Pediatric Multiple Sclerosis in Rio de Janeiro: Secondary Progression and Disability.

BACKGROUND: The onset of multiple sclerosis (MS) in 2% to 10% of cases occurs prior to 18 years of age. Early age onset appears to affect some aspects of multiple sclerosis. The objective of our study was to evaluate the prevalence, the clinical and demographic characteristics, and the disease progression in a sample of pediatric multiple sclerosis patients from a mixed population. METHODS: In a cross-sectional design, the prevalence, demographic characteristics, and initial clinical forms were compared between 75 cases of pediatric multiple sclerosis (PMS) and 689 adults with MS. Sixty-five PMS patients with complete data and 260 randomly selected adults with relapsing-remitting multiple sclerosis were compared. A Kaplan-Meier analysis was conducted to compare the age at and time to Expanded Disability Status Scale (EDSS) 3, EDSS 6, and secondary progressive multiple sclerosis (SPMS). RESULTS: A total of 9.8% of all MS cases with available data were PMS. All cases of PMS consisted of relapsing-remitting multiple sclerosis. Brazilians of African descent comprised 34.6% of the sample, and the female-to-male ratio was 2.4:1. At the first attack, motor alterations were more common. Benign forms were more common in PMS (84.6% versus 62.2%). Fewer PMS patients reached EDSS 6 (11.6% versus 25.4%) (P = 0.0017) and SPMS (11.1% versus 28.1%) (P = 0.005). PMS patients took longer to reach EDSS 3 (P = 0.017), EDSS 6 (P = 0.001), and SPMS (P < 0.001); however, they reached EDSS 3 earlier (P < 0.001). CONCLUSIONS: In this mixed cohort, the prevalence of PMS was similar to that reported in other studies, and the pediatric patients had a more benign course than adults with MS.

Different interleukin-17-secreting Toll-like receptor+ T-cell subsets are associated with disease activity in multiple sclerosis.

Signalling through Toll-like receptors (TLRs) may play a role in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). In the present study, the expression of TLR-2, -4 and -9 was significantly higher on CD4+ and CD8+ T-cells from MS patients compared to healthy individuals. Following in-vitro activation, the proportion of interleukin (IL)-17+ and IL-6+ CD4+ and CD8+ T-cells was higher in the patients. In addition, the proportion of IFN-γ-secreting TLR+ CD8+ T-cells was increased in MS patients. Among different IL-17+ T-cell phenotypes, the proportion of IL-17+ TLR+ CD4+ and CD8+ T-cells producing IFN-γ or IL-6 were positively associated with the number of active brain lesions and neurological disabilities. Interestingly, activation of purified CD4+ and CD8+ T-cells with ligands for TLR-2 (Pam3Csk4), TLR-4 [lipopolysaccharide (LPS)] and TLR-9 [oligodeoxynucleotide (ODN)] directly induced cytokine production in MS patients. Among the pathogen-associated molecular patterns (PAMPs), Pam3Csk4 was more potent than other TLR ligands in inducing the production of all proinflammatory cytokines. Furthermore, IL-6, IFN-γ, IL-17 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels produced by Pam3Csk4-activated CD4+ cells were directly associated with disease activity. A similar correlation was observed with regard to IL-17 levels released by Pam3Csk4-stimulated CD8+ T-cells and clinical parameters. In conclusion, our data suggest that the expansion of different T helper type 17 (Th17) phenotypes expressing TLR-2, -4 and -9 is associated with MS disease activity, and reveals a preferential ability of TLR-2 ligand in directly inducing the production of cytokines related to brains lesions and neurological disabilities.

Prognostic factors associated with long-term disability and secondary progression in patients with Multiple Sclerosis.

BACKGROUND: Predicting the long-term prognosis of patients with multiple sclerosis (MS) remains an uncertain and difficult task, with most data having been obtained exclusively from Caucasian cohorts. OBJECTIVE: To investigate clinical prognostic factors in a Brazilian mixed-race cohort. METHODS: Demographic, clinical and therapeutic factors were investigated in 303 patients with relapsing-remitting MS in relation to the following outcomes: time until reaching Expanded Disability Status Scale (EDSS) 3 and EDSS 6, and until secondary progression. RESULTS: Benign course was significantly more frequent among Caucasians when compared to Afrodescendants. Patients with a malignant course had more than one relapse in the first year of the disease and reached EDSS 3 faster if treatment was not started. In the multivariate analysis, the following factors were associated with a significantly shorter time until the established outcomes: male gender, being of African descent, non-recovery after the first relapse, two or more relapses during the first year, a short interval between initial relapses, initial polysymptomatic presentation of pyramidal and cerebellar dysfunction and no treatment prior to reaching EDSS 3. CONCLUSIONS: Being of African descent was found to be an unfavorable factor for all outcomes, reinforcing the need to take ethnicity into consideration when defining treatment, particularly in mixed MS populations.

Interleukin-17- and interleukin-22-secreting myelin-specific CD4(+) T cells resistant to corticoids are related with active brain lesions in multiple sclerosis patients.

Multiple sclerosis (MS) is thought to be an autoimmune disorder. It is believed that immunological events in the early stages have great impact on the disease course. Therefore, we aimed to evaluate the cytokine profile of myelin basic protein (MBP)-specific T cells from MS patients in the early phase of the disease and correlate it to clinical parameters, as well as to the effect of in vitro corticoid treatment. Peripheral T cells from MS patients were stimulated with MBP with our without hydrocortisone for 5 days. The cytokines level were determined by ELISA. The number of active brain lesions was determined by MRI scans, and the neurological disabilities were assessed by Expanded Disability Status Scale scores. Our results demonstrated that MS-derived T cells responded to MBP by producing high levels of T helper type 1 (Th1) and Th17 cytokines. Although the production of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, IL-17 and IL-22 was less sensitive to hydrocortisone inhibition, only IL-17 and IL-22 levels correlated with active brain lesions. The ability of hydrocortisone to inhibit IL-17 and IL-22 production by MBP-specific CD4(+) T cells was inversely related to the number of active brain lesions. Finally, the production of both cytokines was significantly higher in cell cultures from Afrodescendant patients and it was less sensitive to hydrocortisone inhibition. In summary, our data suggest that IL-17- and IL-22-secreting CD4(+) T cells resistant to corticoids are associated with radiological activity of the MS in early stages of the disease, mainly among Afrodescendant patients who, normally, have worse prognosis.

Central Nervous System Idiopathic Inflammatory Demyelinating Disorders in South Americans: A Descriptive, Multicenter, Cross-Sectional Study.

The idiopathic inflammatory demyelinating disease (IIDD) spectrum has been investigated among different populations, and the results have indicated a low relative frequency of neuromyelitis optica (NMO) among multiple sclerosis (MS) cases in whites (1.2%-1.5%), increasing in Mestizos (8%) and Africans (15.4%-27.5%) living in areas of low MS prevalence. South America (SA) was colonized by Europeans from the Iberian Peninsula, and their miscegenation with natives and Africans slaves resulted in significant racial mixing. The current study analyzed the IIDD spectrum in SA after accounting for the ethnic heterogeneity of its population. A cross-sectional multicenter study was performed. Only individuals followed in 2011 with a confirmed diagnosis of IIDD using new diagnostic criteria were considered eligible. Patients' demographic, clinical and laboratory data were collected. In all, 1,917 individuals from 22 MS centers were included (73.7% female, 63.0% white, 28.0% African, 7.0% Mestizo, and 0.2% Asian). The main disease categories and their associated frequencies were MS (76.9%), NMO (11.8%), other NMO syndromes (6.5%), CIS (3.5%), ADEM (1.0%), and acute encephalopathy (0.4%). Females predominated in all main categories. The white ethnicity also predominated, except in NMO. Except in ADEM, the disease onset occurred between 20 and 39 years old, early onset in 8.2% of all cases, and late onset occurred in 8.9%. The long-term morbidity after a mean disease time of 9.28±7.7 years was characterized by mild disability in all categories except in NMO, which was scored as moderate. Disease time among those with MS was positively correlated with the expanded disability status scale (EDSS) score (r=0.374; p=<0.001). This correlation was not observed in people with NMO or those with other NMO spectrum disorders (NMOSDs). Among patients with NMO, 83.2% showed a relapsing-remitting course, and 16.8% showed a monophasic course. The NMO-IgG antibody tested using indirect immunofluorescence (IIF) with a composite substrate of mouse tissues in 200 NMOSD cases was positive in people with NMO (95/162; 58.6%), longitudinally extensive transverse myelitis (10/30; 33.3%) and bilateral or recurrent optic neuritis (8/8; 100%). No association of NMO-IgG antibody positivity was found with gender, age at onset, ethnicity, early or late onset forms, disease course, or long-term severe disability. The relative frequency of NMO among relapsing-remitting MS (RRMS) + NMO cases in SA was 14.0%. Despite the high degree of miscegenation found in SA, MS affects three quarters of all patients with IIDD, mainly white young women who share similar clinical characteristics to those in Western populations in the northern hemisphere, with the exception of ethnicity; approximately one-third of all cases occur among non-white individuals. At the last assessment, the majority of RRMS patients showed mild disability, and the risk for secondary progression was significantly superior among those of African ethnicity. NMO comprises 11.8% of all IIDD cases in SA, affecting mostly young African-Brazilian women, evolving with a recurrent course and causing moderate or severe disability in both ethnic groups. The South-North gradient with increasing NMO and non-white individuals from Argentina, Paraguay, Brazil and Venezuela confirmed previous studies showing a higher frequency of NMO among non-white populations.

The impact of diagnostic criteria for neuromyelitis optica in patients with MS: a 10-year follow-up of the South Atlantic Project.

BACKGROUND: It is recognized that there is a particular geographic and ethnic distribution of neuromyelitis optica (NMO) among Caucasian and non-Caucasian populations. OBJECTIVE: To review the diagnoses of patients whom were enrolled in the South Atlantic Project, a Brazilian multiple sclerosis (MS) survey performed from 1995-1998, and to identify NMO and MS case frequencies. METHODS: We reviewed the data from a 10-year follow-up of MS patients. To apply the current diagnostic criteria, the neurologists were asked to collect clinical and laboratory data from the medical records of study patients treated from 1999-2009. RESULTS: The spectrum of inflammatory demyelinating disease in 322 patients (67% white; 33% African-Brazilian) was: 49 (15%) with NMO; 14 (4%) with NMO syndromes; 10 (3%) with acute disseminated encephalomyelitis (ADEM); one isolated tumefactive brain lesion; 249 (77%) with MS (151 with relapsing-remitting MS (RRMS), 70 with secondary progressive MS (SPMS) and 27 with primary progressive MS (PPMS)). Disability was more severe in NMO and PPMS. One-third of the NMO patients had died. CONCLUSIONS: The frequency of NMO was 6.8% in São Paulo and 20.5% in Rio de Janeiro, and mainly seen in persons of African descent, which strengthens the hypothesis of there being an ethnic association of this disease. We recommend that epidemiological studies on MS that were performed previously be reviewed again, to ensure more accurate diagnoses.

African ancestry is a predictor factor to secondary progression in clinical course of multiple sclerosis.

Background. Studies on the clinical course of multiple sclerosis have indicated that certain initial clinical factors are predictive of disease progression. Regions with a low prevalence for disease, which have environmental and genetic factors that differ from areas of high prevalence, lack studies on the progressive course and disabling characteristics of the disease. Objective. To analyse the long-term evolution to the progressive phase of the relapsing-remitting multiple sclerosis and its prognosis factors in mixed population. Methods. We performed a survival study and logistic regression to examine the influence of demographic and initial clinical factors on disease progression. Among 553 relapsing-remitting patients assisted at a Brazilian reference centre for multiple sclerosis, we reviewed the medical records of 150 patients who had a disease for ten or more years. Results. African ancestry was a factor that conferred more risk for secondary progression followed by age at the onset of the disease and the number of relapses in the year after diagnosis. A greater understanding of the influence of ancestry on prognosis serves to stimulate genetics and pharmacogenomics research and may clarify the poorly understood neurodegenerative progression of MS.

Acute encephalopathy with bilateral thalamotegmental involvement and a benign course: a case report from Brazil.

This rare encephalopathy that generally affects children is preceded by a respiratory infection and fever associated with convulsions and may progress to coma. Outcome is catastrophic in most cases. This case report describes a Brazilian child of African descent with fever, cephalea and bilateral amaurosis, who evolved to coma with pyramidal signs and associated convulsions. MRI showed diffuse, symmetrical lesions in the thalamotegmental region and brainstem. Following administration of methylprednisolone, the clinical condition of the patient improved and the brain lesions regressed, leaving the child with no current neurological deficits. This was a case of acute postinfectious encephalopathy, involving various brain structures. Outcome was favourable with no sequelae following therapy. This case was atypical due to the bilateral visual involvement and extensive encephalic lesions in a child of African descent with no neurological sequelae following therapy. No other similar cases have been reported in the literature.

The clinical course of idiopathic acute transverse myelitis in patients from Rio de Janeiro.

The aim of this study was to describe the demographic, clinical and laboratory features of idiopathic acute transverse myelitis (IATM). Patients with non-compressive ATM receiving care at Hospital da Lagoa, Rio de Janeiro (Brazil) between 2000 and 2008 were selected. Of the 70 cases of acute myelopathies, the idiopathic form was identified in 41 following exclusion of the cases associated with systemic lupus erythematosus (n = 1), Sjogren's syndrome (n = 1), herpes zoster (n = 1), cytomegalovirus in an HIV-positive patient (n = 1), Schistosoma mansoni (n = 1), actinic myelitis (n = 1), infectious myelitis of unknown etiology (n = 2) and those that, following the first attack of myelitis, converted to NMO (n = 19) or to clinically defined MS (n = 2). Of the 41 cases of IATM, the majority of patients were female (68.3%) and white (65.9%). Median age at first myelitis was 37.0 +/- 11.8 years. Over a median observation time of 36 months, 39.0% of patients remained monophasic, while recurrences occurred in 61.0% of cases. The number of ATM/patient ranged from one to seven. Among the recurrent cases the median time between the first and the second ATM was 12 months (range 1-150 months).The first myelitis was characterized mainly by partial myelitis with motor and sensorial dysfunction (63.4%). Complete and severe myelitis occurred more frequently among monophasic patients and partial myelitis with moderate dysfunction at onset in recurrent cases; however, over the long-term, dysfunction and disability were mild in both groups. Serial spine MRI confirmed spinal cord inflammation in 92.0% of cases and extensive spinal cord lesion was identified in 61.0%. Brain MRI was normal or not suggestive of MS in 94.4% of cases. CSF showed pleocytosis in 41.2%, increased IgG index in 24.0% and oligoclonal bands in 38.0% of 34 patients tested. Abnormal visual evoked potentials occurred in 11.5% of 26 patients. Positivity for anti-AQP4 was found in 23.5% of the 17 cases tested, suggesting limited forms of NMO. This study suggests some new aspects of the clinical course of IATM such as the high conversion rate to NMO, the predominance of women and a higher frequency of recurrent forms.

Differences in the progression of primary progressive multiple sclerosis in Brazilians of African descent versus white Brazilian patients.

Recent studies have suggested faster clinical progression and greater disability in multiple sclerosis patients of African descent. This study analysed the effect of ethnicity on progression and disability. Sixty-five patients with primary progressive multiple sclerosis were selected and classified as being of African descent or white. Time from onset of the disease until reaching Expanded Disability Status Scale grades 3, 6, and 8 was assessed, as well as irreversible disability (Expanded Disability Status Scale grade maintained for >or=6 months). In the African descent group, the median time to reach Expanded Disability Status Scale 3 was 1 year shorter (1 year vs 2 years, p= 0.02), and to reach Expanded Disability Status Scale 6 was 2 years shorter (3 years vs 5 years, p= 0.01) than in the group of white patients. According to the Kaplan-Meier survival curves, patients of African descent reached every disability stage faster than white patients (p= 0.03, p = 0.04, and p = 0.03, respectively, for Expanded Disability Status Scale grades 3, 6, and 8). As in United States and European patients of African descent, the more severe and faster progression of multiple sclerosis seen in Brazilian primary progressive multiple sclerosis patients of African descent suggests a possibly greater effect of ethnicity rather than environment on the progression of multiple sclerosis.

The reliability of specific primary progressive MS criteria in an ethnically diverse population.

UNLABELLED: Three different diagnostic criteria for primary progressive MS were recently proposed for Caucasian population of Western European region. OBJECTIVE: The objective of the study was to apply these criteria to a series of Brazilian patients with high ethnic diversity background to evaluate reproducibility and reliability. METHODS: 52 patients classified as form of the disease that is progressive from onset and followed between 2000 and 2006 were included. Thompson, McDonald and Polman criteria were applied based in clinical date and complementary exams. RESULTS: 72% fulfilled all three criteria with moderate agreement (p<0.001). Ten patients fulfilled at least one criterion and four failed to fulfill any of the three criteria. Strong agreement was found between Thompson and McDonald criteria (p<0.001), agreement was moderate between Thompson and Polman criteria (p<0.001) and weak agreement occurred between McDonald and Polman criteria (p=0.042). CONCLUSION: The main difference between these criteria is the change in the role of CSF, previously a prerequisite for diagnosis. Rigid diagnostic criteria as Thompson have higher specificity, should be used in clinical research protocols, while more flexible criteria as Polman facilitate the diagnosis of PPMS in neurological practice, particularly in initial stages of the disease, because of their potentially higher sensitivity.

Efeito do ativador transcricional de genes ®Heat-shock¼ sobre a tolerância ao estresse na levedura Saccharomyces cerevisiae / Effect of ®heat-shock¼ genes transcriptional activator about the tolerance of stress in Saccharomyces cerevisiae

O ®heat shock factor¼ ou HSF é uma proteína mediadora da ativação transcricional de genes que são induzidos pelo choque térmico. Neste trabalho, foi feito um estudo sobre a participação do HSF na tolerância de células de levedura a diferentes tipos de estresse, com o objetivo de esclarecer questões controversas encontradas na literatura. Observou-se que a expressão do gene HSF1, presente num plasmídeo de múltiplas cópias, é suficiente para induzir álcooltolerância e termotolerância à célula hospedeira do plasmídeo, mesmo na ausência de qualquer pré-tratamento de estresse. O aumento de tolerância proporcionado pelo HSF plasmidial foi verificado em diferentes linhagens de levedura, não afetou a velocidade de crescimento destas linhagens e foi acompanhado pela indução de genes repórteres, mostrando que pode ser devido ao aumento de síntese de Hsps e/ou de trealose...

Esclerose múltipla (EM): perfil clínico e evolutivo no município do Rio de Janeiro: análise das manifestaçöes neurológicas prevalentes em 291 surtos de 88 pacientes / Multiple sclerosis: clinical and evolutionary profile in Rio de Janeiro city

Com o objetivo de definir o perfil clínico da esclerose múltipla no município do Rio de Janeiro, os autores analisam uma série de 88 pacientes (21 homens e 67 mulheres) atendidos no Hospital da Lagoa - Rio de Janeiro entre 1985 a 1993. Säo apresentados dados de identificaçäo que apontam para a ocorrência da enfermidade principalmente no sexo feminino (3:1), em pacientes jovens (média de idade de início - 27,9 anos - DP: 11,3) e de cor branca (72 por cento), embora 1/3 da série feminina (25 entre 67 pacientes) seja de cor negra. A análise das manifestaçöes clínicas dos 88 pacientes estudados em 291 surtos indica prevalência das alteraçöes piramidais (62,8 por cento), seguida das sensitivas (42,09 por cento), visuais (31,9 por cento), de tronco (28,5 por cento), coordenaçäo (27,1 por cento), esfincterianas (21,6 por cento) e mentais (6,5 por cento). Estes dados foram comparados a séries nacionais e a de Kurtzke (Army Series), encontrando-se nesta o mais aproximado perfil clínico. O cálculo do EDSS ao final do último surto indicou uma evoluçäo benigna da enfermidade, já que 55,6 por cento dos pacientes apresentavem EDSS até 2,5 e 81,8 por cento - EDSS abaixo de 6,0

Esclerose múltipla (EM): influência do sexo e da etnia no perfil clínico de 88 pacientes no município do Rio de Janeiro / Multiple sclerosis(MS): influence of sex and etnics in clinical profile of 88 patients in Rio de Janeiro city

Com o objetivo de pesquisar a influência da etnia e do sexo na exteriorizaçäo clínica da esclerose múltipla, os autores analisam série de 88 pacientes atendidos no Hospital da Lagoa - Rio de Janeiro entre 1985 a 1993. Nesta casuística de 67 mulheres e 21 homens, negros representaram 31,8 por cento (N = 28) do total de pacientes sendo 37,3 por cento (N = 25) na série feminina e 14,28 por cento (N = 3) na masculina. Säo apresentados e comparados resultados parciais de índices de prevalência de manifestaçöes neurológicas nas séries feminina (236 surtos) e masculina (55 surtos), e entre as pacientes do sexo feminino considerando as brancas e negras. A análise estatística indicou ser a alteraçäo motora significativamente maior na série feminina, porém atribuiu esta diferença à etnia e näo ao sexo

Esclerose multipla (EM): perfil clinico e evolutivo no municipio do Rio de Janeiro

Com o objetivo de definir o perfil clinico da esclerose multipla no municipio do Rio de Janeiro, os autores analisam uma serie de 88 pacientes (21 homens e 67 mulheres) atendidos no hospiatal da Lagoa - Rio de Janeiro entre 1985 a 1993. Sao apresentados dados de identificacao que apontam para a ocorrencia da enfermidade principalmente no sexo feminino (3:1), em pacientes jovens (media de idade de inicio - 27,9 anos - DP: 11,3) e de cor branca (72 por cento), embora 1/3 da serie feminina (25 entre 67 pacientes) seja de cor negra. A analise das manifestacoes clinicas dos 88 pacientes estudados em 291 surtos indica prevalencia das alteracoes piramidais (62,8 por cento), seguida das sensitivas (42,09 por cento), visuais (31,9 por cento), de tronco (28,5 por cento), coordenacao (27,1 por cento), esfincterianas (21,6 por cento) e mentais (6,5 por cento). Estes dados foram comparados a series nacionais e a de Kurtzke (Army Series), encontrando-se nesta o mais aproximado perfil clinico. O calculo do EDSS ao final do ultimo surto indicou uma evolucao benigna da enfermidade, ja que 55,6 por cento dos pacientes apresentavam EDSS ate 2,5 ate 81,8 por cento - EDSS abaixo de 6,0.

Esclerose multipla (EM): influencia do sexo e da etnia no perfil clinico de 88 pacientes no municipio do Rio de Janeiro

Com o objetivo de pesquisar a influencia da etnia e do sexo na exteriorizacao clinica da esclerose multipla, os autores analisam serie de 88 pacientes atendidos no Hospital da Lagoa - Rio de Janeiro, entre 1985 a 1993. Nesta casuistica de 67 mulheres e 21 homens, negros representam 31,8 por cento (N=28) do total de pacientes, sendo 37,3 por cento (N=25) na serie feminina e 14,28 por cento (N=3) na masculina. Sao apresentados e comparados resultados parciais de indice de prevalencia de manifestacoes neurologicas nas series feminina (236 surtos) e masculina (55 surtos), e entre as pacientes do sexo feminino considerando as brancas e negras. A analise estatistica indicou ser a alteracao motora significativamente maior na serie feminina, porem atribuiu esta diferenca a etnia e nao ao sexo.

Síndrome de Miller Fischer: apresentaçäo de quatro casos e revisäo da posiçäo nosológica / Miller Fischer syndrome: 4 cases and the nosological position of this disorder

Neste trabalho säo descritos quatro casos tipicos, recentes, da síndrome de Miller Fisher, acrescidos de revisäo da literatura sobre sua posiçäo nosológica. Na falta de maiores esclarecimentos anatomopatológicos, näo foi possível responder com certeza a questäo da origem da Síndrome. Tanto pela literatura quanto nos casos ora descritos, parece ocorrer envolvimento combinado do sistema nervoso central e do sistema nervoso periférico