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Background Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia, seizures, movement disorders, language delay/regression, progressive visual failure, and early death. Neuronal ceroid lipofuscinosis type 2 (CLN2), caused by biallelic pathogenic variants of the TPP1 gene, is the only NCL with an approved targeted therapy. The laboratory diagnosis of CLN2 is established through highly specific tests, leading to diagnostic delays and eventually hampering the provision of specific treatment for patients with CLN2. Epilepsy is a common and clinically-identifiable feature among NCLs, and seizure onset is the main driver for families to seek medical care.

Background Evaluation and treatment of primary and secondary headaches is a global public health challenge. Recognizing the epidemiological impact of headaches, a group of researchers linked to the Brazilian Headache Society proposed the Brazilian Headache Registry and drew up its initial protocol.

Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative genetic disease that affects children in early life. Its classic form is rapidly progressive, leading to death within the first 10 years. The urge for earlier diagnosis increases with the availability of enzyme replacement therapy. A panel of nine Brazilian child neurologists combined their expertise in CLN2 with evidence from the medical literature to establish a consensus to manage this disease in Brazil. They voted 92 questions including diagnosis, clinical manifestations, and treatment of the disease, considering the access to healthcare in this country. Clinicians should suspect CLN2 disease in any child, from 2 to 4 years old, with language delay and epilepsy. Even though the classic form is the most prevalent, atypical cases with different phenotypes can be found. Electroencephalogram, magnetic resonance imaging, molecular and biochemical testing are the main tools to investigate and confirm the diagnosis. However, we have limited access to molecular testing in Brazil, and rely on the support from the pharmaceutical industry. The management of CLN2 should involve a multidisciplinary team and focus on the quality of life of patients and on family support. Enzyme replacement therapy with Cerliponase α is an innovative treatment approved in Brazil since 2018; it delays functional decline and provides quality of life. Given the difficulties for the diagnosis and treatment of rare diseases in our public health system, the early diagnosis of CLN2 needs improvement as enzyme replacement therapy is available and modifies the prognosis of patients.

Objective: To report a series of atypical presentations of Aicardi–Goutières syndrome. Methods: Clinical, neuroimaging, and genetic data. Results: We report a series of six unrelated patients (five males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val). Conclusions: This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM.

Biallelic loss of function of IMPA1 causes autosomal recessive intellectual developmental disorder 59 (MRT59, OMIM #617323). MRT59 has been reported to present with significant intellectual disability and disruptive behavior, but little is known about the neurocognitive pattern of those patients. Thus, the aims of this study were: (1) to assess the cognitive profile of these patients, and (2) to evaluate their functional dependence levels. Eighteen adults, aged 37 to 89 years, participated in this study: nine MRT59 patients, five heterozygous carriers and four non-carrier family members. All of them were from a consanguineous family living in Northeast Brazil. All IMPA1 patients had the (c.489_493dupGGGCT) pathogenic variant in homozygosis. For cognitive assessment, the WASI battery was applied in nine MRT59 patients and compared to heterozygous carriers and non-carrier family members. Functional dependence was evaluated using the functional independence measure (FIM). Patients showed moderate to severe intellectual disability and severe functional disabilities. Heterozygous carriers did not differ from non-carriers. MRT59 patients should be followed up by health professionals in an interdisciplinary way to understand their cognitive disabilities and functional needs properly.

ABSTRACT Cannabinoids comprehend endocannabinoids, phytocannabinoids, and synthetic cannabinoids, with actions both in the central and peripherical nervous systems. A considerable amount of publications have been made in recent years, although cannabis has been known for over a thousand years. Scientific Departments from the Brazilian Academy of Neurology described evidence for medical use in their areas. Literature is constantly changing, and possible new evidence can emerge in the next days or months. Prescription of these substances must be discussed with patients and their families, with knowledge about adverse events and their efficacy.

ABSTRACT Background: Headache-Specific Locus of Control (LOC) refers to individuals’ beliefs about their control over the onset, course and consequences of headaches. LOC beliefs have been associated with depression, coping strategies, headache-related disability and treatment outcomes. Objective: To test the cross-cultural adaptation and psychometric properties of a Brazilian version of the Headache-Specific Locus of Control Scale (HSLC). Methods: One hundred and thirty-four migraine outpatients completed the HSLC and provided measurements of psychopathological symptoms, pain catastrophizing, depression, anxiety, quality of life and headache-related disability. Results: The three-factor structure of the HSLC (LOC-P, LOC-C and LOC-I) was confirmed in the Brazilian sample. The instrument showed good internal consistency, with Cronbach's α of 0.77 for total HSLC and 0.70, 0.83 and 0.87, for LOC-P, LOC-C and LOC-I, respectively. LOC-C correlated with headache frequency and headache intensity. Along with headache intensity, depression and pain catastrophizing, LOC-I accounted for 45% of the variance (adjusted R2=0.45; F=12.97; p

Abstract Although headaches have recognized impact, there are no public policies in Brazil addressing this problem. The Brazilian Headache Society and the Brazilian Association of Cluster Headache and Migraine promoted a summit to discuss Public Policy and Advocacy for headache disorders. Professionals from various segments, representing various sectors of society, gathered in April 2019 in Brasília, defining the most important points for achieving advances in public policies in headache in Brazil, such as: inclusion in the chronic diseases surveillance agenda; improving public understanding and access to diagnosis and treatment; teaching in colleges and medical residences, structuring care networks, intervention models, clinical protocols and legislation supporting public policies in headache.

ABSTRACT In this article, a group of experts in headache management of the Brazilian Headache Society developed through a consensus strategic measurements to treat a migraine attack in both the child and the adult. Particular emphasis was laid on the treatment of migraine in women, including at pregnancy, lactation and perimenstrual period.

Leukodystrophies are genetically determined white matter disorders. Even though leukodystrophies essentially affect children in early infancy and childhood, these disorders may affect adults. In adults, leukodystrophies may present a distinct clinical and imaging presentation other than those found in childhood. Clinical awareness of late-onset leukodystrophies should be increased as new therapies emerge. MRI is a useful tool to evaluate white matter disorders and some characteristics findings can help the diagnosis of leukodystrophies. This review article briefly describes the imaging characteristics of the most common adult leukodystrophies.

Chronic migraine is a condition with significant prevalence all around the world and high socioeconomic impact, and its handling has been challenging neurologists. Developments for understanding its mechanisms and associated conditions, as well as that of new therapies, have been quick and important, a fact which has motivated the Latin American and Brazilian Headache Societies to prepare the present consensus. The treatment of chronic migraine should always be preceded by a careful diagnosis review; the detection of possible worsening factors and associated conditions; the stratification of seriousness/impossibility to treat; and monitoring establishment, with a pain diary. The present consensus deals with pharmacological and nonpharmacological forms of treatment to be used in chronic migraine.

Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy of motor and sensory impairment with distal predominance. Atrophy and weakness of lower limbs are the first signs of the disease. It can be classified, with the aid of electromyography and nerve conduction studies, as demyelinating (CMT1) or axonal (CMT2). OBJECTIVE: Clinical and neurophysiological investigation of a large multigenerational family with CMT2 with autosomal dominant mode of transmission. METHOD: Fifty individuals were evaluated and neurophysiological studies performed in 22 patients. RESULTS: Thirty individuals had clinical signs of motor-sensory neuropathy. Babinski sign was present in 14 individuals. Neurophysiological study showed motor-sensory axonal polyneuropathy. CONCLUSION: The clinical and neurophysiological characteristics of this family does not differ from those observed with other forms of CMT, except for the high prevalence of Babinski sign.

Joubert syndrome (JS) is an autosomal recessive inherited disorder characterized by hypotonia, cerebellar vermis hypoplasia, ocular abnormalities (e.g, pigmentary retinopathy, oculomotor apraxia and nystagmus), renal cysts and hepatic fibrosis. Respiratory abnormalities, as apnea and hyperpnea, may be present, as well as mental retardation. At least seven JS loci have been determined and five genes identified. Herein, we report five children, belonging to independent families, with JS: they shared the same typical MRI abnormality, known as molar tooth sign, but had an otherwise quite variable phenotype, regarding mostly their cognitive performance, visual abilities and extra-neurological compromise.A síndrome de Joubert (SJ) é uma doença hereditária, autossômica recessiva, caracterizada por hipotonia, hipoplasia do vermis cerebelar, anormalidades oculares (p.ex., retinite pigmentar, apraxia oculomotora e nistagmo), cistos renais e fibrose hepática. Anormalidades respiratórias tais como apnéia e hiperpnéia podem estar presentes, assim como deficiência mental. Pelo menos sete loci e cinco genes diferentes associados à SJ já foram identificados. Este artigo relata cinco crianças com SJ, pertencentes a diferentes famílias. Todos os pacientes compartilham a mesma anormalidade típica da RM, conhecida como sinal do dente molar, e apresentam ampla variabilidade clínica em relação ao desempenho cognitivo, comprometimento visual e alterações extra-neurológicas.

Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive complicated form of hereditary spastic paraplegia, which is clinically defined by congenital optic atrophy, infancy-onset progressive spastic paraplegia and peripheral neuropathy. In this study, which included 61 individuals (age 5-72 years, 42 females) affected by SPOAN, a comprehensive motor and functional evaluation was performed, using modified Barthel index, modified Ashworth scale, hand grip strength measured with a hydraulic dynamometer and two hereditary spastic paraplegia scales. Modified Barthel index, which evaluate several functional aspects, was more sensitive to disclose disease progression than the spastic paraplegia scales. Spasticity showed a bimodal distribution, with both grades 1 (minimum) and 4 (maximum). Hand grip strength showed a moderate inverse correlation with age. Combination of early onset spastic paraplegia and progressive polyneuropathy make SPOAN disability overwhelming.A paraplegia espástica, atrofia óptica e neuropatia (SPOAN) é uma forma complicada de paraplegia espástica de herança autossômica recessiva, caracterizada por atrofia óptica congênita, paraplegia espástica progressiva de início na infância e neuropatia periférica. Este estudo avaliou o desempenho motor e funcional de 61 indivíduos com SPOAN (5 a 72 anos), por meio do índice de Barthel modificado, a escala modificada de Ashworth, da avaliação da força de preensão das mãos com dinamômetro hidráulico de Jamar e escalas de paraplegia espástica hereditária. O índice de Barthel modificado, que investiga aspectos funcionais, mostrou-se mais sensível para avaliar a progressão da doença do que as escalas de paraplegia espástica. A espasticidade apresentou distribuição bimodal, com o grau 1 (mínimo) e 4 (máximo). A força de preensão mostrou correlação inversa moderada com a idade. A combinação de paraplegia espástica de início precoce com polineuropatia progressiva faz da SPOAN uma condição incapacitante.

More than 140 years after the first description of Friedreich ataxia, autosomal recessive ataxias have become one of the more complex fields in Neurogenetics. Currently this group of diseases contains more than 20 clinical entities and an even larger number of associated genes. Some disorders are very rare, restricted to isolated populations, and others are found worldwide. An expressive number of recessive ataxias are treatable, and responsibility for an accurate diagnosis is high. The purpose of this review is to update the practitioner on clinical and pathophysiological aspects of these disorders and to present an algorithm to guide the diagnosis.Mais de 140 anos após a primeira descrição da ataxia de Friedreich, as ataxias autossômicas recessivas se transformaram em um dos mais complexos campos da Neurogenética. Atualmente, este grupo de doenças é composto por mais de 20 entidades clínicas e possui um número ainda maior de genes associados. Algumas doenças são muito raras, tendo sido observadas apenas em populações isoladas, enquanto que outras são encontradas no mundo todo. Um número expressivo de ataxias é tratável, e a responsabilidade em se fazer um diagnóstico correto é alta. A finalidade desta revisão é a de atualizar o neurologista a respeito dos principais aspectos clínicos e fisiopatológicos destas doenças e de apresentar um algoritmo para auxiliar a sua investigação e o seu diagnóstico.

BACKGROUND: Rett syndrome (RS) is a severe neurodevelopmental X-linked dominant disorder caused by mutations in the MECP2 gene. PURPOSE: To search for point mutations on the MECP2 gene and to establish a correlation between the main point mutations found and the phenotype. METHOD: Clinical evaluation of 105 patients, following a standard protocol. Detection of point mutations on the MECP2 gene was performed on peripheral blood DNA by sequencing the coding region of the gene. RESULTS: Classical RS was seen in 68% of the patients. Pathogenic point mutations were found in 64.1% of all patients and in 70.42% of those with the classical phenotype. Four new sequence variations were found, and their nature suggests patogenicity. Genotype-phenotype correlations were performed. CONCLUSION: Detailed clinical descriptions and identification of the underlying genetic alterations of this Brazilian RS population add to our knowledge of genotype/phenotype correlations, guiding the implementation of mutation searching programs.INTRODUÇÃO: A síndrome de Rett é uma grave doença do neurodesenvolvimento ligada ao X dominante, causada por mutações no gene MECP2. OBJETIVOS: Identificar mutações de ponto no gene MECP2 e estabelecer uma correlação entre as principais mutações encontradas e o fenótipo. MÉTODO: Avaliação clínica de 105 pacientes, seguindo um protocolo estabelecido. A identificação de mutações de ponto foi realizada em DNA de sangue periférico por sequenciamento da região codificante do gene amplificada por PCR. RESULTADOS: Em 68% dos pacientes observou-se o quadro clássico da síndrome. Mutações de ponto patogênicas foram encontradas em 64,1% dos pacientes e em 70,42% das pacientes com o quadro clássico. Quatro novas variações de seqüência foram identificadas e sua natureza sugere patogenicidade. Correlações genótipo-fenótipo foram estabelecidas. CONCLUSÃO: Descrições clínicas detalhadas desta população brasileira de pacientes acrescenta conhecimento às correlações genótipo-fenótipo nesta grave condição, que podem auxiliar na implantação de programas de triagem de mutações.

Tradicionalmente, as lipofuscinoses ceróides neuronais (LCN) eram classificadas de acordo com a idade de início e características clínicas em quatro grandes grupos. Recentemente, os estudos genéticos possibilitaram uma classificação mais pormenorizada dessa entidade em oito formas, permitindo o diagnóstico mais preciso de casos previamente considerados atípicos. Por outro lado, foi demonstrado que mutações de um mesmo gene poderiam ser responsáveis por grande variedade de fenótipos clínicos. O objetivo deste estudo é apresentar dois irmãos com achados clínicos e eletrencefalográficos compatíveis com a forma juvenil de LCN mas com alterações ultra-estruturais características da forma infantil tardia dessa doença. Os achados eletrencefalográficos auxiliam no diagnóstico da LCN, mas pouco contribuem na sua classificação.Neuronal ceroid lipofuscinosis (NCL) were traditionally classified according to age of onset and clinical features in four main groups. Recently, a combination of clinical, ultra structural and genetics data led to the recognition of eight forms of NCL, providing a more precise framework to classify atypical cases. By the other hand, it was shown that mutations in the same gene could be responsible for a large variety of clinical phenotypes. The objective of this study is to describe two brothers with clinical and electroencephalographic abnormalities characteristic of juvenile NCL, but with ultra structural abnormalities suggestive of late infantile NCL. Electroencephalogram is useful for clinical diagnosis of NCL but it is not helpful in its classification.

We describe five patients with Schwartz-Jampel syndrome (SJS) examined at the outpatient service for neuromuscular disorders at our Institution from 1996 to 1999 with the objective of emphasizing the characteristic dysmorphic phenotype of SJS and its different clinical forms. Two cases presented SJS-type 1A, two had SJS-type 1B and one manifested SJS-type 2. Two boys with 3 and 13 years of age had generalized stiffness and the characteristic facial as well as osteoarticular changes from birth. Other two boys with 11 and 7 years had less marked dysmorphic changes at birth and manifested myotonia, as a limiting factor, during the second year of age. A girl with two months of age had severe myotonia from birth leading to feeding diffuculties. In all cases the diagnosis was based on dysmorphic features, and on electromyographic changes showing continuous electrical activity of muscle fibers. All were treated with carbamazepine, 20-30 mg/Kg since diagnosis. The four boys (all with normal intelligence) improved of myotonia in daily activities, markedly in three, and moderately in one. The girl did not improve and showed global development delay: by the last follow-up (at 20 months of age) she did not sit unsupported, and had mental retardation. Carbamazepine in SJS-type 1 improves general daily performance and psychological status of the patients.

Creutzfeldt-Jakob disease (CJD), the most known human prion disease, is usually sporadic but approximately 15% of the cases are familial. To date, seven CJD cases with codon 210 mutation (GTT to ATT) have been reported in the literature. We describe a case of a 57 year-old woman who presented gait disturbances and rapidly progressive dementia, leading to death four months after onset. Electroencephalogram revealed periodic activity, diffusion-weighted magnetic resonance imaging showed hypersignal in basal ganglia, and test for 14-3-3 protein was strongly positive in the CSF. The complete prion protein gene coding region was sequenced after PCR amplification, showing a point mutation in codon 210. This is the first case of CJD with codon 210 mutation diagnosed in Brazil. We emphasize the role of genetic search for prion protein gene mutation, even in patients presenting clinical features resembling sporadic CJD.

In two siblings with clinical diagnosis of horizontal gaze palsy associated with progressive scoliosis (HGPPS) we could demonstrate by diffusion tensor imaging: (1) An anterior displacement of the transverse pontine fibers; (2) Posterior clumping of the corticospinal, medial lemniscus and central tegmental tracts and of the medial and dorsal longitudinal fasciculi complex; (3) Absent decussation of superior cerebellar peduncle. Those findings can contribute as surrogate markers for the diagnosis.Em dois irmãos com diagnóstico clínico de paralisia do olhar conjugado horizontal associada a escoliose progressiva, foi possível determinar através de imagens por tensores de difusão: (1) Deslocamento anterior das fibras pontinas transversas; (2) Agrupamento posterior do trato córtico-espinhal, lemnisco medial e trato tegmentar central e complexos dos fascículos longitudinais medial e dorsal; (3) Ausência da decussação dos pedúnculos cerebelares superiores. Tais achados podem contribuir como marcadores para o diagnóstico.

OBJECTIVE: To determine the seroprevalence of neuromyelitis optica antibody (NMO)-IgG in Brazilian patients with clinical diagnosis of relapsing neuromyelitis optica, also known as Devic's disease. METHOD: We determined NMO-IgG titers in 28 patients (25 of them females) that fulfilled the 1999 NMO diagnostic criteria proposed by Wingerchuk et al. RESULTS: NMO-IgG was detected in 18 NMO patients (64.3%). CONCLUSION: Our results showed that seroprevalence of NMO-IgG in Brazilian NMO patients was similar to the observed in other studies.OBJETIVO: Determinar a soroprevalência do anticorpo neuromielite óptica (NMO)-IgG em pacientes brasileiros com diagnóstico de neuromielite óptica recorrente, também conhecida como doença de Devic. MÉTODO: Nós pesquisamos a presença do anticorpo NMO-IgG em 28 pacientes (25 do sexo feminino) que preenchiam os critérios diagnósticos para NMO propostos por Wingerchuk et al. em 1999. RESULTADOS: Dezoito pacientes (64,3%) apresentaram a pesquisa positiva do NMO-IgG. CONCLUSÃO: Nossos resultados demonstraram que a soroprevalência do anticorpo NMO-IgG em pacientes brasileiros com NMO é semelhante àquela encontrada em outros estudos.

Os autores descrevem um caso típico de síndrome de Angelman. A paciente apresenta atraso de desenvolvimento neuropsicomotor, deficiência mental, macrostomia, dentes espaçados, convulsões, ausência de fala, andar com a base alargada e instável, crises de risos. Os estudos citogenéticos e moleculares revelaram deleção do segmento 15q11ql3 de origem materna, confirmando o diagnóstico clínico de síndrome de Angelman.The authors describe the case of a typical Angelman syndrome patient. The proband presents developmental delay, mental retardation, macrostomia, wide-spaced teeth, seizures, absent speech, jerky gait, and paroxysms of laughter. The cytogenetic and molecular studies showed a maternal deletion of 15q11q13. These results are in agreement with the clinical diagnosis of Angelman syndrome.

São descritos 7 casos de crianças com síndrome de espancamento e complicações neurológicas. O quadro clínico inicial na maioria das vezes foi representado pela presença de convulsões e abaulamento de fontanela e ausência de fatores etiológicos evidentes da agressão. O exame clínico mostrando a presença de hemorragia retiniana, sem a presença de história clínica febril ou de outras alterações, foi o sinal mais importante na orientação do diagnóstico definitivo. A alteração tomográfica mais freqüente foi a presença de coleção subdural, porém uma tomografia cerebral aparentemente normal inicialmente não afasta o aparecimento de complicações neurológicas e alterações graves mais tardias. O mecanismo que instrumenta essas lesões difusas deve estar relacionado ao fator aceleração/desaceleração que provavelmente leva a distúrbios circulatórios importantes no momento da agressão, responsáveis últimos pelas imagens de destruição parenquimatosa e evolução clínica mais grave em alguns pacientes.

ABSTRACT Chronic migraine poses a significant personal, social and economic burden and is characterized by headache present on 15 or more days per month for at least three months, with at least eight days of migrainous headache per month. It is frequently associated with analgesic or acute migraine medication overuse and this should not be overlooked. The present consensus was elaborated upon by a group of members of the Brazilian Headache Society in order to describe current evidence and to provide recommendations related to chronic migraine pharmacological and nonpharmacological treatment. Withdrawal strategies in medication overuse headache are also described, as well as treatment risks during pregnancy and breastfeeding. Oral topiramate and onabotulinum toxin A injections are the only treatments granted Class A recommendation, while valproate, gabapentin, and tizanidine received Class B recommendation, along with acupuncture, biofeedback, and mindfulness. The anti-CGRP or anti-CGRPr monoclonal antibodies, still unavailable in Brazil, are promising new drugs already approved elsewhere for migraine prophylactic treatment, the efficacy of which in chronic migraine is still to be definitively proven.

ABSTRACT Gerstmann-Sträussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity.

ABSTRACT In this opinion paper, the authors discuss historical and etymological aspects of the term “migrânea” and refute the most common criticisms regarding its adoption by the Brazilian Headache Society in the official translation of the International Classification of Headache Disorders.