Marcos Papais Alvarenga

Kinetics and incidence of anti-natalizumab antibodies in multiple sclerosis patients on treatment for 18 months

Natalizumab is a monoclonal antibody shown to be highly effective in the treatment of relapsing–remitting multiple sclerosis (RRMS). Patients treated with natalizumab can develop antibodies directed against this agent that may affect the efficacy and safety of the drug. In this observational study, the kinetics of the appearance and the incidence of anti-natalizumab antibodies were followed prospectively for 18 months in a cohort of 64 consecutive patients treated with natalizumab for relapsing MS. Blood samples were drawn immediately before starting natalizumab therapy and each month afterwards. The presence of antibodies against natalizumab was assessed by enzyme-linked immunosorbent assay (ELISA) in all patients. Anti-natalizumab antibodies were detected in nine (14.1%) natalizumab-treated patients, three (4.68%) of whom were transiently positive while six (9.37%) were persistently positive (these patients discontinued natalizumab). All positive titres were observed during the first 4 months of treatment. One patient with a hypersensitivity reaction also had persistent antibodies. We conclude that antibodies against natalizumab develop early, within the first 6 months of therapy with natalizumab. Although no antibodies were detected after 4 months of therapy in this particular study, this does not rule out their development later on in exceptional cases.

The efficacy of natalizumab in patients with multiple sclerosis according to level of disability: results of an observational study

Background: Little is known about how the level of disability at the start of treatment with natalizumab affects its efficacy. Objectives: The aim of this study was to investigate the effect of natalizumab on relapses in patients with different levels of baseline disability associated with MS. Methods: This single-centre observational study collected demographic data for patients followed prospectively and who were scheduled to start natalizumab therapy due to the presence of disease activity. The annualized relapse rate (ARR) and Kurtzke Expanded Disability Status Scale scores were analysed for the previous year, on starting treatment (baseline) and 1 year after starting therapy. Results: Seventy-seven patients (mean age: 39.0 years, mean disease duration: 12.4 years) were included. The difference between ARR before and after starting treatment was 0.92 for baseline Expanded Disability Status Scale ≤3.5 (p < 0.0005), 0.70 for Expanded Disability Status Scale 4.0–6.0 (p < 0.007) and 0.57 for Expanded Disability Status Scale ≥6 (p = 0.386). Expanded Disability Status Scale did not vary during the study. One patient discontinued treatment due to an adverse event and nine patients discontinued due to positive anti-natalizumab antibodies. Conclusions: The findings support the efficacy of natalizumab in reducing ARR in the year after starting treatment in patients with baseline Expanded Disability Status Scale ≤6.

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 ≥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 Di...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.

Acute disseminated encephalomyelitis: clinical features, HLA DRB1*1501, HLA DRB1*1503, HLA DQA1*0102, HLA DQB1*0602, and HLA DPA1*0301 allelic association study

We evaluated the frequency, demographic, clinical, disability evolution and genetic association of HLA DRB1*1501, DRB1*1503, DQA1*0102, DQB1*0602 and DPA1*0301 alleles in patients diagnosed as acute disseminated encephalomyelitis (ADEM) among a population of CNS demyelinating diseases. Fifteen patients (8.4%) of our series were diagnosed as ADEM. The mean age onset was 35.23 years (range 12 to 77), 53.3% were male and follow-up range was 8.5 to 16 years. Two cases (13.3%) had a preceding infection before neurological symptoms, one presented a parainfectious demyelinating, and one case had been submitted to hepatitis B vaccination four weeks before the clinical onset. The EDSS range was 3.0 to 9.5. Eight patients (53.3%) presented MRI with multiple large lesions. CSF was normal in 73.3%. The severe disability observed at EDSS onset improved in 86.66% patients. The genetic susceptibility for ADEM was significantly associated with the HLA DQB1*0602, DRB1*1501 and DRB1*1503 alleles (<0.05) in monophasic ADEM.

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 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.

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.

Neuromyelitis optica and optic spinal multiple sclerosis are different diseases

WCN 2013 No: 3080 Topic: 6 — MS & Demyelinating Diseases TLR 3 ligand poly I:C does not induce encephalitogenic T cells nor essentially alter cytokine production in SJL EAE H.H.Hofstetter, C. Zimmermann, A. Weber, B.C. Kieseier, H.P. Hartung. Neurology, Heinrich Heine University, Dusseldorf, Germany Background: Toll-like receptor (TLR) ligands have the ability to alter an autoantigen-specific immune response both when they are present during the priming phase as well as when they are present when the primed T cell reencounters its antigen, e.g. in the inflamed CNS. Objective: Poly I:C, a viral mimic and ligand for TLR 3 is widely used as a paradigm for a viral infection. Since viral infections are both linked with the initiation of multiple sclerosis (MS) as well as with relapses, we here investigated the effect of poly I:C both as an adjuvant as well as a co-stimulant during PLP-specific recall. Material and methods: PLPp 139–151 injected in CFA subcutaneously and systemic administration of Pertussis toxin were generated to induce EAE in female wild-type SJL mice. Alternatively, mice were injected with PLPp 139–151 and poly I:C as an adjuvant. PLPpspecific T cell responses were assessed by cytokine ELISPOT for proand anti-inflammatory cytokine production both in the spleen and in the inflamed CNS. Results: We find that poly I:C as an adjuvant does not prime an encephalitogenic T cell population, nor does it essentially affect the PLPp-specific T cell cytokine signature during recall in the immune periphery or in the inflamed target organ. Conclusion: We conclude that different TLR ligands can have fundamentally different effects on an ongoing CNS-autoantigen specific autoimmune process. doi:10.1016/j.jns.2013.07.1315 Abstract — WCN 2013 No: 3121 Topic: 6 — MS & Demyelinating Diseases Neuromyelitis optica and optic spinal multiple sclerosis are different diseases? WCN 2013 No: 3121 Topic: 6 — MS & Demyelinating Diseases Neuromyelitis optica and optic spinal multiple sclerosis are different diseases? M.P. Alvarenga, M.P. Alvarenga, C.C. Ferreira Vasconcelos, U.C. Linhares, C. Bento, G. Santos, R.M. Papais-Alvarenga. Neurology, UNIRIO, Rio de Janeiro, Brazil; Rede Sarah de Reabilitacao, Rio de Janeiro, Brazil; UNIRIO, Rio de Janeiro, Brazil Objective: To compare neuromyelitis optica (NMO) and optic spinal multiple sclerosis (OS-MS). Method: Consecutive patients with NMO phenotype attended in Rio de Janeiro from 2009 to 2011 were classified in two groups: defined NMO according to Wingerchuk et al. (2006) (recurrent or monophasic) and optic spinal multiple sclerosis (OS-MS). Results: We analyzed 99 patients: 66 were NMO-R, 8 NMO-M and 25 MS-OS. In NMO-R group, 91% were women, 65.2% African–Brazilian, mean age at onset is 13.03 years, median EDSS of 6.0 (2.0 to 10) in the last evaluation after median disease time of 8 years (2–35); the positivity of anti-AQP4 was 56.1%. In group NMO-M, 62.5% were women, 65.5% African–Brazilian, mean age at onset is 19.77 years, median EDSS of 3.0 (2.0 to 6, 0) in the last evaluation after 7 years of median disease time (3–14); the positivity of anti-AQP4 was 0.0%. In MS-OS group 84% were women, 16% African–Brazilian, mean age at onset is 8.12 years, median EDSS of 3.0 (1.0 to 6.5) in the last evaluation after a median disease duration of 8 years (3.0 to 27.0); the positivity of anti-AQP4 was 0%. There was a statistically significant difference between NMO and OS-MS groups concerning to race, long term disability, extension of the MRI vertebral lesion, positivity of anti-AQP4 and frequency of HLA DR2. Conclusion: NMO and OSMS in Brazilian population are different demyelinating inflammatory diseases although they share the same clinical phenotype presentation. doi:10.1016/j.jns.2013.07.1316 Abstract — WCN 2013 No: 3093 Topic: 6 — MS & Demyelinating Diseases Demyelinating inflammatory idiopathic diseases in Latin America— A study of prevalent cases WCN 2013 No: 3093 Topic: 6 — MS & Demyelinating Diseases Demyelinating inflammatory idiopathic diseases in Latin America— A study of prevalent cases R.M. Papais-Alvarenga, C.C. Ferreira Vasconcelos, I. Soto, A. Carra, V. Flores, P. Marinho, S.N. Machado, A.B.C. Gama, M.S.G. Rocha, A.P.G. Neto, D.S. Diniz, Y.D. Fragoso, M.P. Alvarenga, L. Campanella, H.H. Siqueira, A.K. Grzesiuk, M.L.V. Pimentel, M.K.F. Parolin, S. Florentin, L.C. Thuler. Neurology, UNIRIO, Rio de Janeiro, Brazil; Maracaibo University Hospital, Maracaibo, Venezuela; Hospital Britanico de Buenos Aires, Buenos Aires, Argentina; Central Hospital of the Institute of Social Security, Assuncion, Paraguay; Rede Sarah de Reabilitacao, Brasilia, Brazil; Neurologia, Hospital de Florianopolis, Florianopolis, Brazil; Pos Graduacao, UNIRIO, Vassouras, Brazil; Hospital Santa Marcelina, Sao Paulo, Brazil; Santa Casa de Belo Horizonte, Belo Horizonte, Brazil; Universidade de Goias, Goiania, Brazil; Universidade de Santos, Santos, Brazil; Hospital da Lagoa, Brazil; UNIRIO, Rio de Janeiro, Brazil; Universidade deMato Grosso, Brazil; Mato Grosso, Cuiaba, Brazil; Santa Casa do Rio de Janeiro, Rio de Janeiro, Brazil; Hospital dos Bombeiros, Parana, Brazil; Instituto de Prevision Social, Assuncion, Paraguay Background: Epidemiologic studies on multiple sclerosis (MS) and neuromyelitis optic (NMO) have shown that both diseases have particular world of geographic distribution according to population, Caucasians in MS and African ascendants and Asian in NMO. Considering the colonization of Latin America we can distinguish three main ancestries: Caucasians, Mestizos and Afro-descendant populations. Objective: The aim of this study was to describe the frequencies of MS and NMO in different regions of Latin America with diversified ancestry. Methods: It was asked of the physicians of MS treatment centers (one in Argentina, one in Paraguay, one in Venezuela and nine in Brazil) to inform all registered cases of idiopathic inflammatory demyelinating disease (IIDD) the frequencies of MS and NMO in following-up, as well as the ancestry of patients. Results: In Argentina, among the 123 patients (99.2% Caucasians and 0.8% Asians) the frequency of MS and NMO were 93% and 1.6% Abstracts / Journal of the Neurological Sciences 333 (2013) e358–e421 e359