Clinical trials of vitamin-mineral supplementations in people with epilepsy: A systematic review

  • Ali A. Asadi-Pooya
    Correspondence
    Corresponding author. Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
    Affiliations
    Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA
    Search for articles by this author
  • Leila Simani
    Affiliations
    Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
    Search for articles by this author
Published:October 28, 2020DOI:https://doi.org/10.1016/j.clnu.2020.10.045

      Summary

      Objective

      The purpose of the current study was to systematically review the literature on the clinical trials of vitamin-mineral supplementations in people with epilepsy (PWE) to treat their seizures.

      Methods

      MEDLINE and Scopus from inception to August 25, 2020 were searched for related published manuscripts. The search keywords included “vitamin or folate or folic acid or biotin or thiamine or carnitine or zinc or manganese or selenium or omega-3 fatty acid or linoleic acid or micronutrient or trace element or supplementation” AND “epilepsy or seizure”.

      Results

      We could identify 26 related articles. Seventeen studies provided class 2 of evidence and the rest provided class 3 of evidence. Eight studies investigated polyunsaturated fats, seven groups studied folic acid, four studies explored the effects of vitamin D, two investigated vitamin E, and three others studied multivitamin cocktails. There was one study on zinc and one on selenium. There is some evidence on the efficacy of polyunsaturated fats in treating seizures in PWE. The evidence on the efficacy of multivitamin cocktails in adults is promising.

      Conclusion

      High quality data on the efficacy of nutritional (vitamins-minerals) supplementations in treating seizures in PWE is scarce; however, designing future clinical trials of polyunsaturated fatty acid supplementation for drug-resistant seizures in adults with focal epilepsy and in children, and also multivitamin supplementations in adults with focal epilepsy seems reasonable and promising. Such clinical trials should be well-designed, randomized, and placebo controlled, with enough sample size and adequate follow-up of 12 months or more.

      Keywords

      Abbreviations:

      ASMs (Antiseizure medications), PWE (People with epilepsy)
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      References

        • Kotsopoulos I.A.
        • van Merode T.
        • Kessels F.G.
        • de Krom M.C.
        • Knottnerus J.A.
        Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures.
        Epilepsia. 2002; 43: 1402-1409
        • Hirtz D.
        • Thurman D.J.
        • Gwinn-Hardy K.
        • Mohamed M.
        • Chaudhuri A.R.
        • Zalutsky R.
        How common are the "common" neurologic disorders?.
        Neurology. 2007; 68: 326-337
        • Kwan P.
        • Brodie M.J.
        Early identification of refractory epilepsy.
        N Engl J Med. 2000; 342: 314-319
        • Asadi-Pooya A.A.
        • Nikseresht A.R.
        • Yaghoobi E.
        • Nei M.
        Physical injuries in patients with epilepsy and their associated risk factors.
        Seizure. 2012; 21: 165-168
        • Sperling M.R.
        • Barshow S.
        • Nei M.
        • Asadi-Pooya A.A.
        A reappraisal of mortality after epilepsy surgery.
        Neurology. 2016; 86: 1938-1944
        • Tang F.
        • Hartz A.M.S.
        • Bauer B.
        Drug-resistant epilepsy: multiple hypotheses, few answers.
        Front Neurol. 2017; 8: 301
        • Safahani M.
        • Aligholi H.
        • Asadi-Pooya A.A.
        Management of antiepileptic drug-induced nutrition-related adverse effects.
        Neurol Sci. 2020 Jul 14; ([Online ahead of print])https://doi.org/10.1007/s10072-020-04573-5
        • Asadi-Pooya A.A.
        • Mintzer S.
        • Sperling M.R.
        Nutritional supplements, foods, and epilepsy: is there a relationship?.
        Epilepsia. 2008; 49: 1819-1827
        • Silva B.
        • Velosa A.
        • Barahona-Corrêa J.B.
        Reversible dementia, psychotic symptoms and epilepsy in a patient with vitamin B (12) deficiency.
        BMJ Case Rep. 2019; 12e229044
        • Elinder F.
        • Liin S.I.
        Actions and mechanisms of polyunsaturated fatty acids on voltage-gated ion channels.
        Front Physiol. 2017; 8: 43
        • Lee S.W.
        • Chung S.S.
        A review of the effects of vitamins and other dietary supplements on seizure activity.
        Epilepsy Behav. 2010; 18: 139-150
        • Hutton B.
        • Salanti G.
        • Caldwell D.M.
        • Chaimani A.
        • Schmid C.H.
        • Cameron C.
        • et al.
        The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
        Ann Intern Med. 2015; 162: 777-784
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6e1000097
        • Jensen O.N.
        • Olesen O.V.
        Subnormal serum folate due to anticonvulsive therapy.
        Arch Neurol. 1970; 22: 181-182
        • Grant R.H.
        • Stores O.P.
        Folic acid in folate-deficient patients with epilepsy.
        Br Med J. 1970; 4: 644-648
        • Mattson R.H.
        • Gallagher B.B.
        • Reynolds E.H.
        • Glass D.
        Folate therapy in epilepsy: a controlled study.
        Arch Neurol. 1973; 29: 78-81
        • Gibberd F.B.
        • Nicholls A.
        • Wright M.G.
        The influence of folic acid on the frequency of epileptic attacks.
        Eur J Clin Pharmacol. 1981; 19: 57-60
        • Ogunmekan A.O.
        • Hwang P.A.
        A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children.
        Epilepsia. 1989; 30: 84-89
        • Raju G.B.
        • Behari M.
        • Prasad K.
        • Ahuja G.K.
        Randomized, double blind, placebo controlled, clinical trial of D-alpha-tocopherol (vitamin E) as add-on therapy in uncontrolled epilepsy.
        Epilepsia. 1994; 35: 368-372
        • Schlanger S.
        • Shinitzky M.
        • Yam D.
        Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy patients.
        Epilepsia. 2002; 43: 103-104
        • Bromfield E.
        • Dworetzky B.
        • Hurwitz S.
        • Eluri Z.
        • Lane L.
        • Replansky S.
        • et al.
        A randomized trial of polyunsaturated fatty acids for refractory epilepsy.
        Epilepsy Behav. 2008; 12: 187-190
        • DeGiorgio C.M.
        • Miller P.
        • Meymandi S.
        • Gornbein J.A.
        N-3 fatty acids (fish oil) for epilepsy, cardiac risk factors, and risk of SUDEP: clues from a pilot, double-blind, exploratory study.
        Epilepsy Behav. 2008; 13: 681-684
        • Zhou H.
        • Wang N.
        • Xu L.
        • Huang H.-L.
        • Yu C.-Y.
        Clinical study on anti-epileptic drug with B vitamins for the treatment of epilepsy after stroke.
        Eur Rev Med Pharmacol Sci. 2017; 21: 3327-3331
        • Yuen A.W.
        • Sander J.W.
        • Fluegel D.
        • Patsalos P.N.
        • Bell G.S.
        • Johnson T.
        • et al.
        Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial.
        Pilepsy Behav. 2005; 7: 253-258
        • DeGiorgio C.M.
        • Miller P.R.
        • Harper R.
        • Gornbein J.
        • Schrader L.
        • Soss J.
        • et al.
        Fish oil (n-3 fatty acids) in drug resistant epilepsy: a randomised placebo-controlled crossover study.
        J Neurol Neurosurg Psychiatry. 2015; 86: 65-70
        • Yuen A.W.
        • Flugel D.
        • Poepel A.
        • Bell G.S.
        • Peacock J.L.
        • Sander J.W.
        Non-randomized open trial of eicosapentaenoic acid (EPA), an omega-3 fatty acid, in ten people with chronic epilepsy.
        Epilepsy Behav. 2012; 23: 370-372
        • Norris J.W.
        • Pratt R.F.
        A controlled study of folic acid in epilepsy. A controlled study of folic acid in epilepsy.
        Neurology. 1971; 21: 659-664
        • DeGiorgio C.M.
        • Hertling D.
        • Curtis A.
        • Murray D.
        • Markovic D.
        Safety and tolerability of Vitamin D3 5000 IU/day in epilepsy.
        Epilepsy Behav. 2019; 94: 195-197
        • Holló A.
        • Clemens Z.
        • Kamondi A.
        • Lakatos P.
        • Szűcs A.
        Correction of vitamin D deficiency improves seizure control in epilepsy: a pilot study.
        Epilepsy Behav. 2012; 24: 131-133
        • Chang H.H.
        • Sung P.S.
        • Liao W.C.
        • Chang A.Y.W.
        • Hsiao Y.H.
        • Fu T.F.
        • et al.
        An open pilot study of the effect and tolerability of add-on multivitamin therapy in patients with intractable focal epilepsy.
        Nutrients. 2020; 12: E2359
        • Yürekli V.A.
        • Nazıroğlu M.
        Selenium and topiramate attenuates blood oxidative toxicity in patients with epilepsy: a clinical pilot study.
        Biol Trace Elem Res. 2013; 152: 180-186
        • Saad K.
        • El-Houfey A.A.
        • Abd El-Hamed M.A.
        • El-Asheer O.M.
        • Al-Atram A.A.
        • Tawfeek M.S.
        A randomized, double-blind, placebo-controlled clinical trial of the efficacy of treatment with zinc in children with intractable epilepsy.
        Funct Neurol. 2015; 30: 181-185
        • Deopa B.
        • Parakh M.
        • Dara P.
        • Payal V.
        • Chordiya K.
        • Panday A.
        • et al.
        Effect of folic acid supplementation on seizure control in epileptic children receiving long term antiepileptic therapy.
        Indian J Pediatr. 2018; 85: 493-497
        • Ibrahim F.A.S.
        • Ghebremeskel K.
        • Abdel-Rahman M.E.
        • Ahmed A.A.M.
        • Mohmed I.M.
        • Osman G.
        • et al.
        The differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on seizure frequency in patients with drug-resistant epilepsy - a randomized, double-blind, placebo-controlled trial.
        Epilepsy Behav. 2018; 87: 32-38
        • Tombini M.
        • Palermo A.
        • Assenza G.
        • Pellegrino G.
        • Benvenga A.
        • Campana C.
        • et al.
        Calcium metabolism serum markers in adult patients with epilepsy and the effect of vitamin D supplementation on seizure control.
        Seizure. 2018; 58: 75-81
        • Bochyńska A.
        • Lipczyńska-Łojkowska W.
        • Gugała-Iwaniuk M.
        • Lechowicz W.
        • Restel M.
        • Graban A.
        • et al.
        The effect of vitamin B supplementation on homocysteine metabolism and clinical state of patients with chronic epilepsy treated with carbamazepine and valproic acid.
        Seizure. 2012; 21: 276-281
        • Christiansen C.
        • SjÖ O.
        • RØdbro P.
        “Anticonvulsant action” of vitamin D in epileptic patients? A controlled pilot study.
        Br Med J. 1974; 2: 258-259
        • Ralston A.J.
        • Snaith R.P.
        • Hinley J.B.
        Effects of folic acid on fit-frequency and behaviour in epileptics on anticonvulsants.
        Lancet. 1970; 1: 867-868
        • Al Khayat H.A.
        • Awadalla M.M.
        • Al Wakad A.
        • Marzook Z.A.
        Polyunsaturated fatty acids in children with idiopathic intractable epilepsy: serum levels and therapeutic response.
        J Pediatr Neurol. 2010; 8: 175-185
        • Kwan P.
        • Arzimanoglou A.
        • Berg A.T.
        • Brodie M.J.
        • Allen Hauser W.
        • Mathern G.
        • et al.
        Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on therapeutic strategies.
        Epilepsia. 2010; 51: 1069-1077
        • Pourhoseingholi M.A.
        • Vahedi M.
        • Rahimzadeh M.
        Sample size calculation in medical studies.
        Gastroenterol Hepatol Bed Bench. 2013; 6: 14-17