Pumping up the Fight against Multiple Sclerosis: The Effects of High-Intensity Resistance Training on Functional Capacity, Muscle Mass, and Axonal Damage.

BACKGROUND: Resistance training (RT) has been recognized as a beneficial non-pharmacological intervention for multiple sclerosis (MS) patients, but its impact on neurodegeneration is not fully understood. This study aimed to investigate the effects of high-intensity RT on muscle mass, strength, functional capacity, and axonal damage in MS patients. METHODS: Eleven relapsing-remitting MS patients volunteered in this within-subject counterbalanced intervention study. Serum neurofilament light-chain (NfL) concentration, vastus lateralis thickness (VL), timed up-and-go test (TUG), sit-to-stand test (60STS), and maximal voluntary isometric contraction (MVIC) were measured before and after intervention. Participants performed 18 sessions of high-intensity RT (70-80% 1-RM) over 6 weeks. RESULTS: Significant (p < 0.05) differences were observed post-intervention for VL (ES = 2.15), TUG (ES = 1.98), 60STS (ES = 1.70), MVIC (ES = 1.78), and NfL (ES = 1.43). Although moderate correlations between changes in VL (R = 0.434), TUG (R = -0.536), and MVIC (R = 0.477) and changes in NfL were observed, only the correlation between VL and MVIC changes was significant (R = 0.684, p = 0.029). CONCLUSIONS: A 6-week RT program significantly increased muscle mass, functional capacity, and neuromuscular function while also decreasing serum NfL in MS patients. These results suggest the effectiveness of RT as a non-pharmacological approach to mitigate neurodegeneration while improving functional capacity in MS patients.

Effect of resistance exercise training on plasma neurofilaments in multiple sclerosis: a proof of concept for future designs.

Multiple sclerosis (MS) is a dysimmune and neurodegenerative disease of the central nervous system that continues to be one of the main causes of non-traumatic disability in young people despite the recent availability of highly effective drugs. Exercise-based interventions seem to have a positive impact on the course of the disease although pathophysiological mechanisms responsible for this benefit remain unclear. This is a longitudinal study to examine the effects of a short-term training program on neurofilament plasma levels, a biomarker of axonal destruction, measured using the ultrasensitive single molecule array (SiMoA). Eleven patients completed a 6-week supervised resistance-training program of 18 sessions that consisted of 3 sets of 8-10 repetitions of 7 exercises. Median plasma neurofilament levels significantly decreased from baseline (6.61 pg/ml) to 1 week after training intervention (4.44 pg/ml), and this effect was maintained after 4 weeks of detraining (4.38 pg/ml). These results suggest a neuroprotective effect of resistance training in this population and encourage us to investigate further the beneficial impact of physical exercise and to emphasize the importance of lifestyle in MS.

A smartphone sensor-based digital outcome assessment of multiple sclerosis.

BACKGROUND: Sensor-based monitoring tools fill a critical gap in multiple sclerosis (MS) research and clinical care. OBJECTIVE: The aim of this study is to assess performance characteristics of the Floodlight Proof-of-Concept (PoC) app. METHODS: In a 24-week study (clinicaltrials.gov: NCT02952911), smartphone-based active tests and passive monitoring assessed cognition (electronic Symbol Digit Modalities Test), upper extremity function (Pinching Test, Draw a Shape Test), and gait and balance (Static Balance Test, U-Turn Test, Walk Test, Passive Monitoring). Intraclass correlation coefficients (ICCs) and age- or sex-adjusted Spearman's rank correlation determined test-retest reliability and correlations with clinical and magnetic resonance imaging (MRI) outcome measures, respectively. RESULTS: Seventy-six people with MS (PwMS) and 25 healthy controls were enrolled. In PwMS, ICCs were moderate-to-good (ICC(2,1) = 0.61-0.85) across tests. Correlations with domain-specific standard clinical disability measures were significant for all tests in the cognitive (r = 0.82, p < 0.001), upper extremity function (|r|= 0.40-0.64, all p < 0.001), and gait and balance domains (r = -0.25 to -0.52, all p < 0.05; except for Static Balance Test: r = -0.20, p > 0.05). Most tests also correlated with Expanded Disability Status Scale, 29-item Multiple Sclerosis Impact Scale items or subscales, and/or normalized brain volume. CONCLUSION: The Floodlight PoC app captures reliable and clinically relevant measures of functional impairment in MS, supporting its potential use in clinical research and practice.

Menopause does not modify disability trajectories in a longitudinal cohort of women with clinically isolated syndrome and multiple sclerosis followed from disease onset.

BACKGROUND AND PURPOSE: To evaluate the effect of menopause on disability accumulation in women followed from their clinically isolated syndrome (CIS). METHODS: We examined the longitudinal changes in Expanded Disability Status Scale (EDSS) scores from CIS until the last follow-up in women belonging to the Barcelona CIS prospective cohort, followed through their menopausal transition. The analysis is based on 13,718 EDSS measurements, with an average of 28 EDSS measurements per patient. Differences in EDSS trajectories between menopausal and nonmenopausal women, controlling for age and disease duration, were evaluated. We performed two sensitivity analyses in women with confirmed MS and in those experiencing early menopause. RESULTS: From 764 eligible women, 496 (65%) responded to the questionnaire, and 74 (14.9%) reached menopause over the follow-up. We did not find a significant inflection point in EDSS trajectories around menopause (slope change -0.009; 95% CI -0.066; 0.046). The annual increase in EDSS over the complete course of the disease was significantly higher in menopausal women (0.049; 95% CI, 0.026-0.074) versus nonmenopausal (0.019; 95% CI, 0.008-0.031; interaction p value 0.025). This difference was lost when controlling for age and disease duration (EDSS annual increase of 0.059; 95% CI, 0.025-0.094 vs. 0.038; 95% CI, 0.021-0.057, respectively; interaction p value 0.321). No inflection point was detected when the analysis was restricted to women with confirmed MS or with earlier menopause. CONCLUSIONS: Menopause is not associated with an increased risk of disability in a CIS population, considering EDSS trajectories throughout the course of the disease together with age and disease duration.

The long-term outcomes of CIS patients in the Barcelona inception cohort: Looking back to recognize aggressive MS.

OBJECTIVE: To explore the long-term outcomes of patients with clinically isolated syndromes from the Barcelona cohort. METHODS: We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years). RESULTS: In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irreversible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast-enhancing lesions (CEL) was 71 (28-95) versus 7 (1-19) and 3 (1-24) versus 0 (0-1), respectively. The cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL. CONCLUSION: Although MS natural history is changing, a high lesion load at onset is helpful to identify patients at risk of presenting an aggressive MS.

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Correction: Adherence and Satisfaction of Smartphone- and Smartwatch-Based Remote Active Testing and Passive Monitoring in People With Multiple Sclerosis: Nonrandomized Interventional Feasibility Study.

[This corrects the article DOI: 10.2196/14863.].

Adherence and Satisfaction of Smartphone- and Smartwatch-Based Remote Active Testing and Passive Monitoring in People With Multiple Sclerosis: Nonrandomized Interventional Feasibility Study.

BACKGROUND: Current clinical assessments of people with multiple sclerosis are episodic and may miss critical features of functional fluctuations between visits. OBJECTIVE: The goal of the research was to assess the feasibility of remote active testing and passive monitoring using smartphones and smartwatch technology in people with multiple sclerosis with respect to adherence and satisfaction with the FLOODLIGHT test battery. METHODS: People with multiple sclerosis (aged 20 to 57 years; Expanded Disability Status Scale 0-5.5; n=76) and healthy controls (n=25) performed the FLOODLIGHT test battery, comprising active tests (daily, weekly, every two weeks, or on demand) and passive monitoring (sensor-based gait and mobility) for 24 weeks using a smartphone and smartwatch. The primary analysis assessed adherence (proportion of weeks with at least 3 days of completed testing and 4 hours per day passive monitoring) and questionnaire-based satisfaction. In-clinic assessments (clinical and magnetic resonance imaging) were performed. RESULTS: People with multiple sclerosis showed 70% (16.68/24 weeks) adherence to active tests and 79% (18.89/24 weeks) to passive monitoring; satisfaction score was on average 73.7 out of 100. Neither adherence nor satisfaction was associated with specific population characteristics. Test-battery assessments had an at least acceptable impact on daily activities in over 80% (61/72) of people with multiple sclerosis. CONCLUSIONS: People with multiple sclerosis were engaged and satisfied with the FLOODLIGHT test battery. FLOODLIGHT sensor-based measures may enable continuous assessment of multiple sclerosis disease in clinical trials and real-world settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02952911; https://clinicaltrials.gov/ct2/show/NCT02952911.

Engaging across dimensions of diversity: A cross-national perspective on mHealth tools for managing relapsing remitting and progressive multiple sclerosis.

BACKGROUND: Smartphone apps and wearable devices could augment clinical practice by detecting changes in health status for multiple sclerosis (MS). This study sought to investigate potential barriers and facilitators for uptake and sustained use in (i) people with both relapsing remitting MS (RRMS) and progressive MS (PMS) and (ii) across different countries. METHODS: Twenty four participants with MS took part in four focus groups held in three countries (2 in the UK, 1 in Spain, and 1 in Italy) to investigate potential barriers and facilitators for mHealth technology. A systematic thematic analysis was used to extract themes and sub-themes. RESULTS: Facilitators and barriers were organised into functional technology-related factors and non-functional health-related and user-related factors. Twelve themes captured all requirements across the three countries for both RRMS and PMS. Key requirements included accommodation for varying physical abilities, providing information and memory aids. Potential negative effects on mood and providing choice and control as part of overcoming practical challenges were identified. CONCLUSIONS: We took a cross-national perspective and found many similarities between three European countries across people with RRMS and PMS. Future provision should accommodate the key requirements identified to engage people with MS in scalable mHealth interventions.

CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.

OBJECTIVE: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria. RESULTS: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma. CONCLUSIONS: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis.

OBJECTIVE: To investigate the effect of menarche, pregnancies, and breastfeeding on the risk of developing multiple sclerosis (MS) and disability accrual using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndrome (CIS). METHODS: A cross-sectional survey of the reproductive information of female participants in a CIS cohort was performed. We examined the relationship of age at menarche with the risk of clinically definite MS (CDMS), McDonald 2010 MS, and Expanded Disability Status Scale (EDSS) 3.0 and 6.0. The effect of pregnancy (before and after CIS) and breastfeeding in the risk of CDMS, McDonald 2010 MS, and EDSS 3.0 was also examined. Univariate and multivariate analyses were performed and findings were confirmed using sensitivity analyses and a propensity score model. RESULTS: The data of 501 female participants were collected. Age at menarche did not correlate with age at CIS and was not associated with the risk of CDMS or EDSS 3.0 or 6.0. Pregnancy before CIS was protective for CDMS in the univariate analysis, but the effect was lost in the multivariate model and did not modify the risk of EDSS 3.0. Pregnancy after CIS was protective for both outcomes in univariate and multivariate analyses when pregnancy was considered a baseline variable, but the protective effect disappeared when analyzed as a time-dependent event. Breastfeeding did not modify the risk for the 3 outcomes. CONCLUSIONS: These results demonstrate that menarche, pregnancies, and breastfeeding did not substantially modify the risk of CDMS or disability accrual using a multivariable and time-dependent approach.

Frequency and relevance of IgM, and IgA antibodies against MOG in MOG-IgG-associated disease.

OBJECTIVE: To determine the frequency and relevance of IgM, and IgA antibodies against myelin oligodendrocyte glycoprotein (MOG) in MOG-IgG-associated disease. METHODS: Evaluation of IgM, and IgA MOG antibodies in serum of 120 patients with MOG-IgG (53 pediatric and 67 adults), and 114 patients with seronegative-MOG-IgG (35 children with first demyelinating syndrome, 20 adults with clinically isolated syndrome, and 59 adults with other diseases). Antibodies were examined by cell-based assays. RESULTS: IgM or IgA MOG antibodies were identified in 23/120 (19%) patients with MOG-IgG (13/53 [24.5%] pediatric, and 10/67 [15%] adult patients), and 2/114 (1.7%) patients with seronegative-MOG-IgG (2/35 [5.7%] pediatric patients). Of the 25 patients, 14 had IgA, 9 IgM, and 2 both antibodies. Fourteen of the 15 (93%) children with IgM (4), IgA (9), or both (2) had acute demyelinating encephalomyelitis (ADEM), and 7 of the 10 (70%) adults with IgM (5) or IgA (5) had optic neuritis at onset. At the last follow-up, the final diagnoses remained as ADEM in 14 (100%) children and optic neuritis in 6 (86%) adults. The outcome was not different between patients with or without additional classes of antibodies. CONCLUSION: Coexisting IgM and IgA antibodies occurs in 19% of children and adult patients with MOG-IgG-associated disease. The presence of these antibodies does not seem to play a relevant clinical role in the disorder.

Ocrelizumab: a new milestone in multiple sclerosis therapy.

B cells play a central role in the pathogenesis of multiple sclerosis (MS): they are involved in the activation of pro-inflammatory T cells, secretion of pro-inflammatory cytokines and production of autoantibodies directed against myelin. Hence, the use of B cell-depleting monoclonal antibodies as therapy for autoimmune diseases, including MS, has increased in recent years. Previous results with rituximab, the first therapeutic B cell-depleting chimeric monoclonal antibody that showed efficacy in MS clinical trials, encouraged researchers to evaluate the efficacy of a humanized anti-CD20 antibody, ocrelizumab, in MS. A large phase II clinical trial in patients with relapsing-remitting MS (RRMS) designed to explore the effects of two doses of ocrelizumab (600 mg and 2000 mg) compared with placebo showed a pronounced effect on radiological and relapse-related outcomes. These results were confirmed in two phase III trials (OPERA I and II) that compared the efficacies of ocrelizumab with interferon beta-1a in patients with relapsing MS, and showed decreased annualized relapse rates (46% in OPERA I and 47% in OPERA II), as well as fewer numbers of gadolinium-enhanced lesions on magnetic resonance imaging (MRI) scans (94% in OPERA I and 95% in OPERA II). Notably, ocrelizumab is the first drug to lower rates of clinical and MRI-evidenced progression in patients with primary progressive MS (PPMS). The phase III trial (ORATORIO) in patients with PPMS met its primary efficacy endpoint: the percentage of patients with 12-week confirmed disability progression was significantly lower in the active treatment group (32.9%) than in patients receiving placebo (39.3%). In March 2017, this evidence led the US Food and Drug Administration to approve the licence for ocrelizumab (Ocrevus®) as a treatment for MS, as the first treatment approved for PPMS and as the first monoclonal antibody for secondary progressive MS.

The value of oligoclonal bands in the multiple sclerosis diagnostic criteria.

The presence of oligoclonal bands in clinically isolated syndromes is an independent risk factor for developing multiple sclerosis and has been largely excluded from the more recent multiple sclerosis diagnostic criteria. Therefore, our objective was to explore the value of oligoclonal bands in the context of the 2010 McDonald criteria, especially in patients fulfilling exclusively dissemination in space at baseline. For this purpose, we selected 566 patients from a clinically isolated syndrome inception cohort who had IgG oligoclonal bands determination and sufficient data on baseline brain MRI to assess dissemination in space and time. We excluded the cases already fulfilling both dissemination in space and time and divided the remaining 398 into 'no dissemination in space and time' (n = 218), 'dissemination in space' (n = 164) and 'dissemination in time' (n = 16). We assessed Cox proportional hazards regression models with 2010 McDonald as the outcome, using 'no dissemination in space and time' with 0 lesions and negative oligoclonal bands as the reference for different subgroups according to oligoclonal bands status (positive/negative). To assess the diagnostic properties, we selected cases with a follow-up ≥3 years or fulfilling 2010 McDonald within 3 years of the clinically isolated syndrome (n = 314), and compared the performance of all 'dissemination in space' cases (n = 137) versus patients with 'dissemination in space' and positive oligoclonal bands (n = 101). The remaining patients classified as fulfilling 'dissemination in time' or 'no dissemination in space and time' were taken into account to calculate the diagnostic properties. The respective adjusted hazard ratios (95% confidence interval) were 1.5 (0.4-5.7) for 'no dissemination in space and time' with 0 lesions and positive oligoclonal bands, 3.1 (1.4-7.2) for 'no dissemination in space and time' with ≥1 lesions and negative oligoclonal bands, 7.4 (3.5-15.7) for 'no dissemination in space and time' with ≥1 lesions and positive oligoclonal bands, 10.4 (4.8-22.6) for 'dissemination in space' with negative oligoclonal bands, 15.3 (7.5-31.3) for 'dissemination in space' with positive oligoclonal bands, and 9.1 (3.5-23.4) for 'dissemination in time' (not subdivided due to the sample size). The specificity for all cases with 'dissemination in space' was 80.6 and increased to 88.1 after selecting those with positive oligoclonal bands. According to these results, we propose radiological dissemination in space at any time plus positive oligoclonal bands as an additional criterion for diagnosing multiple sclerosis.

Rituximab: eficacia, efectividad y seguridad en el tratamiento de la esclerosis múltiple / Rituximab: its efficacy, effectiveness and safety in the treatment of multiple sclerosis

Introducción. Existe evidencia creciente de que las células B y la inmunidad humoral tienen un papel fundamental en la fisiopatogenia de la esclerosis múltiple (EM). El ocrelizumab, un anticuerpo monoclonal anti-CD20, ha demostrado ser eficaz en el control de la enfermedad y recientemente ha sido aprobado por la Food and Drug Administration estadounidense para el tratamiento de las formas primariamente progresivas y las formas recidivantes de la EM. A la espera de su comercialización, el uso del rituximab, con un mecanismo de acción similar, se ha expandido ampliamente en el área de las enfermedades desmielinizantes. Objetivo. Abordar los principales aspectos de eficacia, efectividad y seguridad del rituximab en el tratamiento de la EM. Desarrollo. Se realizó una revisión bibliográfica a través de PubMed de los ensayos clínicos controlados con placebo, los estudios prospectivos abiertos, los estudios observacionales retrospectivos y las series de casos que utilizaron rituximab en poblaciones adultas afectas de EM. Se valoró su impacto en el control clínico y radiológico de la enfermedad, así como los aspectos relevantes de seguridad. Conclusiones. En todos los estudios revisados, el rituximab demostró un beneficio consistente en cuanto al control de la actividad inflamatoria, tanto clínica, reduciendo la incidencia de brotes, como radiológica, evitando la aparición de lesiones nuevas o activas. Por el contrario, respecto a la progresión de la discapacidad, su efecto es más controvertido. No se hallaron alertas de seguridad destacables. El rituximab parece ser un fármaco eficaz, efectivo y seguro en el tratamiento de la EM (AU)

Introduction. There is increasing evidence that B cells and humoral immunity play key roles in the pathogenesis of multiple sclerosis (MS). Ocrelizumab, an anti-CD20 monoclonal antibody, has been shown to be effective in controlling the disease and has recently been aproved by the Food and Drug Administration for the treatment of primary progressive and relapsing MS. While awaiting its marketing authorization, the use of rituximab, with a similar mechanism of action, has expanded widely in the area of demyelinating diseases. Aim. To address the main aspects of efficacy, effectiveness and safety of rituximab in the treatment of MS. Development. PubMed review of placebo-controlled clinical trials, prospective open label studies, retrospective observational studies, and case series using rituximab in adult MS affected populations were performed. Its impact on the clinical and radiological control of the disease was evaluated, as well as any relevant safety issues. Conclusions. In all of the studies reviewed, rituximab demonstrated a consistent benefit in controlling inflammatory activity, both clinically, reducing the incidence of relapses, and radiologically, avoiding the appearance of new and/or active lesions. On the contrary, with regards to the progression of disability, its effect is more controversial. Safety profile appears acceptable. Rituximab seems to be an effective and safe drug in the treatment of MS (AU)

Varicella-zoster meningovasculitis in a multiple sclerosis patient treated with natalizumab.

BACKGROUND: Natalizumab is associated with the occasional occurrence of progressive multifocal leukoencephalopathy (PML). While natalizumab-associated PML is well described in multiple sclerosis (MS) patients, herpes and other infections have rarely been reported. OBJECTIVE: To report a case of varicella-zoster (VZV) meningovasculitis in a MS patient treated with natalizumab. METHODS: Case report. RESULTS: A 48-year-old woman diagnosed with MS in treatment with natalizumab (Expanded Disability Status Scale (EDSS): 4.0). After 72 infusions, she complained of a holocraneal headache and a new unsteady gait with diplopia (EDSS: 5.0). A brain and spinal cord magnetic resonance (MR) scan showed a multifocal leptomeningeal enhancing nodular lesions and an angiography revealed irregularity of the proximal segments of cerebral arteries. Testing for VZV DNA by polymerase chain reaction (PCR) amplification was positive in cerebrospinal fluid. Treatment with endovenous acyclovir was started. After clinical improvement (EDSS: 4.5), treatment with natalizumab was restarted associated with oral acyclovir as prophylaxis. CONCLUSION: Neurologists should be aware of other possible neuroinfections besides PML in MS patients under natalizumab.

Spinal cord lesions: A modest contributor to diagnosis in clinically isolated syndromes but a relevant prognostic factor.

BACKGROUND: The usefulness of performing a spinal cord (SC) magnetic resonance imaging (MRI) in all clinically isolated syndromes (CIS) is controversial. OBJECTIVE: To assess the value of SC lesions for predicting multiple sclerosis (MS) diagnosis and disability accrual in CIS. METHODS: Concerning SC lesions and MS diagnosis (2010 McDonald), adjusted Cox regression analyses were performed in increasingly specific CIS groups: all cases ( n = 207), non-SC CIS ( n = 143), non-SC CIS with abnormal brain MRI ( n = 90) and non-SC CIS with abnormal brain MRI not fulfilling 2010 MS ( n = 67). For the outcome Expanded Disability Status Scale (EDSS) ≥3.0, similar analyses were performed in all cases ( n = 207), non-SC CIS ( n = 143) and SC CIS ( n = 64). Performance at 2 years was assessed for all outcomes. RESULTS: The presence of SC lesions increased MS risk 2.0-2.6 times independently of factors like brain lesions. If considering lesion number, the risk ranged from 1.6 to 2.1 for one lesion to 2.4-3.3 for ≥2. SC lesions increased the short-term disability risk around fivefold, better demonstrated in non-SC CIS. SC lesions were very specific for evolution to MS and showed very high sensitivity for EDSS ≥3.0. CONCLUSION: SC lesions are independent predictors of MS in all CIS and contribute to short-term disability accrual. SC MRIs in CIS could be useful to estimate their prognosis.

Lesion topographies in multiple sclerosis diagnosis: A reappraisal.

OBJECTIVES: To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). METHODS: Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. RESULTS: Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. CONCLUSIONS: Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases.