Delayed B cell repopulation after rituximab treatment in multiple sclerosis patients with expanded adaptive natural killer cells.

BACKGROUND AND PURPOSE: The aim was to evaluate whether adaptive NKG2C+ natural killer (NK) cells, characterized by enhanced antibody-dependent cell cytotoxicity (ADCC), may influence time to B cell repopulation after rituximab treatment in multiple sclerosis (MS) patients. METHODS: This was a prospective observational study of MS patients treated with rituximab monitoring peripheral B cells for repeated doses. B cell repopulation was defined as CD19+ cells above 2% of total lymphocytes, classifying cases according to the median time of B cell repopulation as early or late (≤9 months, >9 months, respectively). Basal NK cell immunophenotype and in vitro ADCC responses induced by rituximab were assessed by flow cytometry. RESULTS: B cell repopulation in 38 patients (24 relapsing-remitting MS [RRMS]; 14 progressive MS) was classified as early (≤9 months, n = 19) or late (>9 months, n = 19). RRMS patients with late B cell repopulation had higher proportions of NKG2C+ NK cells compared to those with early repopulation (24.7% ± 16.2% vs. 11.3% ± 10.4%, p < 0.05), and a direct correlation between time to B cell repopulation and percentage of NKG2C+ NK cells (R 0.45, p < 0.05) was observed. RRMS cases with late repopulation compared with early repopulation had a higher secretion of tumor necrosis factor α and interferon γ by NK cells after rituximab-dependent NK cell activation. The NK cell immunophenotype appeared unrelated to B cell repopulation in progressive MS patients. CONCLUSIONS: Adaptive NKG2C+ NK cells in RRMS may be associated with delayed B cell repopulation after rituximab, a finding probably related to enhanced depletion of B cells exerted by NK-cell-mediated ADCC, pointing to the use of personalized regimens with anti-CD20 monoclonal antibody therapy in some patients.

Impact of cytomegalovirus infection on B cell differentiation and cytokine production in multiple sclerosis.

BACKGROUND: Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment. METHODS: HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry. RESULTS: HCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNß-treated RRMS patients but not in HCMV(-) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNß. Considering the B cell functional profile, HCMV(-) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001). CONCLUSIONS: Our study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS.

Th1Th17CM Lymphocyte Subpopulation as a Predictive Biomarker of Disease Activity in Multiple Sclerosis Patients under Dimethyl Fumarate or Fingolimod Treatment.

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n = 22) or fingolimod (n = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60 ± 4.17%vs. nonrelapsed: 9.25 ± 3.17%, p < 0.05) and Th1Th17CM cells (relapsed: 15.65 ± 6.15%vs. nonrelapsed: 10.14 ± 4.05%, p < 0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RA-CCR6+CXCR3+) cells > 11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells < 11.48% whose relapse-free survival was 88% (p = 0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%vs. no MRI activity: 9.82 ± 4.06%, p < 0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.

Epidemiology of NMOSD in Catalonia: Influence of the new 2015 criteria in incidence and prevalence estimates.

BACKGROUND: Population-based studies on neuromyelitis optica spectrum disorders (NMOSD) are limited, and it is unclear whether the rates have changed with the implementation of the new 2015 criteria. OBJECTIVES: To estimate the incidence and prevalence of NMOSD in Catalonia (Spain), using both the 2006 and the 2015 criteria. METHODS: In this clinic-based retrospective study, patients diagnosed with NMOSD between 2006 and 2015 were identified using multiple sources, including direct contact to all Catalan hospitals, identification of cases through the Catalan Health Surveillance System, and registry of antibodies to aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) in a reference laboratory. The incidence rate was calculated for the period 1 January 2006-1 January 2016 and prevalence for the date 1 January 2016. RESULTS: We identified 74 patients (by the 2015 criteria). Most patients were Caucasian (81%), and female (76%) with a median age at disease onset of 42 years (range, 10-76 years). In total, 54 (73%) patients were positive for AQP4-IgG, 11 (15%) double-seronegative, and 9 (12%) MOG-IgG-positive. Rates of incidence and prevalence (0.63/1,000,000 person-years and 0.89/100,000, respectively) were 1.5-fold higher than those reported by the 2006 criteria. Lowest rates were seen in children and elder people and highest in women and middle-aged people (40-59 years). The female predominance was lost in incident AQP4-IgG-seronegative children and AQP4-IgG-positive elder people. MOG-IgG and double-seronegativity contributed similarly but did not influence the long-term outcome. CONCLUSION: The new criteria increase the estimates, but NMOSD remains as a rare disease. The differences in age- and sex-specific estimates highlight the importance of the serologic classification.

Adaptive natural killer cell response to cytomegalovirus and disability progression in multiple sclerosis.

BACKGROUND: Human cytomegalovirus (HCMV) causes a highly prevalent infection which may have a multifaceted impact on chronic inflammatory disorders. However, its potential influence in multiple sclerosis (MS) remains controversial. The HCMV-host interaction may induce an adaptive reconfiguration of the natural killer (NK) cell compartment, whose hallmark is a persistent expansion of peripheral NKG2C+ NK-cells. OBJECTIVE: The purpose of this study was to evaluate whether the HCMV-driven NKG2C+ NK-cell expansion is related to the MS clinical course. METHODS: Multicentre analysis of NKG2C expression and genotype according to HCMV serostatus and time of assignment of irreversible disability scores in 246 MS patients prospectively followed up in our institutions. RESULTS: NKG2C expression was unrelated to disease-modifying drugs, remained stable under steady-state conditions, and was higher in HCMV(+) NKG2C(+/+) homozygous individuals. NKG2C+ NK-cell expansion in HCMV(+) patients, as compared to HCMV(+) or HCMV(-) patients with lower NKG2C+ NK-cells proportions, conferred a lower risk of progression in Cox regression analysis (Expanded Disability Status Scale (EDSS)>3.0, hazard ratio (HR)=0.33, 95% confidence interval (CI) 0.15-0.71, p=0.005; EDSS>5.5, HR=0.23, 95% CI 0.07-0.74, p=0.014). Neither HCMV serostatus nor NKG2C genotype appeared to be related to disability progression. CONCLUSIONS: HCMV may exert a beneficial influence on MS, decreasing the risk of disability progression in those patients displaying a virus-driven NKG2C+ NK-cell expansion.

Decreased exercise-induced natural killer cell redistribution in multiple sclerosis.

BACKGROUND: Exercise may have beneficial effects in MS, remaining controversial its possible disease-modifying effects and which mechanisms might be involved. We evaluated whether exercise-induced lymphocyte redistribution differ in MS patients as compared to controls. METHODS: Exercise was assessed in 12 relapsing-remitting MS patients and 11 controls in a cycle ergometer, obtaining blood samples before exercise, at maximal exercise capacity (T1), and after resting (T2). Peripheral lymphocytes were evaluated by flow cytometry, assessing chemokine receptor expression to study cell trafficking properties. RESULTS: Lymphocyte subsets in all cases increased after exercise and decreased at resting. However, total natural killer (NK) cells in patients as compared to controls had a lower exercise-induced redeployment at T1 (696 ± 581 cells/µL vs.1502 ± 641 cells/µL, p < 0.01). Evaluating NK cell subsets, CD56bright NK cells numbers decreased in peripheral blood in MS patients after resting (T2), contrasting with values remaining above baseline in healthy controls. NK cells mobilized after exercise at T1 in controls, as compared to patients, had a higher CX3CR1 expression (1402 ± 564/µL vs. 615 ± 548 cell//µL, p < 0.01). CONCLUSION: Exercise-induced redeployment of NK cells may be reduced in MS patients, as well as their migration capabilities, pointing to potential immunological mechanisms to be enhanced by exercise training programs.

Adverse events during the titration phase of interferon-beta in remitting-relapsing multiple sclerosis are not predicted by body mass index nor by pharmacodynamic biomarkers.

BACKGROUND: This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN ß-1a during treatment titration in patients with relapsing-remitting multiple sclerosis previously naïve to IFN ß. METHODS: Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese. RESULTS: Biomarkers steadily increased during all study period by 45.3% for ß2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration. CONCLUSIONS: BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either.

Dynamics and Predictors of Cognitive Impairment along the Disease Course in Multiple Sclerosis.

(1) Background: The evolution and predictors of cognitive impairment (CI) in multiple sclerosis (MS) are poorly understood. We aimed to define the temporal dynamics of cognition throughout the disease course and identify clinical and neuroimaging measures that predict CI. (2) Methods: This paper features a longitudinal study with 212 patients who underwent several cognitive examinations at different time points. Dynamics of cognition were assessed using mixed-effects linear spline models. Machine learning techniques were used to identify which baseline demographic, clinical, and neuroimaging measures best predicted CI. (3) Results: In the first 5 years of MS, we detected an increase in the z-scores of global cognition, verbal memory, and information processing speed, which was followed by a decline in global cognition and memory (p < 0.05) between years 5 and 15. From 15 to 30 years of disease onset, cognitive decline continued, affecting global cognition and verbal memory. The baseline measures that best predicted CI were education, disease severity, lesion burden, and hippocampus and anterior cingulate cortex volume. (4) Conclusions: In MS, cognition deteriorates 5 years after disease onset, declining steadily over the next 25 years and more markedly affecting verbal memory. Education, disease severity, lesion burden, and volume of limbic structures predict future CI and may be helpful when identifying at-risk patients.

[Lipid profile evolution during the first year of treatment with beta interferon in multiple sclerosis]. / Perfil lipídico durante el primer año de tratamiento con interferón beta en pacientes con esclerosis múltiple.

BACKGROUND AND OBJECTIVE: Treatment with beta interferon (IFNbeta) might alter the lipid profile. Plasmatic levels of total cholesterol and low density lipoprotein-cholesterol have been associated with the number of plaques in magnetic resonance of patients with demyelinating syndromes. PATIENTS AND METHOD: Retrospective analysis of total cholesterol and triglyceride levels during the first year of treatment with IFNbeta in multiple sclerosis patients and association between lipid levels and disease activity, compared to patients using glatiramer acetate (GA). RESULTS: 84 patients under IFNbeta and 23 GA patients were studied. Mean total cholesterol plasmatic levels lowered during the first year, whereas triglyceride levels rose since the first 6 months. These changes were more intense in the IFNbeta(1a) intramuscular group. No changes were observed in the GA group. Lipid changes were not associated with disease activity. CONCLUSIONS: In multiple sclerosis patients, triglyceride levels rise whereas total cholesterol levels decrease during the first year of treatment with IFNbeta. These changes do not seem to be related with disease activity.

Adaptive Features of Natural Killer Cells in Multiple Sclerosis.

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(-), and PLZF(-) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(-) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(-) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-ß therapy was associated with lower proportions of FcRγ(-) CD56dim NK cells in HCMV(+) and increased PLZF(-) CD56bright NK cells in HCMV(-) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(-) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS.

Cannabis use in Spanish patients with multiple sclerosis: fulfilment of patients' expectations?

OBJECTIVE: Medicinal use of cannabis in chronic neurological diseases is a controversial topic of medical research and the subject of intense public debate. The aim of the study was to evaluate the prevalence of cannabis use, related factors, and degree of satisfaction in Spanish patients with multiple sclerosis (MS) prior to the establishment of medically supervised use. METHODS: Cross-sectional, questionnaire-based survey provided during routine medical visits to consecutive patients in two university-based neurology clinics. RESULTS: The questionnaire was returned by 175 MS patients (94.1% response rate). The prevalence of ever-use and medicinal cannabis use were 43% and 17.1%, respectively. At the time of the survey, cannabis was being used by 12.5% (5/45) of recreational and 56.7% (17/30) of medical users (p<0.001). First cannabis consumption was after MS onset in 15 (50%) medicinal users. Clinical improvement was reported by 14 (46.7%) medicinal users. Smoking use, awareness of cannabis potential benefits, pain, higher disability, and lower age were independently associated with the medicinal use of cannabis. Most patients would support a future legalisation of cannabis for the control of their symptoms and were willing to receive cannabis under medical control once legalised (83.4% of never-users, 94.5% of ever-users, p<0.05). CONCLUSION: Almost half of our MS patients had tried cannabis at some time. However, medicinal use was low and clinical improvement after cannabis use was only reported by a subset of patients. Overall, MS patients were highly motivated for a future medically controlled use.

Steno-occlusive arterial disease and early neurological deterioration in acute ischemic stroke.

AIM: To evaluate the influence that steno-occlusive arterial disease may have on the development of early neurological deterioration (END) in a large series of patients with acute ischemic stroke. METHODS: We studied a prospective cohort of 1,093 patients admitted to a single tertiary hospital with presence of neurological symptoms in the first 24 h after stroke onset. END was defined as any increase in the National Institutes of Health Stroke Scale score >or=4 points in the first 72 h. The arterial study assessed the presence of arterial occlusion or significative stenosis in the symptomatic territory. Additionally, age, initial stroke severity, blood pressure, glucose levels, vascular risk factors, lacunar stroke and prior use of antithrombotic treatment were also analyzed in a multivariable analysis. RESULTS: END was detected in 179 patients (16.3%). Steno-occlusive disease (adjusted OR 3.60), initial blood pressure and abdominal obesity were independently associated with END. Both arterial stenosis (adjusted OR 2.33) or occlusions (adjusted OR 3.65) were associated with END. The higher adjusted OR (5.49) was obtained for steno-occlusive arterial disease in the vertebrobasilar system. CONCLUSIONS: An early arterial study may provide key data for the selection of patients with higher risk of END after acute ischemic stroke.

Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients.

AIMS: Fingolimod, an orally active immunomodulatory drug for relapsing-remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the sphingosine-1-phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune-monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod. METHODS: Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow-up in 40 RRMS patients starting fingolimod therapy. RESULTS: Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in Treg (memory Treg : 3.8 ± 1.0% baseline vs 8.8 ± 4.4% month +1; activated Treg : 1.5 ± 0.7% baseline vs 3.7 ± 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 ± 12.3% baseline vs 18.7 ± 14.6% month +1, P < 0.001) was observed. Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 ± 1.4% vs 7.4 ± 1.9%, respectively [P < 0.001]). CONCLUSION: The results support that immune-monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.

Early arterial study in the prediction of mortality after acute ischemic stroke.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the value of the initial arterial study as a predictor of 90-day mortality in patients with acute ischemic stroke. METHODS: A total of 1220 unselected patients assessed during the first 24 hours after stroke onset were prospectively studied. Initial stroke severity was evaluated by the National Institutes of Health Stroke Scale and dichotomized in mild (National Institutes of Health Stroke Scale < or =7) and severe (National Institutes of Health Stroke Scale >7). Severe arterial stenosis (> or =70%) or arterial occlusion in the symptomatic territory was determined by a Doppler study and also by additional explorations (carotid duplex, MR or CT angiography) in the first 24 hours after admission. The following variables were also analyzed: age, gender, previous functional status, smoking, hypertension, hyperlipidemia, diabetes mellitus, peripheral arterial disease, ischemic heart disease, heart failure, atrial fibrillation, previous stroke, and prior use of antithrombotic or statins. Ninety-day mortality was the end point of the study. RESULTS: Ninety-day mortality was 15.7%. A total of 25.5% of all deaths were in patients with mild stroke. In addition to well-known factors related to mortality (age, stroke severity, ischemic heart disease, heart failure, and previous disability), severe arterial stenosis/occlusion was the factor with the highest relationship with 90-day mortality (adjusted OR: stenosis 2.13, occlusion 4.42, both 3.36). Arterial stenosis/occlusion was a higher predictor of 90-day mortality in patients with mild (adjusted OR: 5.38) than severe stroke (adjusted OR: 3.05). CONCLUSIONS: Severe arterial stenosis/occlusion in the early arterial study was highly related with 90-day mortality in an unselected series of patients with stroke. These data achieve special relevance in patients with initial mild stroke.

Atherosclerotic burden and early mortality in acute ischemic stroke.

BACKGROUND: The influence that previous clinical expressions of systemic atherosclerosis may have on evolution and early mortality in patients with acute ischemic stroke is not known. OBJECTIVE: To evaluate the influence that atherosclerotic burden (ATB), assessed by a simple clinical scale, has on the 30-day mortality in patients with first-ever ischemic stroke. DESIGN: Retrospective review of case series from a prospective stroke record. An ATB score ranging from 0 to 2 was created using the history of ischemic heart disease and peripheral arterial disease. The impact of this score on the 30-day mortality was analyzed by multivariate regression analysis. SETTING: Tertiary university hospital. Patients A total of 1527 patients with first-ever ischemic stroke. Main Outcome Measure Thirty-day mortality. RESULTS: The 30-day mortality rate was 13.8%. Multivariate regression analysis showed an association between the ATB score and the 30-day mortality (P<.001). Comparing patients having no previous ATB with those with an ATB score of 1 or 2, the odds ratio (OR) for 30-day mortality increased from 1.71 (95% confidence interval [CI], 1.06-2.75) for patients with an ATB score of 1 to 5.90 (95% CI, 2.48-14.04) for those with an ATB score of 2. Age (OR, 1.05; 95% CI, 1.03-1.08), National Institutes of Health Stroke Scale score at admission (OR, 1.22; 95% CI, 1.18-1.25), atrial fibrillation (OR, 1.61; 95% CI, 1.10-2.35), hyperlipidemia as protector (OR, 0.39; 95% CI, 0.25-0.60), and glycemia at admission (OR, 1.07; 95% CI, 1.02-1.12) were also predictors of 30-day mortality. CONCLUSION: Previous symptomatic atherosclerotic disease evaluated by a simple clinical score is an independent predictor of early mortality in patients with first-ever ischemic stroke.

Comparison of the impact of atrial fibrillation on the risk of early death after stroke in women versus men.

BACKGROUND: Atrial fibrillation (AF) is considered a predictive factor of poor clinical outcome in patients with an ischemic stroke (IS). This study addressed whether the impact of AF on the in-hospital mortality after first ever IS is different according to the patient's gender. METHODS: We prospectively studied 1678 patients with first ever IS consecutively admitted to two University Hospitals. We recorded demographic data, vascular risk factors, and the stroke severity (NIHSS) at admission analyzing their impact on the in-hospital mortality and on the combined mortality-dependency at discharge using a Cox proportional hazards model. Two variable interactions between those factors independently related to in-hospital mortality and combined mortality-dependency at discharge were tested. RESULTS: Overall in-hospital mortality was 11.3%. Cox proportional hazards model showed that NIHSS at admission (HR: 1.178 [95% CI 1.149-1.207]), age (HR: 1.044 [95% CI 1.026-1.061]), AF (HR: 1.416 [95% CI 1.048-1.913]), male gender (HR: 1.853 [95% CI 1.323-2.192) and ischemic heart disease (HR: 1.527 [95% CI 1.063-2.192]) were independent predictors of in-hospital mortality. A significant interaction between gender and AF was found (p = 0.017). Data were stratified by gender, showing that AF was an independent predictor of poor outcome just for woman (HR: 2.183 [95% CI 1.403-3.396]; p < 0.001). The independent predictors of combined mortality-disability at discharge were NIHSS at admission (HR: 1.052 [95% CI 1.041-1.063]), age (HR: 1.011 [95% CI 1.004-1.018]), AF (HR: 1.197 [95% CI 1.031-1.390]), ischemic heart disease (HR: 1.222 [95% CI 1.004-1.488]), and smoking (HR: 1.262 [95% CI 1.033-1.541]). CONCLUSIONS: The impact of AF is different in the two genders and appears as a specific ischemic stroke predictor of in-hospital mortality just for women.

[Protocol for neurophysiological studies of the pelvic floor to appraise anorectal dysfunction in patients with multiple sclerosis]. / Protocolo de estudios neurofisiológicos del suelo pélvico para la valoración de la disfunción anorrectal en pacientes con esclerosis múltiple.

INTRODUCTION: Patients with multiple sclerosis (MS) frequently develop anorectal dysfunction. The neuromuscular structures of the pelvic floor and the mechanisms of voluntary control over defecation can be compromised by the patchy lesions of MS or secondary to the patient's disability. The involvement of multiple factors limits understanding of the pathophysiology of anorectal dysfunction in MS. Specific neurophysiological tests assess the functionality of the elements of the central and peripheral nervous system involved in anorectal dysfunction. AIM: To propose a diagnostic protocol of standardised neurophysiological studies of the pelvic floor in order to characterise the pathophysiology of anorectal dysfunction in patients with MS. PATIENTS AND METHODS: The following studies were conducted on 16 patients with defined MS and who met criteria for constipation or faecal incontinence: external anal sphincter electromyography (EAS-EMG), somatosensory evoked potentials (SSEP) of the internal pudendal nerve, recording of ano-sacral reflexes and pudendal nerve neurography. RESULTS: The clinical and neurophysiological characteristics were heterogeneous. Nine patients presented constipation; two had isolated faecal incontinence; and five, a combination of both. Abolition or delay in the latency of the SSEP was the most frequent finding (n = 12), followed by the detection of paradoxical contraction (n = 11) and deficient recruitment (n = 8) in the EAS-EMG. CONCLUSIONS: The correct interpretation of each available neurophysiological test and the correlation of the findings as a whole enable us to understand the pathophysiology of anorectal dysfunction. The implementation of a protocol for neuro-physiological studies of the pelvic floor makes it possible to adjust the diagnosis by identifying the central or peripheral nervous lesion determining anorectal dysfunction in patients with MS.

TITLE: Protocolo de estudios neurofisiologicos del suelo pelvico para la valoracion de la disfuncion anorrectal en pacientes con esclerosis multiple.Introduccion. Los pacientes con esclerosis multiple (EM) frecuentemente desarrollan disfuncion anorrectal. Las estructuras neuromusculares del suelo pelvico y los mecanismos de control voluntario de la defecacion pueden afectarse por las lesiones parcheadas de la EM o secundarias a la discapacidad del paciente. La implicacion multifactorial limita la comprension de la fisiopatologia de la disfuncion anorrectal en la EM. Tests neurofisiologicos especificos valoran la funcionalidad de los elementos del sistema nervioso central y periferico implicados en las disfunciones anorrectales. Objetivo. Proponer un protocolo diagnostico de estudios neurofisiologicos estandarizados del suelo pelvico para caracterizar la fisiopatologia de la disfuncion anorrectal en los pacientes con EM. Pacientes y metodos. Se realizaron estudios de electromiografia de esfinter anal externo, potenciales evocados somatosensoriales desde el nervio pudendo interno, registro de reflejos sacros anales y neurografia del nervio pudendo a 16 pacientes con EM definida y criterios de estreñimiento o incontinencia fecal. Resultados. Las caracteristicas clinicas y neurofisiologicas fueron heterogeneas. Nueve pacientes presentaron estreñimiento; dos, incontinencia fecal aislada; y cinco, combinacion de ambos. La abolicion o el retraso de la latencia de los potenciales evocados somatosensoriales fue el hallazgo mas frecuente (n = 12), seguido de la deteccion de contraccion paradojica (n = 11) y de reclutamiento deficitario (n = 8) en la electromiografia de esfinter anal externo. Conclusiones. La correcta interpretacion de cada test neurofisiologico disponible y la correlacion de los hallazgos en conjunto permiten comprender la fisiopatologia de la disfuncion anorrectal. La protocolizacion de estudios neurofisiologicos del suelo pelvico permite ajustar el diagnostico al identificar la lesion nerviosa, central o periferica, determinante de disfuncion anorrectal en los pacientes con EM.

Neuromyelitis optica spectrum disorders: Comparison according to the phenotype and serostatus.

OBJECTIVE: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO. METHODS: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays. RESULTS: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presented more often with longitudinally extensive transverse myelitis (LETM) (p < 0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female:male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p < 0.001). CONCLUSIONS: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful.

Previous antiplatelet therapy is an independent predictor of 30-day mortality after spontaneous supratentorial intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes. Despite several existing outcome prediction models for ICH, there are some factors with equivocal value as well as others that still have not been evaluated. PATIENTS AND METHODS: All patients with first ever supratentorial ICH presenting to our institution between December 1995 and December 2002 were prospectively enrolled into the study. Patients with historic modified Rankin Scale > 2 and those under anticoagulant treatment or with multiple ICH were excluded. The following parameters were analyzed in 194 consecutive patients: age, gender, past history of hypertension, diabetes mellitus, hypercholesterolemia, past history of ischemic stroke, presence of ischemic heart disease or cardioembolic disease, current antiplatelet treatment, current alcohol overuse, smoking, Glasgow Coma Scale score (GSS) at admission, volume and location (deep or lobar) of ICH, ventricular extension, glycemia and temperature at admission, and leukoaraiosis. We correlated these data with the 30-day mortality identifying the independent predictors by logistic regression analysis. RESULTS: Factors independently associated with 30-day mortality were: age, Glasgow Coma Scale score at admission, ICH volume, ventricular extension, glucose level at admission, and previous antiplatelet use. CONCLUSIONS: Apart from the classical outcome predictors, the previous use of antiplatelet agents and the glucose value at admission are independent predictors of 30-day mortality in patients suffering a supratentorial ICH.

Influence of the LILRA3 Deletion on Multiple Sclerosis Risk: Original Data and Meta-Analysis.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. OBJECTIVES: In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. RESULTS AND CONCLUSION: Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15:01 risk allele.