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Overview of Dravet Syndrome

Dravet syndrome, which is also referred to as severe myoclonic epilepsy of infancy (SMEI), is a severe form of epilepsy that typically develops during the first year of life. The high frequency of seizures caused by the syndrome commonly causes children to experience difficulty developing language and motor skills. In addition, they often experience hyperactivity and have problems relating to others.

Dravet syndrome typically causes febrile seizures, which are fever-related (associated with a high body temperature but without any attributing health issue). Seizures can be triggered by slight body temperature changes, flashing lights, emotional stress or excitement. In addition, myoclonic seizures, characterized by involuntary muscle spasms, and status epilepticus, a state of continuous seizure that lasts longer than 30 minutes and requires emergency care, can arise.

According to the National Institute of Neurological Disorders and Stroke, 30 to 80% of Dravet syndrome cases are caused by defects in the SCN1A gene, which are essential for the brain cells to properly function.

There is no cure for Dravet syndrome, but in some cases medications can help control seizures. In addition, adjusting the diet so that it’s high in fats and low in carbohydrates may be beneficial. While it’s a lifelong condition, it’s not uncommon for children with Dravet syndrome to experience improvements and better cognitive function with age.

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Findings: Effects of Cannabis on Dravet Syndrome

One of the major cannabinoids found in cannabis, cannabidiol (CBD), has been determined to be a well-tolerated therapeutic treatment that can reduce or even eliminate seizures in a variety of childhood epilepsy disorders3,4,5,7,14,16,17,22,24. Tetrahydrocannabinol (THC) has also demonstrated efficacy at reducing seizures in children with epilepsy14. Preclinical trials have found that cannabis causes significant anticonvulsant effects in mice and rats9,10.

CBD is able to reduce or eliminate seizures because it interacts with cannabinoid receptors (CB1 and CB2) of the body’s endocannabinoid system28. The CB1 receptor can inhibit the release of a particular neurotransmitter and reduces overall neuronal excitability, thus silencing the triggers of seizures2,10,19,24,28. CBD’s influence on the CB2 receptor may indirectly support the dysregulation of the endocannabinoid system in the brain that causes seizures caused by Dravet syndrome25.

One case report analyzing a young girl with Dravet syndrome found that medical marijuana brought the child’s seizure frequency from nearly 50 convulsive seizures per day to 2-3 nocturnal convulsions per month. In addition, the child was able to wean from the additional anti-epileptic drugs she had been taking21.

Double-blind randomized, placebo-controlled studies are currently lacking, but early research suggests that cannabis may be effective in treating a variety of severe pediatric epilepsy disorders like Dravet syndrome. In one questionnaire study, 84% of parents reported a reduction in their child’s seizure frequency following cannabis treatment. Out of those parents, 11% of them responded that their child has reached complete seizure freedom, while 42% reported a greater than 80% reduction in seizure frequency. The parents also reported additional beneficial effects, such as increased alertness, better mood and improved sleep23. Another similar survey found that CBD-enriched cannabis brought about a reduction in seizure frequency in 85% of epileptic children, while 14% experienced complete seizure freedom. The children also reported an improvement in sleep (53%), alertness (71%), and mood (63%) while being treated with CBD16. Another study examining the effect of CBD-enriched medical cannabis on children with epilepsy found that 89 percent of children reported a reduction in seizure frequency with CBD treatment. The children also reportedly saw improvements in behavior and alertness, language, communication,motor skills and sleep25.

Another cannabinoid found in cannabis, cannabidivarin (CBDV) has also shown to have non-psychoactive anticonvulsant effects1,11.

Traditional medicines used to treat epilepsy are not just ineffective for most; they also often come with a number of adverse side effects. Cannabinoids found in cannabis, however, have shown to produce anticonvulsant effects in preclinical and preliminary human studies while producing fewer adverse effects that other antiepileptic drugs8. A questionnaire study found that parents tried an average of 12 different antiepileptic drugs, due to ineffectiveness or unacceptable side effects, before finding gentle effectiveness with cannabis23.

 

References:

  1. Amada, N., Yamasaki, Y., Williams, C.M., and Whalley, B.J. (2013, November 21). Cannabidivarin (CBDV) suppresses pentylenentetrazole (PTZ)-induced increases in epilepsy-related gene expression. Peer J, 1:e214; doi 10.7717/peerj.214. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840466/.

  2. Blair, R.E., Deshpande, L.S., Sombati, S., Falenski, K.W., Martin, B.R., and DeLorenzo, R.J. (2006, June). Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. The Journal of Pharmacology and Experimental Therapeutics, 317(3), 1072-1078. Retrieved from http://jpet.aspetjournals.org/content/317/3/1072.long.

  3. Blair, R.E., Deshpande, L.S., and  DeLorenzo, R.J. (2015, September). Cannabinoids: is there a potential treatment role in epilepsy? Expert Opinion on Pharmacology, 16(13), 1911-4. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845642/.

  4. Cilio, M.R., Thiele, E.A., and Devinsky, O. (2014, June). The case for assessing cannabidiol in epilepsy. Epilepsia, 55(6), 787-90. Retrieved from http://onlinelibrary.wiley.com/doi/10.1111/epi.12635/full.

  5. Cunha, J.M., Carlini, E.A., Pereira, A.E., Ramos, O.L., Pimentel, C., Gagliardi, R., Sanvito, W.L., Lander, N., and Mechoulam, R. (1980). Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology, 21(3), 175-85. Retrieved from https://goo.gl/JKQU41.

  6. Detyniecki, K., and Hirsch, L. (2015, October). Marijuana use in epilepsy: The myth and the reality. Current Neurology and Neuroscience Reports, 15(10), 65. Retrieved from http://link.springer.com/article/10.1007%2Fs11910-015-0586-5.

  7. Devinsky, O., Cilio, M.R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., Katz, R., Di Marzo, V., Jutras-Aswad, D., Notcutt, W.G., Martinez-Orgado, J., Robson, P.J., Rohrback, B.G., Thiele, E., Whalley, B., and Friedman, D. (2014, June). Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55(6), 791-802. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/.

  8. dos Santos, R.G., Hallak, J.E., Leite, J.P., Zuardi, A.W., and Crippa, J.A. (2015, April). Phytocannabinoids and epilepsy. Journal of Clinical Pharmacology and Therapeutics, 40(2), 135-43. Retrieved from http://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235/full.

  9. Filloux, F. M. (2015). Cannabinoids for pediatric epilepsy? Up in smoke or real science? Translational Pediatrics, 4(4), 271–282. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729003/.

  10. Friedman, D., and Devinsky, O. (2015, September 10). Cannabinoids in the Treatment of Epilepsy. The New England Journal of Medicine, 373(11), 1048-58. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMra1407304.

  11. Hill, T.D., Cascio, M.G., Romano, B., Duncan, M., Pertwee, R.G., Williams, C.M., Whalley, B.J., and Hill, A.J. (2013, October). Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. British Journal of Pharmacology, 170(3), 679-92. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792005/.

  12. Hill, A.J., Williams, C.M., Whalley, B.J., and Stephens, G.J. (2012, January). Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacology & Therapeutics, 133(1), 79-97. Retrieved from http://www.sciencedirect.com/science/article/pii/S016372581100180X.

  13. Hill, A., Mercier, M., Hill, T., Glyn, S., Jones, N., Yamasaki, Y., Futamura, T., Duncan, M., Stott, C.G., Stephens, G.J., Williams, C.M., and Whalley, B. (2012). Cannabidivarin is anticonvulsant in mouse and rat. British Journal of Pharmacology, 167(8), 1629–1642. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525866/.

  14. Hoffman, M.E., and Frazier, C.J. (2013, June). Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention. Experimental Neurology, 244, 43-50. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332149/.

  15. Hosseinzadeh, M., Nikseresht, S., Khodagholi, F., Naderi, N., and Maghsoudi, N. (2016, April). Cannabidiol Post-Treatment Alleviates Rat Epileptic-Related Behaviors and Activates Hippocampal Cell Autophagy Pathway Along with Antioxidant Defense in Chronic Phase of Pilocarpine-Induced Seizure. Journal of Molecular Neuroscience, 58(4), 432-40. Retrieved from http://link.springer.com/article/10.1007%2Fs12031-015-0703-6.

  16. Hussain, S.A., Zhou, R., Jacobson, C., Weng, J., Cheng, E., Lay, J., Hung, P., Lerner, J.T., and Sankar, R. (2015, June). Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy & Behavior, 47, 138-41. Retrieved from http://www.epilepsybehavior.com/article/S1525-5050(15)00157-2/fulltext.

  17. Jones, N. A., Hill, A. J., Smith, I., Bevan, S. A., Williams, C. M., Whalley, B. J., and Stephens, G. J. (2010). Cannabidiol Displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo. The Journal of Pharmacology and Experimental Therapeutics, 332(2), 569–577. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819831/.

  18. Jones, N.A., Glyn, S.E., Akiyama, S., Hill, T.D., Hill, A.J., Weston, S.E., Burnett, M.D., Yamasaki, Y, Stephens, G.J., Whalley, B.J., and Williams, C.M. (2012, June). Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure, 21(5), 344-52. Retrieved from http://www.seizure-journal.com/article/S1059-1311(12)00057-X/fulltext.

  19. Karlócai, M. R., Tóth, K., Watanabe, M., Ledent, C., Juhász, G., Freund, T. F., & Maglóczky, Z. (2011). Redistribution of CB1 Cannabinoid Receptors in the Acute and Chronic Phases of Pilocarpine-Induced Epilepsy. PLoS ONE, 6(11), e27196. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208595/.

  20. Lorenz, R. (2004, February-April). On the application of cannabis in paediatrics and epileptology. Neuroendocrinology Letters, 25(1-2), 40-4. Retrieved from http://www.nel.edu/pdf_/25_12/NEL251204A02_Lorenz_.pdf.

  21. Maa, E., and Figi, P. (2014, June). The case for medical marijuana in epilepsy. Epilepsia, 55(6), 783-6. Retrieved from http://onlinelibrary.wiley.com/doi/10.1111/epi.12610/full.

  22. NINDS Dravet Syndrome Information Page. (2001, September 29). National Institute of Neurological Disorders and Stroke. Retrieved from http://www.ninds.nih.gov/disorders/dravet_syndrome/dravet_syndrome.htm.

  23. Porter, B.E., and Jacobson, C. (2013, December). Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior, 29(3), 574-7. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157067/.

  24. Rosenberg, E.C., Tsien, R.W., Whalley, B.J., and Devinsky, O. (2015, August 18). Cannabinoids and Epilepsy. Neurotherapeutics, Epub ahead of print. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604191/.

  25. Rubio, M., Valdeolivas, S., Piscitelli, F., Verde, R., Satta, V., Barroso, E., Montolio, M., Aras, L.M., Di Marzo, V., Sagredo, O., and Fernández‐Ruiz, J. (2016). Analysis of endocannabinoid signaling elements and related proteins in lymphocytes of patients with Dravet syndrome. Pharmacology Research & Perspectives, 4(2), e00220. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804326/.

  26. Szaflarski, J.P., and Bebin, E.M. (2014, December). Cannabis, cannabidiol, and epilepsy–from receptors to clinical response. Epilepsy & Behavior, 41, 277-82. Retrieved from http://www.epilepsybehavior.com/article/S1525-5050(14)00413-2/fulltext.

  27. Tzadok, M., Uliel-Siboni, S., Linder, I., Kramer, U., Epstein, O., Menascu, S., Nissenkorn, A., Yosef, O.B., Hyman, E., Granot, D., Dor, M., Lerman-Sagie, T., and Ben-Zeev, B. (2016, February). CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure, 35, 41-4. Retrieved from http://www.seizure-journal.com/article/S1059-1311(16)00005-4/fulltext.

  28. Wallace, M.J., Wiley, J.L., Martin, B.R., and DeLorenzo, R.J. (2001, September 28). Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. European Journal of Pharmacology, 428(1), 51-7. Retrieved from http://www.sciencedirect.com/science/article/pii/S0014299901012432.

  29. Wallace, M.J., Martin, B.R., and DeLorenzo, R.J. (2002). Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. European Journal of Pharmacology, 452(3), 295-301. Retrieved from http://www.sciencedirect.com/science/article/pii/S0014299902023312.

  30. Wallace, M.J., Blair, R.E., Falenski, K.W., Martin, B.R., and DeLorenzo, R.J. (2003, October). The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. The Journal of Pharmacology and Experimental Therapeutics, 307(1), 129-37. Retrieved from http://jpet.aspetjournals.org/content/307/1/129.long.

  31. What is Dravet syndrome? (2014, March). Epilepsy Foundation. Retrieved from http://www.epilepsy.com/learn/types-epilepsy-syndromes/dravet-syndrome.

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