Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy.

Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for at least 6 months. An open, observational, prospective cohort study was conducted using a before-after design (time series) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina. From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a decrease of less than 50% in seizure frequency. The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild adverse events and no patient reported severe adverse effects. At the end of the study, we found in most patients a significant improvement in the quality of life, in all the items evaluated. Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated, and associated with a significant improvement in their quality of life.

O uso do canabidiol em crianças com epilepsia resistente a medicamento e a diminuição na frequência das crises: revisão rápida / The use of cannabidiol in children with drug-resistant epilepsy and the decrease in the frequency of seizures: quick review

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

Use of cannabidiol in the treatment of epilepsy: Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.

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.

Uso del cannabis medicinal en niños con encefalopatías epilépticas farmacorresistentes. Experiencia en Hospital Garrahan / Use of medicinal cannabis in children with drug-resistant epileptic encephalopathies. Experience at Garrahan Hospital

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)

Cannabidiol for the treatment of refractory epilepsy in children: a critical review of the literature.

OBJECTIVE: The aim of this current report was to present a critical review of the use of cannabidiol (CBD) in the treatment of refractory epilepsies in the pediatric population. DATA SOURCE: Literature review was carried out in the Medline (PubMed), Cochrane, and Scientific Electronic Library Online (SciELO) databases with the descriptors "Cannabidiol" and "Epilepsy." The search was not limited by the date of publication, language, or study design. A total of 69 articles were included in the review. DATA SYNTHESIS: The efficacy of CBD in treating epileptic seizures has been confirmed by randomized controlled trials for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. The incidence of side effects reported in subjects of the studies is high. However, most studies indicate a good safety profile and tolerance to the drug, with most of the adverse effects being mild to moderate and transient. CONCLUSIONS: There is no consensus on the release of CBD as a therapeutic tool by the drug regulatory agencies worldwide. However, the use of CBD is promising since it has presented satisfactory results in crisis control in well-designed studies. In addition, this drug has a good safety and tolerance profile. However, further studies with a long follow-up period are needed to confirm its usefulness and the long-term safety in pediatric patients.

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy.

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

[Transional syndrome: from West to Lennox-Gastaut syndromes]. / Síndrome transicional: del síndrome de West al síndrome de Lennox-Gastaut.

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.

Síndrome transicional: del síndrome de West al síndrome de Lennox-Gastaut / Transional syndrome: from West to Lennox-Gastaut syndromes

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.