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Background and ObjectivesTo test the hypothesis that CT hypoperfusion-hypodensity mismatch identifies patients with ischemic stroke within 4.5 hours of symptom onset.MethodsWe therefore performed the Retrospective Multicenter Hypoperfusion-Hypodensity Mismatch for The identification of Patients With Stroke Within 4.5 Hours study of patients with acute ischemic stroke and known time of symptom onset. The predictive values of hypoperfusion-hypodensity mismatch for the identification of patients with symptom onset within 4.5 hours were the main outcome measure.ResultsOf 666 patients, 548 (82.3%) had multimodal CT within 4.5 hours and 118 (17.7%) beyond 4.5 hours. Hypoperfusion-hypodensity mismatch was visible in 516 (94.2%) patients with symptom onset within and in 30 (25.4%) patients beyond 4.5 hours. CT hypoperfusion-hypodensity mismatch identified patients within 4.5 hours of stroke onset with 94.2% (95% confidence interval [CI] 91.9%–95.8%) sensitivity, 74.6% (95% CI 66.0%–81.6%) specificity, 94.5% (95% CI 92.3%–96.1%) positive predictive value, and 73.3% (95% CI 64.8%–80.4%) negative predictive value. Interobserver agreement for hypoperfusion-hypodensity mismatch was substantial (κ = 0.61, 95% CI 0.53–0.69).DiscussionPatients with acute ischemic stroke with absence of a hypodensity on native CT (NCCT) within the hypoperfused core lesion on perfusion CT (hypoperfusion-hypodensity mismatch) are likely to be within the time window of thrombolysis. Applying this method may guide the decision to use thrombolysis in patients with unknown time of stroke onset.Trial Registration InformationClinicalTrials.gov Identifier: NCT04277728.Classification of EvidenceThis study provides Class III evidence that CT hypoperfusion-hypodensity mismatch identifies patients with stroke within 4.5 hours of onset.

Alemtuzumab is a humanized monoclonal antibody that causes a rapid but long-lasting depletion of the CD52-bearing lymphoid lineage. Selective pulsed depletion is followed by a complex pattern of immune cell reconstitution that reflects the reshaping and potential reprogramming of immune networks, including the development of tolerance.1 Recent studies showed that pulsed-immune reconstitution therapy with alemtuzumab can produce durable efficacy after 2 courses of treatment (year 1 and 2).2–5

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) have developed tremendously over the last 2 decades. Currently, more than 16 different products targeting various immunologic components have been approved for MS treatment in several countries. The authors thank Heike Blum for drawing the figure and Nick Fulcher for language editing.

On behalf of all authors, we would like to thank Mr. Tugemann for his interest in our article.1 It is correct that acute progressive multifocal leukoencephalopathy (PML) can, in some circumstances, lead to high(er) CD62L values. However, as the study was conducted prospectively and, more importantly, alongside treatment, we reported all results of samples shipped to us back to the treating physicians. At the time of measurement and reporting, we were not aware of the patients' disease state. Because this is the situation to be expected in postmarketing settings, we chose to report all measured values, even if the samples turned out to be less than 6 months before PML diagnosis. Although the exclusion of these samples would indeed have led to a perfect sensitivity with the threshold of 36.05, we believed that it would not accurately reflect the real-world situation. Similarly, we chose not to focus on other PML risk stratification factors such as previous immune suppression or anti-JC virus antibody serostatus because we could not rely on having this information for all samples shipped to us. We, therefore, decided to report on the feasibility of measuring one biomarker rather than presenting a holistic approach for risk stratification using all available markers, which was addressed before.2 As supported by this study, CD62L was proven to be a useful biomarker for PML risk stratification also in the real-world setting but could also help with monitoring immunologic changes because of natalizumab-extended interval dosing. Owing to its initial detection in a retrospective cohort, the validated methodology3 still requires a mandatory freeze/thaw cycle, thereby limiting its widespread use. However, we would be more than happy if methodological improvements could be achieved here.

ObjectiveTo report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab.MethodsRetrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells.ResultsWe describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8+ T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8+ T cells with an activated (human leukocyte antigen–DR+), memory (CD45RO+), and type 1 cytokine (interferon-γ + tumor necrosis factor–α) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time.ConclusionThe 3 cases represent a detailed description of vitiligo as a T-cell-mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms.

Objective: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod. Methods: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24. Results: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n 5 41/50; 12 weeks, n 5 31/42; 16 weeks, n 5 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7–2.6]) and 12-week WO groups (1.7 [1.3– 2.2]) and higher in the 16-week WO group (8.2 [7.3–9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2–0.6]; 12 weeks, 2.1 [1.6–2.6]; 16 weeks, 3.6 [3.0–4.2]). Over the 24 weeks from LNI, gadoliniumenhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67–22.53]) than in the 12-week (21.3 [1.41–41.19]) or 16-week (18.5 [8.40–28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred. Conclusions: Initiating fingolimod therapy 8–12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO. Classification of evidence: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods. Neurology® 2015;85:1–11

To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment.Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18-80 months), 21 received other immune-modulatory treatments, and 28 were untreated. We had access to samples from 16 natalizumab PML patients. Eight of these patients had given blood before the diagnosis of PML. We also analyzed non-natalizumab-treated patients who developed PML (n = 10) and age- and sex-matched healthy donors (n = 31). All flow cytometric assessments were done on previously cryopreserved, viable peripheral blood mononuclear cells.The percentage of l-selectin-expressing CD4+ T cells was significantly lower in patients treated long-term with natalizumab (40.2%) when compared with patients not receiving natalizumab treatment (47.2%; p = 0.016) or healthy controls (61.0%; p

Progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment continues to be a severe problem of clinically successful therapy. This is an update of risk stratification developments and discusses the current approach to depict and calculate PML incidence and PML risk. (1) PML incidence and resulting risk used in today's clinical practice are potentially outdated and the risk for patients with prior immunosuppression might have been underestimated. (2) Risk stratification according to treatment duration epochs likely suggests lower risk due to patients stopping treatment within a given epoch. PML incidence within the complete treatment epoch is statistically lowered due to the fact that patients at the beginning of an epoch presumably have a lower PML risk than the patients at the end. Periodic risk is not accurate in assessing risk for long treatment durations. (3) The JC virus (JCV) serostatus risk factor has low specificity concerning PML prediction and anti-JCV seroconversion during treatment with natalizumab further lowers its specificity over time. Specificity of the risk factor treatment duration varies depending on the average treatment duration and the number of short-term patients. These short-term patients reduce overall average treatment duration and thus enhance the specificity of the risk factor and reduce overall PML incidence. It is also suggested that short-term natalizumab patients are exclusively non-PML, even though they might still develop PML. Clinicians have to consider the cumulative risk of patients to stratify efficiently.

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2 inflammatory,3 or vascular4 stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes. Acknowledgment: The authors thank Florence Umuhoza, Lise Scandella, and Sarah Exbrayat for technical assistance and the patients for participation in the study.

Objective: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease. Methods: We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies. Results: In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients9 peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve-infiltrating CD8+ T-cell clones was visualized by immunohistochemistry. Conclusions: Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP.

Alemtuzumab is an effective therapeutic option for patients with active forms of relapsing-remitting multiple sclerosis (RRMS).1 The adverse event profile comprises an increased risk for the development of secondary autoimmune disorders as well as infusion-associated reactions. Alemtuzumab infusion is often associated with an acute cytokine release syndrome.2 Among other side effects, patients may experience headache, rash, pyrexia, and to a lesser extent hypotension, cardiac arrhythmia, and rarely anaphylactic shock. These symptoms are usually limited to the first days of infusion and do not lead to sustained impairment.1

Editors' Note: Commenting on “Natalizumab-related PML 2 weeks after negative anti-JCV antibody assay” Ontaneda and Fox suggest, backed by analysis of progressive multifocal leukoencephalopathy (PML) cases with fingolimod and dimethyl fumarate, that age is a potential risk for PML in patients with multiple sclerosis (MS) and that age should be assessed as a risk stratifier for PML with MS therapies. Gagne Brosseau et al., authors of the initial report, agree and give additional clarification regarding the relation between age and JC virus. Schwab et al. disagree with “CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients,” pointing to how tested samples appear to be compromised and how the assay was changed from published protocols. Cahir-McFarland et al., authors of the study, explain why CD62L is not a reliable biomarker for PML risk, why the assay was changed, and that the samples were not compromised but reflect the differences between CD62L count in healthy volunteers vs patients with MS or natalizumab-treated patients. —Chafic Karam, MD, and Robert C. Griggs, MD Cells for the study …

Rasmussen encephalitis (RE) is characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable seizures. Inflammatory lesions consist of oligoclonally expanded cytotoxic CD8+ T cells attacking neurons and astrocytes.1 Immunotherapies may slow down tissue and function loss, whereas convincing effects on seizure activity have rarely been reported.2 Functional hemispherectomy (HE) is highly effective for elimination of seizures but can only be offered if no indispensable function resides in the affected hemisphere.1 We present a patient with such an HE contraindication who was treated with natalizumab, a blocker of T-cell entry into the CNS. Acknowledgment: The authors thank O. Grauer and C. Gross for supervision of the flow cytometric experiments.

Objective: To investigate the rate of seropositivity of anti-JC virus (JCV) antibodies in a German multiple sclerosis (MS) cohort treated with natalizumab in the postmarketing setting and to assess anti-JCV serostatus in samples obtained before diagnosis of progressive multifocal leukoencephalopathy (PML). Methods: This was a blinded, retrospective cross-sectional and longitudinal analysis for anti-JCV antibodies using a confirmatory 2-step ELISA on 2,782 blood samples obtained from 2,253 patients nationwide for routine testing for anti-natalizumab antibodies during open-label treatment between 2007 and 2010. Results: Of the natalizumab-treated patients with MS, 58.8% tested positive for anti-JCV antibodies. The rate of seropositivity was higher in males and increased with age, with a plateau between age intervals 20–29 and 30–39 years. In longitudinal analyses, 19 of 194 (9.8%) patients converted from anti-JCV antibody-negative to seropositive status over 7.7 months; 4.7% reverted from antibody-positive to seronegative status over 7.9 months. Antibody levels, especially in the latter group, were low, indicating fluctuations around the lower cut point of the assay. Neither anti-JCV serostatus nor antibody levels were associated with immunosuppressive pretreatment, duration of natalizumab treatment, or anti-natalizumab antibodies. All samples obtained from 10 patients who developed PML were seropositive (13 samples before PML diagnosis [2.0–37.6 months]; 2 samples at diagnosis). Antibody levels in these samples were higher than those in samples from seropositive patients who did not develop PML. Conclusions: These data argue for the potential clinical utility of JCV serology for PML risk stratification. However, further investigations of fluctuations in serostatus and of antibody levels for a more precise understanding of the predictive value are warranted.

Interferon β (IFNβ) is an approved immunomodulatory treatment of multiple sclerosis (MS). However, treatment with type I interferons may induce autoimmune diseases.1 This has mainly been shown for interferon α, but is not uncommon for IFNβ. Published results on humoral organ autoimmunity in IFNβ-treated patients with MS are not unequivocal at present.2,3 We therefore measured autoantibodies (AAbs) against major thyroid (thyroperoxidase [TPO] and thyroglobulin [Tg]) and pancreatic β-cell (glutamic acid decarboxylase [GAD65]) autoantigens in a large cohort of patients with MS treated with IFNβ or IFNβ treatment naive. In the former, the presence of IFNβ neutralizing antibody (NABs) was correlated to AAbs seropositivity, as NABs may be an indicator of an activated humoral immune response. ### Methods. AAbs were determined by commercial radioligand assays against GAD65 (Medipan, Leipzig, Germany) and against TPO and Tg (BRAHMS, Hennigsdorf, Germany) with predefined cutoff levels (table) in 209 IFNβ-treated patients with MS and an age- and sex-matched control group of 57 IFNβ-naive patients with MS. In the treated patients, presence of NABs was assessed by capture ELISA and ex vivo MxA real time rtPCR 12 hours after administration of IFNβ as described previously.4 Briefly, detection of binding antibodies by ELISA and demonstration of inhibition of MxA mRNA induction in peripheral blood lymphocytes at least once deemed a sample NAB positive. Statistical tests were performed using GraphPad Prism 4.0. View this table: Table Demographics (upper part) and autoantibody results (lower part) in …

Eight patients with Rasmussen's encephalitis, 40 patients with noninflammatory focal epilepsy, 104 patients with various neurologic diseases, and 16 healthy donors were tested for the prevalence of antibodies against the GluR3 receptor in serum and CSF. Reactivities against different peptides derived from various portions of this glutamate receptor subtype were detectable in a significantly higher number of patients with focal epilepsy than in those with other neurologic diseases, but they were not specific for the diagnosis of Rasmussen's encephalitis.

Pregnancy in multiple sclerosis (MS) has been controversial. For years women with MS were discouraged from considering pregnancy.1,2 The Pregnancy in Multiple Sclerosis (PRIMS) study in Europe provided the first robust data on the influence of pregnancy and delivery on the clinical course of MS.3 It demonstrated a decline in relapse rate during pregnancy, most marked in the third trimester, with a rebound increase in the first 3 months postpartum. Breastfeeding did not show any specific effect on the clinical course after delivery. A 2-year postpartum follow-up of the PRIMS patient cohort corroborated these findings.4 These results changed the prevailing view on the general risk of pregnancy in women with MS. It is now generally accepted that pregnancy per se cannot be regarded as a risk factor in patients with MS.5 That breastfeeding has no impact on clinical relapse activity postpartum was recently challenged by a prospective cohort study conducted by Langer-Gould and colleagues6 in California. They reported that women with MS who breastfed exclusively for the first 2 months postpartum were approximately one-fifth …

Natalizumab (Tysabri®, Biogen Idec Inc., Cambridge, MA) is a recombinant humanized monoclonal antibody that binds to the α4 chain of the integrin very late activation antigen (VLA)-4 and to α4β7 integrin. It was designed to diminish the adherence of activated leukocytes to biologic membranes and their subsequent migration into peripheral tissues, including the brain and the spinal cord. The clinical effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (MS) was evaluated in 2 phase 3 clinical trials (the AFFIRM monotherapy trial1 and the SENTINEL add-on trial with interferon beta-1a [Avonex®, Biogen Idec Inc.]2). In the United States, the Food and Drug Administration first approved natalizumab on November 24, 2004, for the treatment of relapsing forms of MS. Only 3 months later, the manufacturers of natalizumab announced its voluntary withdrawal after 2 patients with MS and 1 patient with Crohn disease who had received natalizumab in clinical trials were diagnosed with progressive multifocal leukoencephalopathy (PML).3–5 PML, a brain demyelinating disorder caused by the human polyomavirus JC, is almost exclusively diagnosed in individuals who experience severe and prolonged immunosuppression. The occurrence of PML in patients with MS treated with natalizumab was unexpected to many because there …

Objective: Evaluate long-term safety, efficacy, and associations between baseline treatment history and postbaseline annualized relapse rate (ARR) in multiple sclerosis (MS) patients treated with natalizumab. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) study is an open-label, multinational, observational study assessing long-term outcomes in relapsing-remitting MS patients in the postmarketing setting in Europe, Australia, and Canada. Design/Methods: As of June 2011, 3484 patients from 15 countries were enrolled. Incidence of serious adverse events (SAEs) was analyzed. ARR and Expanded Disability Status Scale (EDSS) scores were assessed. Associations between baseline therapy and postbaseline ARR were analyzed using negative binomial regression for 5 baseline groups: therapy naive (n=337), interferon (IFN) only (n=1626), glatiramer acetate (GA) only (n=288), switched between GA and IFN in either order (n=595), or immunosuppressant (IS) use (n=487). Results: - 53]) natalizumab infusions. Overall, 5.1% of patients experienced ≥1 SAE; infections (1.1%) and hypersensitivity reactions (0.7%) were most frequent. Seven cases of progressive multifocal leukoencephalopathy (PML) occurred after 35, 29, 28, 26, 24, 24, and 12 natalizumab infusions. Three of them were previously exposed to mitoxantrone. Overall, the mean EDSS score was 3.5 at baseline and 3.4 after 3 years. ARR was significantly decreased regardless of baseline treatment history; mean ARR decreased (n=3458) from baseline (1.98) to postbaseline (0.28; P Conclusions: The overall incidence and type of SAEs reported in TOP are consistent with natalizumab9s known safety profile. EDSS scores were stable and ARR was significantly reduced after 3 years of natalizumab therapy. ARRs were lowest in therapy-naive patients and highest in patients with prior IS. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.

Objective: Evaluate geographic region, enrollment time, baseline characteristics, postbaseline efficacy, and safety in natalizumab-treated multiple sclerosis (MS) patients with and without prior treatment. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) assesses long-term outcomes in natalizumab-treated patients with relapsing-remitting MS in Europe, Australia, and Canada. Design/Methods: Baseline characteristics of treatment-naive and previously treated patients were compared. The association between prior treatment status and postbaseline annualized relapse rates (ARRs) was examined using a negative binomial regression model. Time to improvement on the Expanded Disability Status Scale (EDSS) was analyzed using a Cox proportional hazards model. Serious adverse events (SAEs) were compared using a Pearson chi-square or Fisher exact test. Results: As of June 1, 2011, 337 of 3484 natalizumab-treated patients (10%) had been treatment naive before natalizumab treatment. Proportions of treatment-naive patients varied significantly by country (Slovakia, 0%; Great Britain, 36%) and time since enrollment (0–12 months, 12%; 13–24 months, 7%; >24 months, 9%). Baseline differences between treatment-naive and previously treated patients included mean age (35.8 vs 37.6 years), median disease duration (1.9 vs 7.8 years), and median EDSS score (3.0 vs 3.5) (all P ≤0.013). Treatment-naive patients had a lower postbaseline ARR (0.18 vs 0.26; P =0.002) and were more likely to show improvement in EDSS at 3 years (HR [95% confidence interval]=1.59 [1.14–2.22]; P =0.007). Treatment-naive and previously treated groups did not significantly differ in incidence of SAEs (4.2% vs 5.2%; P =0.340), infection-related SAEs (0.9% vs 1.2%; P =0.640), or progressive multifocal leukoencephalopathy (0.0% vs 0.2%; P =1.00). Conclusions: Treatment-naive patients were younger than previously treated patients, had shorter disease duration and lower baseline EDSS, were more likely to show EDSS improvement, and differed significantly in geographic distribution and enrollment time. While relapses decreased in both groups, postbaseline ARR was significantly lower in treatment-naive patient, whereas SAE incidence was similar. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.