Prognostic indicators in pediatric clinically isolated syndrome.

OBJECTIVE: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. METHODS: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. RESULTS: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46-7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. INTERPRETATION: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729-739.

Defining reliable disability outcomes in multiple sclerosis.

Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.

Seasonal variation of relapse rate in multiple sclerosis is latitude dependent.

OBJECTIVE: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude. METHODS: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. RESULTS: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028). INTERPRETATION: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere.

Comparative effectiveness of glatiramer acetate and interferon beta formulations in relapsing-remitting multiple sclerosis.

BACKGROUND: The results of head-to-head comparisons of injectable immunomodulators (interferon ß, glatiramer acetate) have been inconclusive and a comprehensive analysis of their effectiveness is needed. OBJECTIVE: We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators. METHODS: Pairwise analysis of the international MSBase registry data was conducted using propensity-score matching. The four injectable immunomodulators were compared in six head-to-head analyses of relapse and disability outcomes using paired mixed models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity and power analyses were conducted. RESULTS: Of the 3326 included patients, 345-1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated >95% of the identified indication bias. Slightly lower relapse incidence was found among patients treated with glatiramer acetate or subcutaneous interferon ß-1a relative to intramuscular interferon ß-1a and interferon ß-1b (p≤0.001). No differences in 12-month confirmed progression of disability were observed. CONCLUSION: Small but statistically significant differences in relapse outcomes exist among the injectable immunomodulators. MSBase is sufficiently powered to identify these differences and reflects practice in tertiary MS centres. While the present study controlled indication, selection and attrition bias, centre-dependent variance in data quality was likely.

Risk of relapse phenotype recurrence in multiple sclerosis.

OBJECTIVES: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. METHODS: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. RESULTS: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. CONCLUSION: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.

Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Multiple sclerosis in Latin America: A different disease course severity? A collaborative study from the MSBase Registry.

Limited data suggest that multiple sclerosis (MS) in Latin America (LA) could be less severe than in the rest of the world. The objective was to compare the course of MS between LA and other regions. METHODS: Centers from 18 countries with >20 cases enrolled in the MSBase Registry participated. Patients with MS with a disease duration of >1 year and <30 years at time of EDSS measurement were evaluated. The MS Severity Score (MSSS) was used as a measure of disease progression. Comparisons among regions (North America, Europe, Australia and LA), hemispheres and countries were performed. RESULTS: A total of 9610 patients were included. Patients were from: Europe, 6290 (65.6%); North America, 1609 (16.7%); Australia, 1119 (11.6%); and LA, 592 (6.1%). The mean MSSS in patients from LA was 4.47 ± 2.8, 4.53 ± 2.8 in North America, 4.51 ± 2.8 in Europe and 4.49 ± 2.7 in Australia. Mean MSSS in the northern hemisphere was 4.51 ± 1.6 compared to 4.48 ± 1.9 in the southern hemisphere. No differences were found for MSSS among hemispheres (p = 0.68), regions (p = 0.96) or countries (p = 0.50). CONCLUSIONS: Our analyses did not discover any difference in mean MSSS among patients from different regions, hemispheres or countries.

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis.

OBJECTIVES: To compare treatment persistence between two dosages of interferon ß-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. METHODS: Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon ß-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon ß-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. RESULTS: Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. CONCLUSIONS: Treatment discontinuations were more common in interferon ß-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

Country, sex, EDSS change and therapy choice independently predict treatment discontinuation in multiple sclerosis and clinically isolated syndrome.

OBJECTIVES: We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS). METHODS: The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation. RESULTS: A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-ß-1a (HR 1.38, p = 0.028) and subcutaneous interferon-ß-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation. CONCLUSION: In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation.

Efectividad de un programa de rehabilitación respiratoria en pacientes con esclerosis múltiple / Effectiveness of a respiratory rehabilitation program on patients with multiple sclerosis

Las personas con esclerosis múltiple presentan alteraciones de la comunicación oral relacionadas con una insuficiencia respiratoria, lo que obliga a los especialistas en logopedia a trabajar en este problema desde la óptica de su especialidad. Objetivo Evaluar la efectividad de un programa intensivo de rehabilitación respiratoria en personas con esclerosis múltiple, para aumentar su capacidad respiratoria y mejorar la coordinación fonorrespiratoria. Métodos Estudio de intervención cuasi experimental en un grupo de 30 personas adultas de ambos sexos con esclerosis múltiple. Todos recibieron el programa durante cuatro semanas con una hora diaria de ejercitación. Para valorar la efectividad del programa, se realizó una evaluación inicial y otra final de la capacidad vital inspiratoria y espiratoria forzada y de la coordinación fonorrespiratoria, por personal externo. El deterioro neurológico se midió mediante la Escala Expandida de Discapacidad de Kurtzke. Resultados En la muestra hubo predominio de mujeres, una edad promedio de 40,43 ± 11,46 años y 13,40 ± 7,76 años de evolución de la enfermedad. Se encontró esclerosis múltiple progresiva en 22 pacientes y 8 tenían formas de brote-remisión. El deterioro neurológico fue de 5,8 (±1,51) como promedio, lo que habla a favor de una discapacidad moderada en la muestra. Se encontró un aumento de la capacidad vital inspiratoria y espiratoria forzada y un aumento en el tiempo máximo de fonación, en la emisión de series de palabras bisílabas y en la emisión de series de números. Conclusiones El programa intensivo de rehabilitación respiratoria, contribuye al aumento de la capacidad respiratoria de las personas con esclerosis múltiple, por lo que se recomienda su aplicación en el proceso de neurorrehabilitación(AU)

People with multiple sclerosis present with altered oral communication related to respiratory failure, which forces the speech therapists to work on this problem within their range of specialty. Objective To evaluate the effectiveness la efectividad) of an intensive respiratory rehabilitation program. Methods Quasi-experimental interventional study carried out in a group of 30 adults of both sexes suffering from multiple sclerosis. All these patients were included in the program for 4 weeks, having one-hour training every day. For assessing the effectiveness of the program, an initial and a final evaluation of the forced vital inspiratory and expiratory capacity and of the phonorespiratory coordination was made by outside experts. The neurological deterioration was measured according the Kurtzkeïs extended disability scale. Results Women predominated in the sample; the average age was 40.43 ± 11.46 years and progression of disease was 13.40 ± 7.76 years. Progressive multiple sclerosis was found in 22 patients and the onset-remission forms in 8 patients. The neurological deterioration amounted to 5.8 (±1.51) as an average, which speaks for the moderate disability rate present in the simple. There was observed increased vital forced inspiratory and expiratory capacities and increase in maximum phonation length and in pronouncing series of two-syllable words and series of numbers. Conclusions The intensive respiratory rehabilitation program helps to increase the respiratory capacity of the patients with multiple sclerosis, hence, its implementation in the neurorehabilitation process is recommended(AU)

Efectividad de un programa de rehabilitación respiratoria en pacientes con esclerosis múltiple / Effectiveness of a respiratory rehabilitation program on patients with multiple sclerosis

Las personas con esclerosis múltiple presentan alteraciones de la comunicación oral relacionadas con una insuficiencia respiratoria, lo que obliga a los especialistas en logopedia a trabajar en este problema desde la óptica de su especialidad. Objetivo Evaluar la efectividad de un programa intensivo de rehabilitación respiratoria en personas con esclerosis múltiple, para aumentar su capacidad respiratoria y mejorar la coordinación fonorrespiratoria. Métodos Estudio de intervención cuasi experimental en un grupo de 30 personas adultas de ambos sexos con esclerosis múltiple. Todos recibieron el programa durante cuatro semanas con una hora diaria de ejercitación. Para valorar la efectividad del programa, se realizó una evaluación inicial y otra final de la capacidad vital inspiratoria y espiratoria forzada y de la coordinación fonorrespiratoria, por personal externo. El deterioro neurológico se midió mediante la Escala Expandida de Discapacidad de Kurtzke. Resultados En la muestra hubo predominio de mujeres, una edad promedio de 40,43 ± 11,46 años y 13,40 ± 7,76 años de evolución de la enfermedad. Se encontró esclerosis múltiple progresiva en 22 pacientes y 8 tenían formas de brote-remisión. El deterioro neurológico fue de 5,8 (±1,51) como promedio, lo que habla a favor de una discapacidad moderada en la muestra. Se encontró un aumento de la capacidad vital inspiratoria y espiratoria forzada y un aumento en el tiempo máximo de fonación, en la emisión de series de palabras bisílabas y en la emisión de series de números. Conclusiones El programa intensivo de rehabilitación respiratoria, contribuye al aumento de la capacidad respiratoria de las personas con esclerosis múltiple, por lo que se recomienda su aplicación en el proceso de neurorrehabilitación

People with multiple sclerosis present with altered oral communication related to respiratory failure, which forces the speech therapists to work on this problem within their range of specialty. Objective To evaluate the effectiveness la efectividad) of an intensive respiratory rehabilitation program. Methods Quasi-experimental interventional study carried out in a group of 30 adults of both sexes suffering from multiple sclerosis. All these patients were included in the program for 4 weeks, having one-hour training every day. For assessing the effectiveness of the program, an initial and a final evaluation of the forced vital inspiratory and expiratory capacity and of the phonorespiratory coordination was made by outside experts. The neurological deterioration was measured according the Kurtzkeïs extended disability scale. Results Women predominated in the sample; the average age was 40.43 ± 11.46 years and progression of disease was 13.40 ± 7.76 years. Progressive multiple sclerosis was found in 22 patients and the onset-remission forms in 8 patients. The neurological deterioration amounted to 5.8 (±1.51) as an average, which speaks for the moderate disability rate present in the simple. There was observed increased vital forced inspiratory and expiratory capacities and increase in maximum phonation length and in pronouncing series of two-syllable words and series of numbers. Conclusions The intensive respiratory rehabilitation program helps to increase the respiratory capacity of the patients with multiple sclerosis, hence, its implementation in the neurorehabilitation process is recommended

Morbilidad por enfermedades neurológicas en el servicio de neurología: estudio de un quinquenio / Morbidity due to neurologic diseases in the Departent of Neurology: a quinquennial study

Se realiza un estudio de morbilidad por enfermedades neurológicas en el servicio de Neurología del Hospital Clinicoquirúrgico Docente "Dr. Gustavo Aldereguía LIma", desde noviembre de 1979 a noviembre de 1984. La información se obtuvo en todos los casos con un diagnóstico definido y se recolectó en tarjetas que contenían los datos de identidad personal como: sexo, raza, dirección, diagnóstico positivo y estudios especiales. Se anotó en dichas tarjetas el número correspondiente a una clasificación patogenica empleada que tiene similitud con el estudio realizado en 1979-1980. En los resultados se encontró que los grupos no clasificables, neurovascular, degenerativo-hereditario, malformativo y traumático fueron los más comunes. Se analizan las causas más frecuentes en cada uno de los grups y su comportamiento. Se concluyó enla necesidad de ofrecer un alto grado de atención al paciente neurológico en la provincia, tanto en el aspecto curativo, como en el preventivo y en promover los principios básicos de salud en el futuro

Morbilidad por enfermedades neurológicas en el servicio de neurología: estudio de un quinquenio / Morbidity due to neurologic diseases in the Department of Neurology: a quinquennial study

Se realiza un estudio de morbilidad por enfermedades neurológicas en el servicio de Neurología del Hospital Clinicoquirúrgico Docente "Dr. Gustavo Aldereguía LIma", desde noviembre de 1979 a noviembre de 1984. La información se obtuvo en todos los casos con un diagnóstico definido y se recolectó en tarjetas que contenían los datos de identidad personal como: sexo, raza, dirección, diagnóstico positivo y estudios especiales. Se anotó en dichas tarjetas el número correspondiente a una clasificación patogenica empleada que tiene similitud con el estudio realizado en 1979-1980. En los resultados se encontró que los grupos no clasificables, neurovascular, degenerativo-hereditario, malformativo y traumático fueron los más comunes. Se analizan las causas más frecuentes en cada uno de los grups y su comportamiento. Se concluyó enla necesidad de ofrecer un alto grado de atención al paciente neurológico en la provincia, tanto en el aspecto curativo, como en el preventivo y en promover los principios básicos de salud en el futuro