CRx MAGAZINE

Summer 2020

Cannabis and Pediatric Epilepsy

For a subgroup of young patients, cannabis is a lifesaver.

Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. In 2015, there were an estimated 470,000 children in the United States who were considered to have active epilepsy.1 And while most children with epilepsy become seizure-free with their first trial of an anticonvulsant medication, up to 30% of children are refractory or treatment-resistant to standard anticonvulsant therapy and fail to obtain adequate seizure control with even two or more anticonvulsant treatments at an appropriate dosage.2

For those with treatment-resident pediatric epilepsy, the consequences can be catastrophic and include cognitive delay, behavioral problems, autism, poor quality of life, and early death.3 As a result of these
serious potential outcomes, novel treatments such as the use of cannabis and cannabis-derived products for the treatment of pediatric epilepsy are of significant interest to parents and caregivers.

History of Cannabis for Seizures
It’s well documented that cannabis has been used to treat a number of ailments in Eastern and Mediterranean cultures for several thousand years. Then, in the 19th century, Dr. William O’Shaughnessy, who had observed the use of medicinal cannabis while working in India, introduced the practice to Western medicine. Following his use of medicinal cannabis to stop convulsions (febrile seizures) in a 40-day-old infant, O’Shaughnessy declared that “the profession has gained an anticonvulsive remedy of the greatest value.”4 Subsequently, the use of cannabis extracts became an accepted and widely used treatment for seizures throughout Europe and North America. However, with the implementation of prohibition along with the introduction of other anticonvulsants in the 20th century, medicinal cannabis use fell out of favor as a treatment for epilepsy in Western cultures.

Over the past decade, a number of media accounts have described remarkable and life-changing benefits experienced by some children with severe forms of epilepsy when using medical cannabis. The inspiring case of Charlotte Figi, who suffered from thousands of seizures every week, is one such account that’s helped to influence public awareness about the need for greater availability of medical cannabis. In desperation, Figi’s parents started treating her with medical cannabis. After a few months, the seizures had significantly decreased and she started walking and talking for the first time.5

Today, medical cannabis is increasingly perceived to be a potent, natural, and safe alternative therapy for the treatment of some children with pediatric epilepsy. Sadly, the young poster child for the benefits of medical cannabis died on April 8, 2020, at the Colorado Children’s Hospital following a seizure resulting in respiratory depression and cardiac arrest, with coronavirus potentially complicating her condition.

How Does Cannabis Help Seizures?
Many of the physiologic process underlying epileptic disorder are thought to be regulated in part by the endocannabinoid system. And while the exact mechanisms aren’t fully understood, the activation of cannabinoid receptors appears to provide neuroprotection against excitotoxicity associated with seizures and may explain the anticonvulsant properties of cannabinoids.3,6,7 By modulating the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma-aminobutyric acid, cannabinoids are able to increase seizure threshold.7

Furthermore, cannabinoids cause beneficial changes at the transient receptor potential cation channel subfamily V member 1 (TRPV1), which is the receptor that provides sensation for scalding heat and pain in humans and contributes to the onset and progression of some forms of epilepsy. Recent studies also suggest that some cannabinoids appear to reduce seizure activity by activating and rapidly desensitizing TRPV1, as well as TRP channels of subfamily V type 2, or TRPV2, and subfamily A type 1, or TRPA1.8

Cannabinoids With Anticonvulsant Activity
There are hundreds of compounds including cannabinoids and terpenes that act together to provide cannabis’ medical benefits through the entourage effect. The cannabinoids THC, CBD, cannabidivarin, and tetrahydrocannabivarin have been found to demonstrate anticonvulsant activity and may offer hope for the treatment of seizure disorders used alone or in combination with other anticonvulsants.

Cannabis Seizure Studies
Most of the studies evaluating cannabis preparations for treatment-resistant epilepsy are retrospective or small observational studies. While larger studies are preferred to validate the findings, these smaller studies have shown a number of different cannabis preparations to be beneficial in decreasing seizure
frequency in children with treatment-resistant epilepsy, including Lennox-Gastaut and Dravet syndromes.

Lennox-Gastaut syndrome is a severe condition characterized by recurrent seizures (epilepsy) that begin early in life.9 Dravet syndrome is a rare genetic form of epilepsy that kills up to 20% of patients by the time they are 20 years old.10 The most common cause of death is sudden unexpected death in epilepsy (SUDEP). Roughly 85% of Dravet syndrome cases are due to a mutation in the SCN1A gene that’s required for the proper function of brain cells.11

The main goal of treatment is to reduce seizure frequency and prevent status epilepticus, which is defined as a single seizure lasting more than five minutes or two or more seizures within a five-minute period without the person returning to normal between them. The condition appears during the first year of life as frequent fever-related seizures with progression to other types of seizures, including myoclonus and status epilepticus. Intellectual development typically begins to deteriorate around age 2, and affected individuals often have a lack of coordination, poor language development, hyperactivity, and difficulty relating to others.

THC’s Potential Role
THC is a major constituent of cannabis and is responsible for its psychoactive properties. In a review of 34 studies including six different animal species, THC demonstrated anticonvulsant action in 62% of the seizure models, was found to be a proconvulsant in 3% of the models, was shown to have mixed activity in 3%, and had no effect in 32% of the seizure models.12 In a rodent maximal electroshock model of generalized seizures, THC was shown to be capable of increasing the effects of phenytoin and phenobarbital.13

Despite THC’s apparent anticonvulsant activity, the consequences of high-dose THC on the juvenile and still-developing brain is of concern. There’s increasing evidence that long-term exposure to THC can have serious deleterious effects on neurological functioning, including progressive memory impairment as well as impaired executive function. This potential for neurotoxicity, especially in adolescents, must be assessed carefully while also weighing the potential for catastrophic consequences of treatment-resistant epilepsy.

CBD/THC Formulations
Several studies have reviewed the effectiveness of medical cannabis oil consisting of various ratios of CBD, the most widely studied cannabinoid for seizures, and THC. In addition to its benefits in decreasing seizures, CBD is also believed to help lessen some of the troublesome psychotropic effects of THC.

A retrospective study from Israel described the experience of five pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy.14 The study cohort included 74 patients (age range 1 to 18 years) with intractable epilepsy that was resistant to more than seven antiepileptic drugs. In addition, 49 (66%) of the patients also had failed a ketogenic diet, vagal stimulator implantation, or both. All patients were treated for at least three months (average six months) with a cannabis oil formula consisting of CBD and THC at a ratio of 20:1 dissolved in olive oil. CBD doses for the study ranged from 1 to 20 mg/kg/day. To measure the formula’s efficacy, the frequency of seizures was assessed from parental reporting.

The Israeli study found that 66 of 74 (89%) patients experienced a reduction in seizure frequency, with 13 patients (18%) reporting a 75% to 100% reduction in seizure frequency, 25 (34%) a 50% to 75% reduction, nine (12%) a 25% to 50% reduction, and 19 (26%) a <25% reduction. Five (7%) patients reported aggravation of seizures, which led to withdrawal of the cannabis oil formulation. The study also noted improvement in behavior and alertness, language, communication, motor skills, and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances, and irritability leading to withdrawal of cannabis use in five patients.

Another study (a prospective open label study) evaluated the use of a cannabis oil formula in 20 children with Dravet syndrome.15 The children in the study were given a cannabis oil formula with a CBD to THC ratio of 100:2. In addition to the cannabis oil formula, patients continued to receive any previously ordered anticonvulsants (range of one to four additional anticonvulsants). The dose of CBD ranged from 7 to 16 mg/kg/day (mean 13.3 mg /kg/day CBD). During the 20-week intervention period, median monthly reduction in motor seizures (the primary endpoint) were reduced by 70.6%. Secondary endpoints including quality of life measures and spike index on electroencephalogram also improved. One child in the study died from SUDEP, with primary or secondary input measures for this patient being excluded from all calculations. Of the remaining 19 study participants, five withdrew because they didn’t perceive a benefit in therapy while 14 entered the longitudinal maintenance study after week 20. Adverse events during the titration period included somnolence, anorexia, and diarrhea.

CBD-Only Formulations
CBD, both as artisanal preparations and as a pharmaceutical-grade CBD formula, has been shown to help improve treatment-resistant epilepsy symptoms for many patients.

As part of a retrospective study of 108 pediatric patients, researchers studied the efficacy of artisanal CBD preparations in children with epilepsy. A subgroup of patients in the study also received clobazam to determine whether the addition of clobazam was related to any beneficial effects of CBD.16 The average dose of CBD was 2.9 mg/kg/day in the CBD group and 5.8 mg/kg/day in the CBD and clobazam group. Overall, the addition of CBD resulted in 39% of patients experiencing a >50% reduction in seizures, with 10% of patients becoming seizure-free. Any difference in effect between using CBD alone and CBD with clobazam was found not to be statistically significant. In the CBD group, increased alertness and improved verbal interactions were reported in 14% of patients, vs 8% of patients in the CBD and clobazam group. The positive response to CBD was found to be independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use.

With FDA approval of highly purified pharmaceutical-grade CBD (Epidiolex), there’s been increased access to larger and better-designed clinical studies using a standard reference CBD product.

In an open label trial, Epidiolex was used to help establish the safety and tolerability of CBD and to also evaluate the average change in the monthly frequency of motor seizures at 12 weeks.17 The study enrolled 162 patients aged 1 to 30 with severe, intractable, childhood-onset, drug-resistant epilepsy. Patients received CBD at 2 to 5 mg/kg/day, titrated over a period of two weeks until patients experienced intolerance or up to a maximum dose of 25 to 50 mg/kg/day. Results from the study showed a 36.5% median reduction in monthly motor seizures. Furthermore, caregivers reported that patients experienced improvement with energy/ fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global quality of life. A significantly high rate of adverse events was reported in 128 (79%) patients. The most common adverse events reported included somnolence (25%), decreased appetite (19%), diarrhea (19%), and fatigue (13%). Most of the side effects noted occurred during the titration period, suggesting that too rapid a titration rate increases the risk of side effects.

A subsequent double-blind, placebo-controlled study of Epidiolex was conducted in 120 children and young adults with Dravet syndrome.18 Patients in the treatment group received a CBD dosage of 20 mg/kg/day. The median frequency of convulsive seizures per month decreased from 12.4 (baseline) to 5.9 with CBD as compared with a decrease from 14.9 (baseline) to 14.1 with placebo. The percentage of patients who had at least a 50% reduction in convulsive seizure frequency was 43% with CBD.

In a double-blind, placebo-controlled trial conducted at 24 clinical sites in the United States, the Netherlands, and Poland, researchers investigated the efficacy of CBD as an add-on therapy for drop seizures in patients (eligible patients aged 2 to 55 years) with treatment-resistant Lennox-Gastaut syndrome.19 For the study, 86 patients were assigned to a treatment group (20 mg/kg/day CBD) and another 85 patients were assigned to the placebo group. The median percent reduction from baseline in monthly atonic seizure frequency during the treatment period was 43.9% in the treatment group vs 21.8% in the placebo group. Similar to other Epidiolex studies, the most common adverse events reported in the treatment groups were somnolence, decreased appetite, and diarrhea.

From the literature, researchers also conducted a systematic review of 36 studies (six randomized controlled, 30 observational) conducted to assess the safety and efficacy of pharmaceutical grade CBD in pediatric onset drug-resistant epilepsy.20 The review found that, overall, a CBD dose of 20 mg/kg/day was more effective than was placebo in reducing seizure frequency by 50%. Quality of life improved in 55.8% of patients, while serious adverse events related to treatment with CBD were very low at 2.2% of patients. Researchers also determined that for one patient to achieve a 50% reduction in seizures, the number of patients needed to treat was eight. In pooled data from 17 of the observational studies, CBD at a dose of 20 mg/kg/day resulted in 48.5% of patients achieving a 50% reduction in seizures. Pooled data from 14 of the observational studies showed that 8.5% of patients became seizure-free.

Final Thoughts
Pediatric epilepsy is a severe and debilitating condition that’s frequently resistant to available anticonvulsant medications. For a select number of pediatric seizure patients, the availability of medical cannabis has been lifesaving. While there’s a continued need for additional research to help ensure the safe use of medical cannabis products, there’s growing evidence to support their use in mainstream medicine.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References

1. Epilepsy: data and statistics. Centers for Disease Control and Prevention website. https://www.cdc.gov/epilepsy/data/index.html. Updated January 25, 2019.

2. Huntsman RJ, Tang-Wai R, Shackelford AE. Cannabis for pediatric epilepsy. J Clin Neurophysiol. 2020;37(1):2-8.

3. Alger BE. Endocannabinoids and their implications for epilepsy. Epilepsy Curr. 2004;4(5):169-173.

4. Houlihan B. Sir. William Brooke O’Shaughnessy - medical cannabis pioneer. https://medium.com/@dubhempmuseum/sir-william-brooke-oshaughnessy-medical-cannabis-pioneer-c94798fd7722. Published June 12, 2016.

5. Charlotte Figi’s story: Dravet syndrome. The Epilepsy Network website. http://theepilepsynetwork.com/charlotte-figis-story-dravet-syndrome/. Published August 14, 2013.

6. Hill TDM, Cascio MG, Romano B, et al. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol. 2013;170(3):679-692.

7. Pędracka M, Gawłowicz J. The role of cannabinoids and endocannabinoid system in the treatment of epilepsy. J Epileptol. 2015;23(2):131-138.

8. Iannotti FA, Hill CL, Leo A, et al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014;5(11):1131-1141.

9. Lennox-Gastaut syndrome. Genetics Home Reference website. https://ghr.nlm.nih.gov/condition/lennox-gastaut-syndrome. Updated June 23, 2020.

10. Epileptic encephalopathy, early infantile, 6; EIEE6. Online Mendelian Inheritance in Man website. http://omim.org/entry/607208. Updated July 9, 2016.

11. Shmuely S, Sisodiya SM, Gunning WB, Sander JW, Thijs RD. Mortality in Dravet syndrome: a review. Epilepsy Behav. 2016;64(Pt A):69-71.

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