Effectiveness and Adverse Events of Use of Natalizumab in a Brazilian Cohort of Patients With Multiple Sclerosis.

PURPOSE: Natalizumab (NTZ) is a monoclonal antibody with confirmed efficacy in white populations with recurrent-remitting multiple sclerosis (RRMS); there are few studies, however, in mixed-race populations. Real-world studies of NTZ are needed to better understand the drug's effectiveness. This study evaluated the effectiveness and adverse events of NTZ in a cohort of Brazilian patients with MS, as well as the impact of clinical and demographic factors on patient response to treatment. METHODS: This multicenter, Brazilian observational study was conducted from January 2011 until December 2016 and included patients with RRMS (McDonald criteria 2005 and 2010) aged ≥18 years treated with NTZ for at least 3 months. Demographic, clinical, and radiologic data were obtained from medical records and during follow-up visits. The primary outcomes investigated were the absolute number of relapses and annualized rate of relapses, change in Expanded Disability Status Scale value, and presence of new lesions on magnetic resonance imaging after starting NTZ treatment; the occurrence and type of adverse events were also analyzed. In addition, the impact of demographic and clinical prognostic factors and radiologic activity on the effectiveness of NTZ was measured. Descriptive and univariate statistical analyses used a significance level of P < 0.05. RESULTS: The study enrolled 56 patients; 64% were women, and 36% were of African descent. There was a significant reduction in the mean absolute number (P = 0.001) and in the annualized rate (P = 0.001) of relapses and in the radiologic activity of the disease (P = 0.001). Furthermore, 71% of patients showed no increase in Expanded Disability Status Scale score after 1 year of treatment. The effectiveness of NTZ was not associated with the presence of clinical and demographic prognostic factors, and the most frequent adverse events during the use of NTZ were gastrointestinal symptoms; there were no cases of progressive multifocal leukoencephalopathy. IMPLICATIONS: According to patients' reports and clinicians' observations regarding clinical and radiologic benefits and tolerability to adverse events, the use of NTZ was favorable in this Brazilian MS cohort, regardless of the presence of unfavorable prognostic factors.

Long-term MS secondary progression: Derivation and validation of a clinical risk score.

OBJECTIVE: The risk of progression of multiple sclerosis (MS) related to the association of prognostic factors present at disease onset has rarely been explored. We aimed to construct a clinical risk score for MS long-term progression that could be easily applied in clinical practice. PATIENTS AND METHODS: Among 432 patients with MS, 288 patients were selected as a derivation sample for identification of the knowledge prognostic factors more associated with long-term progression. One point was given to each risk factor identified as statistically significant by the adjusted model, and the sum of the points gave the overall risk score. Subsequently the score was applied to the remaining 144 patients to confirm if those with higher scores had reached MS secondary progression. RESULTS: The prognostic factors identified as independently associated with long-term progression were: no specific MS treatment before EDSS 3, age of onset older than 30 years, pyramidal and cerebellar impairment as the first manifestation of disease, time interval between the first and second relapses less than 2 years, and African ancestry. There was no significant difference between expected and observed number of patients in progression (44 vs. 31, p = 0.966), indicating that the score was able to predict the progression in the validation sample. There was no significant difference between patients with low risk (≤ 2 points) (p = 0.98) and high risk (≥ 3 points) (p = 0.48) in the derivation versus validation samples. In the derivation sample, the patients with three or more points had a 2.8-fold increased risk of progression [hazard ratio (HR): 2.8; 95 % confidence interval (CI): 1.2-6.3; p = 0.014). CONCLUSION: The score proposed was capable of predicting long-term MS progression.

The HLA DRB1*03:01 allele is associated with NMO regardless of the NMO-IgG status in Brazilian patients from Rio de Janeiro.

The aim of this study was to analyze the HLA class II alleles in neuromyelitis optica (NMO) and MS patients from Rio de Janeiro to clarify whether the pattern of genetic predisposition in NMO is different from the one seen in MS or whether it is possible to determine specific alleles of susceptibility or resistance. The DR3 haplotype was over represented in NMO while the DR15 was over represented in MS. The HLA-DRB1*03:01 allele was associated with NMO regardless the NMO-IgG status but did not influence the long term disability. The comparison of the allele and haplotype frequencies significantly discriminated patients with NMO vs. MS.

Multiple sclerosis in Brazil: A systematic review.

BACKGROUND: The natural history of multiple sclerosis (MS) in Brazil has been available in different regions of country. There is no nationwide population-based studies that express general data in Brazil. OBJECTIVE: To review and synthesize available data about MS in Brazil. MATERIAL AND METHODS: Systematic review was performed through a search of medical literature databases to identify Brazilian studies published during 1990-2012. DATA SOURCES: PubMed, SciELO, and Lilacs. KEYWORDS: "Brazil" or "Brazilian" combined with the following terms: "multiple sclerosis", "clinical profile", "demographic profile", "natural history", "clinical course", "pediatric", or "familial form". RESULTS: In total of 45 pediatric and 1922 adult patients, the median age at onset was 10 years in pediatric patients and 32 years in adult patients. Women were more affected. Motor-control complaints and relapsing-remitting phenotype at onset were the most common. Predictors to disability and progression were number of relapses during the first year of disease, older age, male gender and African ancestry. CONCLUSIONS: The profile of the MS in Brazilian seems to correspond to that observed in high-MS-prevalence areas. African ancestry is a risk factor to disability and progression early. In Brazil, factors that limit MS incidence do not interfere with the clinical pattern and outcomes.

A systematic review of the intergenerational aspects and the diverse genetic profiles of Huntington's disease.

Huntington's disease (HD) is a rare progressive and fatal neurogenetic degenerative disease, characterized by movement and personality disorders and by progressive dementia. Its prevalence varies by ethnic origin and different genetic profiles predisposing individuals to HD in each population. The prevalence of HD is 5-10 per 100,000 individuals in Caucasian populations of North America and Western Europe. It is an autosomal dominant disease associated with the expansion of CAG-type repetitive DNA sequences in the HTT gene. This gene, located on the short arm of chromosome 4, encodes the protein huntingtin. In this study, we reviewed 17 articles about HD that report data from 2400 affected individuals from various countries around the world, including Venezuela, China, Croatia, Turkey, Germany, Italy, Brazil, Spain, Taiwan, India, the Netherlands, Russia, and the USA, with a focus on genetic profiles and intergenerational expansions or contractions of expanded alleles responsible for causing HD. We discuss the genetic characteristics of HD in different populations and any atypical cases reported in these studies.

[LACTRIMS consensus document for the pharmacological treatment of the multiple sclerosis and its clinical variants]. / Documento de consenso de LACTRIMS para el tratamiento farmacologico de la esclerosis multiple y sus variantes clinicas.

INTRODUCTION. Multiple sclerosis (MS) it is not considered any more a rare disease in Latin America. Most of the Latin American countries have reported moderate or lower prevalence data. However only very few countries have developed therapeutic guidelines. LACTRIMS prepared this consensus document with specific recommendations for the treatment of the disease. DEVELOPMENT. Experts on treatment and clinical research on MS were invited by LACTRIMS in order to generate a initial document to be discussed in Quito, Ecuador. Several groups were organized in relation of the different clinical variants. These groups were coordinated by experts leaders and prepared a preliminary document that was discussed in Quito during July 8th and 9th, 2011. Finally the final version was submitted to the members and delegates of LACTRIMS in most of the Latin American countries who were able to make modifications and suggest changes to the final manuscript. CONCLUSIONS. Based on the different evidence levels and the AGREE criteria, the clinical variants were reviewed and recommendations were made for the use of drugs and different modifying disease therapeutic agents.

[Neuropsychology of primary progressive multiple sclerosis]. / Neuropsicología de la esclerosis múltiple primaria progresiva.

INTRODUCTION: Cognitive impairment is a symptom of multiple sclerosis (MS); however, in the primary progressive form of the disease (PPMS), data on the prevalence and type of cognitive impairment are controversial. AIM: To evaluate the frequency of cognitive impairment, according to the diagnostic criteria defined by Thompson, in Brazilian patients with PPMS attending a referral center for the treatment of MS in Rio de Janeiro, Brazil. SUBJECTS AND METHODS: A battery of neuropsychological tests was used to evaluate the following cognitive functions: screening for dementia, attention/concentration, speed of information processing, verbal fluency, memory and abstract/conceptual thought. The Beck scale was used to evaluate mood disorders. Twenty-six patients with PPMS and 26 controls paired for gender, age and education level were evaluated. Statistical analysis was based on the study performed by Rao. RESULTS: The frequency of cognitive impairment in the PPMS patients in the present study was 50%. The cognitive functions most affected were: recent memory (60%), verbal fluency (40%) and speed of information processing (40%). Depression was more common in the PPMS patients compared to the control group; however, no association was found between cognitive impairment and depression. CONCLUSION: These results confirm the presence of cognitive impairment in PPMS and emphasize the need for further studies with larger sample sizes.

Clinical course of progressive multiple sclerosis in Brazilian patients.

OBJECTIVE: To describe the clinical course and outcome of multiple sclerosis with progressive onset in Brazilian patients. A total of 238 medical records were reviewed, 26 cases (10.9%) fulfilled Thompson criteria (2000), and 5.80% classified as primary progressive and 5.04% relapsing progressive according to Lublin and Reingold. STUDY POPULATION: 19 Caucasians and 7 non-Caucasians; male:female ratio 1.2:1, mean age at onset was 34 +/- 7.9 years. RESULTS: Non-Caucasian patients had earlier onset of disease. The most common manifestations at onset were pyramidal and cerebellar (89% and 34.6%). After 11.3 +/- 6.35 years of disease more than 50% of the patients had involvement of most of their functional systems. No statistically significant differences were observed between the subgroups. CONCLUSION: The clinical course and outcome of progressive multiple sclerosis in Brazil, a tropical country with low prevalence, were very similar to those in the multiple sclerosis high prevalence areas.

Functional mapping of the cardiorespiratory effects of dorsal and median raphe nuclei in the rat.

The dorsal (DRN) and median (MRN) raphe nuclei are important sources of serotonergic innervation to the forebrain, projecting to sites involved in cardiovascular regulation. These nuclei have been mapped using electrical stimulation, which has the limitation of stimulating fibers of passage. The present study maps these areas with chemical stimulation, investigating their influence on cardiorespiratory parameters. Urethane-anesthetized (1.2 g/kg, iv) male Wistar rats (280-300 g) were instrumented for pulsatile and mean blood pressure (MBP), heart rate, renal nerve activity, and respiratory frequency recordings. Microinjections of L-glutamate (0.18 M, 50-100 nl with 1% Pontamine Sky Blue) were performed within the DRN or the MRN with glass micropipettes. At the end of the experiments the sites of microinjection were identified. The majority of sites within the MRN (86.1%) and DRN (85.4%) evoked pressor responses when stimulated (DRN: DeltaMBP = +14.7 +/- 1.2; MRN: DeltaMBP = +13.6 +/- 1.3 mmHg). The changes in renal nerve activity and respiratory rate caused by L-glutamate were +45 +/- 11 and +42 +/- 9% (DRN; P < 0.05%), +40 +/- 10 and +29 +/- 7% (MRN, P < 0.05), respectively. No significant changes were observed in saline-microinjected animals. This study shows that: a) the blood pressure increases previously observed by electrical stimulation within the raphe are due to activation of local neurons, b) this pressor effect is due to sympathoexcitation because the stimulation increased renal sympathetic activity but did not produce tachycardia, and c) the stimulation of cell bodies in these nuclei also increases the respiratory rate.

Functional mapping of the cardiorespiratory effects of dorsal and median raphe nuclei in the rat

The dorsal (DRN) and median (MRN) raphe nuclei are important sources of serotonergic innervation to the forebrain, projecting to sites involved in cardiovascular regulation. These nuclei have been mapped using electrical stimulation, which has the limitation of stimulating fibers of passage. The present study maps these areas with chemical stimulation, investigating their influence on cardiorespiratory parameters. Urethane-anesthetized (1.2 g/kg, iv) male Wistar rats (280-300 g) were instrumented for pulsatile and mean blood pressure (MBP), heart rate, renal nerve activity, and respiratory frequency recordings. Microinjections of L-glutamate (0.18 M, 50-100 nl with 1 percent Pontamine Sky Blue) were performed within the DRN or the MRN with glass micropipettes. At the end of the experiments the sites of microinjection were identified. The majority of sites within the MRN (86.1 percent) and DRN (85.4 percent) evoked pressor responses when stimulated (DRN: deltaMBP = +14.7 ± 1.2; MRN: deltaMBP = +13.6 ± 1.3 mmHg). The changes in renal nerve activity and respiratory rate caused by L-glutamate were +45 ± 11 and +42 ± 9 percent (DRN; P < 0.05 percent), +40 ± 10 and +29 ± 7 percent (MRN, P < 0.05), respectively. No significant changes were observed in saline-microinjected animals. This study shows that: a) the blood pressure increases previously observed by electrical stimulation within the raphe are due to activation of local neurons, b) this pressor effect is due to sympathoexcitation because the stimulation increased renal sympathetic activity but did not produce tachycardia, and c) the stimulation of cell bodies in these nuclei also increases the respiratory rate.

Optic neuromyelitis syndrome in Brazilian patients.

OBJECTIVES: To report the clinical features and outcome of 24 Brazilian patients with optic neuromyelitis syndrome (ONM); discuss the underlying pathological events associated with the ONM syndrome; review the nosological situation of ONM in the group of inflammatory and demyelinating diseases of the central nervous system. PATIENTS AND METHODS: Patients with ONM treated at the Hospital da Lagoa, Rio de Janeiro were studied. Demographic, clinical, magnetic resonance imaging, cerebrospinal fluid, and pathological data were analysed. RESULTS: The study consisted of 20 women, four men of whom 10 were white and 14 Afro-Brazilians. Clinical course was recurrent in 22 cases and monophasic in two. Neurological manifestations at inclusion were: sensory impairment (66%), bilateral (41.6%) or unilateral blindness (20.8%), paraplegia or quadriplegia (37.5%). The EDSS was moderate/severe in 70.8%. The underlying pathological events were respectively pulmonary tuberculosis and upper respiratory infection in the two monophasic cases; in the 22 recurrent ONM patients: pulmonary tuberculosis (3), neurocysticercosis (1), polyarteritis nodosa (1), antinuclear antibody and rheumatoid factor (1), antiphospholipid antibody primary syndrome (1), diabetes mellitus (1), hypothyroidism (1), and amenorrhea-galactorrhea (4). Normal cerebrospinal fluid was found in 52% and an inflammatory profile in 48%. Only four recurrent ONM white patients had brain and spinal cord magnetic resonance imaging and cerebrospinal fluid findings compatible with the diagnosis of multiple sclerosis. Large lesions were seen in 62% of spinal magnetic resonance images. Six of 12 recurrent ONM Afro-Brazilian died. There were no statistical differences in the demographic data of the two ethnic groups. Afro-Brazilians were significantly more severely impaired and had a higher mortality rate than the white patients. CONCLUSION: These cases were classified as follows: two monophasic acute disseminated encephalomyelitis; one recurrent disseminated encephalomyelitis; three recurrent ONM associated with Hughes syndrome, autoantibodies and polyarteritis nodosa; six recurrent ONM with endocrinopathies; and finally, four multiple sclerosis cases. The remaining cases were not associated with any other condition. It would seem clear that ONM is a syndrome rather than a single disease.

Síndrome de Shy-Grager: relato de um caso clínico / Shy-Drager syndrome: case report

A síndrome de Shy-Drager é uma doença degenerativa do sistema nervoso central, de etiologia desconhecida, caracterizada por falência progressiva do sistema autonômico e atrofia de múltiplos sistemas. É relatado o caso de uma paciente do sexo feminino que aos 41 anos de idade foi estabelecido o diagnóstico de síndrome de Shy-Drager. Provas funcionais autônomas, exames laboratoriais e exame físico, principalmente minucioso exame neurológico, evidenciaram claramente a falência do sistema nervoso autônomo e sinais de atrofia multissistematizada. Seräo ressaltados aspectos clínicos-evolutivos que caracterizaram os 8 anos da enfermidade, de investigaçäo da funçäo autonômica e de diagnóstico diferencial - já que a doença foi confundida durante a fase inicial com outras enfermidades sistêmicas e do sistema nervoso

Sindrome de Shy-Drager: relato de um caso clinico

A sindrome de Shy-Drager e uma doenca degenerativa do sistema nervoso central, de etiologia desconhecida, caracterizada por falencia progressiva do sistema autonomo e atrofia de multiplos sistemas. E relatado o caso de uma paciente do sexo feminino que aos 41 anos de idade foi estabelecido o diagnostico de sindrome de Shy-Drager: Provas funcionais autonomas, exames laboratoriais e exame fisico, principalmente minucioso exame neurologico, evidnciaram claramente a falencia do sistema nervoso autonomo e sinais de atrofia multissistematizada. Serao ressaltados aspectos clinicos-evolutivos que caracterizaram os 8 anos da enfermidade, de investigacao da funcao autonomica e de diagnostico diferencial-ja que a doenca foi confundida durante a fase inicial com outras enfermidades sistemicas e do sistema nervoso.

Esclerose multipla: manifestacoes clinicas, aspectos epidemiologicos e criterios diagnosticos

Os autores dissertam sobre as manifestacoes clinicas da esclerose multipla a partir de revisao historia dos trabalhos originais de Jean Martin Charcot e seus discipulos que, na segunda metade do seculo passado, descreveram as bases de diagnostico clinico desta enfermidade. Apresentam simula das principais investigacoes epidemiologicas que demonstram uma distribuicao geografica unica, com areas de alta prevalencia nos paises frios do hemisferio norte e tem contribuido para o conhecimento da evolucao natural desta doenca cronica do SNC. Finalmente apresentam a metodologia de analise clinica proposta por Kurtzke atraves do FS/EDSS e os protocolos de estudo criados com o objetivo de estabelecer procedimentos uniformes de diagnosticos clinico com especial enfase ao de Poser, 1983, que vem sendo adotado nas pesquisas clinicas realizadas no Brasil.

[Miller Fisher syndrome: a report of 4 cases and review of the nosologic position]. / Síndrome de Miller Fisher: apresentação de quatro casos e revisão da posição nosológica.

Four typical cases of the Miller Fisher syndrome with external ophthalmoplegia, ataxia and generalized areflexia but no muscular weakness or sensory impairment of the limbs are reported. The nosological position of this disorder is reviewed.