Vitamine D in Drug Resistant Epilepsy

Summary

Almost all patients with epilepsy living in the region of Paris have vitamin D deficiency, which is severe in 1/3 of the cases. The impact of this deficiency on epilepsy is unknown, despite the suggested benefits of vitamin D therapy including better seizure control and improvement of comorbidities (fatigue, anxiety, depression) in drug-resistant patients. Recommendations for vitamin D supplementation based on the serum level in the general population cannot be applied to patients with epilepsy due to interference of antiepileptic drugs in the vitamin D metabolism. Animal models, mechanisms of action studies and ecological information provide objective data for a direct antiepileptic effect of vitamin D. Human studies seem to confirm the antiepileptic effect of vitamin D but there are no controlled studies on large populations. The investigators aim to assess prospectively the effect of the treatment of vitamin D deficiency providing a high level of evidence. The investigators propose a multicentre placebo controlled randomized double-blind study, testing vitamin D supplementation against placebo in 400 drug-resistant patients to assess the short-term (3 months) and long-term (1 year) benefits on epilepsy. The investigators hypothesize that the treatment of vitamin D deficiency will result in significant reduction of seizure frequency, and improvement of comorbid symptoms as well as quality of life. The impact on the care of patients is important because better epilepsy control allows reduction of the antiepileptic drugs and side effects. This again is a key for the recovery of social and professional activities, and reduction of costs related to the disease.

Timeline

Start

2018-04-03

Primary completion

2020-03-04

Completion

2020-12-09

Publications

• Background Baxendale S. Seeing the light? Seizures and sunlight. Epilepsy Res. 2009 Mar;84(1):72-6. doi: 10.1016/j.eplepsyres.2008.11.015. Epub 2009 Jan 13.
• Background Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia. 2010 Jan;51(1):7-26. doi: 10.1111/j.1528-1167.2009.02299.x. Epub 2009 Sep 10.
• Background Borowicz KK, Morawska M, Furmanek-Karwowska K, Luszczki JJ, Czuczwar SJ. Cholecalciferol enhances the anticonvulsant effect of conventional antiepileptic drugs in the mouse model of maximal electroshock. Eur J Pharmacol. 2007 Nov 14;573(1-3):111-5. doi: 10.1016/j.ejphar.2007.07.002. Epub 2007 Jul 10.
• Background Callaghan B, Schlesinger M, Rodemer W, Pollard J, Hesdorffer D, Allen Hauser W, French J. Remission and relapse in a drug-resistant epilepsy population followed prospectively. Epilepsia. 2011 Mar;52(3):619-26. doi: 10.1111/j.1528-1167.2010.02929.x. Epub 2011 Jan 26.
• Background Carbone LD, Johnson KC, Robbins J, Larson JC, Curb JD, Watson K, Gass M, Lacroix AZ. Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: findings from the women's health initiative (WHI). J Bone Miner Res. 2010 Apr;25(4):873-81. doi: 10.1359/jbmr.091027.
• Background Carnes J, Quinn S, Nelson M, Jones G, Winzenberg T. Intermittent high-dose vitamin D corrects vitamin D deficiency in adolescents: a pilot study. Eur J Clin Nutr. 2012 Apr;66(4):530-2. doi: 10.1038/ejcn.2011.204. Epub 2011 Dec 21.
• Background Cavalier E, Fache W, Souberbielle JC. A Randomised, Double-Blinded, Placebo-Controlled, Parallel Study of Vitamin D3 Supplementation with Different Schemes Based on Multiples of 25,000 IU Doses. Int J Endocrinol. 2013;2013:327265. doi: 10.1155/2013/327265. Epub 2013 Jan 28.
• Background Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Epilepsy and risk of suicide: a population-based case-control study. Lancet Neurol. 2007 Aug;6(8):693-8. doi: 10.1016/S1474-4422(07)70175-8.
• Background Christiansen C, Rodbro P, Sjo O. "Anticonvulsant action" of vitamin D in epileptic patients? A controlled pilot study. Br Med J. 1974 May 4;2(5913):258-9. doi: 10.1136/bmj.2.5913.258.
• Background Devaux B, Chassoux F, Guenot M, Haegelen C, Bartolomei F, Rougier A, Bourgeois M, Colnat-Coulbois S, Bulteau C, Sol JC, Kherli P, Geffredo S, Reyns N, Vinchon M, Proust F, Masnou P, Dupont S, Chabardes S, Coubes P. [Epilepsy surgery in France]. Neurochirurgie. 2008 May;54(3):453-65. doi: 10.1016/j.neuchi.2008.02.041. Epub 2008 May 7. French.
• Background Duhamel JF, Zeghoud F, Sempe M, Boudailliez B, Odievre M, Laurans M, Garabedian M, Mallet E. [Prevention of vitamin D deficiency in adolescents and pre-adolescents. An interventional multicenter study on the biological effect of repeated doses of 100,000 IU of vitamin D3]. Arch Pediatr. 2000 Feb;7(2):148-53. doi: 10.1016/s0929-693x(00)88084-7. French.
• Background Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet. 2006 Apr 1;367(9516):1087-1100. doi: 10.1016/S0140-6736(06)68477-8.
• Background Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat. 2005 Jan;29(1):21-30. doi: 10.1016/j.jchemneu.2004.08.006.
• Background Fazel S, Wolf A, Langstrom N, Newton CR, Lichtenstein P. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet. 2013 Nov 16;382(9905):1646-54. doi: 10.1016/S0140-6736(13)60899-5. Epub 2013 Jul 22.
• Background Fertig E, Fureman BE, Bergey GK, Brodie MA, Hesdorffer DC, Hirtz D, Kossoff EH, LaFrance WC Jr, Versavel M, French J; National Institute of Neurological Disorders and Stroke. Inclusion and exclusion criteria for epilepsy clinical trials-recommendations from the April 30, 2011 NINDS workshop. Epilepsy Res. 2014 Jul;108(5):825-32. doi: 10.1016/j.eplepsyres.2014.02.011. Epub 2014 Mar 1.
• Background Hamelin S, Kahane P, Vercueil L. Fatigue in epilepsy: a prospective inter-ictal and post-ictal survey. Epilepsy Res. 2010 Oct;91(2-3):153-60. doi: 10.1016/j.eplepsyres.2010.07.006. Epub 2010 Aug 12.
• Background Hermann BP, Seidenberg M, Dow C, Jones J, Rutecki P, Bhattacharya A, Bell B. Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol. 2006 Jul;60(1):80-7. doi: 10.1002/ana.20872.
• Background Hesdorffer DC. Motor vehicle accidents, suicides, and assaults in epilepsy: a population-based study. Neurology. 2011 Oct 25;77(17):1653; author reply 1653-4. doi: 10.1212/WNL.0b013e318230b17e. No abstract available.
• Background Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. doi: 10.1210/jc.2011-0385. Epub 2011 Jun 6.
• Background Hollo A, Clemens Z, Kamondi A, Lakatos P, Szucs A. Correction of vitamin D deficiency improves seizure control in epilepsy: a pilot study. Epilepsy Behav. 2012 May;24(1):131-3. doi: 10.1016/j.yebeh.2012.03.011. Epub 2012 Apr 11.
• Background Hollo A, Clemens Z, Lakatos P. Epilepsy and vitamin D. Int J Neurosci. 2014 Jun;124(6):387-93. doi: 10.3109/00207454.2013.847836. Epub 2013 Nov 7.
• Background Kalueff AV, Minasyan A, Tuohimaa P. Anticonvulsant effects of 1,25-dihydroxyvitamin D in chemically induced seizures in mice. Brain Res Bull. 2005 Sep 30;67(1-2):156-60. doi: 10.1016/j.brainresbull.2005.06.022.
• Background Kalueff AV, Minasyan A, Keisala T, Kuuslahti M, Miettinen S, Tuohimaa P. Increased severity of chemically induced seizures in mice with partially deleted Vitamin D receptor gene. Neurosci Lett. 2006 Feb 6;394(1):69-73. doi: 10.1016/j.neulet.2005.10.007. Epub 2005 Oct 25.
• Background Kanner AM. Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry. 2003 Aug 1;54(3):388-98. doi: 10.1016/s0006-3223(03)00469-4.
• Background Kanner AM. The treatment of depressive disorders in epilepsy: what all neurologists should know. Epilepsia. 2013 Mar;54 Suppl 1:3-12. doi: 10.1111/epi.12100.
• Background Kanner AM. Do psychiatric comorbidities have a negative impact on the course and treatment of seizure disorders? Curr Opin Neurol. 2013 Apr;26(2):208-13. doi: 10.1097/WCO.0b013e32835ee579.
• Background Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000 Feb 3;342(5):314-9. doi: 10.1056/NEJM200002033420503.
• Background Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshe SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010 Jun;51(6):1069-77. doi: 10.1111/j.1528-1167.2009.02397.x. Epub 2009 Nov 3.
• Background Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011 Sep 8;365(10):919-26. doi: 10.1056/NEJMra1004418. No abstract available.
• Background Lazzari AA, Dussault PM, Thakore-James M, Gagnon D, Baker E, Davis SA, Houranieh AM. Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--antiepileptic drug and osteoporosis prevention trial. Epilepsia. 2013 Nov;54(11):1997-2004. doi: 10.1111/epi.12351. Epub 2013 Sep 6.
• Background Mann MW, Pons G. [Drug resistance in partial epilepsy: epidemiology, mechanisms, pharmacogenetics and therapeutical aspects]. Neurochirurgie. 2008 May;54(3):259-64. doi: 10.1016/j.neuchi.2008.02.018. Epub 2008 Apr 15. French.
• Background Menon B, Harinarayan CV. The effect of anti epileptic drug therapy on serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism--a longitudinal study. Seizure. 2010 Apr;19(3):153-8. doi: 10.1016/j.seizure.2010.01.006. Epub 2010 Feb 7.
• Background McGrath J, Feron F, Eyles D, Mackay-Sim A. Vitamin D: the neglected neurosteroid? Trends Neurosci. 2001 Oct;24(10):570-2. doi: 10.1016/s0166-2236(00)01949-4. No abstract available.
• Background Picot MC, Jaussent A, Neveu D, Kahane P, Crespel A, Gelisse P, Hirsch E, Derambure P, Dupont S, Landre E, Chassoux F, Valton L, Vignal JP, Marchal C, Lamy C, Semah F, Biraben A, Arzimanoglou A, Petit J, Thomas P, Macioce V, Dujols P, Ryvlin P. Cost-effectiveness analysis of epilepsy surgery in a controlled cohort of adult patients with intractable partial epilepsy: A 5-year follow-up study. Epilepsia. 2016 Oct;57(10):1669-1679. doi: 10.1111/epi.13492. Epub 2016 Sep 5.
• Background Pierrot-Deseilligny C, Souberbielle JC. Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis? Brain. 2010 Jul;133(Pt 7):1869-88. doi: 10.1093/brain/awq147.
• Background Pierrot-Deseilligny C, Souberbielle JC. Widespread vitamin D insufficiency: A new challenge for primary prevention, with particular reference to multiple sclerosis. Presse Med. 2011 Apr;40(4 Pt 1):349-56. doi: 10.1016/j.lpm.2011.01.003. Epub 2011 Feb 17.
• Background Procopio M, Marriott PK, Williams P. Season of birth: aetiological implications for epilepsy. Seizure. 1997 Apr;6(2):99-105. doi: 10.1016/s1059-1311(97)80062-3.
• Background Saggese G, Vierucci F, Boot AM, Czech-Kowalska J, Weber G, Camargo CA Jr, Mallet E, Fanos M, Shaw NJ, Holick MF. Vitamin D in childhood and adolescence: an expert position statement. Eur J Pediatr. 2015 May;174(5):565-76. doi: 10.1007/s00431-015-2524-6. Epub 2015 Apr 2.
• Background Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology. 2008 Jan 1;70(1):54-65. doi: 10.1212/01.wnl.0000286959.22040.6e.
• Background Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ. 2014 Feb 28;348:g254. doi: 10.1136/bmj.g254.
• Background Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, Cavalcanti D, Baulac M. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology. 1998 Nov;51(5):1256-62. doi: 10.1212/wnl.51.5.1256.
• Background Siegel A, Malkowitz L, Moskovits MJ, Christakos S. Administration of 1,25-dihydroxyvitamin D3 results in the elevation of hippocampal seizure threshold levels in rats. Brain Res. 1984 Apr 23;298(1):125-9. doi: 10.1016/0006-8993(84)91153-3.
• Background Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain. 2002 Jan;125(Pt 1):22-31. doi: 10.1093/brain/awf002.
• Background Souberbielle JC, Benhamou CL, Cortet B, Rousiere M, Roux C, Abitbol V, Audran M, Bachetta J, Beauchet O, Blain H, Breuil V, Briot K, Brunet P, Chanson P, Cormier C, Courbebaisse M, Fardellone P, Fouque D, Friedlander G, Gauvain JB, Groussin L, Houillier P, Jacot W, Jean G, Kamenicky P, Lafage-Proust MH, Legrand E, Levy-Weil F, Linglart A, Mallet E, Marcelli C, Maruani G, Montagnon F, Personne V, Prie D, Raynaud-Simon A, Rolland Y, Salle B, Sault C, Schott AM, Thervet E, Urena-Torres P, Viard JP, Weryha G, Pierrot-Deseilligny C, Young J, Thomas T. [HAS report on vitamin D measurement: don't go from an extreme situation to another as extreme situation]. Presse Med. 2014 Jan;43(1):5-8. doi: 10.1016/j.lpm.2013.12.005. No abstract available. French.
• Background Steinhoff BJ. Efficacy of perampanel: a review of pooled data. Epilepsia. 2014 Jan;55 Suppl 1:9-12. doi: 10.1111/epi.12493.
• Background Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res. 2014 Oct;108(8):1352-6. doi: 10.1016/j.eplepsyres.2014.06.008. Epub 2014 Jul 6.
• Background Tellez-Zenteno JF, Patten SB, Jette N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia. 2007 Dec;48(12):2336-44. doi: 10.1111/j.1528-1167.2007.01222.x. Epub 2007 Jul 28.
• Background Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia. 2004 Nov;45(11):1330-7. doi: 10.1111/j.0013-9580.2004.18804.x.
• Background Vidailhet M, Mallet E, Bocquet A, Bresson JL, Briend A, Chouraqui JP, Darmaun D, Dupont C, Frelut ML, Ghisolfi J, Girardet JP, Goulet O, Hankard R, Rieu D, Simeoni U, Turck D; Comite de nutrition de la Societe francaise de pediatrie. Vitamin D: still a topical matter in children and adolescents. A position paper by the Committee on Nutrition of the French Society of Paediatrics. Arch Pediatr. 2012 Mar;19(3):316-28. doi: 10.1016/j.arcped.2011.12.015. Epub 2012 Jan 27.
• Background Wassenaar M, Leijten FS, Egberts TC, Moons KG, Uijl SG. Prognostic factors for medically intractable epilepsy: a systematic review. Epilepsy Res. 2013 Oct;106(3):301-10. doi: 10.1016/j.eplepsyres.2013.06.013. Epub 2013 Jul 20.
• Background de Zelicourt M, de Toffol B, Vespignani H, Laurendeau C, Levy-Bachelot L, Murat C, Fagnani F. Management of focal epilepsy in adults treated with polytherapy in France: the direct cost of drug resistance (ESPERA study). Seizure. 2014 May;23(5):349-56. doi: 10.1016/j.seizure.2014.01.016. Epub 2014 Jan 30.
• Chassoux F, Navarro V, Quirins M, Laurent A, Gavaret M, Cousyn L, Crepon B, Landre E, Marchi A, Soufflet C, Rusu-Devaux V, Mancusi RL, Piketty ML, Souberbielle JC. Vitamin D deficiency and effect of treatment on seizure frequency and quality of life parameters in patients with drug-resistant epilepsy: A randomized clinical trial. Epilepsia. 2024 Sep;65(9):2612-2625. doi: 10.1111/epi.18050. Epub 2024 Jul 9.

Drugs

Indications