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Introduction Natalizumab en EID presente un moindre risque de leucoencephalopathie multifocale progressive qu’en SID. Les donnees en vie reelle de patients EID peuvent faciliter la determination du profil benefice–risque de l’EID. Objectifs Comparer l’efficacite du natalizumab en SID et en EID a l’aide de mesures quantitatives d’imagerie par resonance magnetique (IRM) a partir d’images en vie reelle hautement standardisees dans MS PATHS. Patients et methodes Un segment IRM est defini comme 2 acquisitions a duree d’intervalle associee. Les patients inclus avaient ≥ 1 segment, ≥ 2 cycles de perfusion (> 21 ≤ 84 jours) et information covariee complete. Les segments IRM avec un cycle moyen de perfusion (AIC) ≤ 35 jours et > 35 jours sont definis comme SID/EID, respectivement. Les nouvelles lesions T2, les variations du volume des lesions T2 (T2LV) et la fraction parenchymale cerebrale (BPF) ont ete comparees pour les segments IRM SID/EID. Resultats L’analyse portait sur 327 patients SID (596 segments) et 67 patients EID (85 segments). L’AIC moyen etait de 29,5 jours (ET : 1,8) en SID et 40,8 jours (4,9) en EID. La proportion de patients sans nouvelles lesions T2 etait semblable entre SID et EID (75,6 %/75,3 % ; p = 0,921). Aucune difference significative n’a ete montree entre groupe en variation ajustee de T2LV (−0,070 mL/0,022 mL ; p = 0,233) ou variation de BPF (−0,1222 %/−0,1442 % ; p = 0,617). Discussion/Conclusion L’activite IRM etait faible entre les deux groupes ; aucune difference significative dans les resultats d’IRM n’a ete montree. NOVA, essai de phase 3b, permettra d’approfondir sur l’efficacite de l’EID.

Visual dysfunction in MS can be quantified using a variety of tests. Many vision tests have not been formally evaluated among MS patients with existing visual dysfunction.Evaluate several versions of visual acuity and contrast sensitivity tests, measures of central and peripheral vision, retina structure, electrophysiologic function, and quality of life among MS patients with moderate/severe visual dysfunction.Cross-sectional study of 46 patients with stable, incompletely recovered optic neuritis. Testing included Snellen eye charts, several Sloan low contrast charts, Pelli Robson (PR) contrast sensitivity charts, optical coherence tomography, visual fields, Farnsworth Munsell 100-hue test, visual evoked potentials (VEP), and visual function quality of life (VFQ-25) testing.98% of eyes could read two lines of the PR chart, while only 43% read the 2.5% contrast chart. Low contrast tests correlated strongly with each other and with retinal nerve fiber layer (RNFL) thickness, visual fields, and color vision but not with VEPs. For patients with RNFL75µm, VFQ-25 scores dropped by approximately 2 points for every 1µm decrease in RNFL.Among MS patients with visual impairment due to optic neuritis, PR contrast sensitivity could be utilized as a single chart. Visual quality of life was associated with RNFL thinning below 75µm.

Background Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with a CNS inflammatory disorder distinct from multiple sclerosis (MS) and aquaporin-4 antibody-positive neuromyelitis optica (NMO). Knowledge of the clinical spectrum of MOG antibody disease (MOGAD) remains incomplete, particularly in comparison to two related inflammatory demyelinating diseases, MS and NMO. Objective Compare demographics, clinical characteristics, estimated disability, laboratory results, and treatment responses of a U.S. MOGAD cohort with age- and sex-matched MS and NMO patients. Design, setting, and participants This observational, case-control, single-center study identified each group via ICD-10 diagnosis code searches through the electronic medical records of adult patients seen at the John L. Trotter MS Center between January 1, 2019 and January 1, 2020. MOGAD and NMO patients were confirmed to have at least one positive antibody test; those in the MS group had a confirmed diagnosis by a physician with MS subspecialty training. Data were collected after IRB approval. Results Twenty-six patients were included in each group. MOGAD patients were predominantly Caucasian (88.5%) with mean onset age of 43.9 years. MOGAD patients had no comorbid other autoimmune diseases and comparatively lower rates of family members with autoimmune disease (20.0%) than either MS (40.0%) or NMO (34.6%) matched cohorts. 91% of MOGAD attacks were monofocal, and over 70% presented with optic neuritis. Severity of MOGAD attacks was similar to that of seropositive NMO, but the robust degree of recovery was more similar to MS. Four MOGAD patients converted to negative antibody status, with no attacks occurring after conversion. Serum ANA and ENA were less frequently elevated in MOGAD (21.7%, 5.0%) than in seropositive NMO patients (66.7%, 42.9%). Elevated IgG synthesis rate and positive CSF-restricted oligoclonal bands were not seen in our MOGAD cohort, and only one MOGAD patient had an elevated IgG index. Despite anti-CD20 therapy, 28.6% of MOGAD patients continued to suffer relapses. Conclusions MOGAD was characterized by a predominantly monofocal presentation (typically optic neuritis) and severe attacks with better recovery than seen with seropositive NMO attacks. Lack of CSF-restricted oligoclonal bands distinguished MOGAD from MS.

Objective: Investigate the relationship between socioeconomic status (SES) and race with self-reported fatigue, depression, and anxiety levels in multiple sclerosis (MS). Methods: Cross-sectional review of the MS Partners Advancing Technology and Health Solutions (MS PATHS) database for adults with MS in the United States. We evaluated race and socioeconomic status (available markers: insurance, employment status, or level of education) as predictors of fatigue, depression, and anxiety sub-scores of the Neuro-QoL (Quality of life in neurological disorders), with particular interest between Caucasians/whites (CA) and African Americans/blacks (AA). Multivariate linear regression models included as covariates age, sex, disability status, smoking status, body mass index, and disease-modifying therapy. Results: 7,430 individuals were included; compared to CA, AA tended to be younger, more female-predominant, and had a higher level of disability. AA had completed slightly less education, had a higher level of Medicaid coverage or uninsured status, and had higher rates of unemployed or disabled status. In the univariate model, markers of lower SES, by whichever definition we used, correlated with worse affective symptoms. In the multivariate model stratified by race, CA showed similar trends. In contrast, in AA, only lower SES by employment status was correlated with worse affective symptoms. In both CA and AA, moderate and severe level of disability correlated with worse affective symptoms. Conclusion: SES and race may influence affective symptoms reported by individuals with MS. The reasons for the correlation are likely multifactorial. Longitudinal studies should strive to identify factors associated with risk of affective symptoms in MS that may be modifiable.

We thank Dr. Avasarala for his comments on our editorial regarding the corresponding study by Xu et al.,1,2 in which the sensitivity of optical coherence tomography (OCT) measures for detecting previous optic neuritis (ON) was examined. Although Naismith et al. reported that OCT was less sensitive than visual evoked potentials (VEP) in detecting previous ON,3 this study used older third-generation time domain OCT. Undoubtedly, the greatest advance in OCT in the past decade has been the development of fourth-generation spectral domain OCT. Current commercially available spectral domain OCT has extremely high resolution (3–5 μm). Moreover, peripapillary retinal nerve fiber layer (RNFL) and composite ganglion cell and inner plexiform layer (GCIPL) thicknesses have excellent reliability and reproducibility, with the intervisit intraclass correlation coefficient for GCIPL thickness being 0.99.4 Furthermore, OCT measures provide invaluable information regarding the global multiple sclerosis (MS) disease process, including mirroring brain atrophy, disease activity, predicting future disability, and conversion to clinically definite MS.5

In vivo human optic nerve diffusion magnetic resonance imaging (dMRI) is technically challenging with two outstanding issues not yet well addressed: (i) non-linear optic nerve movement, independent of head motion, and (ii) effect from partial-volumed cerebrospinal fluid or interstitial fluid such as in edema. In this work, we developed a non-linear optic nerve registration algorithm for improved volume alignment in axial high resolution optic nerve dMRI. During eyes-closed dMRI data acquisition, optic nerve dMRI measurements by diffusion tensor imaging (DTI) with and without free water elimination (FWE), and by diffusion basis spectrum imaging (DBSI), as well as optic nerve motion, were characterized in healthy adults at various locations along the posterior-to-anterior dimension. Optic nerve DTI results showed consistent trends in microstructural parametric measurements along the posterior-to-anterior direction of the entire intraorbital optic nerve, while the anterior portion of the intraorbital optic nerve exhibited the largest spatial displacement. Multi-compartmental dMRI modeling, such as DTI with FWE or DBSI, was less subject to spatially dependent biases in diffusivity and anisotropy measurements in the optic nerve which corresponded to similar spatial distributions of the estimated fraction of isotropic diffusion components. DBSI results derived from our clinically feasible (∼10 min) optic nerve dMRI protocol in this study are consistent with those from small animal studies, which provides the basis for evaluating the utility of multi-compartmental dMRI modeling in characterizing coexisting pathophysiology in human optic neuropathies.

Barry Hendin,1 Robert T Naismith,2 Sibyl E Wray,3 Deren Huang,4 Qunming Dong,5 Terrie Livingston,6 Daniel L Jones,6 Crystal Watson,7 Mehul Jhaveri6 1Phoenix Neurological Associates, Phoenix, AZ, USA; 2Department of Neurology, Washington University School of Medicine, St Louis, MO, USA; 3Hope Neurology MS Center, Knoxville, TN, USA; 4Mount Carmel Neuroscience and MDH Research, Westerville, OH, USA; 5Biostatistics, Biogen, Cambridge, MA, USA; 6US Medical, Biogen, Cambridge, MA, USA; 7Global Value and Access, Biogen, Cambridge, MA, USA Objectives: Posthoc analysis of treatment satisfaction in patients switching to subcutaneous (SC) peginterferon beta-1a in the ALLOW study.Patients and methods: Patients with relapsing multiple sclerosis treated with intramuscular interferon (IFN) beta-1a or SC IFN beta-1a or beta-1b remained on their current therapy for a 4-week run-in period, followed by a switch to SC peginterferon beta-1a 125 mcg every 2 weeks for 48 weeks. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM), which covers effectiveness, side effects, convenience, and global satisfaction. Patients completed the TSQM at baseline (prior to starting the 4-week run-in period) and 4, 12, 24, 36, and 48 weeks after switching, and scores were analyzed for the overall population and compared to baseline. Patients reported the severity of flu-like symptoms (FLS) at baseline and with each peginterferon beta-1a injection; clinicians evaluated the occurrence of injection-site reactions (ISRs) after the first dose of peginterferon beta-1a and every 12 weeks thereafter. TSQM scores were stratified by the presence of FLS or ISRs during the study period and by prior IFN therapy use.Results: For the overall population (n=194), convenience and global satisfaction scores significantly improved from baseline at all time points, and side effect satisfaction scores significantly improved up to week 36. Convenience scores significantly improved regardless of FLS, ISRs, or prior IFN therapy. Patients without FLS during the study period showed significant improvements in global satisfaction, but not side effect satisfaction, versus those with FLS. Patients switching from SC IFN therapies achieved greater improvements in treatment satisfaction than patients who switched from intramuscular IFN beta-1a.Conclusions: Switching relapsing multiple sclerosis patients to SC peginterferon beta-1a from other IFN therapies significantly improved treatment satisfaction and convenience. Keywords: interferon beta-1a, interferon beta-1b, peginterferon beta-1a, relapsing multiple sclerosis, treatmentsatisfaction, Treatment Satisfaction Questionnaire for Medication, TSQM, quality of life, patient-reported outcomes

Background Flu-like symptoms are common adverse events associated with interferon beta relapsing multiple sclerosis therapies. Objectives To evaluate the incidence and severity of flu-like symptoms after transitioning from non-pegylated interferons to peginterferon beta-1a and assess flu-like symptom mitigation using naproxen. Methods ALLOW was a phase 3b open-label study in relapsing multiple sclerosis patients. Patients had received non-pegylated interferon for 4 or more months immediately before beginning a 4-week screening period. At baseline, patients switched to peginterferon beta-1a and were randomly assigned (1:1) to continue their current flu-like symptoms management regimen or start twice-daily naproxen 500 mg for 8 weeks. Patients then switched to their preferred regimen and were followed for 48 weeks in total. Results Of 201 patients, 89.6% did not experience new/worsening flu-like symptoms during their first 8 weeks on peginterferon beta-1a. Flu-like symptom severity remained low in current-regimen and naproxen patients, with no significant between-group differences. Median flu-like symptom duration per injection was 3.2 hours longer with peginterferon beta-1a versus prior interferon, but the 4-week cumulative duration was reduced 49–78%. No new safety signals were identified. Conclusion Most patients who switched from non-pegylated interferon to peginterferon beta-1a did not experience new/worsening flu-like symptoms. Flu-like symptom duration per injection increased, but the cumulative duration significantly decreased. These data may inform flu-like symptom management guidance.

Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD).MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups.Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02).The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (-.4%) or expansion of lateral ventricles (3.5%).

OBJECTIVE: Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS. METHODS: A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration

Acute optic neuritis (ON) results in rapid and prominent peripapillary retinal nerve fiber layer (RNFL) and composite ganglion cell and inner plexiform layer (GCIPL) thinning, as measured with optical coherence tomography (OCT). However, the degree of thinning within these layers following ON is heterogeneous, varying across patients, even within the same disease state.1 Moreover, OCT measures in healthy individuals have a broad range, creating difficulties establishing an absolute diagnostic cutoff for prior ON with good sensitivity and specificity. Whereas earlier generation time-domain OCT could be insensitive to subtle RNFL changes following ON,2 and less sensitive than visual evoked potentials for confirming prior ON,3 later generation spectral-domain OCT has improved resolution and reliability, in addition to the ability to measure the advantageous GCIPL, as well as other discrete retinal layers.1,4

Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies.

Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta–treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.

BackgroundThe efficacy and safety of ocrelizumab in relapsing multiple sclerosis were demonstrated in the double-blind control period of the Phase III OPERA I/II trials (NCT01247324/NCT01412333). Here we assessed the efficacy of switching to or maintaining ocrelizumab therapy after 3 years’ follow-up in the open-label extensions (OLEs) of these studies.MethodsAt OLE commencement, patients continued ocrelizumab (OCR-OCR) or switched from interferon-β-1a (IFN) to ocrelizumab (IFN-OCR). Adjusted annualised relapse rate (ARR) and time-to-onset of 24-week confirmed disability progression (CDP24) were analysed.ResultsAmong IFN-OCR patients, ARR decreased from 0.20 in the year pre-switch to 0.10, 0.08 and 0.07 at Years 1, 2 and 3 post-switch. OCR-OCR continuers maintained low ARRs through the year pre-OLE and the 3 years of OLE (0.13, 0.11, 0.08, 0.07). CDP24 was less frequent in OCR-OCR continuers versus IFN-OCR switchers in the year pre-switch and Years 1, 2 and 3 of OLE (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1% and 16.1%/21.3%; pConclusionsSwitching from IFN to ocrelizumab at the start of the OLE provided rapid reductions in ARR, maintained throughout the 3-year follow-up. After 5 years’ follow-up, patients who initiated ocrelizumab 2 years earlier accrued significant, sustained reductions in disability progression compared with patients switching from IFN.DisclosuresSponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.

IntroductionOpicinumab is a human monoclonal antibody against LINGO-1, a negative regulator of oligodendrocyte differentiation and axonal regeneration. The phase 2 SYNERGY study identified a patient subpopulation with a potentially enhanced response to opicinumab treatment.MethodsAFFINITY (NCT03222973) is an ongoing, randomised, double-blind, placebo-controlled phase 2 study to evaluate the efficacy/safety of opicinumab vs placebo as an add-on to disease-modifying therapies in a targeted population. Inclusion criteria include: age 18–58; relapsing multiple sclerosis (MS) with ≤20-year duration; Expanded Disability Status Scale (EDSS) score 2.0–6.0; evidence of disease activity within 24 months prior to enrolment; brain MRI criteria suggestive of low myelin content but preserved tissue integrity in pre-existing T2 lesions; stably treated ≥24 weeks with interferon-beta, dimethyl fumarate, or natalizumab. Primary endpoint is the multicomponent Overall Response Score (based on EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test). Secondary endpoints will evaluate confirmed improvement in disability measures.ResultsEnrolment began in September 2017 and was completed in September 2018. Participant baseline demographic, disease, and MRI characteristics will be presented.ConclusionsAFFINITY will further investigate the efficacy and safety of opicinumab in a subpopulation of MS patients.Support: Biogen. Disclosures to be included on poster.

A relationship between handedness and clinicodemographic profiles of people with multiple sclerosis was sought using data from the Multiple Sclerosis Partners Advancing Technology Health Solutions network of 10 multiple sclerosis centers in the USA and Europe. Handedness data were available for 8888 multiple sclerosis patients, of which 917 (10.3%) were left-handed. Clinicodemographic profiles of right versus left-handed multiple sclerosis patients were similar except for a slightly increased proportion of men who were left-handed, and slightly reduced performance on the manual dexterity test using the non-dominant hand in left-handed patients. We found no evidence to suggest a prognostic implication of handedness in multiple sclerosis.

This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts.This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex.Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p0.0001). 25FTW was associated with RD and FA in PCs (p0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI.DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.

Although self-regulated learning (SRL) is considered a fundamental skill that must be developed in physician training, many programs of SRL utilize learning goals that are generated only at the beginning of learning experiences or are widely spaced apart in time. These goals are often not formally shared with those actually working with the learner in the clinical setting.We developed a program of written, student-generated weekly learning goals in which students focused on processes of becoming better doctors for their patients. These goals were shared at the beginning of each week with students' clinical teams for feedback and incorporation into the work.The weekly learning goals program was developed and implemented as part of a required 3rd-year neurology clerkship. At the end of each 4-week clerkship, students were asked to evaluate the program through an anonymous electronic survey utilizing quantitative and open-ended qualitative questions.Seventy-six of 82 students completed the evaluation survey (93% response rate). Eighty-six percent reported that the weekly learning goals increased their awareness of their thoughts and actions. Seventy-eight percent reported that the learning goals helped to improve their clinical performance to some degree, and 57% reported that the learning goals increased their focus on patient care. Students described a greater sense of focus on self-assessment and accountability from their goals. Students often commented that engagement from attendings and residents regarding their goals was a key element for successful learning from their goals.Student-generated weekly learning goals on a neurology clerkship appear to be an effective method to operationalize SRL. For most students, the frequency of the goals allowed for close self-monitoring, and the act of sharing goals with the team opened a new avenue for dialogue between students and their supervisors.

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS). Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Results: Of 110 misdiagnosed patients, 51 (46%) were classified as “definite” and 59 (54%) “probable” misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Background Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and − 10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. Methods SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. Results A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. Conclusion SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.

Background Patients with neuromyelitis optica (NMO) and multiple sclerosis (MS) both can present with acute optic neuritis (ON), while differing considerably in their prognosis and management. The clinical course, serologic testing results, and brain and spinal cord imaging of these diseases have been well documented. The purpose of this study was to look systematically for any differences in the imaging appearance of the optic nerve in NMO and MS-related ON. Methods Magnetic resonance imaging (MRI) of brain and orbits obtained within 6 weeks of acute ON in patients with securely diagnosed NMO (n = 6) and MS (n = 11) were retrospectively analyzed by a neuroradiologist masked to the clinical diagnosis. Standardized scoring system was used to assess and analyze the extent and nature of optic pathway involvement. Results No significant differences were observed in the presence, degree, or the type of signal alteration and contrast enhancement of the affected nerve segments between NMO and MS groups. There was a trend toward more posterior involvement of the optic nerve in the NMO group with chiasmatic enhancement exclusively seen in NMO patients. Conclusion We found a higher propensity of NMO-related ON to affect more posterior parts of the optic nerve, including chiasm, and have simultaneous bilateral disease. Further study with larger sample sizes is needed.

Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology. Objective: Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions. Methods: Subjects greater than or equal to 12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS and 10 healthy controls were included. Results: Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared with healthy controls ( pConclusions: Higher radial diffusivity within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared with MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions and may be a surrogate of anterograde and retrograde degeneration.

Optical coherence tomography (OCT) has been applied to multiple sclerosis (MS) to investigate retinal neuroaxonal loss. Reductions in peripapillary retinal nerve fiber layer (pRNFL) thickness have been reported in different MS-related subtypes from clinically isolated syndromes1 to secondary progressive MS.2 A recent meta-analysis additionally confirmed atrophy of the ganglion cell–inner plexiform (GCIP) layer in MS.3 Associations between OCT-derived retinal thicknesses (pRNFL and GCIP) and cerebral atrophy quantified by MRI have also been reported,4,5 leading to the suggestion of using OCT as a biomarker of MS disease progression in the clinic. Despite challenges and lingering questions, several recent studies suggest potential for clinical value. For example, a recent retrospective study provided evidence for differential rates of GCIP atrophy according to DMT usage. Natalizumab-treated patients with MS exhibited the lowest atrophy rates (−0.16 μm/y), similar to healthy controls (−0.14 μm/y), whereas those treated with interferon-β and glatiramer acetate had more atrophy (−0.28 to −0.54 μm/y).6 An earlier study found faster GCIP annualized thinning rates associated with clinical or radiologic MS activity in 161 patients.7 In addition, a recent cohort study identified a cutoff of 88 μm for the pRNFL to predict twice the risk of disability worsening at 2 years and 4 times higher risk at 5 years for the patients (many being treated) below this cutoff.8 This literature implies a potential role for OCT in the clinical monitoring of MS in the future.

The standard functional tool for gait assessment in multiple sclerosis (MS) clinical trials has been the 25-Foot Timed Walk Test, a measure of gait speed. Straight-line gait assessment may not reflect adequately upon balance and coordination. Walking tests with turns may add additional information towards understanding gait and balance status, and be more reflective of ambulation in the community. Understanding the impact of turn parameters on patient-reported outcomes of balance and walking would help MS clinicians better formulate treatment plans for persons with gait limitations. In this study, ninety-one persons with MS (Expanded Disability Status Score; EDSS, range: 0-6.5) were enrolled in an initial cross-sectional study. Twenty-four subjects (EDSS, range:1.0-6.0) completed a follow-up visit an average of 12 months later. Spatiotemporal gait analysis was collected at both visits using APDM Opal wireless body-worn sensors while performing the Timed-Up-and-Go (TUG) and 6-Minute Walk Test (6MWT). For both cross-sectional and longitudinal data, regression analyses determined the impact on the addition of turning parameters to stride velocity (SV), in the prediction of self-reported balance confidence (Activities-Specific Balance Confidence Scale (ABC)) and walking limitation (12-item Multiple Sclerosis Walking Scale (MSWS-12)). The addition of 6MWT peak turn velocity (PTV) to 6MWT SV increased the predictive power of the 6MWT for the ABC from 20% to 33%, and increased the predictive power from 28% to 41% for the MSWS-12. TUG PTV added to TUG SV also strengthened the relationship of the TUG for the ABC from 19% to 28%, and 27% to 36% for the MSWS-12. For those with 1 year follow-up, percent change in turn number of steps (TNS%Δ) during the 6MWT added to 6MWT SV%Δ improved the modeling of ABC%Δ from 24% to 33%. 6MWT PTV%Δ added to 6MWT SV%Δ increased the predictive power of MSWS-12%Δ from 8% to 27%. Conclusively, turn parameters improved modeling of self-perceived balance confidence and walking limitations when added to the commonly utilized measure of gait speed. Tests of longer durations with multiple turns, as opposed to shorter durations with a single turn, modeled longitudinal change more accurately. Turn speed and stability should be qualitatively assessed during the clinic visit, and use of multi-faceted tests such as the TUG or 6MWT may be required to fully understand gait deterioration in persons with MS.

Objective: B cells and the humoral immune system have been implicated in the pathogenesis of multiple sclerosis (MS). This study sought to evaluate the efficacy, safety, and tolerability of add-on therapy with rituximab, a monoclonal antibody that depletes circulating B cells, in subjects with relapsing MS with breakthrough disease defined by clinical and MRI activity (Class III evidence). Methods: Thirty subjects with a relapse within the past 18 months despite use of an injectable disease-modifying agent, and with at least 1 gadolinium-enhancing (GdE) lesion on any of 3 pretreatment MRIs, received rituximab administered at 375 mg/m 2 weekly × 4 doses. Three monthly posttreatment brain MRI scans were obtained beginning 12 weeks after the first infusion. Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) were obtained at baseline and throughout the posttreatment follow-up. Results: GdE lesions were reduced after treatment with rituximab, with 74% of posttreatment MRI scans being free of GdE activity compared with 26% free of GdE activity at baseline ( p p = 0.02). EDSS remained stable. Conclusion: Rituximab add-on therapy was effective based upon blinded radiologic endpoints in this phase II study. In combination with standard injectable therapies, rituximab was well-tolerated with no serious adverse events. B-cell–modulating therapy remains a potential option for treatment of patients with relapsing MS with an inadequate response to standard injectable therapies. Classification of evidence: This study provides Class III evidence that add-on rituximab reduces gadolinium-enhancing brain lesions in multiple sclerosis.

The purpose of this study was to assess pain, fatigue, depression, sleep disturbance, and quality of life (QOL) in women with relapsing-remitting multiple sclerosis (RRMS) compared with healthy controls. A prospective, cross-sectional, matched-control study was conducted in women with RRMS compared with healthy women. Compared with healthy women, women with RRMS had (a) greater pain presence over 7 days (67%), (b) higher pain intensity, and (c) more pain interference. Pain had a negative impact on fatigue, depression, and sleep in both groups. In all participants, fatigue, depression, and sleep disturbance contributed to decreased mental QOL (mental component summary of QOL scores). Pain has significant nursing implications for women with RRMS. Pain often occurs in association with fatigue, depression, and sleep disturbance, which can lead to a decreased mental QOL.

Determine the utility of optical coherence tomography (OCT) to detect clinical and subclinical remote optic neuritis (ON), its relationship to clinical characteristics of ON and visual function, and whether the retinal nerve fiber layer (RNFL) thickness functions as a surrogate marker of global disease severity.Cross-sectional study of 65 subjects with at least 1 clinical ON episode at least 6 months prior. Measures included clinical characteristics, visual acuity (VA), contrast sensitivity (CS), OCT, and visual evoked potentials (VEP).Ninety-six clinically affected optic nerves were studied. The sensitivity of OCT RNFL after ON was 60%, decreasing further with mild onset and good recovery. VEP sensitivity was superior at 81% (p = 0.002). Subclinical ON in the unaffected eye was present in 32%. VEP identified 75% of all subclinically affected eyes, and OCT identified20%. RNFL thickness demonstrated linear correlations with VA (r = 0.65) and CS (r = 0.72) but was unable to distinguish visual categories20/50. RNFL was thinner with severe onset and disease recurrence but was unaffected by IV glucocorticoids. OCT measurements were not related to overall disability, ethnicity, sex, or age at onset. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye.Visual evoked potentials (VEP) remains the preferred test for detecting clinical and subclinical optic neuritis. Optical coherence tomography (OCT) measures were unrelated to disability and demographic features predicting a worse prognosis in multiple sclerosis. OCT may provide complementary information to VEP in select cases, and remains a valuable research tool for studying optic nerve disease in populations.

MRI has revolutionized the diagnosis of multiple sclerosis (MS). In addition, use of MRI has provided a means to monitor disease and the response to therapy and has been used extensively as an adjunct means to evaluate new therapies. Despite its high sensitivity to detect MS lesions, its specificity for the underlying pathology is low. Furthermore, correlation of MS disability with the extent of abnormalities using several different methods of imaging has been modest at best. This chapter discusses the main imaging techniques used for MS diagnosis, MS management and treatment monitoring, and in clinical trials.

Background: African Americans (AAs) experience greater disability from multiple sclerosis (MS) compared with Caucasian Americans (CAs). Interethnic immunologic differences in MS and their relationship to disease-related disability have not been described. Objective: To compare measures of CSF humoral immunity between AAs and CAs with MS. Methods: Using a case–control design, all AA MS patients with CSF immune studies at the Washington University MS center were compared with randomly selected CAs with MS. Two CA controls were selected for every AA case. Immunoglobulin G (IgG) index and synthesis rates, oligoclonal band positivity, white blood cell count, and CSF protein were compared between groups. Survival analysis was conducted to compare times to ambulatory assistance. Results: Sixty-six AA cases and 132 CA controls were identified. Measures of CSF humoral activity were all higher in the AA group. The mean IgG index of AAs was 1.35 (SD 0.62), and that of CAs was 1.05 (SD 0.55), for a mean difference of 0.30 ( p = 0.001). The median IgG synthesis rate was also higher among AAs (13.55 vs 8.20 mg/day), for a median difference of 5.35 mg/day ( p = 0.010). Survival analysis confirmed previous reports of earlier ambulatory assistance requirement among AAs. Despite differences in both humoral immune response and times to ambulatory assistance, Cox proportional hazards modeling did not show IgG index as predictive of earlier ambulatory assistance. Conclusions: The CSF humoral immune response is more active among African Americans (AAs) than among Caucasian Americans (CAs) with multiple sclerosis. AAs also progress to ambulatory assistance earlier than CAs, but high immunoglobulin G index does not predict earlier progression to the disability endpoint.

See Naismith and Cross (doi:10.1093/brain/awv196) for a scientific commentary on this article. Optic neuritis is highly associated with development of multiple sclerosis. Cramer et al. show that MRI measures of blood-brain barrier permeability improve prediction of conversion to multiple sclerosis within 2 years, compared to T2-lesion count alone. Permeability measures also correlate with CSF biomarkers of cellular trafficking and blood-brain barrier breakdown., Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood–brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood–brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood–brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood–brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of 88% and specificity of 72%. We found a significant correlation between permeability and the leucocyte count in cerebrospinal fluid as well as levels of CXCL10 and MMP9 in the cerebrospinal fluid. These findings suggest that blood–brain barrier permeability, as measured by magnetic resonance imaging, may provide novel pathological information as a marker of neuroinflammation related to multiple sclerosis, to some extent reflecting cellular permeability of the blood–brain barrier, whereas T2 lesion count may more reflect the length of the subclinical pre-relapse phase. See Naismith and Cross (doi:10.1093/brain/awv196) for a scientific commentary on this article.

Patients with multiple sclerosis have benefited from an increasingly large number of choices for anti-inflammatory, disease-modifying therapy. One cannot reliably predict how an individual patient will respond to a particular therapy. MRI has become an integral component of therapy selection and monitoring in multiple sclerosis.Number of lesions at baseline and new lesions on therapy have implications for long-term prognosis. To achieve best therapeutic outcomes, patients with accumulating lesions may benefit from a change in their therapy. For patients with established stable disease, MRI may be done less frequently.Practitioners should be obtaining brain MRI scans to supplement their clinical evaluations and assess for subclinical disease activity. In certain circumstances, changing therapy may be warranted based upon MRI alone, despite the appearance of clinical stability. The appearance of two to five T2-weighted lesions or one to two gadolinium-enhancing lesions represents a threshold of concern.

Objectives To preliminarily assess annualised relapse rate (ARR) at 144 weeks among patients with relapsing multiple sclerosis (RMS) who received ocrelizumab or interferon beta-1a (IFNβ−1a) in the Phase III 96 week OPERA I and II trials, followed by ocrelizumab in an open-label extension (OLE). The efficacy and safety of ocrelizumab in RMS have been demonstrated in the OPERA trials. Oon completion of the controlled treatment period, all patients were eligible to enter an ocrelizumab OLE phase. Methods During the controlled treatment period, patients received intravenous ocrelizumab 600 mg every 24 weeks or subcutaneous IFNβ−1a 44 mg three times weekly for 96 weeks. During the OLE, patients from the IFNβ−1a group were switched to ocrelizumab. Results Patients from OPERA I (ocrelizumab, 352/410; IFNβ−1a, 326/411) and OPERA II (ocrelizumab, 350/417; IFNβ−1a, 297/418) enrolled in the OLE. At the time of analysis, 317 (90.1%) and 322 (92.0%) continuous ocrelizumab patients and 307 (94.2%) and 268 (90.2%) patients switching from IFNβ−1a in OPERA I and II, respectively, had ≥48 weeks of follow-up in the OLE (144 weeks total). Across groups, patients received a median of two doses of ocrelizumab in the OLE. Among patients switching from IFNβ−1a to ocrelizumab, the unadjusted ARR improved from 0.245 and 0.254 over 96 weeks in OPERA I and II, respectively, to 0.092 and 0.115 in the OLE. Among continuous ocrelizumab patients, the unadjusted ARR was 0.136 and 0.138 in OPERA I and II, respectively; during the OLE, the ARR in this group was 0.118 and 0.100, respectively. Imaging metrics will be presented. Conclusions Patients who originally received ocrelizumab in the OPERA studies continued to have favourable ARR outcomes in the OLE. Patients who switched from IFNβ−1a to ocrelizumab in the OLE rapidly experienced ARR outcomes consistent with those of patients who received continuous ocrelizumab.

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease-modifying therapies introduced in the 1990s, the beta-interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha-4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long-term postmarketing efficacy and safety data in a general MS population. Because of this lack of long-term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit-to-risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e.g. fingolimod or natalizumab if JC virus antibody-negative). The aim of this review is to discuss the clinical benefits, mechanisms of action, safety profiles and monitoring strategies of current MS disease-modifying therapies in clinical practice and of those expected to enter the market in the near future.

Progranulin has recently attracted attention due to the discovery of mutations in its encoding gene (GRN) in several cases of frontotemporal lobar degeneration, but also for a possible role in inflammatory processes. In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. Progranulin cerebrospinal fluid (CSF) levels were evaluated in 55 patients with multiple sclerosis (MS) as well as in 35 subjects with non-inflammatory neurological diseases (NIND), 7 individuals with other inflammatory neurological disease (OIND) and 8 controls (CON), matched for ethnic background, gender and age. No statistically significant differences were found in patients compared with either NIND, OIND or CON (P > 0.05), even stratifying according to disease subtype or gender. A positive correlation between progranulin CSF levels and age was observed in patients (ρ = 0.29, P = 0.03). According to these data, progranulin does not likely play a major role in the pathogenesis of MS.

Neuromyelitis optica (NMO) is an inflammatory and demyelinating disease characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM).1 NMO is associated with antibodies against the aquaporin-4 (AQP4) water channel.2 NMO–immunoglobulin G (IgG) predicts a relapsing course and is a supportive criterion for NMO.3–5 The high risk of relapse, sometimes with devastating effects, makes early diagnosis important. Early identification permits counseling and consideration for immunosuppressive therapy. The serum NMO-IgG assay, using indirect immunofluorescence, is 73% sensitive and 91% specific for clinically defined NMO.6 While helpful when positive, the sensitivity is insufficient to exclude the diagnosis. We describe 3 of 26 patients with NMO at our institution with NMO-IgG positivity restricted to CSF. ### Case reports. #### Case 1. A 25-year-old African American woman presented with leg numbness and mild tetraparesis that resolved over 1 month. Two months later, she developed a midthoracic sensory level, again with recovery. The next month, bilateral leg weakness impaired her ability to ambulate. MRI (figure, A–C) demonstrated T2 hyperintensities (T2H) and patchy enhancement spanning the medulla through C7 and T2–T11. Brain MRI revealed a single nonspecific T2H. Visual evoked potentials (VEPs) were normal. Serum NMO-IgG was negative but CSF NMO-IgG was positive. IgG index was elevated to 0.79, CSF leukocytes were 24/μL, but albumin index, IgG synthesis, and oligoclonal bands (OCBs) were normal. Serum antinuclear antibodies (ANA) were negative. Treatment included IV glucocorticoids and rituximab with no further exacerbations. After 8 months of disease, Expanded Disability Status Scale (EDSS) was 6.0. Figure Neuroimaging of CSF antibody-positive neuromyelitis optica Case 1: Sagittal T2-weighted STIR …

Our patients with multiple sclerosis (MS) frequently inquire about the safety and efficacy of an annual influenza vaccination. Influenza remains a leading cause of mortality in the United States, with an estimated 20,000 deaths or more annually. Approximately 40% of all adults in the United States are vaccinated annually. The necessity of vaccination is particularly compelling for those with MS, who are twice as likely to be admitted for influenza compared to those without MS.1 What should we tell our patients regarding vaccinations and their disease-modifying therapy?

Emerging evidence underlines the importance of micro(mi)RNAs in the pathogenesis of multiple sclerosis (MS). Free-circulating miRNAs were investigated in serum from MS patients compared to controls. Statistically significant decreased levels of miR-15b, miR-23a and miR-223 were observed in MS patients ( p < 0.05). Results were validated and replicated in two further independent MS populations. A direct correlation between miRNA levels and the EDSS score was determined in PPMS ( p < 0.007). The generalized trend toward miRNA down-regulation could result in over-expression of target genes involved in disease pathogenesis. Circulating miRNA profiling could thus represent a new avenue to identify easily detectable disease biomarkers.

The aim of the study was to establish the concurrent validity, relative and absolute reliability, define the minimal detectable change (MDC), and evaluate the floor and ceiling effects of the Four Square Step Test (FSST) in ambulant persons with multiple sclerosis (pwMS). Twenty-five pwMS performed the FSST on two occasions 8.1 ± 4.1 days apart. During the first testing session participants also reported fall history, performed the Berg Balance Scale (BBS), Dynamic Gait Index (DGI), and completed the Activities-Specific Balance Confidence Scale (ABC). Performance on the FSST was significantly (p < 0.001) and strongly associated with performance on the BBS ([Formula: see text] = −0.84), DGI ([Formula: see text] = −0.81), and ABC ([Formula: see text] = − 0.78). Relative reliability of the FSST was excellent ([Formula: see text] = 0.922). The MDC estimate for the FSST was 4.6 seconds. The FSST is a valid and reliable measure of dynamic standing balance in ambulant pwMS. However, because a substantial change (43%) is required to demonstrate a real change in individual performance, the FSST is unlikely to be sensitive to detecting longitudinal change in dynamic standing balance.

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.

Horseradish peroxidase (HRP) is well known for mediating the electron-transfer oxidation of electron-rich aromatic 'donors' such as phenols and anilines, but has not been described to oxidize aliphatic amines. We here confirm the inability of HRP to oxidize typical aliphatic amines, even those which would exist significantly as free bases at the operative pH. In contrast, trans-2-phenylcyclopropylamine (2-PCPA) is both a substrate (turnover product is cinnamaldehyde) and a time-dependent inactivator of HRP. These activities of 2-PCPA are consistent with either a concerted or rapid sequential one-electron-oxidation/ring-opening to give an intermediate capable of covalent binding to the enzyme. 2-PCPA is the first known example of a simple aliphatic amine which serves as a substrate for HRP under turnover conditions.