The history and rationale of the development of new drugs for migraine treatment.

Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers,: flunarizine,: valproic acid,: topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.

A migrânea é uma das doenças mais prevalentes e incapacitantes do mundo. O tratamento da crise de migrânea e o tratamento profilático da doença são essenciais para diminuir o seu impacto individual, social e econômico. Este é um artigo de revisão narrativa. Revisamos as principais drogas usadas para a migrânea e os modelos experimentais e referenciais teóricos que levaram ao seu desenvolvimento. Foram abordados os derivados do ergot, triptanas, anti-inflamatórios não hormonais, antidepressivos tricíclicos, betabloqueadores, flunarizina, ácido valproico, topiramato, toxina onabotulínica do tipo A, os ditans, anticorpos monoclonais contra o CGRP e seu receptor e os gepants. Também foram abordados possíveis alvos terapêuticos para o desenvolvimento de novas drogas e drogas que estão em desenvolvimento para o tratamento da migrânea. Muitas das drogas usadas atualmente foram desenvolvidas para o tratamento de outras doenças e se mostraram efetivas para o tratamento da migrânea. Essas ajudaram a ampliar o conhecimento sobre a doença. Com o melhor entendimento da fisiopatologia da migrânea, novas drogas foram e estão sendo desenvolvidas especificamente para o tratamento dessa doença.

The history and rationale of the development of new drugs for migraine treatment / A história e os fundamentos do desenvolvimento de novos medicamentos para o tratamento da migrânea

Abstract Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers, flunarizine, valproic acid, topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.

Resumo A migrânea é uma das doenças mais prevalentes e incapacitantes do mundo. O tratamento da crise de migrânea e o tratamento profilático da doença são essenciais para diminuir o seu impacto individual, social e econômico. Este é um artigo de revisão narrativa. Revisamos as principais drogas usadas para a migrânea e os modelos experimentais e referenciais teóricos que levaram ao seu desenvolvimento. Foram abordados os derivados do ergot, triptanas, anti-inflamatórios não hormonais, antidepressivos tricíclicos, betabloqueadores, flunarizina, ácido valproico, topiramato, toxina onabotulínica do tipo A, os ditans, anticorpos monoclonais contra o CGRP e seu receptor e os gepants. Também foram abordados possíveis alvos terapêuticos para o desenvolvimento de novas drogas e drogas que estão em desenvolvimento para o tratamento da migrânea. Muitas das drogas usadas atualmente foram desenvolvidas para o tratamento de outras doenças e se mostraram efetivas para o tratamento da migrânea. Essas ajudaram a ampliar o conhecimento sobre a doença. Com o melhor entendimento da fisiopatologia da migrânea, novas drogas foram e estão sendo desenvolvidas especificamente para o tratamento dessa doença.

Case report: Successful autologous hematopoietic stem cell transplantation in a patient with GAD antibody-spectrum disorder with rapidly progressive dementia.

The prevalence of neurological syndromes associated with antibodies to glutamic acid decarboxylase is increasing. While cognitive impairment is a common feature of this condition, it seldom emerges as the primary symptom. In this study, we discuss a case of refractory dementia associated with the glutamic acid decarboxylase spectrum disorder. Interestingly, this case showed a favorable outcome following autologous hematopoietic stem cell transplantation. We also provide an in-depth review of the current literature on the use of this therapeutic approach for the treatment of this disease.

Brazilian autoimmune encephalitis network (BrAIN): antibody profile and clinical characteristics from a multicenter study.

Background: The frequency of antibodies in autoimmune encephalitis (AIE) may vary in different populations, however, data from developing countries are lacking. To describe the clinical profile of AIE in Brazil, and to evaluate seasonality and predictors of AIE in adult and pediatric patients. Methods: We evaluated patients with possible AIE from 17 centers of the Brazilian Autoimmune Encephalitis Network (BrAIN) between 2018 and 2022. CSF and serum were tested with TBAs and CBAs. Data on clinical presentation, complementary investigation, and treatment were compiled. Seasonality and predictors of AIE in adult and pediatric populations were analyzed. Results: Of the 564 patients, 145 (25.7%) were confirmed as seropositive, 69 (12.23%) were seronegative according to Graus, and 58% received immunotherapy. The median delay to diagnosis confirmation was 5.97 ± 10.3 months. No seasonality variation was observed after 55 months of enrolment. The following antibodies were found: anti-NMDAR (n=79, 54%), anti-MOG (n=14, 9%), anti-LGI1(n=12, 8%), anti-GAD (n=11, 7%), anti-GlyR (n=7, 4%), anti-Caspr2 (n=6, 4%), anti-AMPAR (n=4, 2%), anti-GABA-BR (n=4, 2%), anti-GABA-AR (n=2, 1%), anti-IgLON5 (n=1, 1%), and others (n=5, 3%). Predictors of seropositive AIE in the pediatric population (n=42) were decreased level of consciousness (p=0.04), and chorea (p=0.002). Among adults (n=103), predictors of seropositive AIE were movement disorders (p=0.0001), seizures (p=0.0001), autonomic instability (p=0.026), and memory impairment (p=0.001). Conclusion: Most common antibodies in Brazilian patients are anti-NMDAR, followed by anti-MOG and anti-LGI1. Only 26% of the possible AIE patients harbor antibodies, and 12% were seronegative AIE. Patients had a 6-month delay in diagnosis and no seasonality was found. Findings highlight the barriers to treating AIE in developing countries and indicate an opportunity for cost-effect analysis. In this scenario, some clinical manifestations help predict seropositive AIE such as decreased level of consciousness, chorea, and dystonia among children, and movement disorders and memory impairment among adults.

Executive functions in migraine patients: a systematic review with meta-analysis.

Introduction: Migraine, a common neurological disease, is known to impact the quality of life of individuals with this condition.Methods: We performed a systematic review with meta-analysis to investigate the abnormalities associated with executive functions of migraineurs as compared with healthy controls. In addition, we investigated the differences between patients with and without aura.Results: A total of 25 studies were included in the systematic review and 19 in the meta-analysis. Meta-analysis was conducted using random effects models, with the unit of analysis as the standardised mean difference (calculated as Hedges'g). Patients with migraine had worse performance in the trail making test A (g = 0.40; 95% confidence interval [CI] 0.05-0.74; p = 0.0271) and B (g = 0.40; 95% CI 0.16-0.64; p = 0.0026), and digit span backward test (g = -0.20; 95% CI - 0.31, - 0.09; p = 0.0105). Subgroup analysis revealed no difference between migraine with and without aura.Conclusion: These results suggest that migraine patients may present worse performance for specific executive functional domains, including attention, working memory, and mental flexibility.

Consensus of the Brazilian Headache Society (SBCe) for prophylactic treatment of episodic migraine: part II.

BACKGROUND: Migraine affects 1 billion people worldwide and > 30 million Brazilians; besides, it is an underdiagnosed and undertreated disorder. OBJECTIVE: The need to disseminate knowledge about the prophylactic treatment of migraine is known, so the Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee of authors with the objective of establishing a consensus with recommendations on the prophylactic treatment of episodic migraine based on articles from the world literature as well as from personal experience. METHODS: Meetings were held entirely online, with the participation of 12 groups that reviewed and wrote about the pharmacological categories of drugs and, at the end, met to read and finish the document. The drug classes studied in part II of this Consensus were: antihypertensives, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, calcium channel blockers, other drugs, and rational polytherapy. RESULTS: From this list of drugs, only candesartan has been established as effective in controlling episodic migraine. Flunarizine, venlafaxine, duloxetine, and pizotifen were defined as likely to be effective, while lisinopril, enalapril, escitalopram, fluvoxamine, quetiapine, atorvastatin, simvastatin, cyproheptadine, and melatonin were possibly effective in prophylaxis of the disease. CONCLUSIONS: Despite an effort by the scientific community to find really effective drugs in the treatment of migraine, given the large number of drugs tested for this purpose, we still have few therapeutic options.

ANTECEDENTES: Migrânea afeta um bilhão de pessoas em todo o mundo e mais de 30 milhões de brasileiros; além disso, é um distúrbio subdiagnosticado e subtratado. OBJETIVO: Sabe-se sobre a necessidade de difundir o conhecimento sobre o tratamento profilático da migrânea; por isso, a Sociedade Brasileira de Cefaleias (SBCe) nomeou um comitê de autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da migrânea episódica com base em artigos da literatura mundial, assim como da experiência pessoal. MéTODOS: As reuniões foram realizadas inteiramente online, com a participação de 12 grupos que revisaram e escreveram sobre as categorias farmacológicas dos medicamentos e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de medicamentos estudadas na parte II deste Consenso foram: anti-hipertensivos, inibidores seletivos de recaptação de serotonina, inibidores de recaptação de serotonina e noradrenalina, bloqueadores dos canais de cálcio, outros medicamentos e politerapia racional. RESULTADOS: Desta lista de medicamentos, apenas o candesartan foi estabelecido como eficaz no controle da migrânea episódica. Flunarizina, venlafaxina, duloxetina e pizotifeno foram definidos como provavelmente eficazes, enquanto lisinopril, enalapril, escitalopram, fluvoxamina, quetiapina, atorvastatina, sinvastatina, ciproheptadina e melatonina foram possivelmente eficazes na profilaxia da doença. CONCLUSõES: Apesar do esforço da comunidade científica em encontrar medicamentos realmente eficazes no tratamento da migrânea, dado o grande número de medicamentos testados para este fim, ainda dispomos de poucas opções terapêuticas.

Consensus of the Brazilian Headache Society (SBCe) for the Prophylactic Treatment of Episodic Migraine: part I.

The Brazilian Headache Society (Sociedade Brasileira de Cefaleia, SBCe, in Portuguese) nominated a Committee of Authors with the aim of establishing a consensus with recommendations regarding prophylactic treatment for episodic migraine based on articles published in the worldwide literature, as well as personal experience. Migraine affects 1 billion people around the world and more than 30 million Brazilians. In addition, it is an underdiagnosed and undertreated disorder. It is well known within the medical community of neurologists, and especially among headache specialists, that there is a need to disseminate knowledge about prophylactic treatment for migraine. For this purpose, together with the need for drug updates and to expand knowledge of the disease itself (frequency, intensity, duration, impact and perhaps the progression of migraine), this Consensus was developed, following a full online methodology, by 12 groups who reviewed and wrote about the pharmacological categories of the drugs used and, at the end of the process, met to read and establish conclusions for this document. The drug classes studied were: anticonvulsants, tricyclic antidepressants, monoclonal anti-calcitonin gene-related peptide (anti-CGRP) antibodies, beta-blockers, antihypertensives, calcium channel inhibitors, other antidepressants (selective serotonin reuptake inhibitors, SSRIs, and dual-action antidepressants), other drugs, and polytherapy. Hormonal treatment and anti-inflammatories and triptans in minimum prophylaxis schemes (miniprophylaxis) will be covered in a specific chapter. The drug classes studied for part I of the Consensus were: anticonvulsants, tricyclic antidepressants, monoclonal anti-CGRP antibodies, and beta-blockers.

A Sociedade Brasileira de Cefaleia (SBCe) nomeou um Comitê de Autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da enxaqueca episódica com base em artigos da literatura mundial e da experiência pessoal. A enxaqueca é um distúrbio subdiagnosticado e subtratado que acomete um bilhão de pessoas no mundo e mais de 30 milhões de brasileiros. É conhecido na comunidade médica de neurologistas e, sobretudo, dos especialistas em cefaleia, a necessidade de se divulgar o conhecimento sobre o tratamento profilático da enxaqueca. Com esta finalidade, aliada às necessidades de atualizações de drogas e de se aumentar o conhecimento sobre a doença em si (frequência, intensidade, duração, impacto e talvez a progressão da enxaqueca), foi elaborado este Consenso, com metodologia totalmente on-line, por 12 grupos que revisaram e escreveram sobre as categorias farmacológicas das drogas e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de drogas estudadas para este Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais do antipeptídeo relacionado ao gene da calcitonina (peptídeo relacionado ao gene da calcitonina ­ anti-CGRP), betabloqueadores, anti-hipertensivos, inibidores dos canais de cálcio, outros antidepressivos (inibidores seletivos de recaptação de serotonina, ISRSs, e antidepressivos de ação dual), outras drogas, e politerapia. O tratamento hormonal, bem como anti-inflamatórios e triptanas em esquema de profilaxia mínima (miniprofilaxia), será abordado em um capítulo próprio. As classes de drogas estudadas na parte I do Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais anti-CGRP, e betabloqueadores.

Consensus of the Brazilian Headache Society (SBCe) for prophylactic treatment of episodic migraine: part II / Consenso da Sociedade Brasileira de Cefaleia (SBCe) para o tratamento profilático da migrânea episódica: parte II

Abstract Background Migraine affects 1 billion people worldwide and > 30 million Brazilians; besides, it is an underdiagnosed and undertreated disorder. Objective The need to disseminate knowledge about the prophylactic treatment of migraine is known, so the Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee of authors with the objective of establishing a consensus with recommendations on the prophylactic treatment of episodic migraine based on articles from the world literature as well as from personal experience. Methods Meetings were held entirely online, with the participation of 12 groups that reviewed and wrote about the pharmacological categories of drugs and, at the end, met to read and finish the document. The drug classes studied in part II of this Consensus were: antihypertensives, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, calcium channel blockers, other drugs, and rational polytherapy. Results From this list of drugs, only candesartan has been established as effective in controlling episodic migraine. Flunarizine, venlafaxine, duloxetine, and pizotifen were defined as likely to be effective, while lisinopril, enalapril, escitalopram, fluvoxamine, quetiapine, atorvastatin, simvastatin, cyproheptadine, and melatonin were possibly effective in prophylaxis of the disease. Conclusions Despite an effort by the scientific community to find really effective drugs in the treatment of migraine, given the large number of drugs tested for this purpose, we still have few therapeutic options.

Resumo Antecedentes Migrânea afeta um bilhão de pessoas em todo o mundo e mais de 30 milhões de brasileiros; além disso, é um distúrbio subdiagnosticado e subtratado. Objetivo Sabe-se sobre a necessidade de difundir o conhecimento sobre o tratamento profilático da migrânea; por isso, a Sociedade Brasileira de Cefaleias (SBCe) nomeou um comitê de autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da migrânea episódica com base em artigos da literatura mundial, assim como da experiência pessoal. Métodos As reuniões foram realizadas inteiramente online, com a participação de 12 grupos que revisaram e escreveram sobre as categorias farmacológicas dos medicamentos e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de medicamentos estudadas na parte II deste Consenso foram: anti-hipertensivos, inibidores seletivos de recaptação de serotonina, inibidores de recaptação de serotonina e noradrenalina, bloqueadores dos canais de cálcio, outros medicamentos e politerapia racional. Resultados Desta lista de medicamentos, apenas o candesartan foi estabelecido como eficaz no controle da migrânea episódica. Flunarizina, venlafaxina, duloxetina e pizotifeno foram definidos como provavelmente eficazes, enquanto lisinopril, enalapril, escitalopram, fluvoxamina, quetiapina, atorvastatina, sinvastatina, ciproheptadina e melatonina foram possivelmente eficazes na profilaxia da doença. Conclusões Apesar do esforço da comunidade científica em encontrarmedicamentos realmente eficazes no tratamento da migrânea, dado o grande número de medicamentos testados para este fim, ainda dispomos de poucas opções terapêuticas.

Consensus of the Brazilian Headache Society (SBCe) for the Prophylactic Treatment of Episodic Migraine: part I / Consenso da Sociedadade Brasileira de Cefaleia (SBCe) para o tratamento profilático da migrânea episódica: parte I

Abstract The Brazilian Headache Society (Sociedade Brasileira de Cefaleia, SBCe, in Portuguese) nominated a Committee of Authors with the aim of establishing a consensus with recommendations regarding prophylactic treatment for episodic migraine based on articles published in the worldwide literature, as well as personal experience. Migraine affects 1 billion people around the world and more than 30 million Brazilians. In addition, it is an underdiagnosed and undertreated disorder. It is well known within the medical community of neurologists, and especially among headache specialists, that there is a need to disseminate knowledge about prophylactic treatment for migraine. For this purpose, together with the need for drug updates and to expand knowledge of the disease itself (frequency, intensity, duration, impact and perhaps the progression of migraine), this Consensus was developed, following a full online methodology, by 12 groups who reviewed and wrote about the pharmacological categories of the drugs used and, at the end of the process, met to read and establish conclusions for this document. The drug classes studied were: anticonvulsants, tricyclic antidepressants, monoclonal anti-calcitonin gene-related peptide (anti-CGRP) antibodies, beta-blockers, antihypertensives, calcium channel inhibitors, other antidepressants (selective serotonin reuptake inhibitors, SSRIs, and dual-action antidepressants), other drugs, and polytherapy. Hormonal treatment and anti-inflammatories and triptans in minimum prophylaxis schemes (miniprophylaxis) will be covered in a specific chapter. The drug classes studied for part I of the Consensus were: anticonvulsants, tricyclic antidepressants, monoclonal anti-CGRP antibodies, and beta-blockers.

Resumo A Sociedade Brasileira de Cefaleia (SBCe) nomeou um Comitê de Autores com o objetivo de estabelecer um consenso com recomendações sobre o tratamento profilático da enxaqueca episódica com base em artigos da literatura mundial e da experiência pessoal. A enxaqueca é um distúrbio subdiagnosticado e subtratado que acomete um bilhão de pessoas no mundo e mais de 30 milhões de brasileiros. É conhecido na comunidade médica de neurologistas e, sobretudo, dos especialistas em cefaleia, a necessidade de se divulgar o conhecimento sobre o tratamento profilático da enxaqueca. Com esta finalidade, aliada às necessidades de atualizações de drogas e de se aumentar o conhecimento sobre a doença em si (frequência, intensidade, duração, impacto e talvez a progressão da enxaqueca), foi elaborado este Consenso, com metodologia totalmente on-line, por 12 grupos que revisaram e escreveram sobre as categorias farmacológicas das drogas e, ao final, reuniram-se para a leitura e conclusão do documento. As classes de drogas estudadas para este Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais do antipeptídeo relacionado ao gene da calcitonina (peptídeo relacionado ao gene da calcitonina — anti-CGRP), betabloqueadores, anti-hipertensivos, inibidores dos canais de cálcio, outros antidepressivos (inibidores seletivos de recaptação de serotonina, ISRSs, e antidepressivos de ação dual), outras drogas, e politerapia. O tratamento hormonal, bem como anti-inflamatórios e triptanas em esquema de profilaxia mínima (miniprofilaxia), será abordado em um capítulo próprio. As classes de drogas estudadas na parte I do Consenso foram: anticonvulsivantes, antidepressivos tricíclicos, anticorpos monoclonais anti-CGRP, e betabloqueadores.

Prevalence of trigeminocervical convergence mechanisms in episodic and chronic migraine / Prevalência de mecanismos de convergência trigeminocervical na migrânea episódica e crônica

Abstract Background: Migraine pain location and trigeminocervical convergence have limited diagnostic value and have usually been assessed using non-standard verbal descriptors in a small number of centers. Objective: To use non-verbal descriptors of migraine pain location to determine the prevalence of trigeminocervical convergence mechanisms in patients with episodic and chronic migraine. In addition, we explored the factors associated with the presence of convergence. Methods: A multicenter study was carried out. The explicit pain location was explored by asking subjects to indicate, on an electronic form, three points on the anterolateral side and three points on the posterolateral side of the head and neck that represented the common locations of their migraine pain. We evaluated associations of the pain pattern with demographic and psychological features, comorbidities, lifestyle and other headache characteristics. Results: 97 episodic and 113 chronic migraine patients were included. Convergence was present in 116 migraineurs (55%) who indicated dominance of pain in the posterior cervical region. This site was more often involved in the chronic migraine group (21 vs. 33%; p=0.034). The number of migrainous/altered sensitivity symptoms (OR=1.39; 95%CI 1.14-1.71) was associated with convergence independently of the chronification status. In this symptom group, there were statistical associations between convergence and vomiting (p=0.045), tactile allodynia (p<0.001), nuchal rigidity (p<0.001) and movement allodynia (p=0.031). Conclusions: Trigeminocervical convergence is common in migraineurs and, in practice, it might be found frequently in chronic migraineurs. Some features commonly found in this group, such as altered sensitivity symptoms, are associated with this phenomenon.

RESUMO Antecedentes: A localização da dor da migrânea e a convergência trigeminocervical têm valor diagnóstico limitado geralmente sendo avaliadas por meio de descritores verbais não padronizados em um pequeno número de centros. Objetivo: Usar descritores não verbais da localização da dor migranosa para determinar a prevalência de mecanismos de convergência trigeminocervical em pacientes com migrânea episódica e crônica. Além disso, exploramos os fatores associados à presença de convergência. Métodos: Um estudo multicêntrico foi realizado. A localização explícita da dor foi explorada solicitando aos migranosos que indicassem, em um formulário eletrônico, três pontos no lado anterolateral e três pontos no lado posterolateral da cabeça e pescoço representando a localização comum de sua dor migranosa. Avaliamos a associação do padrão de dor com características demográficas e psicológicas, comorbidades, estilo de vida e outras características da cefaleia. Resultados: 97 pacientes com migrânea episódica e 113 com migrânea crônica foram incluídos. A convergência esteve presente em 116 migranosos (55%) que indicaram um predomínio da dor na região cervical posterior. Este local estava mais frequentemente envolvido no grupo migrânea crônica (21 vs. 33%; p=0,034). O número de sintomas de migrânea/sensibilidade alterada (OR=1,39; IC95% 1,14-1,71) foi associado à convergência independentemente do estado de cronificação. Nesse grupo de sintomas, houve associações entre convergência e vômito (p=0,045), alodinia tátil (p<0,001), rigidez de nuca (p<0,001) e alodinia ao movimento (p=0,0031). Conclusões: A convergência trigeminocervical é comum em pacientes com migrânea e, na prática, podemos encontrá-la com frequência em pacientes com migrânea crônica. Algumas características comumente encontradas nesse grupo, como sintomas de sensibilidade alterada, estão associadas a esse fenômeno.

Prevalence of trigeminocervical convergence mechanisms in episodic and chronic migraine.

BACKGROUND: Migraine pain location and trigeminocervical convergence have limited diagnostic value and have usually been assessed using non-standard verbal descriptors in a small number of centers. OBJECTIVE: To use non-verbal descriptors of migraine pain location to determine the prevalence of trigeminocervical convergence mechanisms in patients with episodic and chronic migraine. In addition, we explored the factors associated with the presence of convergence. METHODS: A multicenter study was carried out. The explicit pain location was explored by asking subjects to indicate, on an electronic form, three points on the anterolateral side and three points on the posterolateral side of the head and neck that represented the common locations of their migraine pain. We evaluated associations of the pain pattern with demographic and psychological features, comorbidities, lifestyle and other headache characteristics. RESULTS: 97 episodic and 113 chronic migraine patients were included. Convergence was present in 116 migraineurs (55%) who indicated dominance of pain in the posterior cervical region. This site was more often involved in the chronic migraine group (21 vs. 33%; p=0.034). The number of migrainous/altered sensitivity symptoms (OR=1.39; 95%CI 1.14-1.71) was associated with convergence independently of the chronification status. In this symptom group, there were statistical associations between convergence and vomiting (p=0.045), tactile allodynia (p<0.001), nuchal rigidity (p<0.001) and movement allodynia (p=0.031). CONCLUSIONS: Trigeminocervical convergence is common in migraineurs and, in practice, it might be found frequently in chronic migraineurs. Some features commonly found in this group, such as altered sensitivity symptoms, are associated with this phenomenon.

EEG education in Brazil: a national survey of adult neurology residents / Educação em EEG no Brasil: uma pesquisa nacional com residentes de neurologia de adultos

ABSTRACT Background: In light of the established challenges of resident EEG education worldwide, we sought to better understand the current state of neurology resident EEG education in Brazil. Objective: To define Brazilian EEG practices including in-residency requirements for EEG training and competency. Methods: We assessed the perspectives of adult residents (PGY1-3) on EEG education and their level of confidence interpreting EEG with a 24-question online survey. Results: We analyzed 102 responses from 52 Brazilian neurology residency programs distributed in 14 states. There were 18 PGY1s, 45 PGY2s, and 39 PGY3s. Ninety-six percent of participants reported that learning how to read EEG during residency was very or extremely important. The most commonly reported barriers to EEG education were insufficient EEG exposure (70%) and ineffective didactics (46%). Residents believed that standard EEG lectures were the most efficient EEG teaching method followed by interpreting EEG with attendings' supervision. Roughly half of residents (45%) reported not being able to read EEG even with supervision, and approximately 70% of all participants did not feel confident writing an EEG report independently. Conclusion: Despite the well-established residency EEG education requirements recommended by the Brazilian Academy of Neurology (ABN), there seems to be a significant lack of comfort interpreting EEG among Brazilian adult neurology residents. We encourage Brazilian neurology residency leadership to re-evaluate the current EEG education system in order to ensure that residency programs are following EEG education requirements and to assess whether EEG benchmarks require modifications.

RESUMO Antecedentes: Diante dos desafios da educação em EEG estabelecidos em todo o mundo, buscamos compreender melhor o estado atual da educação em EEG durante a residência de neurologia no Brasil. Objetivo: Investigar práticas de EEG no Brasil, incluindo requisitos para treinamento e competência durante a residência de neurologia. Métodos: Avaliamos as perspectivas dos residentes (R1-3) de neurologia (adulto) sobre educação em EEG e nível de confiança ao interpretá-lo através de questionário online de 24 perguntas. Resultados: Foram analisadas 102 respostas de 52 programas de residência distribuídos em 14 estados. Dezoito R1s, 45 R2s e 39 R3s responderam à pesquisa. Noventa e seis por cento dos participantes relataram que aprender a ler EEG durante a residência é muito ou extremamente importante. As barreiras mais relatadas para educação em EEG foram exposição insuficiente ao EEG (70%) e didática ineficaz (46%). Os participantes apontaram aulas como método de ensino mais eficaz, seguido pela interpretação do EEG supervisionada pelos chefes. Aproximadamente metade dos residentes (45%) relatou não ser capaz de ler EEG mesmo com supervisão e cerca de 70% não se sente confiante para escrever um laudo de EEG de forma independente. Conclusões: Apesar dos requisitos estabelecidos pela Academia Brasileira de Neurologia (ABN) sobre ensino de EEG durante a residência, há significativa falta de confiança na sua interpretação pelos residentes de neurologia (adulto). Incentivamos as lideranças a reavaliar o sistema de educação para garantir que os programas de residência sigam requisitos de educação em EEG e se os benchmarks de EEG requerem modificações.

EEG education in Brazil: a national survey of adult neurology residents.

BACKGROUND: In light of the established challenges of resident EEG education worldwide, we sought to better understand the current state of neurology resident EEG education in Brazil. OBJECTIVE: To define Brazilian EEG practices including in-residency requirements for EEG training and competency. METHODS: We assessed the perspectives of adult residents (PGY1-3) on EEG education and their level of confidence interpreting EEG with a 24-question online survey. RESULTS: We analyzed 102 responses from 52 Brazilian neurology residency programs distributed in 14 states. There were 18 PGY1s, 45 PGY2s, and 39 PGY3s. Ninety-six percent of participants reported that learning how to read EEG during residency was very or extremely important. The most commonly reported barriers to EEG education were insufficient EEG exposure (70%) and ineffective didactics (46%). Residents believed that standard EEG lectures were the most efficient EEG teaching method followed by interpreting EEG with attendings' supervision. Roughly half of residents (45%) reported not being able to read EEG even with supervision, and approximately 70% of all participants did not feel confident writing an EEG report independently. CONCLUSION: Despite the well-established residency EEG education requirements recommended by the Brazilian Academy of Neurology (ABN), there seems to be a significant lack of comfort interpreting EEG among Brazilian adult neurology residents. We encourage Brazilian neurology residency leadership to re-evaluate the current EEG education system in order to ensure that residency programs are following EEG education requirements and to assess whether EEG benchmarks require modifications.

Use of Buspirone in the Treatment of Nonpharmacological Bruxism: About 4 Cases.

OBJECTIVE: The aim of the study was to describe the efficacy of buspirone in controlling nonpharmacological awake and sleep bruxism. METHODS: Four cases of nonpharmacological awake and sleep bruxism, one of them with a 20-year-long history, in which buspirone succeeded to control bruxism, are described and discussed. RESULTS: Two of the 4 cases had sleep bruxism, and the other 2 cases had sleep and awake bruxism. Besides anxiety, no other predisposing condition was identified. Buspirone was effective in reducing bruxism symptoms in the 4 cases. Mean percentage of bruxism reduction after buspirone was ranked as 65% by subjects. CONCLUSIONS: In this small series of cases, buspirone proved effective in the control of nonpharmacological awake and sleep bruxism.

Efficacy and safety of levetiracetam as adjunctive therapy for refractory focal epilepsy.

BACKGROUND: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. OBJECTIVE: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. METHODS: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. RESULTS: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. CONCLUSION: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy.

Serial Tap Test of patients with idiopathic normal pressure hydrocephalus: impact on cognitive function and its meaning.

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is characterized by gait disturbance, urinary incontinence and cognitive decline. Symptoms are potentially reversible and treatment is based on cerebrospinal fluid shunting. The tap test (TT) is used to identify patients that will benefit from surgery. This procedure consists of the withdrawal of 20 to 50 mL of cerebrospinal fluid (CSF) through a lumbar puncture (LP) after which the symptoms of the triad are tested. Improvement in the quality and speed of gait are already recognized but cognitive improvement depends on several factors such as tests used, the time elapsed after LP for re-testing, and the number of punctures. Serial punctures may trigger similar conditions as external lumbar drainage (ELD) to the organism. OBJECTIVE: This study aimed to identify how serial punctures affect cognition to increase the sensitivity of the test and consequently the accuracy of surgical indication. METHODS: Sixty-one patients with INPH underwent baseline memory and executive tests repeatedly following the 2-Step Tap Test protocol (2-STT - two procedures of 30 mL lumbar CSF drainage separated by a 24-h interval). The baseline scores of INPH patients were compared with those of 55 healthy controls, and with intragroup post-puncture scores of the 2-STT. RESULTS: The group with INPH had lower performance than the control group in all cognitive tests (RAVLT, Stroop, CFT, FAR-COWA, FAB, MMSE, orientation, mental control), except for the forward digit span test (p = 0.707). After conducting LP procedures, the Stroop test (words, colors and errors), RAVLT (stage A1, A6 and B1), and CFT (immediate and delayed R) scores were equal to those of the control group (p > 0.05). The INPH group presented significant improvement after the first puncture in MMSE (p = 0.031) and in the Stroop Test (points) (p < 0.001). After the second puncture, subjects improved in orientation, MMSE, RAVLT (B1), Stroop (points, words, errors) and CFT (IR). CONCLUSION: Progressive cognitive improvement occurred over the 2-STT and changes were more significant after the second LP in all cognitive domains except for RAVLT (A7). Encephalic alert system 'arousal' seems to participate in early improvements observed during 2-STT. The second LP increased the sensitivity of the drainage test to detect changes in cognitive variables, and consequently improved the quality of the method.

Efficacy and safety of levetiracetam as adjunctive therapy for refractory focal epilepsy / Eficácia e segurança do levetiracetam como terapia adjunta na epilepsia focal refratária

ABSTRACT Background: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. Objective: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. Methods: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. Results: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. Conclusion: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy.

RESUMO Introdução: A epilepsia afeta cerca de 50 milhões de pessoas em todo o mundo e aproximadamente 30% desses pacientes apresentam epilepsia refratária, com possíveis consequências na qualidade de vida, morbidade e mortalidade prematura. Objetivo: O objetivo do tratamento com fármacos antiepilépticos (FAEs) é permitir que os pacientes permaneçam sem crises epilépticas com boa tolerabilidade. O levetiracetam (LEV) é um FAE de amplo espectro, com mecanismo de ação único, diferente dos demais e que demonstra ser eficaz e seguro no tratamento de adultos e crianças. Métodos: Estudo de fase III, multicêntrico, randomizado, duplo-cego e controlado por placebo avalia a eficácia e a segurança do LEV em crianças e adultos (4-65 anos) como tratamento adjuvante para crises de início focal em 114 pacientes já tratados com até três FAEs. A análise de eficácia primária foi baseada na proporção de pacientes que apresentaram redução ≥50% no número médio de crises epilépticas focais semanais, durante 16 semanas. Os pacientes foram randomizados para receber placebo ou LEV, titulado a cada duas semanas de 20 mg/kg/dia ou 1.000 mg/dia até 60 mg/kg/dia ou 3.000 mg/dia. Resultados: LEV foi significativamente superior ao placebo (p=0,0031), com 38,7% dos participantes no grupo LEV e 14,3% no grupo controle que apresentaram redução das crises focais. LEV apresenta bom perfil de segurança com eventos adversos semelhantes ao placebo. Conclusão: Corroborando com os resultados da literatura, o levetiracetam mostra-se eficaz e seguro para crianças e adultos com epilepsia focal refratária.

Post-dural puncture headache incidence after cerebrospinal fluid aspiration. A prospective observational study.

BACKGROUND: Post-dural puncture headache (PDPH) is an iatrogenic condition following lumbar puncture (LP). Incidence is variable and often associated with young females. Technical features of the procedure (i.e. needle gauge) have been investigated; however there is no investigation on the method of cerebrospinal fluid (CSF) collection. OBJECTIVE: To investigate whether mild CSF aspiration is associated with increased PDPH in selected patients. METHODS: 336 subjects were eligible to the study. Data on 237 patients from a tertiary neurology hospital who underwent diagnostic LP from February 2010 to December 2012 were analysed. Patient demographics, lumbar puncture method, CSF biochemical characteristics, opening pressures, and a follow-up inquire on PDPH occurrence were collected. CSF was collected either by allowing free flow or by mild aspiration. RESULTS: The aspiration arm (n=163) was comprised of 55.8% females with mean age of 52(35‒69) years. Sex distribution was not different between the two arms (p=0.191). A significant larger amount of CSF was obtained in the aspiration arm (p=0.011). The incidence of PDPH in the aspiration arm was 16.5% versus 20.2% in the free flow arm, not statistically significant (p=0.489). No relevant associations emerged from the analyses in the subgroup aged <65 years. CONCLUSIONS: Aspiration of the CSF during LP was not associated with increased rates of PDPH compared to the standard method, particularly when larger amounts of CSF are required and ideal conditions are met. This is the first study looking into this matter, aiming to add safety to the procedure. Further randomized trials are required.

Post-dural puncture headache incidence after cerebrospinal fluid aspiration. A prospective observational study / Incidência de cefaleia pós-punção dural após aspiração do líquido cefalorraquidiano. Um estudo observacional prospectivo

Abstract Background: Post-dural puncture headache (PDPH) is an iatrogenic condition following lumbar puncture (LP). Incidence is variable and often associated with young females. Technical features of the procedure (i.e. needle gauge) have been investigated; however there is no investigation on the method of cerebrospinal fluid (CSF) collection. Objective: To investigate whether mild CSF aspiration is associated with increased PDPH in selected patients. Methods: 336 subjects were eligible to the study. Data on 237 patients from a tertiary neurology hospital who underwent diagnostic LP from February 2010 to December 2012 were analysed. Patient demographics, lumbar puncture method, CSF biochemical characteristics, opening pressures, and a follow-up inquire on PDPH occurrence were collected. CSF was collected either by allowing free flow or by mild aspiration. Results: The aspiration arm (n=163) was comprised of 55.8% females with mean age of 52(35‒69) years. Sex distribution was not different between the two arms (p=0.191). A significant larger amount of CSF was obtained in the aspiration arm (p=0.011). The incidence of PDPH in the aspiration arm was 16.5% versus 20.2% in the free flow arm, not statistically significant (p=0.489). No relevant associations emerged from the analyses in the subgroup aged <65 years. Conclusions: Aspiration of the CSF during LP was not associated with increased rates of PDPH compared to the standard method, particularly when larger amounts of CSF are required and ideal conditions are met. This is the first study looking into this matter, aiming to add safety to the procedure. Further randomized trials are required.

Resumo Introdução: Cefaleia pós-punção dural (CPPD) é uma condição iatrogênica após punção lombar (LP). Incidência é variável; frequentemente associada a mulheres jovens. Características técnicas do procedimento (ex: calibre da agulha) foram investigadas; no entanto, não há investigação sobre o método de coleta do líquido cefalorraquidiano (LCR). Objetivo: Avaliar se aspiração leve do LCR está associada ao aumento da CPPD em pacientes selecionados. Métodos: 336 indivíduos foram elegíveis para o estudo. Dados de 237 pacientes em um hospital neurológico terciário que foram submetidos à PL diagnóstica de fevereiro de 2010 a dezembro de 2012 foram analisados. Coletamos dados demográficos dos pacientes, método da PL, características bioquímicas do LCR, pressões de abertura e ocorrência da CPPD. Todos as PLs ocorreram em decúbito lateral. O LCR foi coletado permitindo livre fluxo ou aspiração leve. Resultados: O grupo aspiração (n=163) apresentava 55,8% de mulheres, idade média de 52(35‒69) anos. A distribuição por sexo não foi diferente entre os dois grupos (p=0,191). Uma quantidade maior de LCR foi obtida no grupo aspiração (p=0,011). A incidência de CPPD no grupo de aspiração foi de 16,5% versus 20,2% no fluxo livre, não estatisticamente significante (p=0,489). Nenhuma associação emergiu das análises no subgrupo com idades <65 anos. Conclusões: A aspiração do LCR durante PL não está associada ao aumento da CPPD em comparação com a método padrão, particularmente quando quantidades maiores de LCR são necessárias e condições ideais são satisfeitas. Este é o primeiro estudo a investigar o topico, visando aumentar a segurança do procedimento. Necessita-se futuros estudos randomizados.

Stroke and transient ischemic attacks related to antiplatelet or warfarin interruption.

OBJECTIVE: Patients on anticoagulant or antiplatelet therapy are often required to discontinue these medications before and during surgical or invasive procedures. In some cases, the patient stops the treatment without medical supervision. These situations may increase stroke risk. To identify the ischemic stroke and transient ischemic attack (TIA) prevalence related to length of time of discontinuation of antiplatelet or vitamin K antagonist therapy, in a group of inpatients from a specialized neurological hospital in Brazil. METHODS: Cross-sectional, retrospective and descriptive study of stroke inpatients for three years. Medical reports were reviewed to find study participants, stroke characteristics, risk factors, reasons and time of drug interruption. RESULTS: In three years, there were 360 stroke and TIA inpatients, of whom 27 (7.5%) had a history of antiplatelet or vitamin K antagonist interruption correlated with the time of the event (81% ischemic stroke, 19% TIA). The median time between antiplatelet interruption and an ischemic event was five days, and 62% of events occurred within seven days after drug suspension. For vitamin K antagonists, the average time to the ischemic event was 10.4 days (SD = 5.7), and in 67% of patients, the time between drug discontinuation and the event was 7-14 days. The most frequent reason for drug suspension was patient negligence (37%), followed by planned surgery or invasive examination (26%) and side effects, including hemorrhage (18.5%). CONCLUSION: Antiplatelet or vitamin K antagonist suspension has a temporal relationship with the occurrence of stroke and TIA. Since these events are preventable, it is crucial that healthcare professionals convince their patients that drug withdrawal can cause serious consequences.