Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations.

BACKGROUND: Autoimmune encephalitis (AIE) is a group of inflammatory diseases characterized by the presence of antibodies against neuronal and glial antigens, leading to subacute psychiatric symptoms, memory complaints, and movement disorders. The patients are predominantly young, and delays in treatment are associated with worse prognosis. OBJECTIVE: With the support of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, ABN) and the Brazilian Society of Child Neurology (Sociedade Brasileira de Neurologia Infantil, SBNI), a consensus on the diagnosis and treatment of AIE in Brazil was developed using the Delphi method. METHODS: A total of 25 panelists, including adult and child neurologists, participated in the study. RESULTS: The panelists agreed that patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques. Children should also be screened for anti-myelin oligodendrocyte glucoprotein antibodies (anti-MOG). Treatment should be started within the first 4 weeks of symptoms. The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis, the second-line includes rituximab and/or cyclophosphamide, while third-line treatment options are bortezomib and tocilizumab. Most seizures in AIE are symptomatic, and antiseizure medications may be weaned after the acute stage. In anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the panelists have agreed that oral immunosuppressant agents should not be used. Patients should be evaluated at the acute and postacute stages using functional and cognitive scales, such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Modified Rankin Scale (mRS), and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). CONCLUSION: The present study provides tangible evidence for the effective management of AIE patients within the Brazilian healthcare system.

ANTECEDENTES: Encefalites autoimunes (EAIs) são um grupo de doenças inflamatórias caracterizadas pela presença de anticorpos contra antígenos neuronais e gliais, que ocasionam sintomas psiquiátricos subagudos, queixas de memória e distúrbios anormais do movimento. A maioria dos pacientes é jovem, e o atraso no tratamento está associado a pior prognóstico. OBJETIVO: Com o apoio da Academia Brasileira de Neurologia (ABN) e da Sociedade Brasileira de Neurologia Infantil (SBNI), desenvolvemos um consenso sobre o diagnóstico e o tratamento da EAIs no Brasil utilizando a metodologia Delphi. MéTODOS: Um total de 25 especialistas, incluindo neurologistas e neurologistas infantis, foram convidados a participar. RESULTADOS: Os especialistas concordaram que os pacientes com critérios de possíveis EAIs devem ser submetidos ao rastreio de anticorpos antineuronais no soro e no líquido cefalorraquidiano (LCR) por meio das técnicas de ensaio baseado em tecidos (tissue-based assay, TBA, em inglês) e ensaio baseado em células (cell-based assay, CBA, em inglês). As crianças também devem ser submetidas ao rastreio de de anticorpo contra a glicoproteína da mielina de oligodendrócitos (anti-myelin oligodendrocyte glycoprotein, anti-MOG, em inglês). O tratamento deve ser iniciado dentro das primeiras 4 semanas dos sintomas, sendo as opções de primeira linha metilprednisolona combinada com imunoglobulina intravenosa (IGIV) ou plasmaférese. O tratamento de segunda linha inclui rituximabe e ciclofosfamida. Bortezomib e tocilizumab são opções de tratamento de terceira linha. A maioria das crises epilépticas nas EAIs são sintomáticas, e os fármacos anticrise podem ser desmamadas após a fase aguda. Em relação à encefalite antirreceptor de N-metil-D-aspartato (anti-N-methyl-D-aspartate receptor, anti-NMDAR, em inglês), os especialistas concordaram que agentes imunossupressores orais não devem ser usados. Os pacientes devem ser avaliados na fase aguda e pós-aguda mediante escalas funcionais e cognitivas, como Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Modified Rankin Scale (mRS), e Clinical Assessment Scale in Autoimmune Encephalitis (CASE). CONCLUSãO: Esta pesquisa oferece evidências tangíveis do manejo efetivo de pacientes com EAIs no sistema de saúde Brasileiro.

Assessment of health-related quality of life after mild COVID-19 infection.

INTRODUCTION: Coronavirus disease 19 (COVID-19) affected the health-related quality of life (HRQoL), and its impact on well-being is not sufficiently understood yet. The worsening of HRQoL and symptoms such as fatigue, anxiety, depression, chronic Headache, Myalgia, ageusia, olfactory disorders, and cognitive impairment can be seen in people of different ages and genders after COVID-19 infection, even mild infections without hospitalization. These issues generate a disease burden that can reduce work skills and cause social, psychological, and neuropsychiatric challenges. OBJECTIVE: To evaluate the HRQoL of patients affected by COVID-19, the domains most affected, and their relationship with fatigue, anxiety, depression, chronic Headache and Myalgia, ageusia, olfactory disorders, and cognitive impairment. METHODS: An analytical transverse was conducted with 143 patients after COVID-19 infection. The patient-reported outcomes measures (PROMS) were collected by the 36-item Short Form survey (SF-36), Fatigue Severity Scale (FSS), Hospital Anxiety and Depression Scale (HADS), Mini-Mental State Examination-2 (MMSE-2), Symbol Digit Modalities Test (SDMT), and a questionnaire regarding symptoms such as chronic Headache, myalgia, and olfactory disorders. Spearman's correlation test was used to correlate the performance of the patients on different PROMS. RESULTS: Fatigue, depression, and anxiety were negatively correlated with all the SF-36 domains, and patients with subjective cognitive complaints had low scores in all SF-36 domains. Furthermore, those with chronic Headaches had low scores in physical functioning, role-physical functioning, and vitality. Regarding myalgia complaints, the worst scores were observed in the physical functioning and vitality domains. Patients with ageusia had low scores in general health perceptions, and those with olfactory dysfunction had low scores in the vitality and mental health domains. CONCLUSIONS: Although the acute phase of COVID-19 has resolved, knowledge about HRQoL after this period is essential since many individual and collective changes have been taking place until today-patients with neuropsychiatric manifestations that persisted after the acute phase showed lower overall quality of life.

Long COVID: plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms.

It is well known the potential of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection to induce post-acute sequelae, a condition called Long COVID. This syndrome includes several symptoms, but the central nervous system (CNS) main one is neurocognitive dysfunction. Recently it has been demonstrated the relevance of plasma levels of neurofilament light chain (pNfL), as a biomarker of early involvement of the CNS in COVID-19. The aim of this study was to investigate the relationship between pNfL in patients with post-acute neurocognitive symptoms and the potential of NfL as a prognostic biomarker in these cases. A group of 63 long COVID patients ranging from 18 to 59 years-old were evaluated, submitted to a neurocognitive battery assessment, and subdivided in different groups, according to results. Plasma samples were collected during the long COVID assessment and used for measurement of pNfL with the Single molecule array (SIMOA) assays. Levels of pNfL were significantly higher in long COVID patients with neurocognitive symptoms when compared to HC (p = 0.0031). Long COVID patients with cognitive impairment and fatigue symptoms presented higher pNfL levels when compared to long COVID patients without these symptoms, individually and combined (p = 0.0263, p = 0.0480, and 0.0142, respectively). Correlation analysis showed that levels of cognitive lost and exacerbation of fatigue in the neurocognitive evaluation had a significative correlation with higher pNfL levels (p = 0.0219 and 0.0255, respectively). Previous reports suggested that pNfL levels are related with higher risk of severity and predict lethality of COVID-19. Our findings demonstrate that SARS-CoV-2 infection seems to have a long-term impact on the brain, even in patients who presented mild acute disease. NfL measurements might be useful to identify CNS involvement in long COVID associated with neurocognitive symptoms and to identify who will need continuous monitoring and treatment support.

Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations / Consenso brasileiro sobre o diagnóstico e o tratamento de encefalites autoimunes nas populações adulta e pediátrica

Abstract Background Autoimmune encephalitis (AIE) is a group of inflammatory diseases characterized by the presence of antibodies against neuronal and glial antigens, leading to subacute psychiatric symptoms, memory complaints, and movement disorders. The patients are predominantly young, and delays in treatment are associated with worse prognosis. Objective With the support of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, ABN) and the Brazilian Society of Child Neurology (Sociedade Brasileira de Neurologia Infantil, SBNI), a consensus on the diagnosis and treatment of AIE in Brazil was developed using the Delphi method. Methods A total of 25 panelists, including adult and child neurologists, participated in the study. Results The panelists agreed that patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques. Children should also be screened for anti-myelin oligodendrocyte glucoprotein antibodies (anti-MOG). Treatment should be started within the first 4 weeks of symptoms. The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis, the second-line includes rituximab and/or cyclophosphamide, while third-line treatment options are bortezomib and tocilizumab. Most seizures in AIE are symptomatic, and antiseizure medications may be weaned after the acute stage. In anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the panelists have agreed that oral immunosuppressant agents should not be used. Patients should be evaluated at the acute and postacute stages using functional and cognitive scales, such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Modified Rankin Scale (mRS), and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Conclusion The present study provides tangible evidence for the effective management of AIE patients within the Brazilian healthcare system.

Resumo Antecedentes Encefalites autoimunes (EAIs) são um grupo de doenças inflamatórias caracterizadas pela presença de anticorpos contra antígenos neuronais e gliais, que ocasionam sintomas psiquiátricos subagudos, queixas de memória e distúrbios anormais do movimento. A maioria dos pacientes é jovem, e o atraso no tratamento está associado a pior prognóstico. Objetivo Com o apoio da Academia Brasileira de Neurologia (ABN) e da Sociedade Brasileira de Neurologia Infantil (SBNI), desenvolvemos um consenso sobre o diagnóstico e o tratamento da EAIs no Brasil utilizando a metodologia Delphi. Métodos Um total de 25 especialistas, incluindo neurologistas e neurologistas infantis, foram convidados a participar. Resultados Os especialistas concordaram que os pacientes com critérios de possíveis EAIs devem ser submetidos ao rastreio de anticorpos antineuronais no soro e no líquido cefalorraquidiano (LCR) por meio das técnicas de ensaio baseado em tecidos (tissue-based assay, TBA, em inglês) e ensaio baseado em células (cell-based assay, CBA, em inglês). As crianças também devem ser submetidas ao rastreio de de anticorpo contra a glicoproteína da mielina de oligodendrócitos (anti-myelin oligodendrocyte glycoprotein, anti-MOG, em inglês). O tratamento deve ser iniciado dentro das primeiras 4 semanas dos sintomas, sendo as opções de primeira linha metilprednisolona combinada com imunoglobulina intravenosa (IGIV) ou plasmaférese. O tratamento de segunda linha inclui rituximabe e ciclofosfamida. Bortezomib e tocilizumab são opções de tratamento de terceira linha. A maioria das crises epilépticas nas EAIs são sintomáticas, e os fármacos anticrise podem ser desmamadas após a fase aguda. Em relação à encefalite antirreceptor de N-metil-D-aspartato (anti-N-methyl-D-aspartate receptor, anti-NMDAR, em inglês), os especialistas concordaram que agentes imunossupressores orais não devem ser usados. Os pacientes devem ser avaliados na fase aguda e pós-aguda mediante escalas funcionais e cognitivas, como Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Modified Rankin Scale (mRS), e Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Conclusão Esta pesquisa oferece evidências tangíveis do manejo efetivo de pacientes com EAIs no sistema de saúde Brasileiro.

SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice.

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

Cognitive Complaints Assessment and Neuropsychiatric Disorders After Mild COVID-19 Infection.

OBJECTIVES: This study aimed to analyze cognitive impairment associated with long-term coronavirus disease 2019 (COVID-19) syndrome and its correlation with anxiety, depression, and fatigue in patients infected with severe acute respiratory syndrome coronavirus. METHODS: This was a cross-sectional study of 127 patients with COVID-19. Tests to screen for neuropsychiatric symptoms included the Fatigue Severity Scale, Mini-Mental State Exam 2 (MMSE-2), Symbol Digit Modalities Test (SDMT), and Hospital Anxiety and Depression Scale. RESULTS: In cognitive tests, SDMT was abnormal in 22%, being more sensitive than MMSE-2 to detect cognitive changes. Furthermore, although manifestations such as fatigue, depression, and anxiety were frequent in the post-COVID-19 phase, these 3 conditions, known to contribute to cognitive impairment, were slightly correlated with worse performance on the rapid screening tests. CONCLUSIONS: In patients with mild COVID-19 and cognitive complaints, SDMT helped to confirm disturbances in the attention domain and processing speed.

Major depression favors the expansion of Th17-like cells and decrease the proportion of CD39+Treg cell subsets in response to myelin antigen in multiple sclerosis patients.

BACKGROUND: Mood disorders have been associated with risk of clinical relapses in multiple sclerosis (MS), a demyelinating disease mediated by myelin-specific T cells. OBJECTIVES: We aimed to investigate the impact of major depressive disorder (MDD) and cytokine profile of T-cells in relapsing remitting MS patients. METHODS: For our study, plasma and PBMC were obtained from 60 MS patients (30 with lifetime MDD) in remission phase. The PBMC cultures were stimulated with anti-CD3/anti-CD28 beads or myelin basic protein (MBP), and effector and regulatory T cell phenotypes were determined by flow cytometry. The cytokine levels, both in the plasma or in the supernatants collected from PBMC cultures, were quantified by Luminex. In some experiments, the effect of serotonin (5-HT) was investigated. RESULTS: Here, higher Th17-related cytokine levels in response to anti-CD3/anti-CD28 and MBP were quantified in the plasma and PBMC cultures of the MS/MDD group in comparison with MS patients. Further, elevated frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF was observed in depressed patients. Interestingly, the percentage of myelin-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells directly correlated with neurological disabilities. In contrast, the occurrence of MDD reduced the proportion of MBP-specific CD39+Tregs subsets. Notably, the severity of both neurological disorder and depressive symptoms inversely correlated with these Tregs. Finally, the addition of 5-HT downregulated the release of Th17-related cytokines in response to anti-CD3/anti-CD28 and myelin antigen. CONCLUSIONS: In summary, our findings suggested that recurrent major depression, by favoring imbalances of effector Th17 and Treg cell subsets, contributes to MS severity.

Post-COVID-19 olfactory dysfunction: carbamazepine as a treatment option in a series of cases.

Olfactory dysfunction is reported frequently in patients with coronavirus disease 2019. However, an effective treatment for this dysfunction is unknown. The present study evaluated carbamazepine as a treatment option for olfactory dysfunction based on its use in cases of neuralgia, especially of the V cranial nerve. The study included 10 patients with coronavirus disease with olfactory complaints who were part of a cohort of 172 coronavirus disease patients monitored for late neurological manifestations. Carbamazepine was administered for 11 weeks. The adverse effects reported were drowsiness (9/10) and dizziness (2/10); 9 of the 10 patients reported improved olfactory function after carbamazepine treatment. While the role of carbamazepine in the control of post-coronavirus disease olfactory dysfunction could not be confirmed in this study, the satisfactory response observed in most patients in this series suggests that further studies are warranted.

"Dry oral and ocular manifestations and autoantibodies characteristic of primary Sjögren's syndrome in multiple sclerosis".

INTRODUCTION: The relationship between primary Sjögren syndrome (pSS) and demyelinating diseases is still not well understood. These diseases seem to coexist amidst autoimmunity, raising questions about clinical characteristics, relationship with immunomodulatory treatment, and possible common immunological background underlying their pathogenesis. OBJECTIVE: calculate the frequency of dry oral and ocular manifestations and autoantibodies characteristic of primary Sjögren's Syndrome in Multiple Sclerosis. METHODS: 202 patients with multiple sclerosis answered a questionnaire to identify complaints of xerostomia and xerophthalmia, according to diagnostic criteria for primary Sjögren's syndrome; 43 answered positively to at least one question; 27 had comorbidities or used drugs that cause dry symptoms and were excluded; 16 patients were selected for examinations for oral, ocular and serum anti-Ro/SS-A autoantibody evaluation. RESULTS: Eleven (68.75%) patients complained of xerostomia; 14 (87.5%) of xerophthalmia. Sialometry < 0.1 ml/min was observed in three (18.8%); 13 patients underwent minor salivary gland biopsy and histopathological examination: focal score > 1 in three (23.1%). Schirmer test was < 5 mm/5 min in four (25%). Lyssamine green/fluorescein dye score was > 5 in three (18.8%). Anti-Ro/SS-A > 10 UI/mm in two (12.5%). Three (1,49%) patients met current criteria for primary Sjögren's syndrome. CONCLUSIONS: Patients with MS may report xerostomia and/or xerophthalmia even in the absence of comorbidities and use of medications capable of causing these symptoms, which may fulfill the diagnostic criteria for pSS. In this study, the frequency of pSS according to current criteria was within the range observed in the literature with older criteria. But the question remains whether the association between these diseases is fortuitous or whether there is a pathogenic link.

Evaluation of diagnosis and treatment practices of Brazilian neurologists among patients with multiple sclerosis.

BACKGROUND: Recent changes to the diagnostic criteria for multiple sclerosis (MS) and new medications have had a major impact on the way in which specialists manage the disease. OBJECTIVE: To investigate factors considered by Brazilian neurologists in managing MS, and to identify how these contribute to diagnosis and treatment. METHODS: Potential participants were selected by a steering committee (MS experts who developed this survey). Only MS specialists were included in the study (neurologists who had completed a neuroimmunology fellowship or who were treating more than 30 MS patients). Links to the online questionnaire were distributed between March 2019 and January 2020. This questionnaire was composed of sections with hypothetical MS scenarios. RESULTS: Neurologists from 13 Brazilian states responded to the survey (n = 94). In the clinically isolated syndrome (CIS) scenario, the respondents agreed to treat patients with a high risk of MS diagnosis, whereas in the radiologically isolated syndrome (RIS) half of the respondents opted not to treat, even among high-risk patients. In cases of low-activity relapsing-remitting MS (RRMS), the choice of treatment was distributed among interferon beta, glatiramer acetate and teriflunomide, which were changed to fingolimod and natalizumab, as RRMS severity increased. The topics in which disagreement was found included practices regarding use of disease-modifying therapy (DMT) for pregnant patients and the washout period required for some DMTs. CONCLUSIONS: This study enabled identification of areas of agreement and disagreement about MS treatment among Brazilian neurologists, which can be used to update future protocols and improve patient management.

Optic neuritis in Asian type opticospinal multiple sclerosis (OSMS-ON) in a non-Asian population: A functional-structural paradox.

BACKGROUND: Biomarkers have improved the classification of autoimmune inflammatory disorders, including optic neuritis (ON) as a frequent presentation of multiple sclerosis, neuromyelitis spectrum disorders, MOG antibody-related disease (MOGAD), and opticospinal multiple sclerosis (OSMS). The phenotype of OSMS in non-Asian populations is less well known. OBJECTIVE: We investigated the clinical features and prognosis of OSMS-ON in a Brazilian cohort. METHODS: This was a single-center cohort study of patients from Rio de Janeiro (Brazil) with OSMS. All individuals were MOG- and AQP4-seronegative, clinically diagnosed with ON, and had magnetic resonance imaging-confirmed transverse myelitis (TM). Subjects and healthy controls (HCs) were assessed for visual acuity (logMAR VA), automated perimetry mean deviation (MD), intraocular pressure, and spectral-domain optical coherence tomography (OCT), followed by automated retinal layer segmentation of the peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (mGCIPL). Receiver operator characteristic curves were plotted and the area under the curve (AUC) was calculated for group comparisons of retinal asymmetry of the pRNFL and mGCIPL. RESULTS: The 30 patients with OSMS were predominantly female and white. The mean age was 48 years (range 20-70 years). Unilateral ON was the index event in 83.3% of patients. Over the average 18-year follow-up period, there were 89 relapses of ON. In individuals with OSMS, the average VA was 0.07±0.14 in the right eye (RE) and 0.13±0.30 in the left eye (LE). The MD was -5.37±5.88 dB and -5.23±3.34 dB for the RE and LE, respectively. There was a significant cumulative loss of VA (p = 0.0003) and MD (p = 0.0001) with a higher number of recurrent episodes. Atrophy of the pRNFL thickness was significant in OSMS (RE, 78.62 ± 16.01 µm; LE, 79.86 ± 13.79 µm) relative to the HC group (RE, 98.87 ± 10.68 µm; LE, 97.87 ± 10.85 µm, p = 0.0001). Likewise, there was significant mGCIPL atrophy in patients with OSMS (RE, 74.96 ± 14.46 µm; LE, 73.88 ± 13.79 µm) relative to the HC group (RE, 90.50 ± 6.74 µm; LE, 90.41± 6.89 µm; p = 0.0001). Retinal asymmetry, inter-eye percentage, and absolute differences accurately separated patients with unilateral ON from HCs (AUC=0.89 and AUC=0.85, respectively). CONCLUSION: A structural-functional paradox was found in OSMS with a high diagnostic value for a novel metric based on retinal asymmetry. The functional visual outcome are excellent despite significant structural damage to the inner retinal layers in patients with a high ON relapse rate and long-term bilateral sequential involvement.

Clinical and magnetic resonance imaging patterns of extensive Chikungunya virus-associated myelitis.

Chikungunya fever is an arbovirus infection transmitted by the same mosquito vector of dengue and Zika virus. Besides high fever, common clinical symptoms include articular pain and general malaise. Neurological involvement is unusual, but some patients may develop peripheral and central nervous system involvement, including meningoencephalitis, myelitis, Guillain-Barré syndrome, and acute disseminated encephalomyelitis. We present three cases of Chikungunya fever complicated with extensive myelitis. The spinal cord magnetic resonance imaging (MRI) pattern is characterized by multiple dotted-like and longitudinal hyperintense lesions, with contrast enhancement, mostly distributed in the peripheral regions of the spinal cord. It seems that these lesions are mostly located in the perivascular spaces (PVS), related or not to virus attack. Involvement of brain PVS can also be demonstrated, as shown in two of the cases described. Considering the MRI pattern, extensive spinal cord lesion should include Chikungunya as a differential diagnosis, especially during an outbreak.

Exome-Wide Search for Genes Associated With Central Nervous System Inflammatory Demyelinating Diseases Following CHIKV Infection: The Tip of the Iceberg.

Chikungunya virus (CHIKV) is a re-emergent arbovirus that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia, although <1% of cases develop severe neurological manifestations such as inflammatory demyelinating diseases (IDD) of the central nervous system (CNS) like acute disseminated encephalomyelitis (ADEM) and extensive transverse myelitis. Genetic factors associated with host response and disease severity are still poorly understood. In this study, we performed whole-exome sequencing (WES) to identify HLA alleles, genes and cellular pathways associated with CNS IDD clinical phenotype outcomes following CHIKV infection. The cohort includes 345 patients of which 160 were confirmed for CHIKV. Six cases presented neurological manifestation mimetizing CNS IDD. WES data analysis was performed for 12 patients, including the CNS IDD cases and 6 CHIKV patients without any neurological manifestation. We identified 29 candidate genes harboring rare, pathogenic, or probably pathogenic variants in all exomes analyzed. HLA alleles were also determined and patients who developed CNS IDD shared a common signature with diseases such as Multiple sclerosis (MS) and Neuromyelitis Optica Spectrum Disorders (NMOSD). When these genes were included in Gene Ontology analyses, pathways associated with CNS IDD syndromes were retrieved, suggesting that CHIKV-induced CNS outcomesmay share a genetic background with other neurological disorders. To our knowledge, this study was the first genome-wide investigation of genetic risk factors for CNS phenotypes in CHIKV infection. Our data suggest that HLA-DRB1 alleles associated with demyelinating diseases may also confer risk of CNS IDD outcomes in patients with CHIKV infection.

Accuracy of the Brazilian version of the DYMUS questionnaire for the screening of oropharyngeal dysphagia in multiple sclerosis.

BACKGROUND: Oropharyngeal dysphagia is a common symptom of many neurological diseases, including Multiple Sclerosis (MS). Early identification of the risk of dysphagia in neurological patients is very important for early referral for specialized evaluations of oropharyngeal swallowing and treatments. The Dysphagia in Multiple Sclerosis (DYMUS) questionnaire has been translated and validated in different countries over the last 10 years. We aimed to analyze the accuracy of the Brazilian Portuguese version of the DYMUS (DYMUS-BR) questionnaire in identifying dysphagia in patients with MS. METHODS: The DYMUS questionnaire and a videofluorographic swallowing study (VFSS) were conducted in 30 patients with MS. Dysphagia was identified by at least one abnormal response and was considered alarming when the DYMUS scores were equal to or higher than 3. Patients were considered to have dysphagia in the VFSS when one or more signs of impairment in the efficiency and/or safety of swallowing were detected. RESULTS: According to the initial self-assessment, 37% (N = 11) of patients with MS self-reported with dysphagia. According to the DYMUS-BR scores, 53% (N = 16) of the patients with MS were classified as having dysphagia. The sensitivity, specificity, and positive and negative predictive values of the DYMUS-BR questionnaire for the detection of dysphagia as measured by the VFSS were 50% [95% confidence interval (CI) 29-71], 78% (95% CI 61-90), 60% (95% CI 42-76), and 70% (95% CI 60-78), respectively. The area under the receiver-operating characteristic curve for detecting dysphagia was 64% (95% CI 49-79). CONCLUSION: The accuracy of the DYMUS-BR questionnaire is poor to detect mild swallowing impairment in patients with MS. However, we suggest longitudinal follow-up in patients with low DYMUS-BR scores for early detection of oropharyngeal dysphagia.

Patients and neurologists have different perceptions of multiple sclerosis symptoms, care and challenges.

BACKGROUND: Basic steps in the management of patients with Multiple Sclerosis (MS), such as good patient understanding of the disease and active participation in its management are extremely important, as they directly influence treatment adherence and success. Therefore, this study aimed to evaluate the perception of MS patients and neurologists pertaining to the most common disease symptoms, disabilities that impact on quality of life, and patient concerns and difficulties during medical visits, as information that can be used to improve the doctor-patient relationship. METHODS: A cross-sectional study involving two groups: the first composed of neurologists and the second of patients. Participants of the first group were selected by a Steering Committee (15 predetermined neurologists representing each region of Brazil and specialized in MS and neuroimmunological disorders, who also assumed the role of creating the survey and questionnaire). Participants of the second group were selected following dissemination of a questionnaire on the AME's social networks (Amigos Múltiplos pela Esclerose, a non-governmental organization to support patients with MS). Questions about sociodemographic data, disease impact on quality of life, symptoms perception, and concerns and issues regarding disease care were put to both groups. RESULTS: A total of 317 patients and 182 neurologists answered the questionnaires. Significant divergences were found between the perceptions of patients and neurologists in relation to orientation and information given during medical appointments, and also regarding patient participation in treatment and therapy choice. Considering the topic assessing impact on quality of life, more than 70% of neurologists perceived that autonomy to work and travel, and future planning were aspects that most affected patient lives, however, almost 50% of patients reported that disease monitoring did not affect their life in any way. Analysis of data regarding MS symptoms revealed neurologists to consider physical symptoms, such as ambulation issues, imbalance, falls and urinary incontinence, to be those most interfering with patient quality of life, whereas patients considered non-physical symptoms, such as fatigue, pain, cognitive and memory problems to be more significant. Patients with primary progressive MS complained more about ambulation issues, imbalance and falls (p<0.05), when compared to patients with other disease phenotypes. CONCLUSION: Significant differences in disease perception were found in this study. While neurologists tended to overestimate the consequences and symptoms of the disease, for most patients, the disease impact on activities did not appear to be as significant, with more complaints regarding non-physical symptoms. Although neurologists described involving patients in treatment decisions and providing them with appropriate orientation during medical appointments, the opposite was reported by patients. These results may help to improve treatment adherence and disease outcomes by redefining the doctor-patient relationship.

Neuromyelitis optica is an HLA associated disease different from Multiple Sclerosis: a systematic review with meta-analysis.

Neuromyelitis Optica and Multiple Sclerosis are idiopathic inflammatory demyelinating diseases of the central nervous system that currently are considered distinct autoimmune diseases, so differences in genetic susceptibility would be expected. This study aimed to investigate the HLA association with Neuromyelitis Optica by a systematic review with meta-analysis. The STROBE instrument guided research paper assessments. Thirteen papers published between 2009 and 2020 were eligible. 568 Neuromyelitis Optica patients, 41.4% Asians, 32.4% Latin Americans and 26.2% Europeans were analyzed. Only alleles of the DRB1 locus were genotyped in all studies. Neuromyelitis Optica patients have 2.46 more chances of having the DRB1*03 allelic group than controls. Ethnicity can influence genetic susceptibility. The main HLA association with Neuromyelitis Optica was the DRB1*03:01 allele in Western populations and with the DPB1*05:01 allele in Asia. Differences in the Multiple Sclerosis and Neuromyelitis Optica genetic susceptibility was confirmed in Afro descendants. The DRB1*03 allelic group associated with Neuromyelitis Optica has also been described in other systemic autoimmune diseases.

Is Asian type MS an MS phenotype, an NMO spectrum disorder, or a MOG-IgG related disease?

BACKGROUND: A specific particularity of neurological diseases in Asia is the relative commonality of neuromyelitis optica (NMO) and Asian type MS (OSMS). Both conditions also occur in South American patients. The Brazilian population differs from the European and the Asian populations due to the mixture of ancestralities between European colonizers and African slaves. To better know the clinical characteristics of Brazilian patients with Asian type MS this study aimed to analyze the clinical, radiological and serological data that would help to distinguish between OSMS and NMO and clarify, in a Non-Asian population, if OSMS is an MS phenotype, an NMO spectrum disorder by 2015 classification, or a complement activating antibody to myelin oligodendrocyte glycoprotein (MOG-IgG) antibody-related disease. METHODS: We selected cases retrospectively with NMO and OSMS in the medical registry of patients with idiopathic inflammatory demyelinating diseases under follow-up since 1997 in Federal Hospital da Lagoa, the principal reference center for MS treatment in Rio de Janeiro, Brazil. OSMS has selective involvement of the optic nerve and spinal cord with no cerebral or cerebellar symptoms associated with small spinal cord lesions and negativity for the aquaporin-4 antibody (AQP4-IgG). NMO full-filled the revised criteria (2006) associated with longitudinally extensive transverse myelitis (LETM). We recorded the following data: ethnicity/skin color, neurologic impairment "at nadir" and "at recovery" of the index events (optic neuritis and transverse myelitis), long term disability, mortality, health quality of life scores by the SF-36 questionnaire, CSF IgG oligoclonal bands and serological AQP4-IgG and MOG-IgG antibodies tested by Cell-based assay. The last brain MRIs were classified as either satisfying or not satisfying MAGNIMS radiologic criteria for MS or typical or not typical for NMOSD. The new classification of NMO spectrum disorders (2015) was applied. RESULTS: Forty-one OSMS and 122 NMO cases were analyzed. OSMS affected mainly young white women, causing unilateral optic neuritis and partial myelitis with excellent recovery. After a mean disease duration of 20 years, 90% of the patients had free ambulation, and 70% had a mild disability or no disability. Only 7.2% presented a secondary progressive course, and no deaths occurred. All cases had negativity to AQP4-IgG and MOG-IgG biomarkers. 95% had resonance criteria for MS. OSMS differed from NMO by ethnicity, morbidity, and mortality: most were African descendants, with severe motor and visual dysfunction, and one third died. Only NMO cases full-filled the new NMOSD classification (52 AQP4-IgG positive, 29 AQP4-IgG negative, and 41 AQP4-IgG unknown). CONCLUSION: In Brazilian patients, OSMS and NMO are different immune-mediated diseases. OSMS is a milder MS phenotype.

Familial multiple sclerosis in a Brazilian sample: Is HLA-DR15 involved in susceptibility to the disease?

BACKGROUND: The HLA-DR15 extended haplotype HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 comprises the strongest genetic risk factor for multiple sclerosis (MS). The aim of this work was to investigate whether HLA-DR15 alleles were significantly associated with the susceptibility to MS familial forms (MSf) in an admixed Brazilian population. METHODS: Association analyses between DR15 and the clinical and demographic variables were made. RESULTS: We have genotyped 25 familial cases. The DR15 was detected in 11/25 (44%) of them and in none of controls (P < .00001). DR15 was significantly associated to a foreign ancestor background (P = .029) and later age of onset (P = .018).

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.

Practical Evidence-Based Recommendations for Patients with Multiple Sclerosis Who Want to Have Children.

Multiple sclerosis (MS) management presently aims to reach a state of no (or minimal) evidence of disease activity. The development and commercialization of new drugs has led to a renewed interest in family planning, since patients with MS may face a future with reduced (or no) disease-related neurological disability. The advice of neurologists is often sought by patients who want to have children and need to know more about disease control at conception and during pregnancy and the puerperium. When MS is well controlled, the simple withdrawal of drugs for patients who intend to conceive is not an option. On the other hand, not all treatments presently recommended for MS are considered safe during conception, pregnancy and/or breastfeeding. The objective of the present study was to summarize the practical and evidence-based recommendations for family planning when our patients (women and men) have MS.Funding TEVA Pharmaceutical Brazil.