Category Archives: Epilepsia

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Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.

Category : Epilepsia

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Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.

Epilepsy Behav. 2018 Feb 08;:

Authors: Porcari GS, Fu C, Doll ED, Carter EG, Carson RP

Abstract
Medically refractory epilepsy continues to be a challenge worldwide, and despite an increasing number of medical therapies, approximately 1 in 3 patients continues to have seizures. Cannabidiol (CBD), one of many constituents of the Cannabis sativa or marijuana plant, has received renewed interest in the treatment of epilepsy. While highly purified CBD awaits Food and Drug Administration (FDA) approval, artisanal formulations of CBD are readily available and are seeing increased use in our patient population. Although randomized controlled trials of CBD are ongoing and promising, data regarding artisanal formulations of CBD are minimal and largely anecdotal. Here, we report a retrospective study to define the efficacy of artisanal CBD preparations in children with epilepsy. Given the known interaction between CBD and clobazam, we also conducted a subgroup comparison to determine if clobazam use was related to any beneficial effects of CBD. Additionally, we compared response rates with CBD and with clobazam alone within an overlapping patient cohort. A pediatric cohort with epilepsy of 108 patients was identified through a medical record search for patients using CBD oil. The addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The responder rate for clobazam was similar. No patients achieved CBD monotherapy, although the weaning of other antiepileptic drugs (AEDs) became possible in 22% of patients. A comparable proportion had AED additions during CBD therapy. With concomitant use of clobazam, 44% of patients had a 50% reduction in seizures upon addition of CBD compared with 33% in the population not taking clobazam; this difference was not statistically significant. The most common reported side effect of CBD was sedation in less than 4% of patients, all of whom were also taking clobazam. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. Benefits were more marked in the CBD alone group, in contrast to the CBD and clobazam group, but this difference was not statistically significant. In summary, these findings support efficacy of artisanal CBD preparations in seizure reduction with few significant side effects. The response to CBD was independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use.

PMID: 29429908 [PubMed – as supplied by publisher]

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The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users.

Category : Epilepsia

The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users.

Cannabis Cannabinoid Res. 2018;3(1):1-10

Authors: Batalla A, Lorenzetti V, Chye Y, Yücel M, Soriano-Mas C, Bhattacharyya S, Torrens M, Crippa JAS, Martín-Santos R

Abstract
Introduction: Hippocampal neuroanatomy is affected by genetic variations in dopaminergic candidate genes and environmental insults, such as early onset of chronic cannabis exposure. Here, we examine how hippocampal total and subregional volumes are affected by cannabis use and functional polymorphisms of dopamine-relevant genes, including the catechol-O-methyltransferase (COMT), dopamine transporter (DAT1), and the brain-derived neurotrophic factor (BDNF) genes. Material and Methods: We manually traced total hippocampal volumes and automatically segmented hippocampal subregions using high-resolution MRI images, and performed COMT, DAT1, and BDNF genotyping in 59 male Caucasian young adults aged 18-30 years. These included 30 chronic cannabis users with early-onset (regular use at <16 years) and 29 age-, education-, and intelligence-matched controls. Results: Cannabis use and dopaminergic gene polymorphism had both distinct and interactive effects on the hippocampus. We found emerging alterations of hippocampal total and specific subregional volumes in cannabis users relative to controls (i.e., CA1, CA2/3, and CA4), and associations between cannabis use levels and total and specific subregional volumes. Furthermore, total hippocampal volume and the fissure subregion were affected by cannabis×DAT1 polymorphism (i.e., 9/9R and in 10/10R alleles), reflecting high and low levels of dopamine availability. Conclusion: These findings suggest that cannabis exposure alters the normal relationship between DAT1 polymorphism and the anatomy of total and subregional hippocampal volumes, and that specific hippocampal subregions may be particularly affected.

PMID: 29404409 [PubMed]

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Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

Category : Epilepsia

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Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

Lancet. 2018 Jan 25;:

Authors: Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K, GWPCARE4 Study Group

Abstract
BACKGROUND: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.
METHODS: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690.
FINDINGS: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.
INTERPRETATION: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.
FUNDING: GW Pharmaceuticals.

PMID: 29395273 [PubMed – as supplied by publisher]

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An interaction between warfarin and cannabidiol, a case report.

Category : Epilepsia

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An interaction between warfarin and cannabidiol, a case report.

Epilepsy Behav Case Rep. 2018;9:10-11

Authors: Grayson L, Vines B, Nichol K, Szaflarski JP, UAB CBD Program

Abstract
•An interaction between warfarin and cannabidiol is described•The mechanisms of cannabidiol and warfarin metabolism are reviewed•Mechanism of the interaction is proposed•INR should be monitored in patients when cannabinoids are introduced.

PMID: 29387536 [PubMed]

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Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

Category : Epilepsia

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Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

Mol Neurobiol. 2018 Jan 25;:

Authors: Upadhya D, Castro OW, Upadhya R, Shetty AK

Abstract
The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population. Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy. Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed. In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.

PMID: 29372545 [PubMed – as supplied by publisher]

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Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?

Category : Epilepsia

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Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?

J Epilepsy Res. 2017 Dec;7(2):61-76

Authors: Perucca E

Abstract
The interest in cannabis-based products for the treatment of refractory epilepsy has skyrocketed in recent years. Marijuana and other cannabis products with high content in Δ(9) – tetrahydrocannabinol (THC), utilized primarily for recreational purposes, are generally unsuitable for this indication, primarily because THC is associated with many undesired effects. Compared with THC, cannabidiol (CBD) shows a better defined anticonvulsant profile in animal models and is largely devoid of adverse psychoactive effects and abuse liability. Over the years, this has led to an increasing use of CBD-enriched extracts in seizure disorders, particularly in children. Although improvement in seizure control and other benefits on sleep and behavior have been often reported, interpretation of the data is made difficult by the uncontrolled nature of these observations. Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of three high-quality placebo-controlled adjunctive-therapy trials of a purified CBD product in patients with Dravet syndrome and Lennox-Gastaut syndrome. In these studies, CBD was found to be superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome. For the first time, there is now class 1 evidence that adjunctive use of CBD improves seizure control in patients with specific epilepsy syndromes. Based on currently available information, however, it is unclear whether the improved seizure control described in these trials was related to a direct action of CBD, or was mediated by drug interactions with concomitant medications, particularly a marked increased in plasma levels of N-desmethylclobazam, the active metabolite of clobazam. Clarification of the relative contribution of CBD to improved seizure outcome requires re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies controlling for the confounding effect of this interaction.

PMID: 29344464 [PubMed]

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Strokes are possible complications of cannabinoids use.

Category : Epilepsia

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Strokes are possible complications of cannabinoids use.

Epilepsy Behav. 2017 May;70(Pt B):355-363

Authors: Wolff V, Jouanjus E

Abstract
It is critically important to identify all factors that may play a role in the recent increase of the incidence of stroke among the young population. Considering the worldwide use of cannabinoids (cannabis and synthetic cannabinoids), the recent legalization of their consumption in some countries, and their supposed involvement in cardiovascular events, we evaluated their role in the occurrence of neurovascular complications among the young. Ninety-eight patients were described in the literature as having a cannabinoids-related stroke (85 after cannabis use and 13 after synthetic cannabinoids). The distribution by type of stroke was as follows: 4 patients with an undetermined type of stroke, 85 with an ischemic stroke and/or a transient ischemic attack, and 9 with a hemorrhagic stroke. The mean age of patients was 32.3±11.8years (range 15-63), and the majority of them were male with a sex ratio of 3.7:1. Cannabis was often smoked with tobacco in 66% of cases. Most of the patients with cannabinoids-related strokes were chronic cannabis users in 81% of cases, and for 18% of them, there was a recent increase of the amount of cannabis consumption during the days before the occurrence of stroke. Even if the prognosis of stroke was globally favorable in 46% of cases, with no or few sequelae, 5 patients died after the neurovascular event. One striking element reported in the majority of the reports was a temporal relationship between cannabinoids use, whether natural or synthetic, and the occurrence of stroke. However, a temporal correlation does not mean causation, and other factors may be involved. Cannabis may be considered as a risk factor of stroke until research shows evidence of an underlying mechanism that, alone or in association with others, contributes to the development of stroke. As of today, reversible cerebral vasoconstriction triggered by cannabinoids use may be a convincing mechanism of stroke in 27% of cases. Indeed, despite the widespread use of cannabinoids, the low frequency of neurovascular complications after their use may be due to a genetic predisposition to their neurovascular toxicity in some individuals. Further studies should focus on this point. More importantly however, this low frequency may be underestimated because the drug consumption may not be systematically researched, neither by questioning nor by laboratory screening. Besides this vascular role of cannabinoids in the occurrence of stroke, a cellular effect of cannabis on brain mitochondria was recently suggested in an experimental study. One of the mechanisms involved in young cannabis users with stroke may be the generation of reactive oxygen species leading to an oxidative stress, which is a known mechanism in stroke in humans. It is useful to inform the young population about the real potential risk of using cannabinoids. We suggest to systematically ask all young adults with stroke about their drug consumption including cannabinoids, to screen urine for cannabis or to include a specific diagnostic test to detect synthetic cannabinoids, and to obtain non-invasive intracranial arterial investigations (i.e. CT-angiography or cerebral MRA) in order to search for cerebral vasoconstriction. However, several questions remained unresolved and further research is still needed to assess the pathophysiological mechanisms involved in young cannabinoids users with stroke. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.

PMID: 28237318 [PubMed – indexed for MEDLINE]

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Cannabinoids for epilepsy: What do we know and where do we go?

Category : Epilepsia

Cannabinoids for epilepsy: What do we know and where do we go?

Epilepsia. 2017 Dec 06;:

Authors: Brodie MJ, Ben-Menachem E

Abstract
Over the past decade there has been an increasing interest in using cannabinoids to treat a range of epilepsy syndromes following reports of some remarkable responses in individual patients. The situation is complicated by the fact that these agents do not appear to work via their attachment to endogenous cannabinoid receptors. Their pharmacokinetics are complex, and bioavailability is variable, resulting in difficulty in developing a suitable formulation for oral delivery. Drug interactions also represent another complication in their everyday use. Nevertheless, recent randomized, placebo-controlled trials with cannabidiol support its efficacy in Dravet and Lennox-Gastaut syndromes. Further placebo-controlled studies are underway in adults with focal epilepsy using cannabidivarin. The many unanswered questions in the use of cannabinoids to treat epileptic seizures are briefly summarized in the conclusion.

PMID: 29214639 [PubMed – as supplied by publisher]

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Simple and fast gas-chromatography mass spectrometry assay to assess delta 9-tetrahydrocannabinol and cannabidiol in dogs treated with medical cannabis for canine epilepsy.

Category : Epilepsia

Simple and fast gas-chromatography mass spectrometry assay to assess delta 9-tetrahydrocannabinol and cannabidiol in dogs treated with medical cannabis for canine epilepsy.

Curr Pharm Biotechnol. 2017 Nov 21;:

Authors: Rotolo MC, Graziano S, Pellegrini M, Corlazzoli D, Antinori L, Porcarelli L, Pichini S

Abstract
BACKGROUND: To date, an increasing number of pet owners, especially in the USA, are using cannabis-derived products containing generally delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) to help their animals’ health. Unfortunately, studies on the clinical use of cannabinoids in veterinary medicine are still limited, and the application of analytical methodologies for the determination of cannabinoids in animal (especially dog) biological matrices such as plasma, is still missing.
METHODS: A reliable, fast, accurate, simple gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the quantification of THC and CBD in plasma samples of eight dogs under therapeutic treatment for epilepsy and receiving oral administration of medical cannabis (Bediol).
RESULTS: The method was linear for both the analytes under investigation with coefficients of determination (r2) of at least 0.99. Absolute analytical recovery (mean ± SD) ranged from 80.6 ± 6.2% for THC and 81.7 ± 4.3% for CBD. The matrix effect showed less than 10% analytical suppression due to endogenous substances for both the analytes. The intra-assay and inter-assay precision values ranged from 4.9% to 12.7%, and from 5.2% to 8.7% respectively. The intra-assay and inter-assay accuracy values ranged from 2.3% to 9.6% and from 3.4% to 13.0% respectively. The validated method was successfully applied to real samples; moreover to assess the potential of the method applicability and robustness in future veterinary clinical studies on cannabinoids therapy, we attempted to follow the kinetic of THC and CBD in the plasma of two dogs under therapy at different times after Bediol administration.

PMID: 29173160 [PubMed – as supplied by publisher]

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