we designed a randomized, double- blind, placebo—controlled clinical trial to determine whether weekly intramuscular injections of interferon beta-1a (Avonex) in patients with a first demyelinating event and with MRI evidence of prior subclinical demyelination in the brain reduced the incidence of clinically definite multiple sclerosis. 75 METHODS Patients The study was conducted at 50 clinical centers in the United States and Canada from April 1996 until March 2000. The protocol and infon'ned-consent forms were approved by the institutional review board at each site, and all patients gave written informed consent. Study oversight was provided by an independent data and safety monitoring committee. Eligible subjects were patients between the ages of 18 and 50 who had a first isolated, well—defined neurologic event consistent with demyelination and involving the optic nerve (unilateral optic neuritis), spinal cord (incomplete transverse myelitis), or brain stem or cerebellum (brainstem or cerebellar syndrome) that was confirmed on ophthalmologic or neurologic examination. Patients also had to have two or more clinically silent lesions of the brain that were at least 3 mm in diameter on MRI scans and were characteristic of multiple sclerosis (at least one lesion had to be periventricular or ovoid). The onset of the visual or neurologic symptoms had to have been no more than 14 days before intravenous corticosteroid therapy was started (as described below) and no more than 27 days before randomization. Patients with a prior neurologic or visual event consistent with the occurrence of demyelination that lasted longer than 48 hours were excluded. 76 Treatment Assignment and Monitoring All patients received 1 g of methylprednisolone per day intravenously for 3 days, followed by 1 mg of prednisone per kilogram of body weight per day orally for 11 days and a 4-day period of tapering in which 20 mg was given on the first day, 10 mg on the second, 0 mg on the third, and 10 mg on the fourth. In order to achieve balance with respect to the number of lesions on T2-weighted MRI scans (two, three or four, five to seven, and eight or more) and the type of initial clinical event (optic neuritis, spinal cord syndrome, or brain-stem or cerebellar syndrome), we used a minimization procedure14 to assign patients randomly in approximately equal numbers to the two treatment groups. The distribution of the treatment groups according to study site was what would be expected by chance (P=0.88). One group received 30 pg of interferon beta-1a (Avonex, Biogen) weekly by intramuscular injection, whereas the other group received a matching placebo. The treatment period was planned to be three years. Patients and site personnel were unaware of the treatment assignments. Treatment began after the course of intravenous methylprednisolone was completed while the patient was still receiving oral prednisone. To minimize the symptoms of the interferon-related influenza-like syndrome, patients were instructed to take 650 mg of acetaminophen before each injection and then every 6 hours after each injection for 24 hours during the first six months of treatment. 77 We assessed compliance with the protocol by reviewing the patients’ diaries and counting the number of empty vials that were returned. Each center was instructed to report all adverse events during the first six months of treatment, but thereafter to report only serious adVerse events, as well as depression, seizures, cardiac events, and injection-site reactions, whether or not they were serious. An influenza-like syndrome was defined as the presence of influenza-like symptoms, fever, or chills. Every six months, blood was obtained for hematologic and serum chemical tests and physical examinations were performed. Laboratory values that exceeded prespecified ranges were considered abnormal. Serum was assayed for the presence of neutralizing antibodies every six months; we report the incidence of titers greater than or equal to 1:20 — the level that has been associated with reduced biologic activity of interferon beta-1a.15 Study Procedures and End Points At the end of the first month (and again at the end of the second month, if the patient’s condition was not considered to be stable or improving at month 1), each patient was examined by a treating and an examining neurologist, both of whom were unaware of the patient’s treatment assignment. Subsequent examinations were scheduled at month 6 and every six months thereafter; additional examinations were performed within seven days after a patient reported new visual or neurologic symptoms. The treating neurologist was responsible for asking the patient about adverse events and visual or neurologic 78 symptoms, whereas the examining neurologist performed a structured neurologic examination without knowledge of the patient’s history during or before the study. The primary prespecified end point‘was the development of clinically definite multiple sclerosis. For patients whose condition was neurologically stable or improving one month after the initiation of treatment with the study drug, the end point was defined as the occurrence of either a new visual or neurologic event or progressive neurologic deterioration. The former required documentation of a new clinical abnormality consistent with the patient’s report of neurologic or visual symptoms that lasted more than 48 hours and that were attributable to a part of the central nervous system that differed from that of the initial episode at study entry. The latter was defined as an increase from month 1 of at least 1.5 points in the score on the Expanded Disability Status Scale.16 On this scale, scores range from 0 to 10, with higher scores indicating more severe disability. A patient whose initial demyelinating event was clinically worse one month after the initiation of treatment was considered to have reached the primary end point if either further worsening was documented at two months or the patient withdrew from the study before completing two months of treatment. All end points were confirmed by a central end-point committee whose members were unaware of the patients’ treatment assignments. Patients in whom clinically definite multiple sclerosis developed discontinued treatment and were withdrawn from the study. Patients who discontinued 79 treatment but who did not reach the end point were encouraged to return for follow-up assessments. Findings on MRI of the brain served as a secondary prespecified end point. A screening MRI of the brain was performed to determine the patients’ eligibility. Unenhanced T2-weighted and enhanced T1 -weighted MRI scans of the brain were obtained with use of a standardized protocol at base line and at months 6, 12, and 18 in patients who were still in the study at those times. The baseline scan was obtained four or more days after the patient completed the course of intravenous methylprednisolone but while the patient was still receiving oral prednisone. MRI of the brain was not performed after 18 months because of the expectation that the rate of clinical outcomes would differ between treatment groups (since patients were withdrawn from the trial on receipt of a diagnosis of clinically definite multiple sclerosis) and could therefore skew the interpretation of the results. All scans that could be evaluated were graded at a central reading center without knowledge of the patients’ treatment assignments. The number of new or enlarging lesions and the volume of lesions on T2-weighted MRI scans and the number of gadolinium-enhancing lesions on T1-weighted MRI scans were assessed according to a standardized method. Statistical Analysis We calculated that 380 patients would be needed for the study, given an estimated three-year rate of clinically definite multiple sclerosis in the placebo 80 group of 50 percent, a relative effect of treatment of 33 percent, a 5 percent probability of a type I error (two tailed), and a power of 80 percent. The calculation was adjusted to allow for 15 percent of the patients to be withdrawn or lost to follow-up before the development of clinically definite multiple sclerosis. Primary analyses included all randomized patients and followed the intention-to- treat principle. All reported P values are two-tailed. The cumulative probability of clinically definite multiple sclerosis was calculated for each group according to the Kaplan-Meier product-limit method and compared with use of the Mantel log-rank test, beginning after one month of treatment (since by definition the end point could not be reached before one month). Data on patients in whom clinically definite multiple sclerosis did not develop were censored on the date they were last seen by the treating neurologist at either a scheduled or unscheduled visit. Unadjusted and adjusted rate ratios were determined from a proportional-hazards model. Differences in the size of effects in subgroups classified according to the initial clinical event and the number of brain lesions on T2-weighted MRI scans at screening were assessed separately with use of interaction terms in the proportional-hazards model. The data on the volume of lesions and the number of lesions on MRI were evaluated with the use of the Mann-Whitney rank-sum test. The trial was terminated in March 2000 at the recommendation of the data and safety monitoring committee after the single preplanned interim analysis of 81 efficacy. This analysis revealed that treatment with interferon beta-1a was significantly better than treatment with placebo and met the stopping guidelines, which included a P value of 0.029. RESULTS Base-Line Characteristics Between April 1996 and April 1998, 383 patients were enrolled in the trial: 193 were randomly assigned to the interferon beta-1a group and 190 to the placebo group. The base-line characteristics of the two groups were similar (Table 1). Development of Clinically Definite Multiple Sclerosis and Brain Lesions on MRI The cumulative probability of the development of clinically definite multiple sclerosis during the three-year follow-up period was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002) (Fig. 1). At three years, the cumulative probability was 35 percent in the interferon beta-1a group and 50 percent in the placebo group. After adjustment for age, type of initial event, the volume of lesions on T2-weighted MRI scans, and the number of gadolinium- enhancing lesions on T1-weighted scans, the effect of treatment with interferon beta-1a appeared to be stronger (adjusted rate ratio, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). The effect of treatment was similar among subgroups classified according to the type of initial event (P=0.49 for the 82 interaction) and the number of lesions on the T2-weighted MRI scan at screening (P=0.88 for the interaction). The diagnosis of clinically definite multiple sclerosis was the result of a second acute demyelinating event in all but five patients. One patient in each group had progressive neurologic worsening during the first two months of the study treatment, and one patient in the interferon beta-1a group and two patients in the placebo group had progressive neurologic disability without an acute exacerbation. Corticosteroids were prescribed for a neurologic event that did not qualify as clinically definite multiple sclerosis in the case of 9 patients in the interferon beta1a group (3 of whom later met the criteria for clinically definite multiple sclerosis) and 22 patients in the placebo group (7 of whom later met the criteria). The changes in the volume of brain lesions on T2-weighted MRI scans differed significantly between the interferon beta-1a group and the placebo group at 6 months (P<0.001), 12 months (P=0.004), and 18 months (P<0.001) (Table 2). At 18 months, the median increase in lesion volume was 1 percent in the interferon beta-1a group, as compared with 16 percent in the placebo group. At 6, 12, and 18 months, there were also fewer new or enlarging lesions on T2-weighted MRI scans (P=0.001, P<0.001, and P<0.001, respectively) and fewer gadolinium- enhancing lesions on T1-weighted scans (P=0.03, P=0.02, and P< 0.001, respectively) in the interferon beta-1a group than in the placebo group (Table 2). 83 As compared with the placebo group, the interferon beta-1a group had 42 percent fewer gadolinium-enhancing lesions at 6 months, 55 percent fewer at 12 months, and 67 percent fewer at 18 months. Completeness of Follow-up Follow-up was discontinued early for a reason other than the development of clinically definite multiple sclerosis in 30 of the 193 patients in the interferon beta- 1a group (16 percent) and in 27 of the 190 patients in the placebo group (14 percent). The mean (:80) duration of follow-up for the remaining patients in whom clinically definite multiple sclerosis had not developed and who were still being followed when the trial was stopped or who had completed the 3-year final examination was 30.9149 months in the interferon beta-1a group and 30615.1 months in the placebo group, and the respective rates of completed visits were 99.4 percent and 99.5 percent. All of these patients completed at least 22 months of follow-up. Adverse Events, Development of Neutralizing Antibodies, and Compliance During the first six months, an influenza-like syndrome was reported by 54 percent of the patients in the interferon beta-1a group and by 26 percent of the patients in the placebo group (P<0.001). Depression was the only other adverse event whose incidence was at least 5 percentage points higher in the interferon beta-1a group than in the placebo group (incidence, 20 percent and 13 percent; P=0.05). Serious adverse events, none of which were attributed to treatment, 84 occurred in 12 patients in the interferon beta-1a group and 19 patients in the placebo group. Neutralizing antibodies were detected in less than 1 percent of patients in the interferon beta-1a group at 12 and 18 months and in 2 percent at 24 and 30 months. Treatment was discontinued because of an adverse event in one patient in the interferon beta-1a group (<1 percent) and in seven patients in the placebo group (4 percent). Treatment was stopped early for other reasons in 37 patients in the interferon beta-1a group (19 percent; 7 were lost to follow-up, 1 died in an automobile accident, 2 had disease activity, and 27 asked to withdraw or withdrew for other reasons) and in 28 patients in the placebo group (15 percent; 9 were lost to follow-up, 4 had disease activity, and 15 asked to withdraw or withdrew for other reasons). Treatment was not discontinued in any patient because of an abnormal laboratory value. The treatment assignment was revealed in the case of one patient who became pregnant. Ninety-three percent of the patients in the interferon beta-1a group and 99.5 percent of the patients in the placebo group took the study medication at least 80 percent of the time; 88 percent and 94 percent, respectively, were at least 90 percent compliant. 85 50 1 Placebo Interferon beta-1a Clinically Definite MS (%I I 1471013161192'2222831131137 Figure 1. Kaplan—Meier Estimates of the Cumulative Probability of the Development of Clinically Definite Multiple Sclerosis (MS) According to Treatment Group. The cumulative probability of the development of clinically definite multiple sclerosis during the three-year follow-up period was significantly lower in the interferon beta-1a group than in the placebo group (P=0.002 by the Mantel log-rank test). The numbers of patients at risk are the numbers in whom clinically definite multiple sclerosis had not developed at the beginning of each three-month period. The end point was assessed beginning at one month, since according to the protocol that was the earliest possible time at which the end point could be reached. The “early-withdrawal” row indicates the number of patients in whom multiple sclerosis did not develop and whose follow-up ended before the study ended. Data were censored at the time of a patient’s last completed neurologic examination. 86 DISCUSSION The results of our trial add to the indications for interferon beta-1a in the treatment of multiple sclerosis. In addition to the previously demonstrated benefit of interferon beta in patients with established multiple sclerosis,9-13 our results show that once-weekly intramuscular injections of interferon beta-1a, initiated at the time of a first clinical demyelinating event, are beneficial in patients who have MRI evidence of prior subclinical demyelination in the brain. In our study of 383 patients, interferon beta-1a reduced the rate of development of clinically definite multiple sclerosis within three years by about half. Findings on MRI scans of the brain provided additional objective support for the observation that the effects of treatment with interferon beta-1a were rapid and sustained. Interferon beta-1a was well tolerated, with no serious treatment-related adverse effects. The base-line characteristics of the two groups were similar, and there was no evidence of confounding in the analyses. The percentage of patients who were withdrawn from the study for reasons other than the development of clinically definite multiple sclerosis was similar in the two groups. Most patients continued treatment until their protocol-specified follow-up concluded, and the rates of compliance were good in both groups. The occurrence of the influenza-like syndrome related to interferon beta-1a therapy could have provided some patients with a clue to the treatment assignment, but given that the examining neurologist was unaware of the patients’ histories and that a separate, central 87 end-point committee was used to verify all outcomes, this possibility should not have appreciably biased the results. Because approved treatments for multiple sclerosis are available, we could not ethically keep patients in their assigned groups once clinically definite multiple sclerosis was diagnosed. Thus, the trial design could not provide any direct data on the long-term effect of interferon beta-1a on the rate of exacerbations or the progression of disability. However, the beneficial effects seen on MRI scans of the brain provide indirect evidence of a long-term benefit of treatment. A prior longitudinal study of patients with acute isolated demyelinating events found that the volume and number of brain lesions on T2-weighted MRI scans both at the time of the initial demyelinating event and subsequently were predictive of the degree of neurologic disability 10 years after the initial event.7,8 There has been controversy about the importance of performing MRI of the brain at the time of a first acute demyelinating event, particularly in patients who present with optic neuritis, since a clinical diagnosis of this syndrome generally can be established without ancillary testing.17 The results of our study provide justification for obtaining MRI scans of the brain at the time of a first event to determine whether there is further evidence of multiple sclerosis. Our results indicate that once-weekly treatment with intramuscular interferon beta-1a is beneficial in patients who are deemed to be at high risk for clinically definite multiple sclerosis because they have subclinical demyelinating lesions on MRI of 88 the brain. Our study does not provide the long-term follow-up data required to determine whether early initiation of treatment has long-term effects. However, the weight of current knowledge suggests that preventing or delaying a second attack of multiple sclerosis and reducing the progression of central nervous system demyelination as demonstrated on MRI scans of the brain will have long- term clinical benefits. Supported by Biogen. Drs. Jacobs, Beck, Simon, Kinkel, Brownscheidle, and Murray are paid consultants to Biogen. APPENDIX Other participants in the study were as follows: Clinical Centers — University of Toronto: P. O’Connor, P. Fleming, T. Gray; Buffalo General Hospital: C. Miller, R. Bakshi, F. Munschauer; Cleveland Clinic Foundation: D. Bolibrush, J. Cohen; Ottawa General Hospital: M. Freedman, U. Webb, H. Rabinowicz; Foothills Hospital: L. Metz, A. Davis, R. Ranawaya; Vancouver Hospital and Health Sciences Center: S. Hashimoto, W. Morrison, J. Oger; University of Maryland Hospital: H. Panitch, K. Costello, C. Bever; Multiple Sclerosis Center at Shepherd: W. Stuart, D. Court, D. Stuart; Georgetown University Hospital: C. Tomatore, D. Bartlett, J. Richert; Hopital Notre Dame: P. Duquette, R. Dubois, G. Bemier; Allegheny Neurological Associates: T. Scott, L. Pappert, J. Brillman; Medical College of Virginia, Richmond Eye and Ear Hospital: W. Fenton, III, T. 89 Anderson, J. Astruc; Salt Lake City Veterans Affairs Medical Center: J. Rose, J. Kline, J. Burns; Victoria General Hospital: P. Weldon, F. Bhan; University of Iowa College of Medicine: M. Wall, L. \fining, T. Grabowski; New York Hospital- Cornell Medical Center: B. Apatoff, K. Arapello, J. Friedman; University of Pennsylvania Medical Center: S. Galetta, D. Pfohl, G. Liu; London Health Sciences Centre University Hospital: G. Rice, T. Bental, P. Mandalfino; Michigan State University: E. Eggenberger, D. Snider, D. Kaufman; Yale School of Medicine: J. Guarnaccia, M. Shepard, J. Goldstein; Beta Research, Inc.: M. Reiss, E. Carter, G. Glista; Marshfield Clinic: L. Rolak, L. Scheller, D. Jacobson; University of Rochester: A. Goodman, M. Petrie, D. Mattson; Rush- Presbyterian—St. Luke’s Medical Center: K. Karlin, A. Wallin, D. Stefoski; University of Texas Health Science Center: S. Brod, E. Cerretta, J. Wolinsky; Montreal Neurological Institute: D. Arnold, R. Arnoutelis, L. Durcan; Beth Israel Medical Center: M. Kupersmith, L. Cappolino, J. Herbert; Southern California Kaiser Permanente Medical Center: J. Rosenberg, D. McHugh, A. Blumenfeld; Swedish Medical Center: C. Smith, D. Kuder, S. Hamilton; Neurological Associates, Inc.: S. Thurston, J. McGee, J. O’Bannon; Carolinas Medical Center: M. Kaufman, M. Butler, S. Putnam; Ohio State University: K. Rammohan, A. Siffort, J. Lynn; St. Louis University Health Sciences Center: J. Selhourst, E. Holzemer, G. Hayat; Wayne State University School of Medicine: A. Tselis, C. Caon, R. Lisak: Massachusetts General Hospital: S. Wray, P. Sexton, J. Leh- rich; University of Medicine and Dentistry of New Jersey Medical School: S. Cook, A. Jotkowitz, S. Bansil; Emory Clinic: N. Newman, J. Brown, P. Pennell; 90 Mayo Clinic Arizona: J. Carter, J. Buckner, R. Caselli; Neurology Group: L. Kerson, M. Camasso, G. Donneief; East Bay Neurology, Inc.: J. Cooper, D. Salkovsky, H. Shale; University of Illinois Eye and Ear lnfinnary: J. Goodwin, T. Johnson, A. Gulati; New England Medical Center: T. Hedges, C. Yardley, T. Tran; University of Missouri: S. Horowitz, A. Bon-nett, R. Burger; Kaiser Permanente Medical Center: J. Javerbaum, C. Griffin, R.J. Whaley; Bowman Gray School of Medicine of Wake Forest University: D. Jeffery, S.E. Jackson, E. Bastings; Dartmouth-Hitchcock Medical Center: L. Kasper, K. Ryan, J. Bernat; Oregon Health Sciences University: M. Mass, S. Cooper Hanel, D. Bourdette; University of Florida: J. Guy, M. Wilson, M. Greer; Mayo Clinic: C. Lucchinetti, M. Botten, J. Noseworthy; Medical University of South Carolina: A. Walker, B. Muntz, W. Tyor; MRI Reading Center, University of Colorado Health Sciences Center— M. Meyer, R. Leek, C. Gustafson, D. Singel, B. Quandt, D.E. Miller, B. Coombs, A. Cajade-Law, M. Lajaunie; End-Point Committee — A. Miller (chair), J. Richert, J. Cohen, T. Vollmer, J. Oger; Advisory Committee — L. Jacobs (cochair), R. Beck (cochair), R.P. Kinkel, C. Brownscheidle, T.J. Murray, J. Simon; Data and Safety Monitoring Committee — J. Antel (chair), L. Myers, G. Bimbaum, S. Reingold, R. Burde, W. Sibley, J. Ware; Biogen — N. Blanchard, K. Lloyd, H. Park, F. Votruba, K. 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[Erratum, Lancet 1999; 353:678.] The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-61. Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of intramuscular interferon b-1a for relapsing multiple sclerosis. Ann Neurol 1998;43:79-87. Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L, Multiple Sclerosis Collaborative Research Group. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999; 53:1698-704. Taves DR. Minimization: a new method of assigning patients to treatment and control groups. Clin Pharmacol Ther 1974;15:443-53. Rudick R, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Neurology 1998;50:1266- 72. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983;33:1444-52. 93 The Optic Neuritis Study Group. The clinical profile of optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1991; 109:1673-8. 94 Chapter 4: CHAMPS study data A natural research avenue stemming from the LONS data involved the use of therapeutics in the MRI-defined high risk population. We next participated in the Controlled High-MS risk Avonex Multiple Sclerosis Prevention Study (CHAMPS) investigating the effects of early therapeutic intervention with interferon. Subjects at high risk for the development of MS based on their initial clinical presentation (clinically isolated syndrome, or CIS) and an abnormal baseline MRI (as exemplified by the LONS data) were all treated with a course of ONTT-style high- dose intravenous methylprednisolone, then randomized to receive either weekly interferon or placebo, and followed with both clinical and MRI parameters. Inclusion criteria included a first, well-defined clinical episode consistent with demyelination, and a baseline MRI with at least 2 asymptomatic T2 lesions at least 3 mm in size typical of MS (at least 1 lesion had to be periventricular or ovoid). Subjects were between the ages of 18 and 50-years, and could not have experiences a prior neurological episode suggestive of demyelination lasting more than 48 hours. Clinical events (inclusion CIS, or clinically isolated syndromes) could include optic neuritis, a brainstem syndrome (e.g., diplopia from an abducens nerve palsy, or an internuclear ophthalmoplegia), or partial transverse myelitis. The onset of symptoms had to be within 14 days of intravenous corticosteroid initiation and no more than 27 days before randomization to interferon or placebo. The primary endpoint of the study was clinically definite MS, attained by either a new clinical event or a worsening of the clinically-derived disability score performed by a masked neurologist. Secondary 95 endpoints were MRI features: T2 lesion number and volume, and gadolinium- enhanced lesion number and volume. The trial recruited 383 subjects with an average age of 33-years between 1996 and 1998, among which 76% were female. Optic neuritis comprised 50% of the entrance events, with brainstem or cerebellar syndrome 28% and spinal cord syndrome 22% making up the total. The median duration before intravenous steroids were initiated was 8 days. The baseline MRI contained 2 lesions in 17%, 3-4 lesions in 33%, 5-7 lesions in 21% and 38 lesions in 29%; gadolinium- enhancing lesions were present in 30% at baseline [CHAMPS Study Group, MS 2002i The subjects in the CHAMPS trial were followed with clinical exams every 6 months. The cumulative probability of developing MS was significantly lower in the interferon group than the placebo group (rate ratio 0.56; 95% confidence interval 0.38 - 0.81; p = 0.002). At 3-years, the cumulative probability of developing MS was 35% in the interferon group and 50% in the placebo group. The adjusted rate ratio (adjusted for age, initial event, T2-Iesion volume and gadolinium enhancing lesion number) was 0.49 (95% confidence interval 0.33 — 0.73, p < 0.001). The diagnosis of MS was based on a second clinical attack in all but 5 patients (2 progressive from onset, and 3 subjects with progressive disability without a clinical exacerbation). The clinical treatment effect was present and significant for all 3 types of presenting events (optic neuritis, partial 96 transverse myelitis and brainstem/cerebellar syndrome) [CHAMPS Study Group, 2001} Magnetic resonance imaging was“ performed at 6, 12, and 18 months during the study. Only patients who had not reached endpoint (another clinical change consistent with the development of MS) remained eligible for serial MRIs, a feature potentially biasing against treatment effect because the more active patients, with their presumably more active MRI scans exited the study. At all time frames during the study, the interferon group demonstrated significantly fewer MRI changes than the placebo group, including T2 lesion volume, T2 lesion number, and gadolinium enhancing lesion number and volume. T2 lesion volume was significantly less in the treated group at 6 (p<0.001), 12 (p=0.004) and 18 months (p<0.001). At 18 months, the median increase in T2 lesion volume was 1% in the interferon group and 16% in the placebo group. The interferon group had 42% fewer gadolinium-enhancing lesions than the placebo group at 6 months, 55% fewer at 12 months and 67% fewer at 18 months. These secondary endpoints helped validate the primary clinical effect. The most common side effect of interferons is a flu-Iike syndrome, and during the first 6 months of study, this was reported in 54% of interferon-treated patients and 26% of the placebo patients. Depression was the only other adverse event noted with 5% or higher greater incidence in the treated group (20% versus 13%; 97 p=0.05). Compliance was generally very good, with at least 90% compliance in 88% of the interferon group and 94% of the placebo group. This trial changed the treatment paradigm of MS therapy. Before the CHAMPS trial, treatment was restricted to patients who had clinically definitely MS and were progressing. After the CHAMPS trial, clinical practice shifted toward early therapy, even before a formal diagnosis was made. The trial demonstrated the safety and efficacy of prescribing interferon early in this high-risk population [Jacobs et al, 2000]. CHAMPIONS: The CHAMPS study cohort remains active as the open-label extension study, CHAMPIONS (Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance). This study sought to determine if the benefits of IFN [3 -1a observed in CHAMPS were sustained for up to 5 years. CHAMPS patients at participating sites were eligible for enrollment into this extension study. All patients were offered, but not required to take, interferon beta 1a (IFN B-1a) 30 mcg IM once weekly for up to 5 years (from CHAMPS randomization). Patients who received placebo in CHAMPS were considered the delayed treatment (DT) group, and patients who received lF N [3 -1a in CHAMPS were considered the immediate treatment (IT) group. The primary outcome measure was the rate of development of CDMS. Additional outcomes included 98 disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years. The 5-year CHAMPIONS findings were published in 2006 [CHAMPIONS Study Group, 2006]. Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS. The median time to initiation of IFN 8 -1a therapy in the DT group was 29 months. The cumulative probability of development of clinically definite MS (CDMS) was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs. 49 +/- 10%; p = 0.03). Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of neurologic symptoms. Few patients in either group developed major disability within 5 years. These results support the use of IM interferon [3 -1a after a first clinical demyelinating event in this MRI-defined high risk cohort, and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment. 99 Chapter 5 Rudick RA, Stuart WH, CalabresiPA et al. Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis. N Engl J Med 2006;354:911-23. (A summary overview of this article will be found on page 129 of this thesis.) 100 Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis Richard A. Rudick, M.D., William H. Stuart, M.D., Peter A. Calabresi, M.D., Christian Confavreux, M.D., Steven L. Galetta, M.D., Emst-Wilhelm Radue, M.D., Fred D. Lublin, M.D., Bianca Weinstock-Guttman, M.D., Daniel R. Wynn, M.D., Frances Lynn, M.Sc., Michael A. Panzara, MD, MPH, and Alfred W. Sandrock, MD, Ph.D., for the SENTINEL lnvestigators* 101 Abstract Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an 04 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P =0.02). Kaplan—Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T2-weighted magnetic resonance imaging (0.9 vs. 5.4, 102 P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. Conclusions Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTriaIs.gov number, NCT00030966.) [figures and tables appear in the original text]. From the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland (R.A.R.); the MS Center of Atlanta, Atlanta (W.H.S.); the Johns Hopkins Multiple Sclerosis Center, Baltimore (P.A.C.); H6pital Neurologique, Lyon, France (C.C.); University of Pennsylvania School of Medicine, Philadelphia (S.L.G.); University Hospital Basel, Basel, Switzerland (E.-W.R.); Mt. Sinai School of Medicine, New York (F.D.L.); Baird Multiple Sclerosis Center, State University of New York at Buffalo, Buffalo (B.W.- 6.); Consultants in Neurology Multiple Sclerosis Center, Northbrook, Ill. (D.R.W.); and Biogen Idec, Cambridge, Mass. (F.L., M.A.P., A.W.S.). Address reprint requests to Dr. Rudick at the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, or at rudickr@ccf.org. *The Safety and Efficacy of Natalizumab in Combination 103 with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) Investigators are listed in the Supplementary Appendix, available with the full text of this article at www.nejm.org. N Engl J Med 2006;354:911-23. The adhesion moleculed4B1 integrin is a key initiator of the inflammatory cascade involved in the pathogenesis of multiple sclerosis.1-4 Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is the first (:4 integrin antagonist in a new class of selective adhesion-molecule inhibitors for the treatment of multiple sclerosis. Natalizumab binds to 04 integrin on the surface of leukocytes, inhibiting their migration into the brain and thereby reducing inflammation. Current disease-modifying therapies for relapsing—remitting multiple sclerosis (interferon beta and glatiramer acetate) are only partially effective,5-8 and most patients with multiple sclerosis have breakthrough disease activity despite therapy with these agents. Hence, there is a need for additional treatment options in multiple sclerosis. Natalizumab is an attractive therapy to add to current disease-modifying therapies in patients with breakthrough disease because preliminary efficacy9 and safety10 data have been favorable and because the mechanism of action of natalizumab may complement those of other disease modifying therapies.1 1-17 104 The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study was a two-year, phase 3 clinical trial designed to determine whether natalizumab, when added to interferon beta-1a, has efficacy in addition to that associated with interferon beta-1a alone. The trial was also designed to confirm the safety of natalizumab when added to interferon beta-1a. Methods Patients One hundred twenty-four clinical centers in Europe and the United States enrolled 1196 patients beginning on January 14, 2002. All patients gave written informed consent. The study protocol was developed by the investigator advisory committee and the sponsors and was approved by central and local ethics committees, and the study was overseen by an independent safety-monitoring committee. Data were collected by the investigators and an independent organization (PPD International) and were held and analyzed by Biogen Idec and Elan Pharmaceuticals. During the study, the investigator advisory committee and representatives of Biogen Idec met at least monthly to review and manage the study. The manuscript was written by Drs. Rudick and Panzara, with input from each of the other authors; all the authors vouch for the veracity and completeness of the data and analyses. 105 Eligible patients were 18 to 55 years of age; had a diagnosis of relapsing— remitting multiple sclerosis.18 a score on the Expanded Disability Status Scale (EDSS) (possible scores range from 0 to 10, with higher scores indicating more severe disease) between 0 and 5.0,19 and a magnetic resonance imaging (MRI) scan revealing lesions consistent with a diagnosis of multiple sclerosis; had received treatment with interferon beta-1a for at least 12 months before randomization; and had had at least one relapse during the 12-month period before randomization. Patients were ineligible if they had primary progressive, secondary progressive, or progressive relapsing multiple sclerosisZO; if they had had a relapse within 50 days before randomization; or if they had been treated with an approved disease-modifying therapy other than interferon beta-1a intramuscularly once weekly within the 12-month period before randomization. Study Design and Randomization This study was a randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial. Data from 1171 of the 1196 patients enrolled were analyzed, because a single center with 25 patients was excluded before unblinding owing to irregularities in data. Patients were randomly assigned, in a 1:1 ratio, to receive 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks in addition to interferon beta-1a (Avonex, Biogen ldec) at a dose of 30 pg intramuscularly once weekly for up to 116 weeks. Randomization was stratified according to study site in blocks of four (two active and two placebo) with the use of a computer-generated schedule and a multidigit 106 identification number, implemented by way of an interactive voice-response system. All study personnel, patients, sponsor personnel involved in the conduct of the study, and members of the investigator advisory committee were blinded to the treatment assignments throughout the study. Study Procedure and End Points Each site designated primary and backup examining neurologists and treating neurologists. The examining neurologists performed the EDSS and neurologic examinations but were otherwise not involved in the patients’ medical care. The treating neurologists were responsible for all patient care, including the management of adverse events and relapses of multiple sclerosis. Clinical visits every 12 weeks included assessment of relapses, EDSS evaluation, blood chemical and hematologic tests, assessment of any adverse events, and immunogenicity studies. Patients were also seen by a treating neurologist during unscheduled visits within 72 hours after the development of new symptoms so that they could be assessed for possible relapses or adverse events. If a relapse was suspected, the patient was evaluated by the examining neurologist. Relapses were defined as the development of new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new, objective neurologic findings. At the discretion of the treating neurologist, relapses were treated with intravenous methylprednisolone at a dose of 1000 mg per day for three or five days. Patients 107 who had disability progression that was sustained for 12 weeks were asked to provide consent to continue study participation and were given the option of adding an available multiple sclerosis treatment as rescue medication, according to protocol, while continuing to receive the study drug. Patients who discontinued the study drug were strongly encouraged to remain in the study for follow-up assessments, and all patients who continued to participate in the study were evaluated (according to the intention-to-treat principle). Proton-density, T2-weighted MRI scans and gadolinium-enhanced T1-weighted MRI scans of the brain were obtained at baseline and at weeks 52 and 104. Forty contiguous, 3-mm-thick axial slices were acquired. MRI analyses were performed centrally at the MS-MRI Evaluation Center (Basel, Switzerland) by blinded raters. The scans were checked for artifacts, compliance with scanning requirements, and repositioning. The primary efficacy end point was the rate of clinical relapse at one year. Secondary end points at one year were the number of new or enlarging T2- hyperintense lesions, the number of gadolinium-enhancing lesions, and the proportion of patients free of relapse. The primary efficacy end point at two years was the cumulative probability of sustained disability progression, defined as an increase by at least 1.0 point in the EDSS score from a baseline score of at least 1.0 or an increase by at least 1.5 points in the EDSS score from a baseline score of 0, sustained for 12 weeks; progression could not be confirmed during a 108 relapse. Secondary end points at two years were the rate of clinical relapse, the volume of T2-hyperintense lesions, the number of new T1-hypointense lesions, and disability as measured by the Multiple Sclerosis Functional Composite.21 This report presents data pertaining to primary end points and key secondary efficacy end points, as well as safety data. Results pertaining to additional secondary end points and tertiary end points are not included in this report. Binding antibodies against natalizumab were assessed with use of an enzyme- linked immunoscrbent assay. Positive samples (0.5 pg per milliliter) were further tested in a flow-cytometry assay to determine whether these antibodies interfered with the binding of natalizumab to (:4 integrin. Statistical Analysis The sample size was estimated, on the basis of data from previous trials of natalizumab9 and interferon beta-1a,6 with the use of two-sided tests with an experiment-wise alpha of 0.05. The annualized rate of relapse among patients receiving combination therapy at one year was predicted to be 0.6, as compared with 0.9 among patients receiving interferon beta-1a alone. For the annualized relapse rate, the likelihood-ratio test was used to determine the sample size with half the patients receiving active drug and half receiving placebo. With an assumed dropout rate of 17 percent, rounding, a type I error rate of 2.5 percent, and a type II error rate of 90 percent, the number of patients needed was estimated to be 1200. To power the study for the two-year end point of disability 109 progression, we assumed a progression rate of 34.9 percent at the end of two years in the group assigned to interferon beta-1a alone and a progression rate of 22.7 percent at the end of two years (a 35 percent improvement) in the combination-therapy group. SimUIations of the log-rank test were run with 60 percent of the accrual in the first 24 weeks and the remainder in the next 24 weeks. With an assumed dropout rate of 20 percent, the sample size of 1200 provided at least 92 percent power with a Bonferroni adjustment for multiple end points and with the type I error rate maintained at 5 percent. The baseline characteristics of the patients were analyzed with the use of a t- test, with the exceptions of sex, race, and diagnosis of multiple sclerosis (based on the McDonald criteria18), which were analyzed with the use of a chi-square test. The time to the onset of disability progression sustained for 12 weeks was used to determine the cumulative probability of disability progression estimated by the Kaplan-Meier method. The Cox proportional-hazards model, adjusted for the baseline EDSS score, was used to compare the Kaplan—Meier curves. The annualized relapse rate was calculated by Poisson regression and adjusted for the number of relapses in the year before randomization; data pertaining to relapses that occurred after rescue treatment was initiated (per protocol) were censored. Additional baseline factors were tested for inclusion in each of the models: EDSS score (53.5 or >3.5), gadolinium-enhancing lesions (present or absent), the number of T2-hyperintense lesions (<9 or 29), and age (<40 or 240 years).22-24 Each covariate was tested in the model for statistical significance by 110 a backward-selection procedure, and only statistically significant covariates (P5010) were included in the final models. No additional covariates were included in the analysis of disability progression. Three additional covariates (baseline EDSS score, the presence or absence of gadolinium-enhancing lesions at baseline, and age) were included in the analysis of relapse rate. A sensitivity analysis of disability progression (based on the change in EDSS score) sustained for 24 weeks was also conducted. For the annualized rate of relapse, sensitivity analyses were performed with and without censoring, as well as with and without adjustment for significant covariates. The unadjusted rate of relapse was calculated as the total number of relapses divided by the total number of subject-years of follow-up in each treatment group. The Hochberg procedure25 for multiple comparisons was used in the analysis of the two primary end points; hence, the significance level was set such that if the higher of the P values for the analyses of these end points was less than or equal to 0.05, then both end points were considered to be statistically significant; otherwise, the lower of the P values was tested at a significance level of 0.025. Secondary efficacy end points were rank-ordered, and a closed testing procedure was used such that if statistical significance was not achieved for a given end point, then end points of a lower rank were considered not statistically significant. Secondary efficacy end points were analyzed by logistic regression with a term for treatment group and with their respective baseline values as 111 covariates; missing values were imputed by using the mean in the study population. Adverse events were analyzed With use of the chi-square test, and serious adverse events were analyzed with use of Fisher’s exact test. Poisson regression was used to calculate the difference between the rates of infection in each treatment group. All analyses followed the intention-to-treat principle. All reported P values are two-tailed. The date on which the database was locked for the two-year analyses was May 31, 2005, and as a result there were 2528 patient-years of observation and 1222 patient-years of exposure to natalizumab. Results Patients SENTINEL was stopped approximately one month early, on February 28, 2005, because of two reports of progressive multifocal leukoencephalopathy (PML). Of the 1171 patients, a total of 1003 (86 percent) completed the 120-week study; 168 patients (14 percent overall; 12 percent of the group assigned to interferon beta-1a plus natalizumab and 16 percent of the group assigned to interferon beta-1a alone) withdrew from the study (Fig. 1). Sixty-four patients discontinued the study drug but completed follow-up (5 percent overall; 5 percent of the combination-therapy group and 6 percent of the group assigned to interferon 112 beta-1a alone). There were no significant differences in demographic or disease- related characteristics at baseline between the two treatment groups, with the exception of the duration of disease (median, seven years in the combination- therapy group and eight years in "the group assigned to interferon beta-1a alone; P =0.02) (Table 1). The SENTINEL data represent 28 percent of the placebo-controlled experience with natalizumab (in terms of patient-years of exposure) in both multiple sclerosis and Crohn’s disease and 44 percent of the overall experience in multiple sclerosis. Efficacy Kaplan—Meier estimates of the cumulative probability of sustained disability progression at 2 years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone (Fig. 2 and Table 2). Combination therapy resulted in a 24 percent decrease in the risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P =0.02). In the sensitivity analysis of the risk of disability progression sustained for 24 weeks, estimates of the cumulative probability of progression by 2 years were 15 percent for combination therapy and 18 percent for interferon beta-1a alone (representing an 18 percent reduction with combination therapy); however, this difference was not statistically significant (P=0.17). 113 Combination therapy reduced the annualized rate of relapse at one year, which was 0.82 with interferon beta-1a alone, to 0.38 (P<0.001) — a 54 percent reduction (Table 2). This difference was maintained at two years, at which time the rate was 0.75 with interferon beta-1a alone and 0.34 with combination therapy (a 55 percent reduction with combination therapy, P<0.001). Subgroup analyses (according to relapse history, EDSS score, age, sex, the presence or absence of gadolinium-enhancing lesions, and the number of T2-hyperintense lesions) and a sensitivity analysis of relapse rate showed consistent results. The proportion of patients who were relapse-free at two years was 54 percent in the combination-therapy group, as compared with 32 percent in the group assigned to interferon beta-1a alone (P<0.001). The risk of relapse was 50 percent lower with combination therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.43 to 0.59; P<0.001). The number of new or enlarging T2-hyperintense lesions over the two-year period was reduced from 5.4 with interferon beta-1a alone to 0.9 with combination therapy (P<0.001), representing an 83 percent reduction with combination therapy (Table 2). The mean number of gadolinium-enhancing lesions at two years was 0.9 with interferon beta-1a alone and 0.1 with combination therapy, representing an 89 percent reduction (P<0.001). 114 Safety At least one adverse event was reported by 584 patients assigned to receive interferon beta-1a plus natalizumab (>99 percent) and 578 assigned to receive interferon beta-1a alone (>99 percent). Adverse events significantly associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema (Table 3). The worst adverse events associated with combination therapy were mild in 10 percent of the patients, moderate in 54 percent, and severe in 35 percent; the respective percentages for interferon beta- 1a alone were 5 percent, 57 percent, and 37 percent. Serious adverse events were observed in 18 percent of the patients assigned to combination therapy and 21 percent of those assigned to interferon beta-1a alone (P=0.23). The most common serious adverse event was a relapse of multiple sclerosis, which occurred in 5 percent of the patients in the combination-therapy group and 9 percent of those in the interferon beta-1a group (P=0.002). One of the serious adverse events reported was PML, which occurred in a patient who had received 29 doses of natalizumab. A second patient received a diagnosis of PML after her completion of the two-year study and after she had received 37 doses of natalizumab. The details of these cases of PML have been reported previously.26,27 Two of the patients assigned to interferon beta-1a alone died: one was a 47-year-old woman with a history of sinus arrhythmia and heart murmur, and the other was a 23-year-old woman with a history of headache, pain, and use of prescribed methadone who died during sleep. 115 Depression was assessed every six months with use of the Beck Depression Inventory ".28 There were no differences between the treatment groups in Beck Depression Inventory ll scores during the study (data not shown). The incidence of infection was 83 percent in the combination-therapy group and 81 percent in the group assigned to interferon beta-1a alone; infections occurred at a rate of 1 per patient-year in each group. When the data pertaining to infection were reanalyzed to include multiple occurrences, the rate increased in each group, as expected. However, there remained no significant difference between the groups, with infection rates of 1.54 per patient-year with combination therapy and 1.53 per patient-year with interferon beta-1a alone (P=0.95). Common infections were nasopharyngitis (39 percent vs. 35 percent); urinary tract infection, not othenrvise specified (18 percent vs. 19 percent); sinusitis, not othenlvise specified ( 18 percent vs. 15 percent); upper respiratory tract infection, not othenrvise specified (17 percent vs. 18 percent); and influenza (17 percent vs. 15 percent). Serious infections occurred in 2.7 percent and 2.9 percent of the patients assigned to combination therapy and interferon beta-1a alone, respectively. There were no cases of tuberculosis. The incidence of cancer was 1 percent in the combination-therapy group and 2 percent in the group assigned to interferon beta-1a alone. Infusion reactions, defined as any event occurring within two hours after the start of an infusion, occurred in 24 percent of the patients in the combination-therapy 116 group and 20 percent of those in the group assigned to interferon beta-1a alone (P=0.11). The most common infusion reaction was headache. Most reactions were treated symptomatically and did not result in discontinuation of the study drug. Hypersensitivity reactions included all events reported on the basis of clinical judgment as hypersensitivity, an allergic reaction, an anaphylactic or anaphylactoid reaction, urticaria, or hives by the investigator and were categorized according to severity. Eleven patients assigned to combination therapy (1.9 percent) had a hypersensitivity reaction; 8 of the 11 hypersensitivity reactions were isolated cases of urticaria (2 of which were severe). In addition, two patients assigned to interferon beta-1a alone (0.3 percent) had hypersensitivity reactions associated with the infusion of placebo; both were cases of mild urticaria. There was no cardiopulmonary compromise associated with any event. Natalizumab was discontinued, and the episodes resolved without sequelae. Eight percent of the patients in the combination-therapy group and 7 percent of those in the group assigned to interferon beta-1a alone discontinued the study drug because of an adverse event. Three percent and 2 percent, respectively, withdrew from the study because of an adverse event. Natalizumab-treated patients had increases in lymphocytes, monocytes, eosinophils, and basophils — changes consistent with the drug’s known pharrnacodynamic effects and the presence of 04 integrins on these cell types. 117 Increases in nucleated red cells also were seen transiently in a small number of patients. These laboratory changes were not associated with any clinical manifestations and were reversible, with values returning to baseline within 16 weeks after the last dose. Elevations in neutrophils were not observed. No increase in the incidence of chemical abnormalities, including the results of liver- function tests, was observed with combination therapy. lmmunogenicity Seventy patients (12 percent of the combination-therapy group) had antibodies to natalizumab. Persistent antinatalizumab antibodies (detectable on at least two occasions 42 or more days apart) developed in 38 patients (6 percent), resulting in a loss of efficacy and an increase in infusion-related adverse events. The incidence of new neutralizing antibodies to interferon beta-1a was 1 percent among patients assigned to combination therapy and less than 1 percent among those assigned to interferon beta-1a alone. Discussion Phase 3 trials have shown that over a two-year period, 62 to 75 percent of patients have clinical relapses while receiving interferon beta therapy.5,6,8 For patients who have breakthrough disease while receiving disease-modifying therapies, clinical practice includes the addition of a second partially effective agent; however, there is no class I evidence to support this treatment strategy. The primary objective of SENTINEL was to address this common clinical 118 scenario — specifically, to determine whether the addition of natalizumab to interferon beta-1a would reduce breakthrough disease activity in patients already receiving interferon beta-1a therapy. This approach has been used effectively in the development of combination therapy for rheumatoid arthritis.29-32 The addition of natalizumab to interferon beta-1a reduced the risk of disability progression by 24 percent over a two-year period as compared with interferon beta-1a alone (P=0.02). The sensitivity analysis of disability sustained for 24 weeks did not reach statistical significance (P=0.17); however, that analysis was exploratory, and the study was not adequately powered to assess the treatment effect on the basis of this definition. We also found that combination therapy reduced the annualized rate of relapse by 55 percent over a two-year period as compared with interferon beta-1a alone (P<0.001). Accumulation of T2-hyperintense MRI lesions has been linked to future progression of brain atrophy33 and long-term disability34,35 in relapsing multiple sclerosis. The number of new or enlarging T2-hyperintense lesions in patients receiving interferon beta-1a alone was similar to the findings of another study of interferon beta-1a in relapsing multiple sclerosis that used the same imaging methods.36 The addition of natalizumab to interferon beta-1a further reduced the number of new or enlarging T2-hyperintense lesions by 83 percent, and approximately two thirds of the patients assigned to combination therapy remained free of new lesions for two years. 119 Natalizumab interferes with the activity of (14 integrin, altering cell migration into the central nervous system and possibly blocking interactions between (:4 integrin and its ligands within the central nervous system itself.1-4 Interferon beta has pleiotropic effects on cellular functions that are relevant to efficacy in multiple sclerosis and distinct from those of natalizumab.11-14 In addition, studies have shown that, like natalizumab, interferon beta may prevent leukocyte migration across the blood—brain barrier by altering the expression of adhesion molecules.15-17 The additional efficacy of the combination over that conferred by interferon beta alone suggests that the interaction between 0481 integrin and its targets is a key mediator of inflammation and subsequent demyelination in multiple sclerosis. In February 2005, administration of natalizumab was suspended when two cases of PML were identified. In one of the cases, PML was diagnosed during SENTINEL, and in the other it was diagnosed after the patient had completed SENTINEL and had begun participating in an open-label safety study of natalizumab and interferon beta-1a. Later, an additional case of PML was identified postmortem in a patient with Crohn’s disease who had previously received a diagnosis of astrocytoma. Details of these three cases have recently been published.26,27,37 An extensive safety evaluation of patients in clinical trials who were receiving natalizumab at the time of the drug suspension did not identify additional cases of PML (see the article by Yousry et al. in this issue of the Journal38). The mechanisms by which natalizumab may increase the risk of 120 PML are unknown, but they may involve altered trafficking of lymphoid cells harboring latent JC virus, decreased immune surveillance, or a combination of these processes.39 The role of interferon beta in combination with natalizumab is also not clear, given that PML has never been associated with interferon beta alone. SENTINEL was designed to determine whether natalizumab added to interferon beta-1a is better than interferon beta-1a alone. The results of all prespecified analyses of primary and secondary end points were positive and statistically significant. A natalizumab-monotherapy group was not included in the trial because this design would have required withdrawal of an approved therapy in order to switch to an experimental one at a time (in 2001) when the long-term safety and efficacy of natalizumab were unknown. This approach was believed to be unacceptable by the investigator advisory committee. Hence, additional studies would be required to determine whether combination therapy with natalizumab and interferon beta-1a is more efficacious than natalizumab alone and to define further the role of natalizumab combination therapy in clinical practice. The results of another trial of natalizumab, administered without interferon beta-1a, also appear in this issue of the Journal.40 SENTINEL systematically evaluated combination therapy as compared with standard interferon beta therapy in relapsing multiple sclerosis. The study showed that in patients with multiple sclerosis who have breakthrough disease 121 during interferon beta treatment, combination therapy has significant benefits when compared with interferon beta-1a alone. Additional studies will be required for further assessment of the long-term safety of combination therapy with natalizumab and for assessment of its efficacy relative to that of natalizumab alone. Supported by Biogen ldec and Elan Pharmaceuticals. Drs. Rudick and Stuart report having received consulting fees, lecture fees, and grant support from Biogen ldec. Dr. Calabresi reports having received consulting fees from Biogen ldec, Teva, Schering, and Novartls; lecture fees from Biogen ldec and Teva; and grant support from Biogen ldec and Genentech. Dr. Confavreux reports having received consulting and lecture fees from Biogen ldec, Sanofi-Aventis, Schering, Serono, and Teva. Dr. Galetta reports having received consulting fees, lecture fees, and grant support from Biogen ldec. Dr. Radue reports having received lecture fees from Biogen ldec. Dr. Lublin reports having received grant support from Biogen ldec, Teva, Acorda, and Merck and consulting or lecture fees from Biogen ldec, Berlex, Teva, Novartis, Schering-Plough, Serono, Pfizer, Amgen, and Antisense Therapeutics. Dr. Weinstock-Guttman reports having received lecture fees from Biogen ldec and Teva and grant support from Biogen ldec. Dr. Wynn reports having received consulting fees from Biogen ldec, Teva, Serono, and Avanir Pharmaceuticals and lecture fees from Biogen ldec, Teva, Pfizer, and Serono. Ms. Lynn, Dr. Panzara, and Dr. Sandrock report having equity interest in 122 and being employees of Biogen ldec. No other potential conflict of interest relevant to this article was reported. References Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against c461 integrin. Nature 1992;356:63-6. Baron JL, Madri JA, Ruddle NH, Hashim G, Janeway CA Jr. Surface expression of (14 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med 1993;177:57-68. Lobb RR, Hemler ME. The pathophysiologic role of alpha 4 integrins in vivo. J Clin Invest 1994;94:1722-8. Carman CV, Springer TA. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. 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A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75:800-2. Langer—Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-81. Kleinschmidt—DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005:3532 369-74. Beck AT, Steer RA, Brown GK. Manual for Beck Depression Inventory Il (BDl-ll). San Antonio, Tex.: Psychology Corporation, 1996. Lehman AJ, Esdaile JM, Klinkhoff AV, Grant E, Fitzgerald A, Canvin J. A 48- week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study. Arthritis Rheum 2005;52:1360-70. St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004;50:3432-43. 126 Gerards AH, Landewe RB, Prins AP, et al. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum Dis 2003;62:291-6. [Erratum, Ann Rheum Dis 2003;62:1126.] Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human antitumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:35-45. [Errata, Arthritis Rheum 2003;48:855, 2004;50:144.] Rudick RA, Lee JC, Simon J, Ransohoff RM, Fisher E. Defining interferon beta response status in multiple sclerosis patients. Ann Neurol 2004;56:548-55. Schreiber K, Sorensen PS, Koch-Henriksen N, et al. Correlations of brain MRI parameters to disability in multiple sclerosis. Acta Neurol Scand 2001;104:24-30. Traboulsee A, Dehmeshki J, Peters KR, et al. Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities. Mult Scler 2003;9z566-73. Clanet M, Radue EW, Kappos L, et al. A randomized, double-blind, dose- comparison study of weekly interferon B-1a in relapsing MS. Neurology 2002;59:1507-17. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353: 362-8. 127 Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-33. Berger JR, Koralnik IJ. ProgresSive multifocal leukoencephalopathy and natalizumab — unforeseen consequences. N Engl J Med 2005;353:414-6. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899- 910. 128 Chapter 5: SENTINEL and other combination studies in MS MS is thought to be an “autoimmune” disease in which white blood cells, such as lymphocytes, enter the central nervous system inappropriately to trigger immune mediated damage to components of the nervous system. Natalizumab is the first “designer drug” targeting a specific aspect of this suspected immune mediated MS pathophysiology. This monoclonal antibody is directed against alpha-4 integrin, a component of the docking system used by lymphocytes to traffic from the intravascular space into the central nervous system. Natalizumab appeared effective in phase II trials, and a phase III trial was initiated using this agent in combination with interferon. The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study assessed the efficacy of Natalizumab as add-on therapy to interferon. The SENTINEL randomly assigned 1171 patients who, despite interferon beta-1a therapy, had experienced at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence 129 interval, 0.61 to 0.96; P = 0.02). Kaplan—Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualiZed rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T2-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. The primary conclusion of this study was that Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. In a parallel multi-center, double-masked randomized placebo-controlled trial conducted primarily outside the US, natalizumab was compared to placebo and demonstrated a statistically significant relapse rate reduction and MRI effect. The drug was FDA approved based on these data in November 2004. Natalizumab was increasingly being used in clinical practice until three cases of polyomavirus infection emerged in study patients in February 2005. Two of these cases occurred in the SENTINEL MS study groups, while 1 occurred in a Natalizumab study of Crohn disease. Polyomavirus infection within the central nervous system causes a condition known as progressive multifocal leukoencephalopathy (PML), a generally fatal destructive disease involving oligodendrocytes (white matter). One of the MS patients survived, but was left 130 with severe motor impairment. All three of the infected patients were on combination therapy with interferon and natalizumab (MS patients), or prednisone, methotrexate and Natalizumab (Crohn patient). These infectious cases led to the withdrawal of the agent from the US market in February 2005. The JC virus (PML) is latent in most people and does not produce disease. The re-activation of this virus in patients on natalizumab combinations is presumably the result of the exclusion of white blood cell trafficking through the central nervous system, a degree of which appears to be a normal and necessary function. The medication was reviewed at the FDA subcommittee level 3/06, and approval to use the medication in the trial setting was granted; the drug was re- released to the US market 7/06. The natalizumab trial will resume summer 2006, utilizing natalizumab monotherapy in a yet-to-be finalized protocol [Yousry et al, 2006]. ACT (Avonex Combination Trial): Recognizing that all available MS therapies are only partially effective, numerous clinicians have sought to combine these therapies akin to chemotherapy protocols, which utilize lower doses of partial effective treatments. Similarly, we have become involved in several other research outgrowths from the LONS and CHAMPS that remain ongoing, including the ACT (Avonex Combination Trial) trial and Combin trial. The ACT trial is a randomized, multi-center, double masked placebo-controlled trial evaluating interferon in combination with serial methylprednisolone, methotrexate or both. The serial methylprednisolone arm 131 was based in part on the LONS data demonstrating the short term efficacy of methylprednisolone in reducing the development of clinically definite MS over 2-3 years in patients with an abnormal baseline MRI. The primary objectives of the ACT study is to determine whether adding weekly oral methotrexate to standard interferon or standard interferon plus every other month serial intravenous methylprednisolone was effective in reducing MRI activity (new or enlarging T2 lesions at month 12; the secondary outcomes included MRI gadolinium enhancing lesions number, relapse rate, progression of functional impairment (Multiple Sclerosis Functional Composite core), and MRI atrophy at 12 months. The study population is relapsing-remitting MS patients ages 18-55 inclusively, and EDSS 0 - 5.5 with a documented breakthrough of disease while on interferon beta-1a therapy (at least 1 relapse or 1 gadolinium enhancing lesion). Subjects were randomized in a 1:1 :1 :1 ratio to one of four treatment groups: group 1 - interferon beta-1a weekly + placebo PO weekly; group 2 - interferon beta-1a weekly + methotrexate 20 mg PO weekly; group 3 - interferon beta-1a weekly + placebo PO weekly + intravenous methylprednisolone 1000 mg/day x 3 days every 2 months; or group 4 - interferon beta-1a weekly + methotrexate 20 mg PO weekly + intravenous methylprednisolone 1000 mg/day x 3 days every 2 months. Safety monitoring includes physical exams, blood chemistry and hematology, pregnancy testing, urinalysis, chest x-rays and DEXA bone density scans for 132 subjects on intravenous methylprednisolone. This trial remains on-going with data expected September 2006. Combin The two standard therapies for relapsing MS are interferon beta (in various routes and dosage regiments) and glatiramer acetate. The Combin trial is an NIH-sponsored trial designed to assess the efficacy of the combination of interferon and glatiramer for MS. The study population is male and female subjects age 18 - 60 inclusively with a diagnosis of relapsing-remitting MS (McDonald or Poser criteria) with an EDSS score 0 - 5.5 inclusively and at least 2 attacks in the prior 3 years. Primary exclusion criteria include prior use of interferon or glatiramer, steroid therapy within 1 month of entrance, abnormal screening labs, or inability to perform the study procedures. Study subjects are randomized to interferon beta 1a (30 mcg IM every week) and placebo subcutaneous every day (25% of the study population), glatiramer acetate (20 mg subcutaneously every day) and placebo intramuscular every week (25% of the study population), or interferon 30 mcg IM every week and glatiramer acetate 20 mg subcutaneously every day (50% of the study population). Clinical visits are scheduled at baseline and then every 3 months for 36 months. The primary objective of the study is to determine whether combined treatment with interferon beta-1a and glatiramer acetate is more effective than either agent alone in treating relapsing-remitting MS as determined by a reduction in the relapse rate. 133 Chapter 6: Optical coherence tomography studies in MS The 15-year follow up of the LONS cohort re-opened 2006. In addition to the clinical measurements, we authored and will analyze a LONS sub-study involving optical coherence tomography (OCT). The study proposal leading to this trial is summarized below: Multiple sclerosis (MS) is not only an inflammatory demyelinating disease, but also produces axonal damage and loss, which likely accounts for a large degree of the neurological disability and cerebral atrophy. MRI measures of cerebral atrophy correlate better with disability than do MRI measures of inflammatory activity, and axonal loss may represent the primary substrate for permanent disability in MS. The optic nerve is an excellent anatomic study site in MS, with well-defined myelin and axonal components, common and quantifiable dysfunction, and direct visibility. The most anterior portion of the optic nerve originates in the retinal ganglion cells and lacks myelin, rendering it accessible to optical imaging techniques. Optical coherence tomography (OCT) is a non- invasive method that employs light in a manner analogous to ultrasound’s use of sound energy to provide an image. OCT is able to quantify the thickness of the optic nerve fiber layer within the retina, and diminutions of the retinal nerve fiber layer are conceptually analogous to cerebral atrophy (axonal loss). OCT has demonstrated a relationship with visual function and global disability measures in patients with MS. By measuring the retinal nerve fiber layer, it may be possible to enhance our understanding of the effects of MS on visual function and axonal 134 integrity within the cerebrum with a quick, non-invasive, inexpensive and repeatable tool. LONS 15-year OCT Research Plan Hypothesis-driven specific aims The hypotheses driving the OCT study are explained below, and will be analyzed with correlations and multivariate regression models. 1. Hypothesis: Optical coherence tomography nerve fiber layer (NFL) measurements will be diminished in the LONS population compared to age- and gender-matched control data. Comparison: total and quadrantic retinal nerve fiber layer measurements from study subjects will be compared to age-matched controls. 2. Hypothesis: patients with diminished visual function will have diminished NFL thickness compared to patients with normal visual acuity, contrast, and fields. Comparison: total and quadrantic/temporal retinal nerve fiber layer (RNF L) measurements from patients with visual acuity _<_20/40, and 520/200 will be compared to subjects with visual acuity 320/20 and >20/40. 3. Hypothesis: retinal ganglion cell layer loss will be present as assessed by OCT macular imaging (thickness and volume) in patients within the LONS cohort compared to age-matched controls. 135 4. Hypothesis: OCT regions of diminished NFL will correlate with visual function (most notably visual field defects). Comparison: total and temporal retinal nerve fiber layer (RNF L) measurements will be related to visual acuity, contrast sensitivity, Humphrey MD and visual field patterns. 5. Hypothesis: OCT nerve fiber layer measurements will be worse in patients with a diagnosis of MS compared to those without a diagnosis of MS. Comparison: total and quadrantic retinal nerve fiber layer (RNF L) measurements from patients with and without a diagnosis of MS will be compared. 6. Hypothesis: there will be a correlation between worse Expanded Disability Status Score (EDSS) and diminished nerve fiber layer as assessed by optical coherence tomography (OCT). Comparison: total and quadrantic retinal nerve fiber layer measurements will be correlated to EDSS scores. 7. Hypothesis: thinning of the retinal NFL will correlate with baseline and follow up MRI results; greater thinning will be present in patients with abnormal baseline and follow up MRI scans. Comparison: total and quadrantic retinal nerve fiber layer measurements will be compared between subjects with abnormal baseline MRI scans and normal baseline MRI scans. Total and quadrantic retinal nerve fiber layer measurements 136 will be compared between subjects with abnormal baseline or follow up MRI versus those with normal baseline and follow up MRI. 8. Hypothesis: Retinal NFL thinning will be greater in those subjects with worse National Eye Institute Visual Functioning Questionnaire (NEI VFQ25) scores. Comparison: NEI VFQ25 in subjects with normal RNFL thickness compared to NEI VFQ25 score in subjects with abnormal RNF L thickness. LONS 15-year OCT: Background & significance Our knowledge of multiple sclerosis (MS) has significantly increased over the last 20 years, in large part related to the advent and availability of magnetic resonance imaging (MRI). The most readily apparent and commonly used features of MS change on MRI are T2 hyperintensities within the white matter. Nonetheless, MRI T2 hyperintensities have only modest correlation with clinical measures of interest, such as scales of MS-related disability [Schreiber et al. 2001], which remain the gold standard impact measure of disease. MS is not only inflammatory demyelination, but also a disease of axons [Trapp et al, 1998]. Cerebral white matter consists predominantly of axons (46%) followed by myelin (24%), then glial cells (17%), and blood vessels 8. fluid (13%) [Adams, 1989]. Atrophy implies loss of these structures, especially axons. Indeed, magnetic resonance imaging (MRI) measures of axonal loss, such as atrophy, 137 correlate better with MS-related disability than the more apparent T2 hyperintensities [Kalkers NF et al. 2001]. Optic neuritis is the presenting symptom in approximately 15-20% of MS cases, and a common clinical condition during the disease course [Paty & Ebers, 1998; Miller et al, 2005]. Over 50% of clinically definite MS patients have evidence of optic nerve dysfunction [Davis & Rizzo, 1998]. The optic nerve is an excellent microcosm of MS because it is commonly affected by the disease, has quantifiable measures of function, has both axons and myelin in known distribution patterns, and portions of the nerve are readily visible. Optical coherence tomography (OCT) is a direct, non-invasive method to measure anatomic features of tissues. OCT utilizes echo time delay, backscatter and back-reflected light related to tissue microstructure in a manner analogous to the use of sound in ultrasound B-mode imaging [Schuman et al, 2004]. The technique is especially well suited for tissue with high light penetration, like the eye. Using standard protocols such as the 3.4 mm circumpapillary scan, OCT can quantify the thickness of the peripapillary nerve fiber layer. The scan can be preformed in undilated eyes, uses infrared light (800 nm wavelength) at very low power (<1 milliwatt) assuring safety, and is acquired in seconds, enhancing tolerability and minimizing motion artifact. Although MRI is an excellent tool to investigate MS, it is a lengthy and expensive exam, contraindicated or difficult in certain patients, and primarily highlights inflammatory-based lesions, which have 138 only modest correlation with disability. OCT has the potential to be a rapid, non- invasive, inexpensive surrogate marker of axonal loss in multiple sclerosis. The LONS 15-year follow up when is a superb population to investigate the relationship of retinal nerve fiber layer parameters in optic neuritis. The cohort is large and well-characterized, has historic MRI and clinical data, and provides “real-time” EDSS scores and visual function, affording an ideal opportunity to study the long term of optic neuritis on the nerve fiber layer [ONSG, 1997]. LONS 15-year OCT_Preliminary studies Although no large long-term study of optic neuritis and OCT has been published, there are a few studies investigating the short term relationship between OCT and optic neuritis, attest to reliability of measurements, and document usefulness in other optic nerve disorders. The reliability of OCT in assessing retinal NFL thickness was investigated by several groups [Carpineto et al, 2003; Paunescu et al, 2004]. Carpineto et al. prospectively studied 24 subjects with glaucoma and 24 age- and gender-matched controls using 5 repetitions of OCT performed within 0.5 months. The OCT provided reproducible and reliable measurements within both the normal and glaucomatous populations [Carpineto et al, 2003]. OCT has a longer experience with subjects with glaucoma. Several authors have documented the usefulness and reliability of OCT in detecting early NFL loss in this population, and the general correlation between NFL thickness and the presence of glaucoma [Kanamori et al, 2003; Guedes et al, 2003]. 139 Paresi et al investigated 14 patients with MS and optic neuritis using OCT. This group reported a significant decrease in retinal NFL (overall and temporal values) compared to control eyes. The NFL overall and NFL temporal values were significantly correlated with the VEP (P50 and N95 amplitude with 15 minute check size) and pattern ERG (P50 latency) measurements in these eyes. Despite VEP delays in the affected eyes, there was no correlation between this measure and retinal NFL thickness, perhaps due to low patient numbers [Paresis et al, 1999]. Costello and colleagues presented a series of 66 patients with acute unilateral optic neuritis assessed by OCT. Among this cohort, approximately 73% demonstrated significant thinning 3 or more months after the acute optic neuritis event of the retinal nerve fiber layer as assessed by 3.4 mm circumpapillary OCT. Thinning of the retinal NFL occurred 3 - 6 months after the acute episode of optic neuritis. OCT testing also detected RNFL loss which correlated with sub- clinical optic neuritis among 4 patients in this cohort within a year of follow up, highlighting the potential of OCT to detect subtle changes. The 11 patients with more extensive visual loss and poor recovery demonstrated more severe retinal NFL loss [Costello et al, 2005]. Trip et al reported on OCT findings in 25 optic neuritis patients with a selection bias toward incomplete visual recovery. The average time from optic neuritis onset and OCT imaging was 3 years. These authors found significant reductions 140 in retinal nerve fiber layer thickness and macular volumes in the affected eyes of patients compared with the fellow unaffected eye and compared with control data, including relationship between OCT findings and acuity visual field, color and visual evoked potential amplitude [Trip et al, 2005]. Retinal nerve fiber layer thickness was reduced 33% while macular volume was reduced 11% compared to control data. The VEP latency was not associated with OCT findings, suggesting the distinction between demyelination and axonal loss in this disease. This population is not representative of the Optic neuritis population as a whole due to the stated selection bias, but this data provides further evidence of OCT correlation with visual function and adds a macular correlate. LONS 15-year OCT_Research design 8. methods The Longitudinal Optic Neuritis Study (LONS) is the follow up cohort of patients originally recruited into the Optic Neuritis Treatment Trial (ONTT) from 1988 to 1991. Subjects with optic neuritis onset 58 days were randomized to receive IV methylprednisolone, PO prednisone, or placebo. Long-term visual function was not different according to treatment group; however, PO prednisone therapy was associated with a higher recurrence rate of optic neuritis compared to the other groups. The LONS includes approximately 328 patients eligible for 15-year follow up commencing February 2006. LONS 15-year follow up exams include a medical history, ophthalmologic examination (with visual acuity, Polly-Robson contrast sensitivity, and 30-2 full 141 threshold Humphrey perimetry). neurologic examinations (with EDSS), and the NEI VFQ25. All participating clinics within the LONS have access to OCT, and under this proposal, OCT will be performed on all patients within the LONS as part of 15-year clinical follow up. ' OCT Protocol: A standard 3.4 mm circumpapillary scan and radial macular scan (6 line) utilizing the Stratus OCT 3 (version 4) will be used to collect data on right and left eyes in dilated LONS 15-year follow up subjects. Figure 3. 0 20 40 60 80 100 120 140 160 180 200 220 240 TEMP SLP NAS NF TEMP Figure 3. OCT printout of a patient several years status post optic neuritis right eye demonstrates nerve fiber layer loss preferentially affecting the temporal aspect of the nerve. The top figure is a linear tracing of the nerve fiber layer thickness demonstrating decline below age and gender-matched controls in the temporal portion; the bottom circular depiction demonstrates the nerve as it appears per fundus view with the temporal section labeled “T” measuring 42-micron thickness 142 Quality assurance: data from readouts with signal-to-noise ratio <30 and acceptable A-scan percent 3 95% will be accepted for analysis. Data collection: the standard print out from the OCT 3.4 mm circumpapillary and macular scans will be sent to and housed at the LONS OCT reading center at the University of Iowa (Dr. Randy Kardon) and at Michigan State University (Dr. Eric Eggenberger). OCT parameters of interest include retinal nerve fiber layer thickness (sectoral average, quadrant average and total average nerve fiber layer thickness), and macular thickness and volume. Data collection is currently undenrvay with the participation of 14l15 centers. 143 Chapter 7: CONCLUSIONS AND DIRECTIONS FOR FUTURE RESEARCH The Optic Neuritis Treatment Trial and the Longitudinal Optic neuritis Study investigated the effects of corticosteroid treatment on optic nerve recovery, and the relationship of optic neuritis to MS. The trials found that the speed of visual recovery was enhanced by a course of intravenous methylprednisolone as compared to placebo or oral prednisone alone, although the final visual outcome was equivalent across the treatment groups. The trials also demonstrated that oral prednisone alone was associated with an increased rate of recurrent optic neuritis as compared to placebo, findings that in large part help define the American Academy of Neurology Practice Parameter statement concerning treatment of optic neuritis. The ONTT and LONS further defined the risk of MS after an isolated episode of optic neuritis in relationship to the baseline MRI features; at 5 years, a normal MRI is associated with a 16% chance of MS, while a baseline MRI with at least 3 MRI T2 lesions was associated with a 56% chance of MS. The ONTT and LONS suffer from some limitations inherent to randomized controlled trials, which include strict inclusion criteria that may not always be generalizable to the average clinician’s population. The Controlled High risk Avonex Multiple Sclerosis Study (CHAMPS) built upon these results by randomizing patients with a clinically isolated syndrome such as optic neuritis and a high risk MRI to early interferon therapy or placebo. This trial demonstrated the value of early interferon institution in this high-risk population establishing a new treatment paradigm in MS. This study has the randomized, 144 controlled trial-related limitations as noted above; in addition, not all patients with a high risk MRI will develop MS, and the trial does not address further stratifying the MS risk in these patients. Combination trials and novel imaging are the current research avenues resulting from this prior research. The SENTINEL add-on natalizumab trial produced great hope because of the dramatic effects (demonstrating a larger magnitude of effect on relapse rates than currently available therapies), but also re-emphasized the complexity of the immune system and the potential dangers of combination therapies. Other combination trials such as the ACT study (Avonex Combination Trial randomizing patients on interferon to serial methylprednisolone, methotrexate or both), the Combin (interferon and/or glatiramer) are currently ongoing. This line of research and other similar combination trials will continue because of the relatively modest effect of current MS therapies in the face of the progressive and often devastating effects of MS. Lastly, we have initiated an optical coherence tomography (OCT) study in optic neuritis utilizing the LONS cohort. The aims of this study include an assessment of the correlation between optic nerve axonal loss and MRI, disability, and visual parameters. The future directions of our research will continue to exploit the quantifiable linkage between neuro-ophthalmology and MS. The LONS cohort will remain 145 under active study. Combination trials remain under active investigation. The application of imaging technology including MRI and other non-invasive means such as OCT to these clinical issues will continue to produce practice altering information and further lines of inquiry into disease pathophysiology and therapeutics. Future studies utilizing modalities such as OCT are in the formulation stages presently. The implications and relationship of these studies for current and future research on the epidemiology of MS and associated optic nerve disturbances is complex. Epidemiologic studies will remain an important component of MS research and relate to clinical studies in several ways. The natural history of MS is quite variable, but crucial to understand as more complex therapeutic trials are initiated. The ability to predict which subgroup of patients will follow a more aggressive course is of critical importance; our knowledge and ability to prognosticate will be derived from epidemiologic, genetic, immunologic, clinical and imaging-based research. In addition, these approaches will likely continue to shed light on the pathophysiology of MS, pushing us closer to a cure. 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