RESUMO
There is currently no efficacious intervention for preventing post-traumatic epilepsy (PTE). Preclinical studies support the potential use of anticholinergics for this condition. The purpose of this study was to evaluate the effects of biperiden as an intervention for preventing PTE. A randomized, double-blinded clinical trial was conducted at HC/FMUSP between 2018-2022. Adults with acute traumatic brain injury (TBI) were randomly assigned to receive biperiden or placebo, for 10 days. The primary outcome was the incidence of PTE while the secondary outcomes included the frequency of seizures, the frequency of any adverse events and mortality after 24 months. The study was powered at a planned enrolment of 132 patients. The trial began in January 2018 and was halted by researchers on March 2020 (and terminated in December 2022) in the face of the global COVID-19 pandemic. Overall, 123 participants were randomized and 112 contributed with data for modified mITT analysis, being that 61 (49.5%) participants completed the 24-month follow-up consult. Data analysis indicated lack of evidence of biperiden for either, the incidence of post-traumatic epilepsy (2.6, 95%CI, 0.65-10.57; p = 0.170) or the mortality rate (1.57, 95%CI, 0.73-3.38; p = 0.248). The frequency of late post-traumatic seizures was higher for biperiden group (2.03, 95%CI = 0.912-3.1597; p <0.001). The present study suggests that there was insufficient evidence regarding the effect of biperiden in preventing PTE after TBI, which underpins the need for larger studies. Clinical trial registration: ClinicalTrials.gov, identifier: NCT01048138.
RESUMO
The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10-20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.
Assuntos
Preparações Farmacêuticas , Estado Epiléptico , Animais , Modelos Animais de Doenças , Humanos , Pilocarpina/toxicidade , ConvulsõesRESUMO
SIRPIDs, an acronym for stimulus-induced rhythmic, periodic, or ictal discharges, were first named in 2004. This is a pattern observed in continuous electroencephalogram (CEEG) consistently elicited by stimulation in comatose patients. The pathophysiology of SIRPIDs probably involves dysregulation of subcortico-cortical projections, particularly thalamocortical circuit, in a markedly abnormal brain with hyperexci-table cortex. This may explain some studies found an association of prolonged periodic epileptiform discharges (PEDs) activity and a higher incidence of concurrent electrographic seizures and SIRPIDs. An association of SIRPIDs and poor prognosis has already been described. However, it is not yet possible to assert whether these discharges can cause neuronal injury or if they are simply a marker of severe brain injury. Objective of this paper is to review clinical relevance and pathophysiology of SIRPIDs, as well as its role as a brain response in the critically ill patient.
Assuntos
Periodicidade , Convulsões/fisiopatologia , Estado Terminal , Eletroencefalografia , Feminino , HumanosRESUMO
SIRPIDs, an acronym for stimulus-induced rhythmic, periodic, or ictal discharges, were first named in 2004. This is a pattern observed in continuous electroencephalogram (CEEG) consistently elicited by stimulation in comatose patients. The pathophysiology of SIRPIDs probably involves dysregulation of subcortico–cortical projections, particularly thalamocortical circuit, in a markedly abnormal brain with hyperexcitable cortex. This may explain some studies found an association of prolonged periodic epileptiform discharges (PEDs) activity and a higher incidence of concurrent electrographic seizures and SIRPIDs. An association of SIRPIDs and poor prognosis has already been described. However, it is not yet possible to assert whether these discharges can cause neuronal injury or if they are simply a marker of severe brain injury. Objective of this paper is to review clinical relevance and pathophysiology of SIRPIDs, as well as its role as a brain response in the critically ill patient.
O termo SIRPIDs é um acrônimo do inglês que pode ser traduzido como: descargas ictais, periódicas ou rítmicas induzidas por estímulos e foi utilizado pela primeira vez em 2004. Este padrão é observado no eletroencefalograma contínuo (CEEG) obtido pela estimulação de pacientes comatosos. A fisiopatologia dos SIRPIDs provavelmente envolve uma falha na regulação das projeções corticais e subcorticais, particularmente nos circuitos talamocorticais, num cérebro anormal com o córtex hiperexcitável. Isso pode explicar a associação encontrada por alguns estudos entre as descargas epileptiformes periódicas (PEDs) prolongadas e uma maior incidência de crises eletrográficas, bem como de SIRPIDs. É descrita associação entre os SIRPIDs e pior prognóstico. Ainda não é possível determinar se estas descargas podem causar dano neuronal ou se elas são simplesmente marcadoras de lesão cerebral grave. O objetivo deste artigo é revisar a relevância clínica, a fisiopatologia dos SIRPIDs e seu papel como resposta cerebral no paciente crítico.
Assuntos
Feminino , Humanos , Periodicidade , Convulsões/fisiopatologia , Estado Terminal , EletroencefalografiaRESUMO
OBJECTIVES: Deletion of the chromosome 15q11-q13, the most common genetic mechanism associated with Angelman syndrome (AS), is highly associated with a severe phenotype. However, deletion is not a genetically homogeneous group as it is composed by two main groups: Class I with breakpoints at BP1 (proximal) and BP3 (distal) and Class II present breakpoints at BP2 (proximal) and BP3 (distal). In this study, we aimed to evaluate the impact of the breakpoint on the electroclinical profile. METHODS: We evaluated 16 patients with AS caused by 15q11-13 deletion (6 were Class I; 10 were Class II). We characterized epilepsy features by clinical history obtained from parents and caretakers with a pre-standard questionnaire. These data were corroborated by medical records, contact with previous physicians, and video-EEG monitoring. Suggestive EEG patterns for AS were classified according to the classical description of Boyd et al. (1988). RESULTS: AS patients with BP1-BP3 deletion had significantly more daily and disabling seizures than AS patients with BP1-BP2 deletion. They also presented a significant higher frequency of status epilepticus and epilepsy aggravated by fever. Need for polytherapy was significantly more frequent in BP1-BP3 patients. EEG features were similar in both groups. CONCLUSION: This study shows a significant correlation between the two deletion classes and AS clinical, but not the electrographic phenotype. Epilepsy is more severe and refractory to treatment in patients with larger deletions. Deletion is not a homogeneous group and knowledge on the breakpoint may have a clinical implication and represent an important factor in parental counseling.
Assuntos
Síndrome de Angelman/genética , Pontos de Quebra do Cromossomo , Deleção de Genes , Estudos de Associação Genética/métodos , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/fisiopatologia , Criança , Eletroencefalografia/métodos , Seguimentos , Humanos , Estudos ProspectivosRESUMO
BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retardation, speech disorder, stereotyped jerky movements, and a peculiar behavioral profile, with a happy disposition and outbursts of laughter. Most patients with AS present with epilepsy and suggestive electroencephalographic patterns, which may be used as diagnostic criteria. OBJECTIVE: To study epilepsy and response to treatment in a series of patients with AS determined by deletion. DESIGN: Parent and caregiver interview and medical record review. SETTING: Epilepsy Center at the University of São Paulo. PATIENTS: Nineteen patients with AS determined by deletion of chromosome 15q11-13. MAIN OUTCOME MEASURES: Epilepsy severity, epilepsy evolution, and response to antiepileptic drug treatment. RESULTS: All patients with AS in this group had generalized epilepsy, and 10 (53%) also had partial epilepsy. Main seizure types were atypical absences and myoclonic and tonic-clonic seizures. Mean age at onset was 1 year 1 month. Epilepsy aggravated by fever occurred in 10 patients (53%) and status epilepticus in 16 (84%). Eighteen patients (95%) had previous or current history of daily seizures, of which 14 (64%) had disabling seizures. Multiple seizure types were observed in 13 patients (53%). History of refractory epilepsy was reported in 16 patients (84%). Parents reported improvement, characterized by decrease in seizure frequency or seizure control, at the mean age of 5.3 years. Therefore, most of these patients had a period of refractory epilepsy; however, improvement occurred during late childhood and puberty. The best therapeutic response was obtained with valproic acid alone or in association with phenobarbital or clonazepam. Epilepsy was aggravated by carbamazepine, oxcarbazepine, and vigabatrin. CONCLUSIONS: Patients with AS with deletion have epilepsy with early onset and stereotyped electroclinical profile regarding seizure type, severity, and response to antiepileptic drug treatment. Another feature of AS is the age-related improvement, even in refractory cases, during late childhood and puberty. These characteristics are not specific to this syndrome but, when inserted in the proper clinical context, may anticipate diagnosis. We believe that AS should be considered a differential diagnosis in developmentally delayed infants with severe, generalized, cryptogenic epilepsy; however, a proper electroclinical delineation of each genetic group is mandatory.
Assuntos
Síndrome de Angelman/complicações , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Epilepsia/etiologia , Epilepsia/genética , Adolescente , Idade de Início , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Progressão da Doença , Eletroencefalografia/métodos , Epilepsia/classificação , Epilepsia/tratamento farmacológico , Feminino , Febre/etiologia , Seguimentos , Humanos , Masculino , Resultado do TratamentoRESUMO
The authors describe the electroclinical phenotype of four patients with Angelman syndrome (AS) determined by its rarest genetic mechanism-uniparental disomy (UPD). The analysis of ours and published patients showed that in UPD, when epilepsy occurred, it was milder compared to patients with deletion, although a suggestive EEG was observed in most patients. We found that UPD patients do not completely fit the scenario delineated for AS, suggesting that patients determined by different mechanisms should be distinctly addressed, for a better understanding of this syndrome.
Assuntos
Síndrome de Angelman/genética , Síndrome de Angelman/fisiopatologia , Eletroencefalografia , Epilepsia/genética , Dissomia Uniparental/genética , Dissomia Uniparental/fisiopatologia , DNA/genética , Epilepsia/etiologia , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
PURPOSE: This study aimed to evaluate the sensitivity of the EEG in Angelman syndrome (AS), to verify the age at onset of suggestive EEGs and to study EEG patterns, analyzing variations and comparing our findings with nomenclature previously used. METHODS: Seventy EEG and 15 V-EEGs of 26 patients were analyzed. Suggestive EEG patterns of AS were classified in delta pattern (DP), theta pattern (TP), and posterior discharges (PDs). Generic terms were used to simplify the analysis. RESULTS: Suggestive EEGs were observed in 25 (96.2%) patients. DP occurred in 22 patients with four variants-hypsarrhythmic-like: irregular, high-amplitude, generalized delta activity (DA) with multifocal epileptiform discharges (EDs); slow variant: regular, high-amplitude, generalized DA with rare EDs; ill-defined slow spike-and-wave: regular, high-amplitude, generalized DA with superimposed EDs characterizing a slow wave, with notched appearance; triphasic-like: rhythmic, moderate-amplitude DA over anterior regions with superimposed EDs. TP was observed in eight patients, as generalized or over the posterior regions. PDs were seen in 19 patients as runs of sharp waves or runs of high-amplitude slow waves with superimposed EDs. TP was the only age-related pattern (younger than 8 years) and observed only in patients with deletion. In 15 patients who had an EEG before the clinical diagnosis, 60% had a suggestive tracing. CONCLUSIONS: Although some EEG descriptions are not very detailed, and every author describes findings in a slightly different manner, obviously a common denominator must exist. In this context, EEG seems to be a very sensitive method for the diagnosis of AS, offering an opportunity to corroborate this etiologic diagnosis. Conversely, we do not believe that these patterns may be accounted as specific, except for the delta pattern, which seems to be extremely unusual in other syndromes. Other EEG patterns observed in AS, such as theta activity and PDs, occur in a wide variety of disorders. Nonetheless, their importance for the EEG diagnosis of AS is supported by the fact that they are associated with other features and may be helpful in a proper clinical setting.
Assuntos
Síndrome de Angelman/diagnóstico , Eletroencefalografia , Adolescente , Adulto , Síndrome de Angelman/genética , Síndrome de Angelman/fisiopatologia , Córtex Cerebral/fisiopatologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 15 , Análise Mutacional de DNA , Ritmo Delta , Diagnóstico Diferencial , Potenciais Evocados/fisiologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Processamento de Sinais Assistido por Computador , Síndrome , Ritmo TetaRESUMO
Estudamos 36 pacientes com epilepsia mioclônica juvenil, com idade de 10 a 54 anos e tempo de doença de 4 meses a 42 anos (média 8,3 anos). Mioclonias ocorreram em todos os casos, crises clônico-tônico-clônicas e/ou tônico-clôncias generalizadas em 29 pacientes (80,5 por cento ) e ausências em 10 (27,7 por cento ). Um paciente apresentou mioclonias palpebrais. As mioclonias inauguraram o quadro em 61,1 por cento dos casos, precedendo em 47,2 por cento os outros tipos de crises. A epilepsia teve início entre 5 e 22,2 anos (média 12,7). O eletroencefalograma (EEG) mostrou base normal e complexos de espícula-onda e/ou multispícula-onda generalizados, bilaterais e síncronos, ativados pela hiperpnéia, fotostimulaçäo e sono leve em 63,3 por cento , 38,2 por cento e 55,1 por cento , respectivamente. Valproato de sódio na dose de 145mg/dia (nível sérico de 75,7ug/ml) controlou todas as crises em 93,5 por cento dos pacientes. Foram registrados EEG normais em alguns pacientes com ulterior reaparecimento das anormalidades, apesar do controle das crises. Em 1 paciente as crises foram controladas apenas com organizaçäo dos hábitos de vida