Epilepsy - randomised controlled trials and other studies

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29 August 2017
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Randomised controlled trials

Randomized, double-blind, placebo-controlled trial
Grade 1- high

Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. New England Journal of Medicine 2017; 376: 2011-20.

120 children and adolescents aged 2-18 with Dravet syndrome and drug-resistant seizures were treated with 20mg/kg/day oral cannabidiol (CBD) (Epidiolex, available at some US sites via an Expanded Access Scheme) or placebo, taken orally for 2 weeks, with a 12-week maintenance period. The cannabidiol formulation under study reduced the frequency of convulsive seizures among children and young adults with Dravet syndrome over a 14-week period but was associated with adverse events including somnolence and elevation of liver-enzyme levels. 3 CBD patients achieved total seizure freedom during the test period; no placebo patients achieved seizure freedom. 43% of CBD patients had a greater than 50% reduction in seizures, compared to 27% of placebo patients. Caregivers of placebo patients were more likely to report an improvement in overall condition. Adverse events included somnolence, diarrhea, decreased appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection and convulsion.

Randomized, double-blind, placebo-controlled study
Grade 1- high

French J, Thiele E, Mazurkiewicz-Beldzinska M, Benbadis S, Marsh E, Joshi C, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a multi-center, randomized, double-blind, placebo controlled trial (GWPCARE4). Neurology 2017; 88: s21.

171 patients 2-55 years old with Lennox-Gastaut syndrome were treated with 20mg/kg/day purified oral 100 mg/ml CBD extract (Epidiolex) or placebo. A 2 week test period was followed by 12 weeks maintenance, as an adjunctive treatment. The CBD formulation under study resulted in a significantly greater median percent reduction in monthly drop seizure frequency, versus placebo during the first 4 weeks of the maintenance period. 5 CBD patients were seizure free during the maintenance period. CBD patients/ caregivers were more likely to report an improvement in overall condition. 86% of CBD and 69% of placebo patients had adverse events, most commonly diarrhea, somnolence, pyrexia, decreased appetite, and vomiting. Treatment-related serious adverse events were reported in 9 CBD patients and 1 placebo patient. 12 CBD patients withdrew from the study due to adverse events.

Randomized, double-blind, placebo-controlled trial
Grade 2- moderate

Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 1980; 21: 175-85.

15 adolescent/adult patients aged 14-49 with treatment resistant secondary generalized epilepsy were treated with 200-300 mg CBD isolated from Lebanese hashish supplied by the Israeli police or placebo per day for 8-18 weeks (8 treatment, 7 placebo). Four patients in the cannabidiol group and 1 in the placebo group were seizure-free for the duration of the study; somnolence was a reported side effect. 50% (4) of patients receiving CBD showed considerable improvement in condition. 2 patients showed small improvement, 1 did not improve at all. 1 placebo patient showed complete improvement; the other 7 showed no improvement.

Double-blind, cross-over, placebo controlled add-on trial
Grade 2- moderate

Trembly B, Sherman M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant (abstract only). Paper presented at the Marijuana '90 International Conference on Cannabis and Cannabinoids; 1990 July; Kolympari, Crete.

12 adult patients with incompletely controlled epilepsy were treated with CBD or placebo (300 mg/day). No significant difference was reported between cannabidiol and placebo on seizure pattern, character or frequency; somnolence was a reported side effect.

Case control trial
Grade 3- low

Ames FR, Cridland S. Anticonvulsant effect of cannabidiol (letter to the editor). South African Medical Journal 1986; 69: 14.

12 institutionalized adults with intellectual disability and epilepsy and uncontrolled frequent seizures were treated with isolated oral cannabinoids (cannabidiol) 200-300 mg/day or placebo for 4 weeks (6 treatment, 6 placebo). No statistically significant difference in seizure frequency between the two groups at the end of 4 weeks was reported; a reported side effect was somnolence for some participants. The trial was abandoned when the CBD supply was interrupted.

Other studies

Open-label intervention trial
Grade 2- moderate

Abati E, Hess EJ, Morgan A, Bruno PL, Thiele E. Cannabidiol treatment of refractory epileptic spasms: an open-label study (abstract only). Paper presented at the American Epilepsy Society annual meeting; 2015; Philadelphia.

9 patients aged 2-16 years with refractory epilepsy and a diagnosis of infantile or epileptic spasms were given purified oral 100 mg/ml CBD extract (Epidiolex) as an adjunctive treatment. The overall response rate to CBD was 37.5, 43, 50, and 30% at 3, 6, 9, and 12 months. Three patients were seizure free after 2 months of treatment. Patients reported improvement in alertness, verbal capacity/ communications, and cognitive abilities. 3 of 9 patients became spasm free after 2 months of treatment, and remained so for the remainder of the trial. Adverse events included drowsiness, ataxia, appetite loss, diarrhoea, and agitation.

Open-label intervention trial
Grade 2- moderate

Chez MG. Cannabadiol in genetic refractive epilepsy in Dravet and non-Dravet cases (abstract only). Paper presented at the American Epilepsy Society annual meeting; 2015; Philadelphia.

3 patients aged 3.5, 12, and 21 years with genetic refractive epilepsy (SCN1A, GABR3, and SCN2A) were treated with purified oral 100 mg/ml CBD extract (Epidiolex) for 8-12 weeks as an adjunctive treatment; all 3 patients responded dramatically to CBD. Maximal dose was tolerated in all cases with noted seizure reductions. All patients reported improved moods, improved social or cognitive skills, and all tolerated initial dose reductions of some of their concurrent chronic antiepileptic drugs. There were no serious adverse events. Patients' results are at 8 weeks post initiation to CBD. Post-CBD seizure reduction ranged between 75% and 90%. Mild adverse events included ataxia and diarrhoea.

Open-label interventional trial
Grade 2- moderate

Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurology 2016; 15: 270-8.

214 patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy at 11 sites were treated with purified oral 100 mg/ml CBD extract (Epidiolex) for 12 weeks as an adjunctive treatment. The add-on treatment with pure cannabidiol led to a clinically meaningful reduction in seizure frequency in many patients, and had an adequate safety profile in a population with highly treatment-resistant epilepsies. Median monthly frequency of motor seizures decreased from 30.0 at baseline to 15.8 over 12 weeks. Median reduction of monthly motor seizures was 36.5%. The 20% rate of serious adverse events including somnolence, diarrhea, decreased appetite, fatigue, convulsion, and status epilepticus was higher than expected. Adverse events were reported by 79% of patients in the safety assessment group. Adverse events experienced by more than 10% of patients were somnolence, decreased appetite, diarrhoea, fatigue, and convulsion. Few who experienced adverse events stopped treatment, possibly because of parental beliefs, media attention, reduced seizure frequency outweighing the serious adverse event, or occurrence of similar events such as status epilepticus before cannabidiol treatment.

Open-label intervention trial
Grade 2- moderate

Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 2016; 57: 1617-24.

18 pediatric and adult patients aged 2-31 with epilepsy and tuberous sclerosis complex enrolled in investigators' expanded access study were given purified oral 100 mg/ml CBD extract (Epidiolex) for 6-12 months as an adjunctive treatment. Median weekly seizure rate decreased from 22 (IQR 14.8-57.4) to 13.3 (IQR 5.1-22.1) after 3 months of treatment. Median reduction in seizure frequency of 49% and >50% reduction in seizures in around half of patients was maintained during the 12-month follow-up. Treatment responder rate ranged from 38.9%-50% over the 12 months of treatment. Those taking clobazam and CBD had a higher responder rate. Side effects including drowsiness, ataxia, diarrhea, and agitation, were reported in 66.7% of patients; none considered serious.

Retrospective chart review
Grade 3- low

Ladino LD, Hernandez-Ronquillo L, Tellez-Zenteno JF. Medicinal marijuana for epilepsy: a case series study. Canadian Journal of Neurological Sciences 2014; 41: 753-8.

18 adult outpatients authorized to use cannabis for medical purposes were identified at a Canadian adult epilepsy clinic during May-November 2013. Ten patients reported withdrawal seizure exacerbation when they stopped the marijuana. Only two patients reported side effects, and all patients found medicinal marijuana helped control seizures and improved mood disorders. The effect was complicated to estimate because of concurrent use of other antiseizure medications.

Retrospective chart review; parent report
Grade 3- low

Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy & Behavior 2015; 45: 49-52.

Parents of 75 children known to the neurology service at the Children's Hospital Colorado who had given their children oral cannabis extracts of varying concentrations not always known and usually untested reported on treatment response. 57% reported improved seizure duration and frequency; with reduction of >50% in frequency of seizures in 25 patients. 15% discontinued use – 7 had an adverse event, and 10 did not respond. Side effects reported included somnolence, fatigue, and increased seizures; rarely, developmental regression, and status epilepticus. Investigators found a striking difference in responder rate for families who had moved to Colorado for oral cannabis extracts treatment. 56% reported additional improvements including increased alertness/behaviour, language, motor skills, and sleep.

Retrospective study
Grade 3- low

Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure 2016; 35: 41-4.

74 patients (aged 1–18 years) with refractory epilepsy were given CBD-enriched medical cannabis taken orally for 6 months on average; 66 reported a reduction in seizure frequency; 13 reported 75–100% reduction; 25 reported 50–75% reduction; 9 reported 25–50% reduction; and 19 less than 25% reduction. Side effects included somnolence, fatigue, gastrointestinal disturbances, and irritability. 7% of patients reported aggravation of seizures which led to CBD withdrawal. 5 patients experienced adverse effects.

Retrospective chart study
Grade 3- low

Sulak D, Saneto R, Goldstein B. The current status of artisanal cannabis for the treatment of epilepsy in the United States. Epilepsy & Behavior 2017; 70: 328-33.

272 patients aged 2-46 with medically refractory epilepsy with mixed etiologies in Washington State and California, plus 4 case reports from Maine reported on the use of various artisanal preparations. 86% of patients experienced some clinical benefit, and 10% experienced a complete clinical response. Adverse effects were mild, though 4% of patients experienced an exacerbation of seizures in response to cannabis; beneficial side effects such as improved cognition were reported. Investigators concluded patients and families should not rely on product labels, but test every batch for cannabinoid potencies and potential contaminants at industry-standard laboratories.

Case study
Grade 4- very low

Lorenz R. On the application of cannabis in paediatrics and epileptology. Neuroendocrinology Letters 2004; 25: 40-4.

8 children aged 3-14 with neurodegenerative disease, mitochondriopathy, post-hypoxic state, epilepsy (4), or "posttraumatic reaction" were treated with dronabinol (THC) taken orally. Of 4epilepsy cases, in 1 an effect could not be assessed, in 1 there was no effect on seizures, in 2 seizure frequency decreased; an explicit decrease measure was lacking.

Case study
Grade 4- very low

Crippa JA, Crippa AC, Hallak JE, Martin-Santos R, Zuardi AW. Delta9-THC intoxication by cannabidiol-enriched cannabis extract in two children with refractory epilepsy: full remission after switching to purified cannabidiol. Frontiers in Pharmacology 2016; 7: 359.

Two children with treatment-resistant epilepsy (left frontal dysplasia and Dravet Syndrome) were treated with CBD-enriched extract initially, followed by a change to purified CBD supplied by UK STI Pharm and European partners to Brazilian investigators. Follow up assessments at 1 year (Case A) and 1 year and 10 months (Case B) showed remission of seizures and clear progressive improvement of the remaining general symptoms with the use of pure CBD. The other medications remained stable before and during the time of transition from the cannabinoid extract to the purified CBD in both cases. Likewise, there were no changes in the dose or frequency of administration of the purified CBD oil. No side-effects were reported for any dose of CBD used.

Case study
Grade 4- very low

Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia 2014; 55: 783-6.

A 5 year old girl with severe Dravet syndrome was treated with oral cannabis extracts of a medical cannabis product produced in Colorado with a high ratio of cannabidiol to delta9-THC (16:1) known as Realm Oil or "Charlotte's Web". Reduction of >90% in frequency of generalized tonic–clonic seizures was reported, which allowed for reduction of other drugs taken for epilepsy. Side effects reported were somnolence and fatigue.

Case study
Grade 4- very low

Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. Reviews in Neurological Diseases 2007; 4: 103-6.

A 45-year-old man with cerebral palsy and refractory focal epilepsy used smoked marijuana at bedtime and was reported to achieve a 90% reduction in nocturnal seizures and tonic-clonic seizures without adverse events.

Case study
Grade 4- very low

Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatric Neurology 2015; 52: 544-7.

A boy with malignant migrating partial seizures in infancy at 4 and 10 months was treated with purified oral 100 mg/ml CBD extract (Epidiolex) obtained by emergency application to the Expanded Access Scheme by an Iowa physician. Six months after initiation of CBD, the patient was still on levetiracetam and daily clonazepam, with a reported reduced seizure frequency from 10-20 per day to 5 per week with up to 9 days of clinical seizure freedom. Other reported improvements were improved alertness and no subclinical seizures.

Self-report survey
Grade 4- very low

Gedde M, Maa E. Whole cannabis extract of high concentration cannabidiol may calm seizures in highly refractory pediatric epilepsies 9abstract only). Paper presented at the American Epilepsy Society annual meeting; 2013; Seattle, Washington.

Eleven parents of pediatric patients with Doose, Dravet, Lennox-Gastaut, and other refractory epilepsies were treated with Realm Oil, oral cannabis extracts of a medical cannabis product produced in Colorado with a high ratio of cannabidiol to delta9-THC (16:1) also known as "Charlotte's Web". After an average dose of 4–12 mg/kg per day for at least 3 months, parents reported on reduction in weekly frequency of motor type seizures. Nine reported over 75% reduction in seizures, and 2 reported 20-45% relative to baseline. Seven children achieved this reduction in the first month of treatment. At three months, 5 were seizure-free. Side effects included sedation and unsteadiness.

Self-report telephone survey
Grade 4- very low

Gross DW, Hamm J, Ashworth NL, Quigley D. Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center. Neurology 2004; 62: 2095-7.

Twenty-eight past year users of smoked cannabis were identified among 136 epilepsy patients who participated in a survey. Reduction in severity of seizures was reported by 19 patients; 15 patients reported reduction in frequency of seizures. Almost a quarter of all respondents believed that marijuana was an effective treatment for epilepsy. Cannabis use among patients was higher than the general population without the usual pattern of higher use by male sex, younger ages and unemployment. At least weekly use was associated with greater seizure frequency and disease duration, possibly related to failure of conventional treatment.

Self-report online survey
Grade 4- very low

Hussain SA, Zhou R, Jacobson C, Weng J, Cheng E, Lay J, et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: a potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy á Behavior 2015; 47: 138-41.

117 parents of children with epilepsy (infantile spasms and Lennox–Gastaut syndrome) who gave their children CBD-enriched cannabis extracts of varying or unknown concentration ("CBD content even when reported could not be verified") for a median exposure of around 6 months responded to the survey. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Limitations of the study included participation bias and lack of blinded outcome ascertainment.

Parent online self-report survey
Grade 4- very low

Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior 2013; 29: 574-7.

Nineteen parents of children aged 2-16 with treatment-resistant epilepsy belonging to a Facebook group of 150 parents who reported they gave cannabidiol-enriched cannabis treatments to their children responded to the survey. Parents gave artisanal preparations of cannabidiol-enriched oral cannabis extracts of varying or unknown composition/dose (CBD up to 28 mg/kg/day and THC up to 0.8 mg/kg/day) taken from 2-3 months to a year or more. Sixteen parents reported a reduction in seizure frequency; others reported beneficial effects like improved sleep and mood. Drowsiness, fatigue, and decreased appetite were reported by some parents.