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Efficacy and Safety of Adjunctive Cannabidiol in Patients with Lennox–Gastaut Syndrome: A Systematic Review and Meta-Analysis

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Abstract

Background

Lennox–Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy, and available interventions fail to control seizures in most patients. Cannabidiol (CBD) is a major chemical of marijuana, which has anti-seizure properties and different mechanisms of action compared with other approved antiepileptic drugs (AEDs).

Objective

The aim was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with LGS using meta-analytical techniques.

Methods

Randomized, placebo-controlled, single- or double-blinded trials were identified. Main outcomes included the ≥ 50% reduction in baseline drop and non-drop seizure frequency, and the incidence of treatment withdrawal and adverse events (AEs). Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated through the inverse variance method.

Results

Two trials were included involving 396 participants. Patients presenting ≥ 50% reduction in drop seizure frequency during the treatment were 40.0% with CBD and 19.3% with placebo [RR 2.12 (95% CI 1.48–3.03); p < 0.001]. The rate of non-drop seizure frequency was reduced by 50% or more in 49.4% of patients in the CBD and 30.4% in the placebo arms [RR 1.62 (95% CI 1.09–2.43); p = 0.018]. The RR for CBD withdrawal was 4.93 (95% CI 1.50–16.22; p = 0.009). The RR to develop any AE during CBD treatment was 1.24 (95% CI 1.11–1.38; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea and increased serum aminotransferases.

Conclusions

Adjunctive CBD resulted in a greater reduction in seizure frequency and a higher rate of AEs than placebo in patients with LGS presenting seizures uncontrolled by concomitant AEDs.

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References

  1. Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology. 2007;68:326–37.

    Article  CAS  PubMed  Google Scholar 

  2. Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini M. Seizure course during pregnancy in catamenial epilepsy. Neurology. 2014;83:339–44.

    Article  PubMed  Google Scholar 

  3. Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the national general practice study of epilepsy. Lancet. 1995;346:140–4.

    Article  CAS  PubMed  Google Scholar 

  4. Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Lacosamide monotherapy for partial onset seizures. Seizure. 2015;27:71–4.

    Article  PubMed  Google Scholar 

  5. Lattanzi S, Cagnetti C, Foschi N, Lorusso A, Provinciali L, Silvestrini M. Eslicarbazepine acetate as adjunctive treatment in partial-onset epilepsy. Acta Neurol Scand. 2018;137:29–32.

    Article  CAS  PubMed  Google Scholar 

  6. Arzimanoglou A, French J, Blume WT, Cross JH, Ernst JP, Feucht M, Genton P, Guerrini R, Kluger G, Pellock JM, Perucca E, Wheless JW. Lennox–Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8:82–93.

    Article  PubMed  Google Scholar 

  7. Kim HJ, Kim HD, Lee JS, Heo K, Kim DS, Kang HC. Long-term prognosis of patients with Lennox–Gastaut syndrome in recent decades. Epilepsy Res. 2015;110:10–9.

    Article  PubMed  Google Scholar 

  8. Camfield PR. Definition and natural history of Lennox–Gastaut syndrome. Epilepsia. 2011;52(Suppl 5):3–9.

    Article  PubMed  Google Scholar 

  9. Doring JH, Lampert A, Hoffmann GF, Ries M. Thirty years of orphan drug legislation and the development of drugs to treat rare seizure conditions: a cross sectional analysis. PLoS One. 2016;11:e0161660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Montouris GD, Wheless JW, Glauser TA. The efficacy and tolerability of pharmacologic treatment options for Lennox–Gastaut syndrome. Epilepsia. 2014;55(suppl 4):10–20.

    Article  CAS  PubMed  Google Scholar 

  11. Cersosimo RO, Bartuluchi M, Fortini S, Soraru A, Pomata H, Caraballo RH. Vagus nerve stimulation: effectiveness and tolerability in 64 paediatric patients with refractory epilepsies. Epileptic Disord. 2011;13:382–8.

    PubMed  Google Scholar 

  12. Kang HC, Kim YJ, Kim DW, Kim HD. Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience. Epilepsia. 2005;46:272–729.

    Article  CAS  PubMed  Google Scholar 

  13. Douglass LM, Salpekar J. Surgical options for patients with Lennox–Gastaut syndrome. Epilepsia. 2014;55(suppl 4):21–8.

    Article  PubMed  Google Scholar 

  14. Kossoff EH, Shields WD. Nonpharmacologic care for patients with Lennox–Gastaut syndrome: ketogenic diets and vagus nerve stimulation. Epilepsia. 2014;55(suppl 4):29–33.

    Article  CAS  PubMed  Google Scholar 

  15. Lattanzi S, Cagnetti C, Matricardi S, Silvestrini M. Palliative non-resective surgery for drug-resistant epilepsy. Brain Dev. 2018;40:512–3.

    Article  PubMed  Google Scholar 

  16. Perucca E. Cannabinoids in the treatment of epilepsy: hard evidence at last? J Epilepsy Res. 2017;7:61–76.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12:699–730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332:569–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.

    Article  CAS  PubMed  Google Scholar 

  20. Ružić Zečević D, Folić M, Tantoush Z, Radovanović M, Babić G, Janković SM. Investigational cannabinoids in seizure disorders, what have we learned thus far? Expert Opin Investig Drugs. 2018 Jun 6. https://doi.org/10.1080/13543784.2018.1482275. [Epub ahead of print].

  21. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Niedermeyer E. The Lennox–Gastaut syndrome and its frontiers. Clin Electroencephalogr. 1986;17:117–26.

    CAS  PubMed  Google Scholar 

  23. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Higgins JPT, Green S, editors. The Cochrane Collaboration, 2011. Available at http://handbook-5-1.cochrane.org/. Accessed October 2017.

  24. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  26. Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology. 2016;86:1344–52.

    Article  PubMed  Google Scholar 

  27. Lattanzi S, Brigo F, Grillo E, Cagnetti C, Verrotti A, Zaccara G, Silvestrini M. Adjunctive eslicarbazepine acetate in pediatric patients with focal epilepsy: a systematic review and meta-analysis. CNS Drugs. 2018;32:189–96.

    Article  CAS  PubMed  Google Scholar 

  28. Lattanzi S, Grillo E, Brigo F, Silvestrini M. Efficacy and safety of perampanel in Parkinson’s disease. A systematic review with meta-analysis. J Neurol. 2018;265:733–40.

    Article  CAS  PubMed  Google Scholar 

  29. Lattanzi S, Cagnetti C, Danni M, Provinciali L, Silvestrini M. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017;264:1697–704.

    Article  CAS  PubMed  Google Scholar 

  30. Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. How should we lower blood pressure after cerebral hemorrhage? A systematic review and meta-analysis. Cerebrovasc Dis. 2017;43:207–13.

    Article  PubMed  Google Scholar 

  31. Lattanzi S, Brigo F, Cagnetti C, Di Napoli M, Silvestrini M. Patent foramen ovale and cryptogenic stroke or transient ischemic attack: to close or not to close? A systematic review and meta-analysis. Cerebrovasc Dis. 2018;45:193–203.

    Article  PubMed  Google Scholar 

  32. Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE. Zuberi SM; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378:1888–97.

    Article  CAS  PubMed  Google Scholar 

  33. Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C. Sommerville K; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox–Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–96.

    Article  CAS  PubMed  Google Scholar 

  34. Ng YT, Conry JA, Drummond R, Stolle J. Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology. 2011;77:1473–81.

    Article  CAS  PubMed  Google Scholar 

  35. Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology. 2008;70:1950–8.

    Article  CAS  PubMed  Google Scholar 

  36. Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K, GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51.

    Article  CAS  PubMed  Google Scholar 

  38. Thiele EA, Devinsky O, Checketts D, Knappertz V. Cannabidiol (CBD) treatment responders analysis in patients with Lennox–Gastaut syndrome (LGS) on and off clobazam (CLB). The American Epilepsy Society Annual Meeting; Washington, DC; December 1–5, 2017. Abst. 1.436. Available at: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381224 (Accessed on July, 2018)].

  39. US Department of Health and Human Services. Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation. 2009. https://www.fda.gov/downloads/Guidances/UCM174090.pdf. Accessed Jun 11, 2018.

  40. Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, Herkes GK, Farrell M, Degenhardt L. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018 Mar 6. https://doi.org/10.1136/jnnp-2017-317168. [Epub ahead of print].

  41. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270.

  42. Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, Beal JC, Laux LC, De Boer LM, Wong MH, Lopez M, Devinsky O, Lyons PD, Zentil PP, Wechsler R; CBD EAP study group. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018 Jul 12. https://doi.org/10.1111/epi.14477. [Epub ahead of print].

  43. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S, Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–20.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Via Conca 71, 60020, Ancona, Italy

    Simona Lattanzi, Claudia Cagnetti & Mauro Silvestrini

  2. Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Verona, Italy

    Francesco Brigo

  3. Division of Neurology, “Franz Tappeiner” Hospital, Merano, BZ, Italy

    Francesco Brigo

  4. Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria

    Eugen Trinka

  5. Center for Cognitive Neuroscience, Salzburg, Austria

    Eugen Trinka

  6. Public Health, Health Services Research and HTA, University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria

    Eugen Trinka

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  1. Simona Lattanzi
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Corresponding author

Correspondence to Simona Lattanzi.

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Funding

No funding was received to conduct this study.

Conflict of interest

Simona Lattanzi, Claudia Cagnetti and Mauro Silvestrini have no conflicts of interest directly relevant to the content of this study. Francesco Brigo acted as a consultant for Eisai. Eugen Trinka received speaker’s honoraria from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc., LivaNova and Novartis; consultancy funds from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, GW Pharmaceuticals, Sunovion Pharmaceuticals Inc., and Novartis; and directorship funds from Neuroconsult GmbH. E. Trinka’s Institution received grants from Biogen, Red Bull, Merck, UCB, European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and Bundesministerium für Wissenschaft und Forschung.

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Lattanzi, S., Brigo, F., Cagnetti, C. et al. Efficacy and Safety of Adjunctive Cannabidiol in Patients with Lennox–Gastaut Syndrome: A Systematic Review and Meta-Analysis. CNS Drugs 32, 905–916 (2018). https://doi.org/10.1007/s40263-018-0558-9

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  • DOI: https://doi.org/10.1007/s40263-018-0558-9

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