RESUMO
OBJECTIVE: Functional network effects of resective or palliative epilepsy surgery in Lennox-Gastaut syndrome (LGS) patients are different according to the seizure outcome. This study aimed to clarify whether the response to antiseizure medications (ASM) can affect to alteration of brain network connectivity. METHODS: In this retrospective study, 37 patients with LGS who underwent 1st electroencephalography (EEG) and 40 healthy controls were enrolled. Among them, 24 LGS patients had follow-up EEG data and were classified as drug responders and non-responders according to the ASM response. Graphical theoretical analysis was used to assess functional connectivity using resting-state EEG. RESULTS: The 1st EEG showed a decreased radius in patients with LGS compared with that in healthy controls (3.987 vs. 4.279, P = 0.003). Follow-up EEG data of patients with LGS revealed significant differences in functional connectivity depending on the ASM response. On follow-up EEG, non-responders (n = 11) demonstrated significant increases in global network parameters, whereas responders (n = 13) showed no significant difference in functional connectivity compared with healthy controls. CONCLUSIONS: The functional connectivity patterns in patients with LGS differed from those in healthy controls. Functional connectivity in drug-responsive patients with LGS tended to preserve the network of brain connections in a pattern similar to that in healthy controls, whereas non-responders showed more disrupted functional connectivity.
Assuntos
Epilepsia , Síndrome de Lennox-Gastaut , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Estudos Retrospectivos , Encéfalo/diagnóstico por imagem , Convulsões , EletroencefalografiaRESUMO
INTRODUCTION: Highly purified cannabidiol (CBD) has a broad spectrum of action and could be useful for the treatment of drug resistant epilepsy regardless of etiology or syndrome. MATERIALS AND METHODS: Multicenter retrospective study that evaluated the efficacy and safety of CBD for the treatment of drug resistant epilepsy of different etiologies in patients >2 years of age. RESULTS: Seventy-eight patients with a median age of 24 years and a wide spectrum of mainly structural and genetic etiologies were included. Patients were using a median of 3 antiseizure drugs (IQR=2-4) and had a median of 30 monthly seizures (IQR=12-100) before starting CBD. The median treatment time with CBD was 14 months (IQR=10-17). The efficacy analysis at the last available visit showed that mean percent reduction in seizures, ≥50% reduction in seizure frequency and seizure freedom was 67.8%, 68.8% and 11.5% respectively. We found no significant impact of concomitant clobazam use on the efficacy and safety of CBD. In the safety analysis, 28.2% (n = 22) of patients presented adverse events related to CBD and drug-retention rate was 78.2%. CONCLUSIONS: In a real-world setting, highly purified CBD has been shown to be safe and effective for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis Complex. Based on these findings, highly purified CBD should be considered as an adjuvant therapy for drug resistant epilepsy, regardless of its underlying cause or specific syndrome. Nevertheless, this assumption should be validated through further controlled trials.
Assuntos
Canabidiol , Epilepsia Resistente a Medicamentos , Epilepsias Mioclônicas , Síndrome de Lennox-Gastaut , Esclerose Tuberosa , Humanos , Adulto Jovem , Adulto , Síndrome de Lennox-Gastaut/tratamento farmacológico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Estudos Retrospectivos , Epilepsias Mioclônicas/tratamento farmacológico , Convulsões/tratamento farmacológicoRESUMO
Uso de canabidiol (CDB) medicinal presente no óleo de canabis. Indicação: Tratamento de crianças portadoras de epilepsia refratária resistente a medicação e síndromes graves decorrentes. Pergunta: O uso do canabidiol em crianças com epilepsia resistente a medicamentos apresentaria diminuição na frequência de crises convulsivas? Objetivo: Investigar a eficácia e a segurança do canabidiol, em comparação a placebo, na manutenção da remissão em crianças com epilepsia refratária. Métodos: Revisão rápida de revisões sistemáticas, por meio de buscas bibliográficas realizadas nas bases PUBMED, SCOPUS, BVS, Cochrane Library. Foram utilizadas estratégias de buscas com vocabulário padronizado e avaliação da qualidade metodológica usando o checklist AMSTAR 2. Resultados: Foram selecionadas duas revisões sistemáticas que atendiam aos critérios de elegibilidade. O CDB quando comparado ao placebo reduziu 50% das convulsões para epilepsia refrataria (RR 1.69 [1.20 2.36]), para a síndrome de Lennox-Gastaut o RR foi 2.98 (IC 95%, 1.83 - 4.85) e para a síndrome de Dravet o RR foi 2.26 (IC 95% ,1.38 - 3.70). O CDB pode resultar em uma diminuição no apetite em dosagens maiores (RR = 2,10, IC 95% [0,964,62], embora não apresente diferença de efeito dos grupos comparadores. Conclusão: Duas revisões sistemáticas recentes o CDB quando comparado ao placebo reduziu 50% das convulsões para epilepsia refrataria e síndromes graves. Entretanto, existem poucos ensaios clínicos publicados na área
: Use of cannabidiol (CBD) present in cannabis oil. Indication: Treatment of children with drug-resistant refractory epilepsy and severe syndromes resulting. Question: Would the use of cannabidiol in children with drug-resistant epilepsy lead to a decrease in seizure frequency? Objective: to investigate the efficacy and safety of cannabidiol, compared to placebos, in maintaining remission in children with refractory epilepsy. Methods: Rapid review of systematic reviews, through a bibliographical search carried out in the PUBMED, SCOPUS, BVS, Cochrane Library databases. Predefined search strategies were followed, and the methodological quality of the included studies was evaluated using the AMSTAR 2 tool. Results: Two systematic reviews were selected, which met the eligibility criteria. CBD when compared to placebo reduce 50% of seizures for refractory epilepsy (RR 1.69, IC 95% [1.20 2.36]), for Lennox-Gastaut Syndrome the RR was foi 2.98 (IC 95%, 1.83 - 4.85) and for Dravet Syndrome o RR FOI 2.26 (IC 95% ,1.38 - 3.70). CBD may result in appetite decrease using high doses (RR = 2.10, 95% IC [0.96 4.62], with no statistical difference. Conclusion: Two recent systematics, CBD, when compared to placebo, presented 50% of seizures for refractory epilepsy and severe syndromes. However, there are few clinical trials published in the area
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Masculino , Feminino , Pré-Escolar , Criança , Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Dronabinol/uso terapêutico , Canabinoides/uso terapêutico , Eficácia , Síndrome de Lennox-Gastaut/tratamento farmacológico , AnticonvulsivantesRESUMO
OBJECTIVE: The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures. METHODS: This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses. RESULTS: Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%. CONCLUSIONS: This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.
Assuntos
Canabidiol , Epilepsias Mioclônicas , Epilepsia , Síndrome de Lennox-Gastaut , Esclerose Tuberosa , Adulto , Criança , Humanos , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/efeitos adversos , Canabidiol/uso terapêutico , Canabidiol/efeitos adversos , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/induzido quimicamente , Síndrome de Lennox-Gastaut/tratamento farmacológico , Convulsões/etiologia , Convulsões/induzido quimicamente , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/induzido quimicamenteRESUMO
INTRODUCTION: Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide. AREAS COVERED: The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies. EXPERT OPINION: Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.
Assuntos
Canabidiol , Epilepsias Parciais , Epilepsia , Síndrome de Lennox-Gastaut , Espasmos Infantis , Esclerose Tuberosa , Adulto , Animais , Humanos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Epilepsia/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Espasmos Infantis/tratamento farmacológico , Esclerose Tuberosa/tratamento farmacológicoRESUMO
Objetivo: Reportamos resultados sobre la efectividad, seguridad y tolerancia del cannabidiol como adyuvante terapéutico en pacientes pediátricos con encefalopatías epilépticas del desarrollo (EED) resistentes al tratamiento farmacológico y no farmacológico tras un seguimiento promedio de 20 meses. Métodos: Se realizó un estudio de cohorte prospectivo para evaluar la eficacia, la seguridad y la tolerancia del aceite de cannabis medicinal enriquecido con CBD añadido a los medicamentos anticonvulsivos estándar en niños con EED resistentes a los medicamentos atendidos en un único centro. Resultados: Entre octubre de 2018 y marzo de 2020, se incluyeron 59 pacientes. La edad media en el momento del inicio del protocolo fue de 10,5 años (rango, 2-17 años). La mediana de la duración del tratamiento fue de 20 meses (rango, 12-32). La mediana de edad en el momento de la primera convulsión fue de 8 meses (rango, 1 día - 10 años). Al final del seguimiento, el 78% de los niños tenía una disminución ≥ 50% en frecuencia de las crisis y el 47,5% tenía una disminución > 75%. Siete pacientes (11,9%) estaban libres de convulsiones. El número de crisis se redujo de una mediana de 305/mes a 90/mes, que supone una reducción media del 57% y una mediana del 71% (p < 0,0001). Los efectos adversos fueron en su mayoría leves o moderados. El CBD se interrumpió en 17 pacientes (28,8%) por falta de respuesta al tratamiento, aumento de la frecuencia de las convulsiones, intolerancia al fármaco o cumplimiento terapéutico insuficiente. Conclusión: En los niños con EED resistentes a los fármacos, el tratamiento a largo plazo del cannabis medicinal enriquecido con CBD como terapia adyuvante resultó ser seguro, bien tolerado y eficaz. Las reducciones sostenidas en la frecuencia de las convulsiones y la mejora de los aspectos de la vida diaria se observaron en comparación con nuestros preliminares (AU)
Objective: We report results on the effectiveness, safety, and tolerance of cannabidiol (CBD) as add-on therapy in children with developmental and epileptic encephalopathies (DEE) resistant to pharmacological and non-pharmacological treatment after a mean follow-up of 20 months. Methods: A prospective cohort study was conducted to evaluate the efficacy, safety, and tolerability of CBD-enriched medical cannabis oil added to standard antiseizure medications in children with drug-resistant DEEs seen at a single center. Results: Between October 2018 and March 2020, 59 patients were included. The median age at protocol initiation was 10.5 years (range, 2-17 years). Median treatment duration was 20 months (range, 12-32). The median age at the time of the first seizure was 8 months (range, 1 day - 10 years). At the end of follow-up, 78% of the children had a decrease ≥ 50% in seizure frequency and 47.5% had a decrease of > 75%. Seven patients (11.9%) were seizure free. The number of seizures was reduced from a median of 305/month to 90/month, accounting for a mean reduction of 57% and a median of 71% (p < 0.0001). Adverse effects were mostly mild or moderate. CBD was discontinued in 17 patients (28.8%) due to lack of response to treatment, increased seizure frequency, drug intolerance, or poor compliance. Conclusion: In children with drug-resistant DEE, long-term treatment with CBD-enriched medicinal cannabis as add-on therapy proved to be safe, well tolerated, and effective. Sustained reductions in seizure frequency and improvement in aspects of daily living were observed compared to our preliminary results (AU)
Assuntos
Humanos , Pré-Escolar , Criança , Adolescente , Canabidiol/uso terapêutico , Resultado do Tratamento , Epilepsia/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Hospitais Pediátricos , Anticonvulsivantes/uso terapêutico , Estudos Prospectivos , Estudos de CoortesRESUMO
PURPOSE: Forced normalization (FN) indicates psychotic episodes associated with seizure remission and disappearance of epileptiform activity on EEG. FN is likely to occur when frequent seizures are abruptly terminated by anti-epileptic drugs (AEDs) or epilepsy surgery. METHODS: We describe an atypical case of a patient with FN induced by lacosamide (LCM). RESULTS: A 23-year-old female patient with Lennox-Gastaut syndrome (LGS) was administered AEDs for LGS and hospitalised with weight loss and abnormal behaviour. Her condition fulfilled the FN criteria, which was considered to be induced by LCM. After a reduction in LCM dose, her abnormal behaviour and appetite improved. During LCM use, the patient developed no seizures, and the high amplitude diffuse sharp and slow wave complexes that were frequently observed before LCM disappeared on EEG. The LCM dose was tapered to 150 mg per day, and she became calmer with socially appropriate behaviours, although a few mild focal seizures relapsed. CONCLUSION: LCM was effective for treating LGS in this patient and induced FN. Initially, it was difficult to recognise FN in cases of psychiatric disorders, especially in patients with intellectual disability. Patients with FN induced by LCM are rare, and only four patients have been previously reported who were treated by antipsychotic drug for psychosis.
Assuntos
Anticonvulsivantes/efeitos adversos , Lacosamida/efeitos adversos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Psicoses Induzidas por Substâncias/etiologia , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Deficiência Intelectual , Lacosamida/administração & dosagem , Lacosamida/uso terapêutico , Adulto JovemRESUMO
Cannabidiol, a non-intoxicating phytocannabinoid, has potential therapeutic effects over a broad range of disorders. Recently, there has been increased interest in CBD, as several studies showed promising anticonvulsant efficacy with few side effects. In 2018, a CBD-based oral solution, Epidiolex®, was approved by the FDA to treat two severe forms of pediatric epilepsy, Dravet syndrome, and Lennox-Gastaut syndrome. Although only these two syndromes are recognized indications for CBD, it has been consumed in an unregulated fashion for a variety of indications including chronic pain, muscle stiffness, inflammation, anxiety, smoking cessation, and even cancer. While CBD legislation in the USA is confusing due to the differences in state and federal laws, CBD has proliferated in the US market in several forms such as CBD oil or capsules, hemp oil/extract, and also as an ingredient in several dietary supplements, syrups, teas, and creams. With the ever-increasing use of CBD and its widespread availability to the general public, it is important to examine and report on possible drug-drug interactions between CBD and other therapeutic agents as well as addictive substances such as alcohol and tobacco. A detailed literature search for CBD's possible interactions was conducted using online databases. As expected, CBD has been reported to interact with anti-epileptic drugs, antidepressants, opioid analgesics, and THC, but surprisingly, it interacts with several other common medications, e.g. acetaminophen, and substances including alcohol. This review provides a comprehensive list of interacting drugs. The possible mechanisms for these drug-drug interactions are presented in table format. Given the growing popularity of CBD as a medication and the dearth of available information on CBD drug-drug interactions, it is critical to be aware of current drug-drug interactions and it will be important to investigate the impact of CBD upon concomitant medication use in future randomized, controlled trials.
Assuntos
Canabidiol , Epilepsias Mioclônicas , Síndrome de Lennox-Gastaut , Espasmos Infantis , Anticonvulsivantes , Canabidiol/uso terapêutico , Criança , Epilepsias Mioclônicas/tratamento farmacológico , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Espasmos Infantis/tratamento farmacológicoRESUMO
OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
Assuntos
Deficiências do Desenvolvimento/epidemiologia , Epilepsias Mioclônicas/epidemiologia , Espasmos Infantis/epidemiologia , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/fisiopatologia , Progressão da Doença , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/fisiopatologia , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/epidemiologia , Síndromes Epilépticas/etiologia , Síndromes Epilépticas/fisiopatologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Lennox-Gastaut/tratamento farmacológico , Síndrome de Lennox-Gastaut/epidemiologia , Síndrome de Lennox-Gastaut/etiologia , Síndrome de Lennox-Gastaut/fisiopatologia , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/cirurgia , Mortalidade , Índice de Gravidade de Doença , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/etiologia , Espasmos Infantis/fisiopatologia , Vitória/epidemiologiaRESUMO
Lennox-Gastaut syndrome (LGS) is a childhood-onset epileptic encephalopathy characterized by multiple types of medically intractable seizures, cognitive impairment, and generalized slow spike-wave discharges in electroencephalography (EEG). Although the onset of this epileptic syndrome occurs typically before eight years of age with a peak age between 3 and 5â¯years, lifelong persistence of the syndrome is usual. The evolution of clinical features, EEG findings, and paucity of knowledge about LGS among adult health care providers can make LGS significantly underdiagnosed in the adult population. Management of LGS remains problematic beyond childhood due to intractable seizures, the difficult transition from pediatric to adult neurologists, challenging behaviors, impaired cognition, poor quality of life, and disabled social life. In focusing on the management of LGS beyond childhood, this narrative review describes medical and surgical management of epilepsy, the transition from pediatric to adult care, and management of other common comorbidities associated with LGS. Several antiepileptic drugs (AEDs) such as lamotrigine, topiramate, felbamate, rufinamide, clobazam, and Epidiolex (pure pharmaceutical grade cannabidiol (CBD) oil) have been noted to be effective in well-designed, randomized controlled trials. Other non-pharmacological therapies, such as vagus nerve stimulation, ketogenic diet, and epilepsy surgery, have been frequently utilized in the management of intractable seizures associated with LGS. However, effective management of LGS requires a broader perspective to not only control seizures but improve the quality of life by addressing cognitive and behavioral problems, sleep disturbances, physical disability, social disability, and educational and employment challenges.
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Síndrome de Lennox-Gastaut , Transição para Assistência do Adulto , Adulto , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Clobazam/uso terapêutico , Eletroencefalografia , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Qualidade de VidaAssuntos
Agonistas de Receptores de Canabinoides/uso terapêutico , Dor Crônica/tratamento farmacológico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Espasticidade Muscular/tratamento farmacológico , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Canabidiol/uso terapêutico , Tomada de Decisão Compartilhada , Dronabinol/análogos & derivados , Dronabinol/uso terapêutico , Controle de Medicamentos e Entorpecentes , Epilepsias Mioclônicas/tratamento farmacológico , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Esclerose Múltipla/complicações , Espasticidade Muscular/etiologia , Náusea/induzido quimicamente , Avaliação das Necessidades , Médicos de Atenção Primária , Guias de Prática Clínica como Assunto , Especialização , Reino Unido , Vômito/induzido quimicamenteRESUMO
Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).
Assuntos
Canabidiol/farmacologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Humanos , Convulsões/tratamento farmacológico , Canais de Cátion TRPV/efeitos dos fármacosRESUMO
Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.
Assuntos
Canabidiol/uso terapêutico , Epilepsia/tratamento farmacológico , Animais , Método Duplo-Cego , Epilepsias Mioclônicas/tratamento farmacológico , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/tratamento farmacológicoRESUMO
Several new antiepileptic medicines became available for clinical use in the last two decades. However, the prognosis of epilepsy remains unchanged, with approximately one-third of patients continuing to have drug-resistant seizures. Because many of these patients are not candidates for curative epilepsy surgery, there is a need for new seizure medicines with better efficacy and safety profile. Recently, social media and public pressure sparked a renewed interest in cannabinoids, which had been used for epilepsy since ancient times. However, physicians have significant difficulty prescribing cannabinoids freely because of the paucity of sound scientific studies. Among the two most common cannabinoids, cannabidiol has better antiepileptic potential than tetrahydrocannabinol. The exact antiepileptic mechanism of cannabidiol is currently not known, but it modulates a number of endogenous systems and may have a novel anticonvulsant effect. However, it has broad drug-drug interactions with several agents, including inducer and inhibitor of CYP3A4 or CYP2C19. Cannabidiol can cause liver enzyme elevation, especially when co-administered with valproate. The US Food and Drug Administration (FDA) has approved pharmaceutical-grade cannabidiol oil for two childhood-onset catastrophic epilepsies: Dravet syndrome and Lennox-Gastaut syndrome. The Drug Enforcement Agency also reclassified this product as a schedule V agent. However, other cannabidiol products remain as a schedule I substance and are primarily used without regulation. Additionally, the FDA-approved pharmaceutical-grade cannabidiol oil is expensive, and insurance companies might approve this only for the designated indications. In despair, many individuals may resort to unregulated medical cannabis products in an attempt to control seizures. Rather than spontaneous treatment without medical supervision, adequate medical oversight is indicated to monitor and manage the proper dose, side effects, validity of the product, and drug-drug interactions.
Assuntos
Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Epilepsias Mioclônicas/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Resultado do Tratamento , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/efeitos adversos , HumanosRESUMO
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
El síndrome de West o espasmos infantiles, es una encefalopatía epiléptica clasificada como epilepsias y síndromes generalizados. Hay múltiples informes de la evolución de síndrome de West a síndrome de Lennox-Gastaut de un 25 hasta 60%, sin reconocerse una causa específica. Se ha comunicado que pueden ser solo una entidad epiléptica dependiente de la edad y que estaría en relación con el grado de inmadurez cerebral. En esta revisión retrospectiva de 130 casos de espasmos infantiles, solo 14 (10.7%) evolucionaron a Lennox-Gastaut. El haber recibido en todos los casos vigabatrina como tratamiento nos hace suponer que la baja incidencia podría estar relacionada con el uso de este fármaco. Dado que la vigabatrina tiene una acción gabaérgica y aumenta los niveles de ACTH podría explicar esta relación, pero esto deberá confirmarse con el mejor conocimiento de los mecanismos íntimos de estas graves encefalopatías.
West syndrome or infantile spasms is an epileptic encephalopathy, classified as generalized epilepsies and syndromes. There are multiple reports of the evolution from West to Lennox-Gastaut syndrome of 25 up to 60%, without a specific cause is determined. It has been reported that they may be only an epileptic entity age dependent that it would be in relation to the degree of brain immaturity. In this retrospective review of 130 cases of West syndrome, only 14 (10.7%) evolved to Lennox-Gastaut. Having received in all cases vigabatrin as a treatment, makes us suppose that the low incidence could be related to the use of this drug. Given that vigabatrin has a gabaergic action and increased levels of ACTH, may explain this relationship but this must be confirmed with the best knowledge of the intimate mechanisms of these serious epileptic encephalopathies.
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Humanos , Feminino , Lactente , Espasmos Infantis/complicações , Síndrome de Lennox-Gastaut/etiologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Síndrome , Metilprednisolona/uso terapêutico , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Progressão da Doença , Vigabatrina/uso terapêutico , Eletroencefalografia , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Anticonvulsivantes/uso terapêuticoRESUMO
BACKGROUND: Since the introduction of the orphan drugs legislation in Europe, it has been suggested that the general method of assessing drugs for reimbursement is not necessarily suitable for orphan drugs. The National Institute for Health and Clinical Excellence indicated that several criteria other than cost and efficacy could be considered in reimbursement decisions for orphan drugs. This study sought to explore the multi-criteria decision analysis (MCDA) framework proposed by (Orphanet J Rare Dis 7:74, 2012) to a range of orphan drugs, with a view to comparing the aggregate scores to the average annual cost per patient for each product, and thus establishing the merit of MCDA as a tool for assessing the value of orphan drugs in relation to their pricings. METHODS: An MCDA framework was developed using the nine criteria proposed by (Orphanet J Rare Dis 7:74, 2012) for the evaluation of orphan drugs, using the suggested numerical scoring system on a scale of 1 to 3 for each criterion. Correlations between the average annual cost of the drugs and aggregate MCDA scores were tested and plotted graphically. Different weightings for each of the attributes were also tested. A further analysis was conducted to test the impact of including the drug cost as an attribute in the aggregate index scores. RESULTS: In the drugs studied, the R 2, that statistically measures how close the data are to the fitted regression line was 0.79 suggesting a strong correlation between the drug scores and the average annual cost per patient. CONCLUSION: Despite several limitations of the proposed model, this quantitative study provided insight into using MCDA and its relationship to the average annual costs of the products.
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Técnicas de Apoio para a Decisão , Produção de Droga sem Interesse Comercial , Descoberta de Drogas , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Síndrome de Lennox-Gastaut/tratamento farmacológico , Síndrome de Lennox-Gastaut/metabolismo , Mucopolissacaridose II/tratamento farmacológico , Mucopolissacaridose II/metabolismo , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismoRESUMO
Drop seizures are especially problematic in patients with Lennox-Gastaut syndrome (LGS) because of their potential for serious injury. In this post hoc analysis of phase 3 OV-1012 data, a medical review was conducted of seizure-related injuries based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms from all adverse event (AE) listings. Patients receiving clobazam experienced fewer seizure-related injuries than those receiving placebo (8.9% all clobazam dosages vs. 27.1% placebo, p ≤ 0.05). Significant differences in the rates of seizure-related injuries were observed for the medium- and high-dosage clobazam treatment groups (4.8% and 10.2%, respectively, p ≤ 0.05). A total of 50 of 53 AEs considered seizure-related were mild or moderate in intensity; 3 severe AEs occurred in the placebo group (fall, contusion, and jaw fracture). A single serious AE (jaw fracture, which required hospitalization and surgery) occurred in a placebo-treated patient. Most injuries resolved by the end of the study. This analysis indicates that the reduction in drop-seizure frequency achieved with clobazam provides a clinically meaningful benefit, a reduced likelihood of experiencing seizure-related injuries.
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Anticonvulsivantes/efeitos adversos , Benzodiazepinas/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Síndrome de Lennox-Gastaut/complicações , Síndrome de Lennox-Gastaut/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Clobazam , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletroencefalografia , Feminino , Humanos , Deficiência Intelectual , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Adulto JovemRESUMO
Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by mixed seizures, cognitive decline, and generalized slow (<3 Hz) spike wave discharges on electroencephalography. Atonic seizures result in dangerous drop attacks with risks of injury and impairment of the quality of life. The seizures are frequently resistant to multiple antiepileptic (AED) drugs. Newer AEDs, such as rufinamide, are now available. When multiple AED trials fail, non-pharmacological treatments such as the ketogenic diet, vagus nerve stimulation, and epilepsy surgery, should be considered. The aim of this review is to present an updated outline of LGS and the available treatments. Although the prognosis for complete seizure control remains poor, the addition of newer therapies provides an improved hope for some of these patients and their families. Further long term randomized controlled trials are required to compare different therapeutic interventions in terms of efficacy and tolerability.
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Síndrome de Lennox-Gastaut/tratamento farmacológico , Humanos , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/fisiopatologiaRESUMO
Pelger-Huët anomalies, which are characterized by an abnormal nuclear shape and chromatin organization in blood granulocytes, and are frequently confused with myelodysplastic syndrome. We herein report a case of Lenox syndrome in a patient treated with VPA for more than 25 years who developed significant Pelger-Huët anomalies. Despite the lack of any changes in the total VPA level throughout the patient's clinical course, the free fraction of VPA potently increased, likely due to a reduction in serum albumin. Following the administration of a smaller dose of VPA that reduced the serum free fraction of VPA to the normal range, the Pelger-Huët anomalies completely disappeared. It is necessary to monitor the free fraction of VPA in order to detect an overdose, which may induce adverse effects under conditions of hypoalbuminemia. The present case showed, for the first time, that VPA-induced Pelger-Huët anomalies occur in a dose-dependent and reversible manner.