RESUMO
PURPOSE: Up to half of the children undergoing epilepsy surgery will continue to have seizures (szs) despite a cortical resection or ablation. Functional connectivity has shown promise in better identifying the epileptogenic zone. We hypothesized that cortical areas showing high information outflow during interictal epileptiform discharges are part of the epileptogenic zone. METHODS: We identified 22 children with focal epilepsy who had undergone stereo electroencephalography, surgical resection or ablation, and had ≥1 year of postsurgical follow-up. The mean phase slope index, a directed measure of functional connectivity, was calculated for each electrode contact during interictal epileptiform discharges. The positive predictive value and negative predictive value for a sz-free outcome were calculated based on whether high information outflow brain regions were resected. RESULTS: Resection of high outflow (z-score ≥ 1) and very high outflow (z-score ≥ 2) electrode contacts was associated with higher sz freedom (high outflow: χ 2 statistic = 59.1; P < 0.001; very high outflow: χ 2 statistic = 31.3; P < 0.001). The positive predictive value and negative predictive value for sz freedom based on resection at the electrode level increased at higher z-score thresholds with a peak positive predictive value of 0.86 and a peak negative predictive value of 0.9. CONCLUSIONS: Better identification of the epileptogenic zone has the potential to improve epilepsy surgery outcomes. If the surgical plan can be modified to include these very high outflow areas, more children might achieve sz freedom. Conversely, if deficits from resecting these areas are unacceptable, ineffective surgeries could be avoided and alternative therapies offered.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Humanos , Criança , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/cirurgia , Convulsões , Eletroencefalografia , Epilepsias Parciais/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Bainbridge-Ropers syndrome is caused by monoallelic ASXL3 variants on chromosome 18. Clinical features include dysmorphic facies, developmental delay, intellectual disability, autistic traits, hypotonia, failure to thrive, seizures and hyperventilation. Breath-holding spells with choreathetoid movements have been previously described. CASE PRESENTATION: We describe an 11-year old boy who has daily intractable seizures reported since birth, developmental delay, autistic features and feeding difficulties. He was eventually found to have de novo, heterozygous pathogenic variant (c.1612G > T, p.E538*) in the ASXL3 gene. He has frequent episodes of breath-holding accompanied by dystonic posturing with right leg extension and head turning without ictal EEG correlate. The breath-holding spells have been refractory to several medication trials including iron supplementation, acetazolamide, and desipramine. CONCLUSIONS: This case represents a more severe phenotype of Bainbridge-Ropers Syndrome than previously described with refractory breath-holding spells with dystonia, intractable epilepsy, and progressive cerebral/cerebellar atrophy. Breath-holding spells cause significant morbidity, are poorly understood, and have very limited treatment options.
Assuntos
Epilepsia Resistente a Medicamentos , Suspensão da Respiração , Criança , Deficiências do Desenvolvimento/genética , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/diagnóstico , Humanos , Masculino , Fenótipo , Fatores de Transcrição/genéticaRESUMO
Neuromodulation alters neuronal activity with electrical impulses delivered to the targeted neurologic sites. The various neuromodulation options available today for epilepsy management have proven efficacy primarily in adult trials. These include open-loop stimulation with invasive vagus nerve stimulation and deep brain stimulation, as well as closed-loop responsive neurostimulation. The use of neurostimulation therapy to treat intractable epilepsy in children is growing. This article reviews the literature, historical background, and current principles in pediatric patients.
Assuntos
Estimulação Encefálica Profunda , Epilepsia Resistente a Medicamentos , Epilepsia , Estimulação do Nervo Vago , Criança , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Epilepsia/terapia , Humanos , Estimulação Elétrica Nervosa TranscutâneaRESUMO
Responsive neurostimulation (RNS) is an emerging therapy for patients with refractory focal epilepsy who are not candidates for surgical resection, with limited published experience in the pediatric population. We report a case of refractory multifocal epilepsy following febrile infection related epilepsy syndrome (FIRES) in which surgical resection was not feasible due to multifocal independent seizures and risk of cognitive deficit, and RNS was pursued. Relevant RNS data and neuropsychological testing results were reviewed. By eight months after implantation, decreased frequency and severity of clinical seizures were noted, and RNS data revealed decreased "long episodes," reduced spread of electrographic seizures, and fewer detections. Neuropsychological assessment, though potentially confounded by stimulant medication, revealed significant improvement in multiple cognitive domains, particularly working memory and processing speed, at six months. These findings illustrate success in detecting and aborting seizures, and additionally suggest a neuromodulatory effect of RNS stimulation. Our case demonstrates feasibility, efficacy and safety of RNS in a pediatric patient with FIRES, with evidence to also suggest cognitive improvement.
Assuntos
Disfunção Cognitiva/terapia , Epilepsia Resistente a Medicamentos/terapia , Encefalite Viral/complicações , Epilepsias Parciais/terapia , Febre/complicações , Criança , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/etiologia , Terapia por Estimulação Elétrica , Encefalite Viral/diagnóstico , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/etiologia , Febre/diagnóstico , Humanos , Neuroestimuladores Implantáveis , MasculinoRESUMO
With the licensing of cannabidiol for drug resistant seizures in Dravet and Lennox Gastaut syndromes in the United states in 2018, interest in the potential for cannabis-based-medicinal products to meet currently unmet needs for people with epilepsy continues to grow. This review summarizes current knowledge and discusses the implications for future research and practice. Both cannabidiol and tetrahydrocannabinol, the main components, have been extensively studied in animal models, with multimodal mechanisms of action proposed. Only pure cannabidiol formulations have been rigorously evaluated in controlled trials thus far, with modest but significant improvements in motor seizures. Adverse effects include diarrhoea, somnolence and reduced appetite, with mostly acceptable tolerability, but a not insignificant (up to 1 in 23) risk of serious adverse events. Recognized drug interactions include with valproate (increased risk of hepatotoxicity) and clobazam (contributing to somnolence, increased secretions, probably chest infections, and potentially efficacy). Whilst there is public (and producer) interest in products also containing tetrahydrocannabinol, clinicians have justifiable concerns about exposing a group already vulnerable to mental health and neurobehavioural comorbidities to the associated additional risks in these domains. Artisanal preparations, with often inconsistent/unknown constituents are frequently used but not recommended. A gulf exists between the actual evidence, including a lack of comparative studies and public beliefs, fuelled by media and anecdote. Continued education of the public, policymakers, researchers and healthcare providers about what is and isn't yet known, together with on-going good quality research is essential to mitigate against future potential risks, particularly in relation to vulnerable populations. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
Assuntos
Anticonvulsivantes/uso terapêutico , Canabinoides/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Animais , Canabidiol/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Cultura , Dronabinol/uso terapêutico , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/fisiopatologia , Medicina Baseada em Evidências/métodos , Humanos , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/fisiopatologiaRESUMO
The Epilepsy Therapy Screening Program (ETSP), formerly known as the Anticonvulsant Screening Program (ASP), has played an important role in the preclinical evaluation of many of the antiseizure drugs (ASDs) that have been approved by the FDA and thus made available for the treatment of seizures. Recent changes to the animal models used at the contract site of the ETSP at the University of Utah have been implemented in an attempt to better model the unmet clinical needs of people with pharmacoresistant epilepsy and thus identify improved therapies. In this review, we describe the changes that have occurred over the last several years in the screening approach used at the contract site and, in particular, detail the pharmacology associated with several of the animal models and assays that are either new to the program or have been recently characterized in more depth. There is optimism that the refined approach used by the ETSP contract site, wherein etiologically relevant models that include those with spontaneous seizures are used, will identify novel, potentially disease modifying therapies for people with pharmacoresistant epilepsy and those at risk for developing epilepsy. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
Assuntos
Anticonvulsivantes/uso terapêutico , Programas de Triagem Diagnóstica/tendências , Descoberta de Drogas/tendências , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/farmacologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/tendências , Epilepsia Resistente a Medicamentos/diagnóstico , Humanos , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/fisiologia , Convulsões/diagnósticoRESUMO
This paper aimed to systematically examine the efficacy and adverse event (AE) profile of cannabidiol and medicinal cannabis by analyzing qualitative and meta-analytic data. We used the terms ("Cannabidiol" OR "Cannabis") AND "Epilepsy" AND ("Treatment" OR "Therapeutics") as keywords to retrieve studies indexed on PubMed, ScienceDirect, and CENTRAL databases. The inclusion criteria were as follows: clinical studies with a longitudinal observational design and intervention using cannabinoid derivatives, especially cannabidiol and medicinal cannabis, whereby some results involved the frequency of epileptic seizures. We used Cochrane Collaboration's Review Manager software (RevMan 5.1.6) for the meta-analysis and dichotomized the articles to a confidence interval of 95%. From 236 articles, we selected 16 for descriptive analysis; we selected only 4 for the meta-analysis. According to the results, a statistically meaningful effect of cannabidiol compared with placebo was observed (pâ¯<â¯0.00001). When comparing treatment with cannabidiol or medicinal cannabis, significance was not found for the AE profile (pâ¯=â¯0.74). As AEs for cannabidiol were more common under short-term than under long-term treatment (pâ¯<â¯0.00001), this approach was favorable in the long term. Furthermore, cannabidiol is more effective than placebo, regardless of the etiology of epileptic syndromes and dosage. Overall, the AE profile did not differ across treatments with cannabidiol or medicinal cannabis, though it did differ favorably for long-term than for short-term treatment.
Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Anticonvulsivantes/efeitos adversos , Canabidiol/efeitos adversos , Humanos , Estudos Longitudinais , Maconha Medicinal/efeitos adversos , Estudos Observacionais como Assunto/métodos , Resultado do TratamentoRESUMO
Deep brain stimulation (DBS) has provided new treatment options for refractory epilepsy; however, treatment outcomes of DBS in refractory epilepsy patients previously treated with vagus nerve stimulation (VNS) have not been clarified. Herein, treatment outcomes of DBS of the anterior nucleus of the thalamus (ANT-DBS) in patients who had previously experienced VNS failure are reported. Seven patients who had previously experienced VNS failure underwent ANT-DBS device implantation. VNS was turned off before DBS device implantation. Monthly seizure counts starting from baseline to 12-18 months after DBS were analyzed. Five (71.3%) of the 7 patients experienced a >50% reduction of seizure counts after DBS; 1 responder reached a seizure-free status after DBS therapy. Of the 2 nonresponders, 1 subject showed improvement in seizure strength and duration, which lessened the impact of the seizures on the patient's quality of life. This is the first study in which favorable outcomes of ANT-DBS surgery were observed in individual patients with refractory epilepsy who had not responded to prior VNS. Further studies with a larger number of subjects and longer follow-up period are needed to confirm the feasibility of ANT-DBS in patients who have previously experienced VNS failure.
Assuntos
Núcleos Anteriores do Tálamo/fisiologia , Estimulação Encefálica Profunda/métodos , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Estimulação do Nervo Vago/métodos , Adulto , Criança , Epilepsia Resistente a Medicamentos/fisiopatologia , Feminino , Humanos , Masculino , Qualidade de Vida , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Interest in the use of artisanal cannabinoids in pediatric epilepsy has increased but safety and utility data are lacking. Our aim was to prospectively characterize the use of oral cannabis extracts (OCE) in a refractory pediatric epilepsy population. METHODS: Families considering the use of an OCE were enrolled in a prospective observational study. Baseline seizure frequency was assessed over a period of 4 weeks. Seizure frequency, CBD and THC-COOH levels were assessed every 4 weeks during a 12-week treatment period. Response was defined as at least a 50% reduction in seizure frequency over the final 8 weeks of the study relative to baseline. RESULTS: Consent was obtained in 32 children; 11 were excluded from analysis (3 failed to complete baseline data, 3 started OCE before completing baseline period and 5 did not start OCE) leaving 21 to be included in subsequent analyses. Median age was 10.3 years (IQR 6.8-12.6), 13 (62%) were male and median seizure frequency was 2.7 seizures/day during the baseline period. The median of the high dose of CBD that was administered during the observation period was of 0.9 (0.6-2.2) mg/kg/day. Of the 21 subjects who were included in the analysis, 5 (24%) were responders. OCE was stopped early in 3 subjects (14%) due to a perceived increase in seizures. THC-COOH and CBD blood levels did not have a significant association with response status (pâ¯=â¯0.95 CBD, pâ¯=â¯0.53 THC-COOH, Nâ¯=â¯14). CONCLUSION: The observed response rate in this study is similar to placebo rates in prospective randomized trials of pharmaceutical grade products and the withdrawal rate is greater than rates obtained with retrospective methods. Doses of OCE administered were lower than doses used in randomized trials.
Assuntos
Anticonvulsivantes/administração & dosagem , Cannabis , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Maconha Medicinal/administração & dosagem , Extratos Vegetais/administração & dosagem , Administração Oral , Adolescente , Canabidiol/administração & dosagem , Criança , Pré-Escolar , Dronabinol/administração & dosagem , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
OBJECTIVE: During deep brain stimulation (DBS) surgery, we analysed somatosensory evoked potentials (SSEPs) using microelectrode recordings (MERs) in patients under general anaesthesia. METHODS: We obtained MERs from 5 patients with refractory epilepsy. Off-line analysis isolated local field potentials (LFPs, 2-200â¯Hz) and high frequency components (HFCs, 0.5-5â¯kHz). Trajectories were reconstructed off-line. RESULTS: The ventral caudate (V.c.) nucleus was most frequently recorded from (171â¯mm). Very high frequency oscillations (VHFOs) were recorded up to 8â¯mm in length from all 4 electrodes but were most frequently recorded from the V.c. The properties of VHFOs were similar among all nuclei (frequency >1500â¯Hz, amplitude â¼3⯵V, starting time â¼14â¯ms, duration 8-9â¯ms). Consecutive recordings did not show any synchronization or propagation, but a new kind of potential (high frequency oscillation, HFO) appeared abruptly inside the V.c. (frequencyâ¯=â¯848⯱â¯66â¯Hz, amplitudeâ¯=â¯5.2⯱â¯1.8⯵V starting at 17.7⯱â¯0.5â¯ms, spanning 3.4⯱â¯0.3â¯ms). CONCLUSIONS: VHFOs are widely extending and cannot be ascribed to the V.c. HFOs in patients under general anaesthesia can serve as a landmark to identify the V.c. in thalamic DBS surgery. SIGNIFICANCE: Thalamic processing involves nuclei other than the V.c, and HFO can be used to improve DBS surgery.
Assuntos
Anestesia Geral/métodos , Estimulação Encefálica Profunda/métodos , Epilepsia Resistente a Medicamentos/fisiopatologia , Potenciais Somatossensoriais Evocados/fisiologia , Monitorização Neurofisiológica Intraoperatória/métodos , Tálamo/fisiologia , Adolescente , Adulto , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Feminino , Humanos , Masculino , MicroeletrodosRESUMO
BACKGROUND: Transcutaneous trigeminal nerve stimulation (TNS) has antiepileptic effects in patients with drug-resistant epilepsy (DRE). However, whether and how TNS is able to modulate the electroencephalogram (EEG) background activity in patients with DRE is still unknown. OBJECTIVES: To investigate the effect of short-term TNS on EEG background activity in DRE by qualitative and quantitative analyses. METHODS: Twenty-nine DRE patients participated in the study. Twenty-two were randomly divided into a "sham-TNS" or "real-TNS" group; seven patients underwent stimulation of the median nerve (MNS) at the wrist. Real-TNS was delivered bilaterally to the infraorbital nerve (trains of 1-20â¯mA, 120â¯Hz, cyclic modality for 20â¯min). The sham-TNS protocol mimicked the real-TNS one but at a zero intensity. For MNS, the same parameters as real-TNS were used. EEG was continuously acquired for 40â¯min: 10' pre, 20' during and 10' post stimulation. EEG was visually inspected for interictal epileptiform discharge (IEDs) changes and processed by spectral analysis for changes in mean frequency and absolute power of each frequency band. RESULTS: A significant increase of EEG absolute alpha power was observed during real-TNS compared with the sham-TNS (F34,680â¯=â¯1.748; pâ¯=â¯0.006). Conversely, no significant effects were noticed either for quantitative analysis of other frequency bands or for IEDs detection. MNS proved unable to modulate EEG activity. CONCLUSIONS: Short-term TNS induces an acute and specific effect on background EEG of DRE by increasing the absolute alpha band power. EEG alpha rhythm enhancement may index a cortical functional inhibition and act as a seizure-preventing mechanism.
Assuntos
Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/terapia , Eletroencefalografia/métodos , Estimulação Elétrica Nervosa Transcutânea/métodos , Nervo Trigêmeo/fisiologia , Adulto , Idoso , Epilepsia Resistente a Medicamentos/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.
Assuntos
Ensaios Clínicos como Assunto/métodos , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Criança , HumanosRESUMO
OBJECTIVE: The effect of continuous subthreshold cortical stimulation (CSCS) over the seizure onset zone (SOZ) in epilepsy was analyzed to delineate the affected physiological processes. METHOD: ECoG data was recorded over SOZ and adjacent regions in patients (nâ¯=â¯7) with refractory-epilepsy. Data was reviewed before and during 2â¯Hz cortical electrical stimulation. Group differences were estimated using ANOVA and correlation with Pearson's r. RESULTS: CSCS reduced background ECoG power at SOZ (pâ¯<â¯0.05), increased spectral coherence (pâ¯<â¯0.05) and reduced spike rate (pâ¯<â¯0.01) over all recorded sites. Spectral power and coherence (pâ¯<â¯0.01) correlated with spike rate at SOZ but not with each other at any location. Spike morphology correlated with spike-rate over all recorded sites (pâ¯<â¯0.0001) and with spectral power and coherence at SOZ (pâ¯<â¯0.01). CONCLUSION: This study shows changes in cortical electrophysiology during CSCS over the SOZ where spike rate reduction correlated with two independent electrophysiological parameters, background power and coherence. These results suggest the possibility of a causal relationship between spectral power, coherence and interictal spikes which may be related to seizure rate. SIGNIFICANCE: Improved understanding of the effect of electrical stimulation on epileptic tissue could suggest improvements in stimulation paradigms to reduce seizure frequency.
Assuntos
Potenciais de Ação/fisiologia , Córtex Cerebral/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/terapia , Terapia por Estimulação Elétrica/métodos , Eletrocorticografia/métodos , Adolescente , Adulto , Epilepsia Resistente a Medicamentos/diagnóstico , Terapia por Estimulação Elétrica/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE Drug-resistant epilepsy (DRE) presents a therapeutic challenge in children, necessitating the consideration of multiple treatment options. Although deep brain stimulation (DBS) has been studied in adults with DRE, little evidence is available to guide clinicians regarding the application of this potentially valuable tool in children. Here, the authors present the first systematic review aimed at understanding the safety and efficacy of DBS for DRE in pediatric populations, emphasizing patient selection, device placement and programming, and seizure outcomes. METHODS The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations. Relevant articles were identified from 3 electronic databases (MEDLINE, Embase, and Cochrane CENTRAL) from their inception to November 17, 2017. Inclusion criteria of individual studies were 1) diagnosis of DRE; 2) treatment with DBS; 3) inclusion of at least 1 pediatric patient (age ≤ 18 years); and 4) patient-specific data. Exclusion criteria for the systematic review included 1) missing data for age, DBS target, or seizure freedom; 2) nonhuman subjects; and 3) editorials, abstracts, review articles, and dissertations. RESULTS This review identified 21 studies and 40 unique pediatric patients (ages 418 years) who received DBS treatment for epilepsy. There were 18 patients with electrodes placed in the bilateral or unilateral centromedian nucleus of the thalamus (CM) electrodes, 8 patients with bilateral anterior thalamic nucleus (ATN) electrodes, 5 patients with bilateral and unilateral hippocampal electrodes, 3 patients with bilateral subthalamic nucleus (STN) and 1 patient with unilateral STN electrodes, 2 patients with bilateral posteromedial hypothalamus electrodes, 2 patients with unilateral mammillothalamic tract electrodes, and 1 patient with caudal zona incerta electrode placement. Overall, 5 of the 40 (12.5%) patients had an International League Against Epilepsy class I (i.e., seizure-free) outcome, and 34 of the 40 (85%) patients had seizure reduction with DBS stimulation. CONCLUSIONS DBS is an alternative or adjuvant treatment for children with DRE. Prospective registries and future clinical trials are needed to identify the optimal DBS target, although favorable outcomes are reported with both CM and ATN in children. ABBREVIATIONS ATN = anterior thalamic nucleus; CM = centromedian nucleus of the thalamus; DBS = deep brain stimulation; DRE = drug-resistant epilepsy; RNS = responsive neurostimulation; STN = subthalamic nucleus; VNS = vagus nerve stimulation.
Assuntos
Estimulação Encefálica Profunda/métodos , Epilepsia Resistente a Medicamentos/terapia , Adolescente , Criança , Pré-Escolar , Estimulação Encefálica Profunda/efeitos adversos , Epilepsia Resistente a Medicamentos/diagnóstico , Eletrodos Implantados , Feminino , Hipocampo , Humanos , Masculino , Núcleo Subtalâmico , Tálamo , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy. RECENT FINDINGS: While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD's efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Canabidiol/metabolismo , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Cannabis , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/metabolismo , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/metabolismo , Epilepsia/diagnóstico , Epilepsia/metabolismo , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/metabolismo , Humanos , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Síndrome de Lennox-Gastaut/metabolismo , Maconha Medicinal/metabolismo , Maconha Medicinal/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Estudos Retrospectivos , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/metabolismo , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo , Resultado do TratamentoRESUMO
The efficacy and safety of deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) for epilepsy (SANTE) trial was demonstrated by a randomized trial by Fisher et al. (2010). Based on this trial, the U.S. Food and Drug Administration recently granted approval for DBS therapy for epilepsy; the indication is as follows: "Bilateral stimulation of the anterior nucleus of the thalamus (ANT) for epilepsy is indicated as an adjunctive therapy for reducing the frequency of seizures in individuals 18â¯years of age or older diagnosed with epilepsy characterized by partial onset seizures with or without secondary generalization that are refractory to three or more antiepileptic medications". This paper reviews the experimental data and the clinical experience using DBS for the treatment of epilepsy. "This article is part of the Supplement issue Neurostimulation for Epilepsy."
Assuntos
Estimulação Encefálica Profunda/métodos , Epilepsia Resistente a Medicamentos/terapia , Adolescente , Adulto , Terapia Combinada/métodos , Estimulação Encefálica Profunda/tendências , Epilepsia Resistente a Medicamentos/diagnóstico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Convulsões/diagnóstico , Convulsões/prevenção & controle , Tálamo/fisiologiaRESUMO
Gelastic seizures, usually with onset in early infancy, are the hallmark manifestation of hypothalamic hamartoma. This seizure type is directly generated by hamartoma itself, intrinsically epileptogenic because of its anatomofunctional organization. Other types of seizures, focal or generalized, may appear during the evolution, probably resulting from mechanisms of secondary epileptogenesis. Nevertheless, the clinical expression and the severity of the syndrome, ranging from a focal drug-resistant epilepsy to a catastrophic generalized encephalopathy with severe cognitive and behavioral impairments, depends on the size and the site of attachment of the hamartoma. Early suspicion, timely diagnosis, and appropriate treatment are mandatory to reverse a potential catastrophic evolution of this condition.
Assuntos
Epilepsias Parciais/diagnóstico , Hamartoma/diagnóstico , Doenças Hipotalâmicas/diagnóstico , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/fisiopatologia , Transtornos do Comportamento Infantil/cirurgia , Pré-Escolar , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/cirurgia , Progressão da Doença , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/cirurgia , Diagnóstico Precoce , Intervenção Médica Precoce , Eletroencefalografia , Epilepsias Parciais/fisiopatologia , Epilepsias Parciais/cirurgia , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/fisiopatologia , Epilepsia Generalizada/cirurgia , Hamartoma/fisiopatologia , Hamartoma/cirurgia , Humanos , Doenças Hipotalâmicas/fisiopatologia , Doenças Hipotalâmicas/cirurgia , Hipotálamo/fisiopatologia , Hipotálamo/cirurgia , Lactente , Excitação Neurológica/fisiologia , Tomografia por Emissão de Pósitrons , Prognóstico , Radiocirurgia , Processamento de Sinais Assistido por Computador , SíndromeRESUMO
The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.
Assuntos
Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsias Parciais/fisiopatologia , Hamartoma/fisiopatologia , Doenças Hipotalâmicas/fisiopatologia , Puberdade Precoce/fisiopatologia , Criança , Pré-Escolar , Comorbidade , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/fisiopatologia , Doenças do Sistema Endócrino/terapia , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/terapia , Feminino , Hormônio Liberador de Gonadotropina/sangue , Hamartoma/diagnóstico , Hamartoma/terapia , Hormônios Ectópicos/sangue , Humanos , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/terapia , Hipotálamo/fisiopatologia , Lactente , Masculino , Rede Nervosa/fisiopatologia , Puberdade Precoce/diagnóstico , Puberdade Precoce/terapia , Fator de Crescimento Transformador alfa/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.
Assuntos
Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Animais , Descoberta de Drogas/tendências , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/tendências , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/diagnóstico , Previsões , Humanos , Camundongos , Ratos , Convulsões/diagnósticoRESUMO
The widespread patient use of artisanal cannabis preparations has preceded quality validation of cannabis use for epilepsy. Neurologists and cannabinoid specialists are increasingly in a position to monitor and guide the use of herbal cannabis in epilepsy patients. We report the retrospective data on efficacy and adverse effects of artisanal cannabis in Patients with medically refractory epilepsy with mixed etiologies in Washington State, California, and Maine. Clinical considerations, including potential risks and benefits, challenges related to artisanal preparations, and cannabinoid dosing, are discussed. RESULTS: Of 272 combined patients from Washington State and California, 37 (14%) found cannabis ineffective at reducing seizures, 29 (15%) experienced a 1-25% reduction in seizures, 60 (18%) experienced a 26-50% reduction in seizures, 45 (17%) experienced a 51-75% reduction in seizures, 75 (28%) experienced a 76-99% reduction in seizures, and 26 (10%) experienced a complete clinical response. Overall, adverse effects were mild and infrequent, and beneficial side effects such as increased alertness were reported. The majority of patients used cannabidiol (CBD)-enriched artisanal formulas, some with the addition of delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA). Four case reports are included that illustrate clinical responses at doses <0.1mg/kg/day, biphasic dose-response effects, the use of THCA for seizure prevention, the use of THC for seizure rescue, and the synergy of cannabinoids and terpenoids in artisanal preparations. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".