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Background and Objectives:Rituximab is used widely for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG associated disease (MOGAD), however data regarding the effectiveness and safety of long-term rituximab use in these conditions are limited. In this study we sought to evaluate long-term clinical outcomes in patients with aquaporin-4 IgG seropositive (AQP4-IgG+) NMOSD and MOGAD treated with rituximab.Methods:We performed a retrospective chart review of patients with AQP4-IgG+ NMOSD or MOGAD followed at the Johns Hopkins Neuromyelitis Optica Clinic and included patients who had received at least one dose of rituximab.Results:We identified 111 NMOSD and 23 MOGAD patients who fulfilled inclusion criteria. Median duration of rituximab treatment for the NMOSD patients was 3.7 years (range:0.5 to 13.2) and for the MOGAD patients was 2.1 years (range:0.5 to 7.0). The annualized relapse rate (ARR) decreased after rituximab initiation in both NMOSD (median ARR:pre-treatment 1.1, post-treatment 0; pConclusions:Rituximab treatment is associated with reduced annualized relapse rate in AQP4-IgG seropositive NMOSD, especially in the absence of gaps in treatment and/or B cell reconstitution. In MOGAD, while a reduction in relapses was observed after initiation of rituximab, this association appeared to be less robust than in AQP4-IgG seropositive NMOSD. Severe infections and hypogammaglobulinemia occurred in a significant proportion of patients, highlighting the need for close monitoring of infectious complications.Classification of Evidence:This study provides Class IV evidence that rituximab decreases the annualized relapse rate in AQP4-IgG seropositive NMOSD and MOGAD.

ObjectiveTo evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later.MethodsIn this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was ResultsA total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness p = 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40–6.13; p = 0.04).ConclusionsLower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS.Classification of EvidenceThis study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.

Objectives To explore in vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with multiple sclerosis (MS) using [18F]-DPA714 PET and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening. Methods Thirty-seven patients with MS and 19 healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3-mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening. Results The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p = 6.10e-6) and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p = 0.001). This gradient was found in both periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs = −0.65, p = 1.0e-3). Compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p = 0.025). Conclusions Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and is associated with microstructural damage and disability worsening. This could result from the diffusion of proinflammatory CSF-derived factors into surrounding tissues.

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

ObjectiveTo evaluate whether structural and functional changes occur in the afferent visual system of patients with stiff-person syndrome (SPS) and whether these changes correlate with disease burden, given the high concentration of γ-aminobutyric acid receptors, which are generally thought to be involved in SPS pathogenesis, in the retina.MethodsIn this single-center, cross-sectional study, patients with SPS and healthy controls (HCs) underwent optical coherence tomography (OCT), with a subset undergoing high- and low-contrast visual acuity (VA) assessments. Burden of disease was assessed via the number of body regions affected. Individuals with uncontrolled hypertension or comorbid neurologic or ophthalmologic disorders were excluded. Statistical analyses were performed using mixed-effects linear regression models.ResultsThirty-five patients with SPS and 40 age- and sex-matched HCs underwent OCT. A subset of 23 patients with SPS and 28 HCs underwent VA assessments. Relative to HCs, patients with SPS had lower ganglion cell + inner plexiform layer (GCIPL) thicknesses (SPS: 74.36 µm [SD 5.7]; HCs: 76.33 µm [SD 4.2]; p = 0.005), inner nuclear layer thicknesses (SPS: 44.37 µm [SD 2.7]; HCs: 45.18 µm [SD 2.2]; p = 0.042), and 100% (SPS: 53 [SD 9.6]; HCs: 57.5 [SD 6.1]; p = 0.005), 2.5% (SPS: 24.35 [SD 10.1]; HCs: 30.16 [SD 7.7]; p = 0.006), and 1.25% contrast (SPS: 16.41 [SD 10.6]; HCs: 20.84 [SD 8.6]; p = 0.034) letter acuity scores. GCIPL thicknesses correlated with the number of body regions affected in SPS (decrease of 1.25 µm [95% confidence interval, −2.2 to −0.3 µm; p = 0.008] per additional body region affected).ConclusionsRetinal neuronal pathology can occur in SPS. OCT may have utility as a biomarker of disease burden in SPS.

Objective: To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results.Methods: A panel of experienced OCT researchers (including 11 neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group.Results: We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis.Conclusions: The Advised Protocol for OCT Study Terminology and Elements recommendations include core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will make reporting of quantitative OCT studies more consistent and in line with existing standards for reporting research in other biomedical areas. The recommendations originated from expert consensus and thus represent Class IV evidence. They will need to be regularly adjusted according to new insights and practices.

Objective: To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS). Methods: In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months. Results: Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0–44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0–13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17 + CD4 + T cells ( p = 0.016), CD161 + CD4 + T cells ( p = 0.03), and effector memory CD4 + T cells ( p = 0.021) with a concomitant increase in the proportion of central memory CD4 + T cells ( p = 0.018) and naive CD4 + T cells ( p = 0.04). These effects were not observed in the low-dose group. Conclusions: Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4 + T cells and decreased proportion of effector memory CD4 + T cells with concomitant increase in central memory CD4 + T cells and naive CD4 + T cells. Classification of evidence: This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.

Objective: To assess relationships between spinal cord MRI (SC-MRI) and retinal measures, and to evaluate whether these measures independently relate to clinical disability in multiple sclerosis (MS). Methods: One hundred two patients with MS and 11 healthy controls underwent 3-tesla brain and cervical SC-MRI, which included standard T1- and T2-based sequences and diffusion-tensor and magnetization-transfer imaging, and optical coherence tomography with automated segmentation. Clinical assessments included visual acuity (VA), Expanded Disability Status Scale, MS functional composite, vibration sensation threshold, and hip-flexion strength. Regions of interest circumscribing SC cross-sections at C3-4 were used to obtain cross-sectional area (CSA), fractional anisotropy (FA), perpendicular diffusivity (λ ⊥ ), and magnetization transfer ratio. Multivariable regression assessed group differences and SC, retinal, and clinical relationships. Results: In MS, there were correlations between SC-CSA, SC-FA, SC-λ ⊥ , and peripapillary retinal nerve fiber layer (pRNFL) ( p = 0.01, p = 0.002, p = 0.001, respectively) after adjusting for age, sex, prior optic neuritis, and brain atrophy. In multivariable clinical models, when SC-CSA, pRNFL, and brain atrophy were included simultaneously, SC-CSA and pRNFL retained independent relationships with low-contrast VA ( p = 0.04, p = 0.002, respectively), high-contrast VA ( p = 0.06, p = 0.008), and vibration sensation threshold ( p = 0.01, p = 0.05). SC-CSA alone retained independent relationships with Expanded Disability Status Scale ( p = 0.001), hip-flexion strength ( p = 0.001), and MS functional composite ( p = 0.004). Conclusions: In this cross-sectional study of patients with MS, correlations exist between SC-MRI and retinal layers, and both exhibit independent relationships with clinical dysfunction. These findings suggest that the SC and optic nerve reflect ongoing global pathologic processes that supplement measures of whole-brain atrophy, highlighting the importance of combining measures from unique compartments to facilitate a thorough examination of regional and global disease processes that contribute to clinical disability in MS.

The diagnosis of multiple sclerosis (MS), while often straightforward, may be complex. Tension exists between the desire to make an early diagnosis and the imperative to avoid an inaccurate decision. Prompt, correct diagnosis is important because of increasing evidence that early institution of disease-modifying treatment leads to better outcomes. In this issue of Neurology ®, Cortese et al.1 provide evidence that the central vein sign (CVS), as demonstrated on 3T brain MRI, accurately distinguishes patients with MS from those with seropositive neuromyelitis optica spectrum disorder (NMOSD).

Objective:To assess eyes with neuromyelitis optica (NMO) for morphologic retinal abnormalities utilizing high-definition optical coherence tomography (OCT) imaging.Methods:In this cross-sectional study, 39 patients with NMO spectrum disorders and 39 age- and sex-matched healthy controls underwent spectral-domain OCT and visual function testing.Results:Microcystic macular edema (MME) of the inner nuclear layer (INL) was identified in 10 of 39 patients (26%) and was exclusively found in eyes with a history of optic neuritis (ON). MME eyes had lower high- and low-contrast letter-acuity scores (100%: p = 0.002; 2.5%: p = 0.002; 1.25%: p = 0.004), lower peripapillary retinal nerve fiber layer (RNFL) thickness (p = 0.04), lower macular RNFL thickness (p = 0.004), lower ganglion cell layer + inner plexiform layer (GCIP) thickness (p = 0.007), higher INL thickness (p < 0.001), and a greater number of ON episodes (p = 0.008) relative to non-MME eyes with a history of ON. After adjusting for history of multiple ON episodes, these findings remained significant for macular-RNFL thickness (p = 0.03), INL thickness (p < 0.001), and 100% and 2.5% contrast letter-acuity scores (p = 0.008 and p = 0.03, respectively). NMO spectrum eyes without ON history had lower macular RNFL thickness (p = 0.003), GCIP thickness (p = 0.002), outer nuclear layer thickness (p = 0.02), and low-contrast letter-acuity scores (2.5%: p = 0.03; 1.25%: p = 0.002) compared to healthy controls.Conclusions:We have identified a pattern of retinal morphologic abnormalities in NMO that is associated with severe retinal axonal and neuronal loss and corresponding visual disability. MME may contribute to poor visual outcomes following NMO-associated ON or alternatively represent a marker of ON severity. Additionally, our results support that subclinical involvement of the anterior visual pathway may occur in NMO spectrum disorders.

To determine the effect of clinical and radiologic disease activity on the rate of thinning of the ganglion cell/inner plexiform (GCIP) layer and the retinal nerve fiber layer in patients with multiple sclerosis (MS) using optical coherence tomography (OCT).One hundred sixty-four patients with MS and 59 healthy controls underwent spectral-domain OCT scans every 6 months for a mean follow-up period of 21.1 months. Baseline and annual contrast-enhanced brain MRIs were performed. Patients who developed optic neuritis during follow-up were excluded from analysis.Patients with the following features of disease activity during follow-up had faster rates of annualized GCIP thinning: relapses (42% faster, p = 0.007), new gadolinium-enhancing lesions (54% faster, p0.001), and new T2 lesions (36% faster, p = 0.02). Annual GCIP thinning was 37% faster in those with disability progression during follow-up, and 43% faster in those with disease duration5 years vs5 years (p = 0.003). Annual rates of GCIP thinning were highest in patients exhibiting combinations of new gadolinium-enhancing lesions, new T2 lesions, and disease duration5 years (70% faster in patients with vs without all 3 characteristics, p0.001).MS patients with clinical and/or radiologic nonocular disease activity, particularly early in the disease course, exhibit accelerated GCIP thinning. Our findings suggest that retinal changes in MS reflect global CNS processes, and that OCT-derived GCIP thickness measures may have utility as an outcome measure for assessing neuroprotective agents, particularly in early, active MS.

To test the hypothesis that patients with multiple sclerosis (MS) with intereye asymmetry on low contrast letter acuity, and thickness of the retinal nerve fiber layer (RNFL), would exhibit corresponding changes in cortical timing and amplitude responses on pattern reversal multifocal visual evoked potentials (mfVEP), contingent upon variable stimulus contrast.In a cross-sectional study, we investigated a cohort of 11 normal subjects and 40 patients with MS, 21 of whom had a history of acute optic neuritis (MS-AON) with an intereye asymmetry with respect to RNFL thickness, and on low contrast letter acuity performance. Pattern reversal mfVEP was performed at high (100%), low (33.3%), and very low (14.2%) Michelson-contrast levels.Compared to baseline measures at 100% contrast, the mean amplitude of the mfVEP was reduced in MS-AON eyes, upon pattern-reversal stimulation at the 2 lower contrast levels (p0.0001). With respect to changes in timing responses, the intereye asymmetry was increased in the MS-AON patients upon lower contrast pattern-reversal stimulation (p0.0001 for 33.3% compared to 100%, and p0.001 for 14.2% compared to 100%). The fellow eye in 12 (57%; p0.001) of the patients with an abnormal eye, and a history of AON, revealed abnormal amplitude and timing responses upon low contrast stimulation (signifying unmasking of occult damage).Our findings support the hypothesis that mfVEP metric abnormalities are contingent upon contrast magnitude during pattern reversal stimulation. Further, this paradigm was capable of unmasking occult abnormalities in a significant number of apparently unaffected eyes.

To evaluate the retinal nerve fiber layer (RNFL) thickness and macular volume in neuromyelitis optica (NMO) spectrum patients using optical coherence tomography (OCT).OCT can quantify damage to retinal ganglion cell axons and can identify abnormalities in multiple sclerosis and optic neuritis (ON) eyes. OCT may also be useful in the evaluation of patients with NMO.OCT and visual function testing were performed in 26 NMO spectrum patients with a history of ON, 17 patients with isolated longitudinally extensive transverse myelitis (LETM) without ON, 378 patients with relapsing-remitting multiple sclerosis (RRMS), and 77 healthy controls at 2 centers.Substantial RNFL thinning was seen in NMO ON eyes (63.6 microm) relative to both RRMS ON eyes (88.3 microm, p0.0001) and control eyes (102.4 microm, p0.0001). A first episode of ON was estimated to cause 24 microm more loss of RNFL thickness in NMO than RRMS. Similar results were seen for macular volume. ON also was associated with more severe visual impairment in NMO spectrum patients than in RRMS patients. Eyes in the LETM group and unaffected NMO eyes were not significantly different from controls, though conclusions about these subgroups were limited by small sample sizes.Optical coherence tomography (OCT) shows more severe retinal damage after optic neuritis (ON) episodes in neuromyelitis optica (NMO) than in relapsing-remitting multiple sclerosis. Identification of substantial retinal nerve fiber layer loss (15 microm) after ON in a non-multiple sclerosis patient should prompt consideration of an NMO spectrum condition. OCT may be a useful tool for the evaluation of patients with NMO.

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Optical coherence tomography (OCT) noninvasively quantifies retinal nerve fiber layer (RNFL) thickness. Studies show RNFL thinning in multiple sclerosis (MS), and we assessed its association with brain atrophy.RNFL thickness was measured in 40 patients with MS and 15 controls. Brain parenchymal fraction (BPF) and partial brain volumes were estimated from cranial MRI scans using SIENA-X. Multiple linear regression modeling assessed the association between OCT and MRI measures of atrophy.Minimum RNFL thickness and subject age together predict 21% (p = 0.005) of the variance in BPF in all patients with MS and 43% (p = 0.003) of the variance in BPF in the subgroup with relapsing remitting MS (RRMS; n = 20). The partial correlation coefficient between BPF and minimum RNFL thickness, controlling for age, is 0.46 (p = 0.003) in all patients with MS and 0.69 (p = 0.001) in patients with RRMS. These associations are driven by CSF volume but not by gray or white matter volume. There is no significant association of these variables among controls.In multiple sclerosis (MS), retinal nerve fiber layer thickness is associated with brain parenchymal fraction and CSF volume. These data suggest that quantification of axonal thickness in the retina by optical coherence tomography (OCT) provides concurrent information about MRI brain abnormality in MS. OCT should be examined in longitudinal studies to determine if it could be used as an outcome measure in clinical trials of neuroprotective drugs.

Transverse myelitis is a focal disorder of the spinal cord in which an immune-mediated process results in neural injury. In this large retrospective study, we compare patients who received one of four treatments to identify the most effective therapies. We identified subsets of patients who received clinical benefit from plasma exchange or cyclophosphamide being included in their treatment regimen.

Objective: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). Methods: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). Results: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. Conclusions: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

The symptoms, severity, and course of multiple sclerosis (MS) vary among patients, leading to complex treatment issues. In recent years, research has focused on specific adhesion molecules that participate in the activation and function of lymphocytes, especially the migration of these cells to sites of inflammation. In particular, the integrin, very late activation antigen (VLA)-4, has been implicated in mediating adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-1. VLA-4 is comprised of alpha4/beta1 and is critical in mediating Th-1 cell migration in the animal model of MS, experimental autoimmune encephalomyelitis, and has been the target of several recent clinical trials in MS. The humanized monoclonal antibody to alpha4 integrin, natalizumab (Tysabri, Biogen Idec/Elan), was recently approved in the United States for the treatment of relapsing MS. The authors discuss the mechanisms by which alpha4 integrins alter lymphocyte function as a rationale for anti-alpha4 integrin use in MS.

Editors' Note: Commenting on “Pearls & Oy-sters: Tacrolimus neurotoxicity presenting as an isolated brainstem lesion,” Dr. Chang wonders whether the patient reported had, in fact, posterior reversible encephalopathy syndrome (PRES) rather than a direct neurotoxic effect of tacrolimus. Drs. Saadi and Schmahmann, authors of the article, explain that the patient's blood pressure was within the normal range throughout hospitalization, making PRES unlikely. Critiquing “Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis,” Dr. Kantor comments that the Class I evidence of safety/tolerability is incorrect because the trial was not powered to demonstrate such an effect, and because of differences in urine calcium:creatinine ratio, incidence of nausea, and hypercalcemia between the 2 groups. Sotirchos et al., authors of the article, disagree with these …

Assessing treatment failure in relapsing-remitting multiple sclerosis (MS) remains a difficult clinical challenge. While head-to-head clinical trials in this patient group demonstrated superior efficacy of fingolimod,1 alemtuzumab,2 and daclizumab3 vs β-interferon preparations, the actionable threshold for recommending treatment switch in individual patients remains uncertain.

A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.

Objective: Gait and balance dysfunction frequently occurs early in the multiple sclerosis (MS) disease course. Hence, we sought to determine the longitudinal relationships among quantitative measures of gait and balance in individuals with MS. Methods: Fifty-seven ambulatory individuals with MS (28 relapsing-remitting, 29 progressive) were evaluated using posturography, quantitative sensorimotor and gait measures, and overall MS disability with the Expanded Disability Status Scale at each session. Results: Our cohort9s age was 45.8 ± 10.4 years (mean ± SD), follow-up time 32.8 ± 15.4 months, median Expanded Disability Status Scale score 3.5, and 56% were women. Poorer performance on balance measures was related to slower walking velocity. Two posturography measures, the anterior-posterior sway and sway during static eyes open, feet apart conditions, were significant contributors to walk velocity over time (approximate R 2 = 0.95), such that poorer performance on the posturography measures was related to slower walking velocity. Similarly, the anterior-posterior sway and sway during static eyes closed, feet together conditions were also significant contributors to the Timed 25-Foot Walk performance over time (approximate R 2 = 0.83). Conclusions: This longitudinal cohort study establishes a strong relationship between clinical gait measures and posturography. The data show that increases in static posturography and reductions in dynamic posturography are associated with a decline in walk velocity and Timed 25-Foot Walk performance over time. Furthermore, longitudinal balance measures predict future walking performance. Quantitative walking and balance measures are important additions to clinical testing to explore longitudinal change and understand fall risk in this progressive disease population.

Objective: To report 3 patients with multiple sclerosis (MS) who presented with daclizumab-related adverse events (AEs) in multiple organ systems. Methods: A retrospective chart review was performed of patients with MS who had clinical and histopathologic findings suggestive of daclizumab-induced AEs between 2004 and 2010 at the Johns Hopkins MS Clinic. This study met criteria for exemption from review from the institutional review board. Results: Of 20 total patients with MS who had been treated with daclizumab, 3 patients with clinical and histopathologic findings suggestive of daclizumab-induced AEs were identified. All patients were treated with Zenapax (1 mg/kg monthly IV infusions) outside of a clinical trial setting. Clinical manifestations after a mean treatment duration of 20 months consisted of diffuse rash and alopecia, diffuse lymphadenopathy, and breast nodules. Tissue histopathology demonstrated lymphocytic infiltrates with CD56-expressing cells in 2 patients (lymph node, breast nodule). On daclizumab discontinuation, the rash/alopecia and diffuse lymphadenopathy resolved, while the breast nodules stabilized. Conclusions: Daclizumab-induced AEs can occur in various organ systems after a relatively prolonged duration of exposure and require clinician awareness. Future studies are needed to better understand the relationship between natural killer cells and daclizumab-related AEs.

A 50-year-old man with multiple sclerosis (MS) was admitted with a seizure and coma in the setting of herpes zoster. The patient developed MS in 2003 and was switched to fingolimod in 2011, 4 months after discontinuing natalizumab (54 doses). He was clinically stable, but mostly wheelchair-bound with relatively preserved upper extremity function. Brain MRI obtained before starting fingolimod was stable. He had a history of chicken pox, and he had not received the herpes zoster (shingles) vaccine. Three months after starting fingolimod he developed herpes zoster. Oral valacyclovir was started 4 days after onset of the rash. Four days after initiating valacyclovir, the patient had a generalized seizure and was hospitalized. He was deeply comatose and required intubation. CSF analysis showed 27 leukocytes (84% lymphocytes, 9% neutrophils, 7% monocytes), 217 erythrocytes, glucose 61 mg/dL (normal 50–75), and protein 201 mg/dL (normal 15–45). CSF varicella-zoster virus (VZV) PCR was positive, and CSF showed a low-level positive JC virus PCR in the hospital laboratory. PCR tests for herpes simplex virus (HSV), cytomegalovirus, Epstein-Barr virus, and enteroviruses were negative. Absolute lymphocyte count was 190 cells/μL (normal 1,100–4,800). MRI of the brain revealed 2 new punctate areas of restricted diffusion in the posterolateral medulla, most consistent with focal infarcts (figure). His MS lesions were unchanged. Gadolinium was not administered due to acute renal failure. Magnetic resonance angiography of the head was normal. He was diagnosed with VZV encephalitis, seizures, and a brainstem infarct believed to be a result of VZV vasculitis. There was no clinical evidence of PML. He was treated with levetiracetam, IV acyclovir for 21 days, and prednisone 1 mg/kg daily for 7 days for VZV vasculitis. During a complex hospitalization he slowly improved, and 1 month later he was awake and oriented with significant psychomotor slowing and persistent quadriparesis in this patient who was wheelchair-bound at baseline. He was transferred to a rehabilitation hospital for continued ventilator weaning. The case was reported to the Food and Drug Administration (via MedWatch) and to Novartis.

The clinicoradiologic paradox, or disconnect between clinical and radiologic findings, is frequently encountered in multiple sclerosis (MS), particularly in the spinal cord (SC), where lesions are expected to cause clinical impairment. We aimed to assess whether quantitative diffusion tensor and magnetization transfer imaging measures in the SC can distinguish MS cases of comparable lesion burdens with high and low disability.One hundred twenty-four patients with MS underwent 3-T cervical SC MRI and were categorized into 4 subgroups according to SC lesion count and disability level. Regions of interest circumscribed the SC cross-section axially between C3 and C4. Cross-sectional area, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (λ(⊥)), parallel diffusivity (λ(‖)), and magnetization transfer ratio (MTR) were calculated. Differences between patient subgroups were assessed using t tests and linear regression.FA, MD, λ(⊥), λ(‖), MTR, and SC cross-sectional area were more abnormal in the high- vs low-disability subgroup of patients with low lesion counts (p0.05). MRI measures (except λ(‖) and MTR) were more abnormal in the high- vs low-disability subgroup of patients with high lesion counts (p0.05). In age- and sex-adjusted comparisons of high- vs low-disability subgroups, all MRI measures retained differences in the low-lesion subgroup, except λ(‖), whereas only FA, MD, and λ(⊥) retained differences in the high-lesion subgroup.In this cross-sectional study of patients with MS, quantitative MRI reflects clinically relevant differences beyond what can be detected by conventional MRI. Our findings support the utility of quantitative MRI in clinical settings, where accurate measurement of disease burden is becoming increasingly critical for assessing treatment efficacy.

Studies in children presenting with a first CNS demyelinating event are particularly valuable as a focus for investigation of the early immunologic mechanism occurring during the induction and progression of CNS autoimmune diseases.1 According to our current view, the adaptive immune response has a central role in the pathogenesis of inflammatory demyelinating diseases of the CNS.2 Peripheral priming of antigen-specific T cells and B cells targeting antigens in the CNS will most likely precede the first clinical event. Evolution of additional antigen-specific immune responses may occur, when the disease progresses from the monophasic to the chronic stage. The extent of inflammatory disease activity, determined by relapse rates or new MRI lesions, decreases with age and disease duration, suggesting that the most pronounced immune responses occur in children.3,4 Moreover, the immune system in children has been less exposed to environmental factors and chronic diseases than in adults. It is therefore reasonable to assume that immunologic processes associated with the first demyelinating event possibly leading to multiple sclerosis (MS) should be easier to identify in children than in adults. Although studies in children bear many advantages, they are also challenging given the lower prevalence of MS during childhood. Antigen-specific T cells, B cells, or their released antibodies can be studied in blood or CSF, but the small amount of biomaterial available from children limits broad testing for antigen-specific immune responses to antibodies.

Editors' Note: In reference to the article “In vivo identification of morphologic retinal abnormalities in neuromyelitis optica,” Dr. Borruat reports his own experience in diagnosing microcystic macular edema in patients with noninflammatory optic neuropathies, supporting the hypothesis of retrograde transsynaptic degeneration of inner retinal cells as etiology. Dr. Khoo espouses the benefits of Sniffin’ Sticks, an inexpensive, noninvasive test of olfactory dysfunction, in diagnosing idiopathic intracranial hypertension. Authors Kunte et al. explain the drawbacks of this approach. —Megan Alcauskas, MD, and Robert C. Griggs, MD Sotirchos et al.1 used optical coherence tomography (OCT) …

Since it first came to trial, natalizumab (Tysabri) has kept the multiple sclerosis (MS) world in a constant state of flux. Shortly after its initial launch, the appearance of three cases of progressive multifocal leukoencephalopathy (PML), a devastating infection of the CNS caused by the JC virus, resulted in the drug’s withdrawal from the market. Reintroduced in 2006, it is currently in use as monotherapy in thousands of patients worldwide, but four additional cases of PML were recently reported in patients on natalizumab monotherapy for less than 18 months. While these cases strongly support a mechanistic association between the drug and JC virus reactivation/infection,1 the short-term risk of PML still appears to be quite low (4 confirmed cases out of ∼10,000 patients treated for 18 months). Nonetheless, these new cases are concerning and some patients and physicians will choose to discontinue therapy. Several groups have raised the possibility of a rebound effect in cohorts of patients discontinuing natalizumab.2,3 This has led to the concern that stopping natalizumab might lead to …

To examine retinal nerve fiber layer (RNFL) thickness, macular volumes (MV), and visual acuity in multiple sclerosis (MS) eyes, with and without history of acute optic neuritis (ON).RNFL thickness was measured in 326 MS and 94 control eyes using optical coherence tomography (OCT). MV and vision testing were done in a subset of the cohort. MS subtype was classified as relapsing-remitting (RRMS, n = 135), primary progressive (PPMS, n = 12), and secondary progressive (SPMS, n = 16).MS ON eyes had decreased RNFL thickness (84.2 microm) compared to controls (102.7 microm) (p0.0001). Unaffected fellow eyes of MS ON eyes (93.9 microm) (p0.01) and patients with MS with no history of ON (95.9 microm) (p0.05) also had decreased RNFL. RRMS (94.4 microm) (p0.001), PPMS (88.9 microm) (p0.01), and SPMS (81.8 microm) (p0.0001) (adjusted for age and duration of disease) had decreased RNFL compared to controls. There were significant differences in RNFL thickness within quadrants of peripapillary retina comparing relapsing to progressive MS subtypes. MV was decreased in MS ON eyes (6.2 mm(3)) (p0.0001) and SPMS subjects (6.2 mm(3)) (p0.05) compared to controls (6.8 mm(3)).Retinal nerve fiber layer (RNFL) is significantly decreased in multiple sclerosis (MS) optic neuritis (ON) eyes, unaffected fellow eyes of patients with MS ON, and MS eyes not affected by ON in our cohort. Macular volumes (MV) showed a significant decrease in MS ON eyes. Progressive MS cases showed more marked decreases in RNFL and MV than relapsing-remitting MS. OCT is a promising tool to detect subclinical changes in RNFL and MV in patients with MS and should be examined in longitudinal studies as a potential biomarker of retinal pathology in MS.

To examine the relation between low-contrast letter acuity, an emerging visual outcome for multiple sclerosis (MS) clinical trials, and brain MRI abnormalities in an MS cohort.T2 lesion volume and brain parenchymal fraction were determined for whole brain and within visual pathway regions of interest. Magnetization transfer ratio histograms were examined. Vision testing was performed binocularly using low-contrast letter acuity (2.5%, 1.25% contrast) and high-contrast visual acuity (VA). Linear regression, accounting for age and disease duration, was used to assess the relation between vision and MRI measures.Patients (n = 45) were aged 44 +/- 11 years, with disease duration of 5 years (range1 to 21), Expanded Disability Status Scale score of 2.0 (0 to 6.0), and binocular Snellen acuity of 20/16 (20/12.5 to 20/25). The average T2 lesion volume was 18.5 mm(3). Patients with lower (worse) low-contrast letter acuity and high-contrast VA scores had greater T2 lesion volumes in whole brain (2.5% contrast: p = 0.004; 1.25%: p = 0.002; VA: p = 0.04), Area 17 white matter (2.5%: p0.001; 1.25%: p = 0.02; VA: p = 0.01), and optic radiations (2.5%: p = 0.001; 1.25%: p = 0.02; VA: p = 0.007). Within whole brain, a 3-mm(3) increase in lesion volume corresponded, on average, to a 1-line worsening of low-contrast acuity, whereas 1-line worsening of high-contrast acuity corresponded to a 5.5-mm(3) increase.Low-contrast letter acuity scores correlate well with brain MRI lesion burden in multiple sclerosis (MS), supporting validity for this vision test as a candidate for clinical trials. Disease in the postgeniculate white matter is a likely contributor to visual dysfunction in MS that may be independent of acute optic neuritis history.

Objective: To describe challenges in diagnosis and management of patients with clinical syndromes of immune reconstitution inflammatory syndrome (IRIS) involving the CNS. Methods: The authors describe three patients with clinically distinct neurologic manifestations of IRIS with HIV infection who presented as diagnostic and therapeutic challenges. Results: One patient with cryptococcal meningitis developed acute cerebellitis with mass effect and brainstem compression. Corticosteroid therapy was associated with complete resolution of the cerebellar lesion but the patient developed VZV encephalitis. Another patient with progressive multifocal leukoencephalopathy developed subacute progression of focal neurologic deficits associated with contrast enhancing lesions on brain MRI. This patient had spontaneous resolution of the lesion but was left with residual deficits. One patient developed a progressive dementing syndrome and deterioration over several months resulting in coma during combination antiretroviral therapy. A brain biopsy in this latter patient showed massive infiltration of T lymphocytes predominantly of the CD8 subtype. This patient had a significant improvement with corticosteroids and change in antiretroviral regimen although she was left with residual cognitive impairment. Conclusions: Immune reconstitution inflammatory syndrome should be suspected in patients who show clinical or radiologic deterioration following initiation of antiretroviral therapy accompanied with improvement in CD4 cell count and viral load. Some patients may respond to a brief course of treatment with corticosteroids.

Interferon beta (IFNβ) treatment in multiple sclerosis (MS) has been associated with hepatotoxicity,1 and there have been reported cases of severe hepatitis induced by IFNβ.2,3 Acute autoimmune hepatitis (AIH) as a side effect of IFNβ therapy in MS is rare.2–4 There are no reported cases of IFNβ unmasking previously undiagnosed chronic AIH. We report a case in which chronic AIH only became symptomatic and diagnosed following the initiation of IFNβ therapy, and early recognition resulted in definitive therapy and an excellent outcome. A 43-year-old woman recently diagnosed with MS was started on IFNβ1a (Rebif) 22 μg TIW, and the dose was increased to 44 μg over 1 month as per routine protocol. She did not have any history of liver disease, alcohol abuse, or illicit drug use, and liver function tests (LFTs) were normal prior to treatment. Despite being told to have liver function tests performed 1 month after initiation of IFNβ, she was not heard from until about 6 weeks after the …

In this issue of Neurology ®, Politis et al.1 utilized brain PET and the radioligand 11C-PK11195 to estimate expression of the translocator protein 18 kD (TSPO) as a marker of activated microglia in …

The authors analyzed renal function in 25 patients with progressive MS. The mean glomerular filtration rate (GFR) was 92 mL/min/1.73 m(2), compared to the predicted GFR of 110 (p0.001). Nine of the 25 (36%) patients had abnormally low GFR (90). The mean serum creatinine for patients with MS was lower than predicted normal values and poorly estimated GFR using standard equations. These data document impaired renal function in patients with progressive MS and have implications for treatment of these patients with potentially nephrotoxic drugs.

Disease-modifying drugs are available in the United States for the treatment of relapsing-remitting multiple sclerosis (RRMS), including interferon (IFN) beta-1a, IFNbeta-1b, and glatiramer acetate. Another formulation of IFNbeta-1a is available in Europe, Canada, and other countries. Mitoxantrone is also indicated for the treatment of worsening forms of RRMS and secondary progressive (SP) MS. In addition to reductions in annual relapse rates and other measures of clinical disability, the disease-modifying drugs appear to reduce MRI measures of disease activity. Available data suggest that the efficacy of disease-modifying therapy is sustained for at least for 4 to 6 years. Results of clinical drug trials have been used as a rationale to support treatment of early MS with a disease-modifying drug. Other medical therapies are used in the management of RRMS, including treatments to help manage MS-related symptoms such as spasticity and bladder dysfunction, and corticosteroids to hasten recovery from acute relapses. In some situations, interventions are used to minimize side effects of disease-modifying drug therapy. Several currently marketed treatments, including IV immunoglobulin, methotrexate, and azathioprine, are being evaluated as treatments for RRMS in combination with the approved therapies. Investigational compounds, including oral formulations of glatiramer acetate and interferon, are in various stages of development.

An open-label study was performed to evaluate the safety and efficacy of combination therapy with weekly oral methotrexate (20 mg) and interferon β-1a (IFNβ-1a) in 15 patients with MS who had experienced exacerbations while receiving IFNβ monotherapy. Nausea was the only major side effect. A 44% reduction in the number of gadolinium-enhanced lesions seen on MRI scan was observed during combination therapy (p = 0.02). There was a trend toward fewer exacerbations. This combination therapy appears to be safe and well tolerated, and should be studied in a controlled trial.

The most common imitators of multiple sclerosis (MS) are other autoimmune diseases and infections; however, an increasing number of metabolic diseases have been recognized as uncommon mimics of MS (table). While MRI has revolutionized the diagnosis of MS, it has also led to occasional overinterpretation of white matter disease as MS. In this issue of Neurology ®, Keegan et al.1 describe a series of patients referred for possible MS who were eventually diagnosed with a rare condition: leukoencephalopathy with neuroaxonal spheroids. Their report suggests that degenerative axonal diseases may be more common than we realize. Also, it reminds us that not all MRI white matter spots are due to MS. View this table: Table Primary differential diagnosis of multiple sclerosis The five patients described by Keegan et al.1 were all referred to the Mayo Clinic for evaluation of possible MS. However, atypical features prompted a more …

Ratchford et al.1 reported a patient with fingolimod-related varicella encephalitis and vasculopathy. The patient's baseline mobility was wheelchair-bound, which means that his Expanded Disability Status Scale (EDSS) score2 was at least 7.0. This suggests that he was no longer in the inflammatory stage of multiple sclerosis (MS) and had secondary progressive MS (SPMS). It is unclear whether the patient's condition met criteria for natalizumab but—at a minimum—the condition must have progressed while on natalizumab. There is neither licensing support nor data from pivotal trials for efficacy of this drug in patients with SPMS.3 The evidence supporting the extension of natalizumab beyond the standard 24 months is also lacking. Fingolimod is licensed for patients with active relapsing-remitting MS but Ratchford et al. stated that this patient was clinically stable. This case highlights an interesting and serious consequence of starting therapy with fingolimod, but the evidence for starting and continuing treatment with this medication—and indeed natalizumab—is lacking in this patient group. This case report also emphasizes the need for evidence-based care, which is safer and more cost-effective.

Objective: The ongoing phase 3 ADVANCE trial is evaluating the efficacy and safety of polyethylene glycol (PEG)–conjugated (PEGylated) interferon beta-1a (PEG-IFN beta-1a) in patients with relapsing multiple sclerosis (RMS). Background PEGylation extends the half-life of IFN beta-1a, potentially allowing dosing every 2 or 4 weeks instead of the once-weekly dosing of intramuscular IFN beta-1a. PEG-IFN beta-1a is expected to offer efficacy at least equivalent to that of intramuscular IFN beta-1a 30 μg. Recognizing that PEG-IFN beta-1a may help address unmet patient needs, the US FDA has granted this drug Fast Track designation. Design/Methods: The ADVANCE phase 3 trial is a global, 2-year, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of subcutaneous PEG-IFN beta-1a 125 μg. Eligible patients must be 18–65 years old and have confirmed RMS (McDonald criteria), a baseline Expanded Disability Status Scale (EDSS) score ≤5.0, ≥2 relapses within 3 years of randomization, and ≥1 relapse within 12 months of randomization. Approximately 1500 patients will be randomized 1:1:1 to placebo, PEG-IFN beta-1a every 2 weeks, or PEG-IFN beta-1a every 4 weeks. After 1 year, patients randomized to placebo will be re-randomized to PEG-IFN beta-1a either every 2 weeks or every 4 weeks. Dosing will remain unchanged for the remaining patients. An open-label extension study (ATTAIN) will be available after 2 years for patients participating in the ADVANCE trial. Results: . Patient baseline characteristics will be presented. Conclusions: PEG-IFN beta-1a is being developed to reduce dosing frequency and improve patient convenience while maintaining the proven efficacy, safety, and tolerability of IFN beta-1a. As such, PEG-IFN beta-1a may be an important new addition to the therapeutic armamentarium for MS. Supported by: Biogen Idec Inc. Disclosure: Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Kieseier has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis, Roche Diagnostics, Sanofi-Aventis Pharmaceuticals, and TEVA Neurosciences as speaker. Dr. Kieseier has received research support from Bayer Pharmaceuticals, Biogen Idec, Merck Serono and Teva Neurosciences. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Balcer has received personal compensation for activities with Biogen Idec, Vaccinex and Bayer as a consultant and has received honoraria from Biogen Idec and Novartis. Dr. Boyko has received personal compensation for activities with Novartis, Merck Serono, TEVA, Gensyme, Biogen Idec, Nicomed as a member of advisory boards, a speaker and a participant of clinical trials. Dr. Pelletier has received research support from Sanofi-Aventis, Pharmaceuticals, Inc., Bayer Schering, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Zhu has received personal compensation for activities with Biogen Idec as an employee. Dr. Zhu holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Zhu was involved as an investigator. Dr. Deykin has received personal compensation for activities with Biogen Idec as an employee.

Objective: Ocrelizumab reduced gadolinium-enhancing lesions (primary endpoint) by ≥89% and annualized relapse rate (ARR) by ≥73% vs placebo by Week 24, in a Phase II trial in RRMS. Background To determine long-term efficacy and safety of ocrelizumab up to Week 96. Design/Methods: RRMS patients (n=220) were randomized (1:1:1:1) to intravenous ocrelizumab (days 1, 15) total dose 600 mg (A), 2000 mg (B), placebo (C), or open-label weekly intramuscular interferon beta-1a 30 μg (D). At Weeks 24, 48, and 72, all patients received open-label ocrelizumab: groups A, C, and D received 600 mg/cycle; group B received 1000 mg at Weeks 24 and 48, then 600 mg at Week 72. MRI follow-up occurred only with groups A and B. Results: 183 patients completed 96 weeks. From Weeks 0–96, the ARR was 0.18 [95% CI: 0.11–0.31] and 0.22 [95% CI: 0.13–0.35] for groups A and B; 78.2% and 80.0% of patients, respectively, were relapse-free and 67.3% and 76.4% had no relapses or confirmed EDSS progression (9clinical disease activity free9). ARRs reduced during Weeks 24 to 96 in patients switched from placebo to ocrelizumab (group C) from 0.64 to 0.20 [95% CI: 0.12–0.33] and from 0.36 to 0.16 [95% CI: 0.09–0.28] in those switched from interferon beta-1a to ocrelizumab (group D). At Week 96 there were no gadolinium-enhancing lesions in groups A and B with 1.1% and 1.2% reduction in brain volume, respectively, from Weeks 12–96. Serious infection rates were similar for all groups and did not increase with time on treatment. There were no opportunistic infections or imbalance in rate of serious adverse events across groups over 96 weeks. Conclusions: Ocrelizumab substantially reduced MRI and clinical measures of MS disease activity over 96 weeks. Switching from interferon beta-1a or placebo to ocrelizumab produced similar sustained benefits. Disclosure: Dr. Hauser has received personal compensation for activities with BioMarin, Novartis and Receptos as a consultant and serving on a scientific advisory board.Dr. Hauser has received personal compensation in an editorial capacity for the journal Annals of Neurology and Harrison9s Internal Medical textbook.Dr. Hauser has received compensation for serving on the scientific advisory board of Receptos. 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. Li has received personal compensation for activities with Genzyme, Novartis and Nuron as a consultant.Dr. Li has receved research support from Angiotech, Bayer, Berlex-Schering, Bio-MS, Boehringer-Ingelheim, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences,Sanofi-Aventis, Transition Therapeutics, and Novartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Barkhof has received personal compensation for activities with Novartis, Biogen Idec, Merck-Serono, and Bayer-Schering as a consultant. Mr. Wells has received personal compensation for activities with Roche as an employee. Dr. Leppert has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Leppert has received compensation for serving on the University of British Columbia MS/MRI Research Group of Angiotech, Bayer, Berlex-Schering, Bio-MS, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences, Sanofi-Aventis, and Transition Therapeutics. Dr. Leppert holds stock and/or stock options in F. Hoffmann La Roche Ltd., which sponsored research in which Dr. Leppert was involved as an investigator. Dr. Glanzman has received personal compensation for activities with Hoffmann-LaRoche LTD. Dr. Tinbergen has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Tinbergen holds stock and/or stock options in Roche Diagnostics Corporation.

Objective: To characterize abnormalities of a novel multifocal electroretinographic (mfERG) late response potential, the optic nerve head component (ONHC), in patients with multiple sclerosis (MS)- and neuromyelitis optica (NMO)-associated optic neuropathy. Background The ONHC is generated from the geometric array of the ganglion cell axons in the vicinity of the optic nerve head. Its latency increases with distance of the stimulus from the nerve head, possibly due to the delay in the propagation of action potentials along the unmyelinated axons of the retinal nerve fiber layer (RNFL). At the level of lamina cribrosa, as the unmyelinated axons of the RNFL transition to myelinated axons of the optic nerve, the change from membrane to saltatory conduction is believed to also be responsible for the ONHC generation. Design/Methods: The following metrics were measured in a group of subjects with MS- and NMO-related optic neuropathy and compared to a group of healthy controls: reduced contrast visual acuity (2.5% and 1.25%), optical coherence tomography (OCT), GDx-VCC, multifocal visual evoked potentials (mfVEP) and mfERG. A pseudo-random m-sequence stimulation on an array of 103 hexagons tiling the central 50 degree of the visual field was used to elicit the ONHC. Results: In the group with MS- or NMO-related optic neuropathy, the absence or disorganization of the ONHC was found in the eye(s) previously affected by optic neuritis. Perturnation of this waveform was associated with disruption of other metrics i.e. loss of contrast sensitivity, abnormal mfVEP responses and RNFL thinning (as measured by OCT and GDx-VCC). Conclusions: Our findings validate a novel electrophysiologic method of evaluating MS- and NMO-related optic neuropathy which may serve as a unique marker of disease activity and neurorestorative therapy. The ONHC may represent a more sensitive and site-selective signature of chronic demyelination, and as such could be utilized as a reliable outcome in remyelination trials. Disclosure: Dr. Beh has nothing to disclose. Dr. Schnurman has nothing to disclose. Dr. Frohman has received personal compensation for activities with Biogen Idec and Teva Pharmaceuticals. Dr. Conger has nothing to disclose. Dr. Conger has nothing to disclose. Dr. Sutter has received personal compensation for activities with Electro-Diagnostics Imaging as an employee. Dr. Sutter holds stock and/or stock options in Electro-Diagnostics Imaging. Dr. Balcer has received personal compensation for activities with Biogen Idec, Vaccinex and Bayer as a consultant and has received honoraria from Biogen Idec and Novartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Frohman has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Acorda Therapeutics, Novartis, Astellas, and Abbott Laboratories, Inc.

Objective: To report long-term efficacy and safety of fingolimod in RRMS, from the phase III FREEDOMS study extension. Background RRMS patients randomized to oral, once-daily(o.d), fingolimod (0.5mg or 1.25mg) in the 2-year, double-blind, FREEDOMS core study, demonstrated a significant improvement in clinical and MRI endpoints versus placebo (PBO)-treated patients. We present here end of study (EOS) results from the extension phase of upto 4 years treatment. Design/Methods: In the extension, patients either continued on the core phase dose (continuous-fingolimod), or were re-randomized (1:1) from placebo to fingolimod (1.25 or 0.5mg/o.d) (PBO-fingolimod). All patients received open-label 0.5mg following a decision to discontinue the fingolimod 1.25mg/day treatment arm from all MS studies. Results: 1033/1272 (81.2%) patients enrolled in FREEDOMS completed the 24M core, and 773/920 (84%) patients enrolled in the extension (60.7% of initially randomized) completed the study. Common reasons for discontinuations were withdrawal of consent (7.2%) and adverse events (AE) (3.4%). Annualized relapse rates (ARR) decreased in the switch/PBO-fingolimod group during the extension phase (PBO-1.25mg, 0.22; PBO- 0.5mg, 0.19) versus the core (ARR= 0.4; p Conclusions: Patients who switched from placebo to fingolimod showed significant improvements in clinical and MRI outcomes (including brain atrophy). Continuous fingolimod treatment was associated with sustained low clinical and MRI disease activity and was well-tolerated. Supported by: Novartis Pharma AG, Basel, Switzerland. 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. Radue has received personal compensation for activities with AIM, Biogen Idec, and Novartis as a consultant.Dr. Radue has received research support from Actelion, Bayer Schering, Biogen Idec, Merck Serono, and Novartis. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. Polman has received personal compensation for activities with Biogen Idec, Schering AG, Teva Neuroscience, EMD Serono, Novartis, GlaxoSmithKline, Inc., UCB Pharma, AstraZeneca Pharmaceuticals, Roche Diagnostics and Antisense Therapeutics as a consultant or speaker.Dr. Polman has received research support from Biogen Idec, Schering AG, GlaxoSmithKline, Inc., Novartis, EMD Serono and Teva Neuroscience. Dr. Hohlfeld has received personal compensation for activities with Schering AG, Merck-Serono, Biogen Idec, Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc.,Novartis, Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Hohlfeld has received personal compensation in an editorial capacity for International MS Journal.Dr. Hohlfeld has received research support from Schering AG, Merck-Serono, Biogen Idec, Teva Neuroscience, Norvartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Agoropoulou has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Jin has received personal compensation for activities with Novartis Pharma AG. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee. Dr. Francis has received personal compensation for activities with Novartis as an employee. Dr. Francis holds stock and/or stock options in Novartis, which sponsored research in which Dr. Francis was involved as an investigator.

Objective: To characterize a high precision and clinically useful paradigm for multifocal, digitally generated, visual evoked potential responses. Background Conventional visual evoked potential techniques are performed with sophisticated, multi-focal stimulators, coupled with digital amplifiers that generate a heterogeneity of cortical responses, with wide variability when compared to the traditional black and white CRT stimulators. While contemporary stimulators represent a technical refinement capable of yielding multi-focal data, with high spatial resolution using m-sequence patterns, no paradigm has been validated to produce a physiologic signature commensurate with the p-100 metric. Design/Methods: Patients with a history of unilateral optic neuritis, along with a control group of healthy patients with no known ophthalmic or neurologic disease, were scanned using the Veris FMS3 Stimulator with a Grass Digital Amplifier. Patients were tested using a 7 minute 120 sector m-sequence multi-focal visual evoked potential test. A standard template was used for each patient. Each electrode was monitored for impedance. The Veris Scientific software was used to formulate an analysis paradigm that would yield valid and reproducible signatures reflecting visual cortical responses. Various combinations of analysis patterns were tested. Results: ROC curves were utilized to assess sensitivity and specificity of data. By dividing the central 20 degrees into three rings, and deriving a single wave form for each of the corresponding geometries, a simulated and reproducible metric was derived, the application of which was confirmed as a highly sensitive and specific discriminator for differentiating normal vs abnormal cortical responses. Conclusions: While multi-focal VEP techniques have impressive spatial resolution, and appear to have utility for confirming pathophysiologic evidence for unilateral visual system dysfunction, the results are not yet comparable to the conventional gold standard p-100 metric. Our proposed technique was effective in segregating geometric ring ratios into a single codified waveform metric, from which normative values can be established. Supported by: DADS Foundation, VIRAGH Family Foundation. Disclosure: Dr. Conger has nothing to disclose. Dr. Conger has nothing to disclose. Dr. Frohman has received personal compensation for activities with Biogen Idec and Teva Pharmaceuticals. Dr. Balcer has received personal compensation for activities with Biogen Idec, Vaccinex and Bayer as a consultant and has received honoraria from Biogen Idec and Novartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Beh has nothing to disclose. Dr. Greenberg has received personal compensation for activities with DioGenix, Greater Good Foundation, Biogen Idec, Serono, Inc., Sanofi-Aventis Pharmaceuticals, Inc., the Multiple Sclerosis Association of America and Teva Neuroscience as a consultant and/or speaker. Dr. Greenberg holds stock and/or stock options in Diogeix. Dr. Greenberg has received research support from Guthy-Jackson Charitable Foundation, Amplimmune, Inc. and the Accelerated Cure Project. Dr. Frohman has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Acorda Therapeutics, Novartis, Astellas, and Abbott Laboratories, Inc.