Mohammad Asif Review Article
Role of various vitamins in the patients with epilepsy
Department of Pharmacy, GRD (P.G) Institute of management and Technology, Dehradun, India
Corresponding author*: firstname.lastname@example.org
It is important that people with epilepsy follow a nutritious and well balanced diet. Good nutritional habits and
healthy lifestyle is an important to optimal seizure control. However, no special diet is prescribed for epilepsy patients. But
to avoid dietary deficiencies, ensure proper intake of nutrients, containing adequate vitamins (folic acid, Vitamin B1,
Vitamin D Vitamin B6, Vitamin B12 Vitamin E and vitamin K), inorganic salts (calcium, magnesium and manganese) and
other micronutrients1-3. If patient have some other condition (like diabetes) in addition to epilepsy that requires a special
diet. Problems can generally be avoided with a proper diet4-8. However, in rare cases, more serious problems may arise due
to deficiency of vitamins. For example, anemia can result from severe folic acid deficiency. Weak bones are related to
inadequate amounts of vitamin D. Vitamin supplements can be prescribed as necessary. Self-prescribed “mega-vitamin”
therapy will do no good and could be harmful. For example, excessive folic acid intake may actually decrease seizure
2. Role of vitamins in epilepsy
2.1 Thiamine (B1): Severe thiamine deficiency can cause seizures in both alcoholic and non-alcoholic patients; these
seizures are reversible with thiamine supplementation. Low thiamine status was found in epileptic patients9,10 and
consecutive neurological patients. In a placebo-controlled trial, supplementation of epileptic patients with 50 mg thiamine
daily for six months was associated with significant improvements11. The research suggested that thiamine deficiency
might be considered as one possible cause of late-onset epilepsy. In addition, thiamine deficiency has been reported in
patients with epilepsy and its supplementation may be necessary to prevent or reverse the effects of its deficiency. The
patients chronically treated with phenytoin had subnormal blood thiamine levels and had low folate.
2.2 Pyridoxine (B6): Pyridoxine-dependent seizure (PDS) is a rare autosomal recessive disorder that usually presents with
intractable seizures in early stages of life. The seizures can be completely controlled by administration of large doses of
vitamin B6. Clinical seizures stop within a few minutes and epileptic electroencephalographic (EEG) discharges subside
within a few hours after the intravenous injection of 50–200 mg of pyridoxine 12,13. Pyridoxine should be administered
under EEG monitoring as a diagnostic test in all cases of convulsive disorders in infants and young children in which no
other diagnosis is evident. Intravenous administration of vitamin B6 to infants after a long period of convulsions has been
followed in some cases by acute hypotonia and apnea14,15. Alternatively, the disorder may be diagnosed by giving 15
mg/kg/day of oral pyridoxine to a patient who experiences frequent seizures and noting complete control of the seizures
within a week or so16. Once the diagnosis is confirmed, maintenance therapy (25–200 mg/day) should be continued
indefinitely and doses increased with advancing age or when intercurrent illnesses occur. It is also recommended that
women who have had a child with vitaminB6 dependency receive vitamin B6 supplements during subsequent
pregnancies17-19. In addition, it was observed that pyridoxal phosphate is better than pyridoxine in the treatment of
intractable childhood epilepsy, particularly in the treatment of infantile spasms20. Finally, in patients with epilepsy and
without pyridoxine dependency, vitamin B6 deficiency has been observed, however at the moment, there is not enough
evidence to suggest that vitamin B6 supplementation might help the treatment of patients with non vitamin B6-dependent
refractory seizures21. In addition, supplementation with 80–200 mg/day pyridoxine can reduce serum phenytoin and
IJPR Volume 3 Issue 1 (2013) 1
In this review, we study the effect of various vitamins in the epileptic patients. These vitamins are generally may
reduce seizure frequency and treating adverse effect of anticonvulsant drugs. Supplementation with folic acid, vitamin B6,
vitamin E, biotin, vitamin D, may be needed to prevent or treat deficiencies resulting from the use of anticonvulsant drugs.
Thiamine may improve cognitive function in the epileptic patients. Vitamin K1 has been recommended near the end of
pregnancy for women taking anticonvulsant drugs. Vitamins therapy is not a substitute for anticonvulsant medications.
Key words: Vitamins, Epilepsy, Nutrients, Diet.
International Journal of Pharmacological Research www.ssjournals.com
ISSN: 2277-3312 Journal DOI:10.7439/ijpr
Mohammad Asif Review Artticle
phenobarbital levels22,23 and long-term administration of 500 mg/day or more of pyridoxine may produce neurotoxicity in
adults, which could presumably occur at lower doses in children24.In the early 1950s, numerous infants in the United States
developed convulsions traced to the use of a formula that was deficient in pyridoxine25,26. Seizures also occurred in an
infant fed exclusively on powdered goat’s milk, which had undetectable levels of the vitamin. The seizures resolved after
supplementation with vitamin B6 27. Vitamin B6 deficiency has been found in a high proportion of patients with epilepsy.
In a study, patients with severe epilepsy, had a reduced serum concentration of pyridoxal 28. Low levels of vitamin B6 may
be due in part to treatment with phenytoin, which has been associated with evidence of reduced vitamin B6 status (i.e.,
increased xanthurenic acid excretion following a tryptophan load) 29. However, other factors may be involved as well, since
there does not appear to be a strong relationship between low vitamin B6 levels and use of any specific anticonvulsant
medication. Vitamin B6 supplementation is clearly beneficial in cases of vitamin B6-dependent seizures. Some studies
have demonstrated improvements in patients with non-vitamin B6-dependent epilepsy as well, although the research has
produced conflicting results.
2.3 Vitamin B6-dependent Seizures: Vitamin B6-dependent epilepsy is a rare inherited disorder that usually presents
with intractable seizures in the first six months of life. The seizures can be completely controlled by the large doses of
vitamin B6 30,31 but if the condition is not treated promptly irreversible neurological damage may occur. The diagnosis of
vitamin B6 dependency can be established by intravenous administration of pyridoxine, which results in cessation of
seizures within minutes. Most patients can subsequently be maintained on 25-50 mg/day oral pyridoxine, although one
child required 200 mg/day 32. Long-term supplementation is necessary; discontinuation of pyridoxine after several years of
good seizure control has resulted in death from status epilepticus. Some patients with vitamin B6-dependent seizures
present with an atypical picture, including later onset (up to 19 months of age)33, a seizure-free period before
administration of pyridoxine, a long remission after withdrawal of pyridoxine, and an atypical seizure type. It is also
recommended that women who have a child with vitamin B6 dependency receive vitamin B6 supplements during
2.4 Vitamin B6 for Non-vitamin B6-dependent Epilepsy: Vitamin B6 supplementation has been reported to be
beneficial in some, but not all, patients with non-vitamin B6-dependent epilepsy. The children with epilepsy received 160
mg/day pyridoxine, the patients with laboratory evidence of vitamin B6 deficiency (i.e., increased urinary excretion of
xanthurenic acid following a tryptophan load), had complete or partial amelioration of seizures, and some of these patients
were able to discontinue anticonvulsant medication. Of the patients with a normal tryptophan load test, none responded to
pyridoxine34,35. Of children (ages 3-8 years) with epilepsy associated with impaired intellectual development, progressive
emotional disturbances, and abnormal EEGs, all excreted elevated amounts of xanthurenic acid after a tryptophan load.
After administration of 60-160 mg pyridoxine daily, tryptophan metabolism became normal and substantial
clinical improvement occurred36. Pyridoxine (20 mg, 3-6 times daily) was given for an unspecified length of time to
epileptic patients, ages 2-17 years. All patients had petit mal and one also had grand mal epilepsy. Seizures ceased five
patients and became less frequent37. Epileptic children received 160-200 mg pyridoxine daily for at least six weeks.
Significant clinical improvement was seen in five cases22. A 23-year-old man with recurrent seizures presented with status
epilepticus, which resolved immediately following intravenous administration of 60 mg pyridoxal phosphate. Prior to
treatment, patient serum pyridoxine concentration was markedly decreased (80% below the lower limit of normal).
Pyridoxine was given intravenously to infants and children with acute, recurrent seizures due primarily to acute infections.
A dose of 30 or 50 mg/kg/day was administered over 2-4 hours and given for a few days. The treatment was rated “very
effective” in patients receiving pyridoxine. Aside from transient flushing, no adverse effects were seen. In other studies,
pyridoxine in doses of 20-100 mg/day orally39,40 or 300 mg/day parenterally38 to produced no clinical improvement in
patients with various types of epilepsy.
2.5 Pyridoxine versus Pyridoxal Phosphate: While most patients with vitamin B6-dependent seizures can be effectively
treated with pyridoxine, some patients have only responded to pyridoxal phosphate, the biologically active form of vitamin
B6 19. The average effective oral dose of pyridoxal phosphate-responsive seizures was 30 mg/kg/day (range, 7-38
mg/kg/day), which was significantly higher than the average effective pyridoxine dose (18 mg/kg/day) in pyridoxine
responders20. Because of superior efficacy in certain cases, pyridoxal phosphate should be considered for first-line
treatment of patients in whom a clinical trial of vitamin B6 is indicated. Pyridoxal phosphate should also be considered for
patients with suspected vitamin B6-responsive seizures that are unresponsive to pyridoxine.
3. Vitamin B6 in Clinical Practice
Vitamin B6 should be tried in all infants and young children with intractable epilepsy. For children and adults
whose seizures are well controlled on medication, moderate doses of vitamin B6 (such as 10-50 mg/day) may be
considered to prevent possible drug induced vitamin B6 deficiency. Although larger doses might be appropriate in selected
cases, high-dose vitamin B6 appears to interfere with some anticonvulsant medications. In one study, supplementation with
80-200 mg/day pyridoxine reduced serum phenytoin and phenobarbitone levels in epileptic children22. In addition, long-
term administration of 500 mg/day or more of pyridoxine has resulted in neurotoxicity in some adults 24, which could
presumably occur at lower doses in children. The supplementation with 600 mg/day vitamin B6 reversed phenytoin-
IJPR Volume 3 Issue 1 (2013) 2
Mohammad Asif Review Article
induced gingival hyperplasia in several patients; however, such high doses are probably excessive for most patients with
epilepsy. Lower doses might be effective for phenytoin-induced gingival hyperplasia, particularly when used in
combination with a folic acid mouth rinse. Patients being treated with vitamin B6 should probably also receive a
magnesium supplement, in view of evidence that these nutrients work together and subjective reports that vitamin B6
supplementation increases the requirement for magnesium.
3.1 Biotin (B7): Biotin deficiency has been reported in patients with epilepsy. This has been attributed to antiepileptic
therapy (e.g., with carbamazepine, phenobarbital, and phenytoin)21. Biotin supplementation might reduce seizure
frequency in patients with inborn errors of biotin metabolism. Biotinidase deficiency is an autosomal recessive genetic
disorder. Absence of biotinidase leads to infantile or early childhood encephalopathy, seizure disorder, dermatitis, alopecia,
neural deafness, and optic atrophy. Treatment with biotin results in clinical recovery and normalization of the biochemical,
neuroradiological, and neurophysiological parameters47,21. Serum biotin levels were below normal in epileptic patients on
long-term anticonvulsant therapy48. Low biotin levels appear to result from an acceleration of biotin catabolism by
phenytoin, carbamazepine, and phenobarbital49,50. In addition, carbamazepine and primidone may inhibit intestinal
absorption of biotin51. Interestingly, dermatitis and ataxia, side effects of many anticonvulsants, are also observed in
patients with an inborn error of biotin-dependent enzymes. There is no evidence that biotin supplementation interferes with
the effect of anticonvulsants. To the contrary, correction of biotin deficiency might reduce seizure frequency, as suggested
by the fact that biotin responsive seizures have occurred in some patients with inborn errors of biotin metabolism52.
3.2 Folic acid (B9): Seizures may occur in some infants with cerebral folate deficiency. In this disorder, the seizures begin
between 2 h and 5 days after birth, although intrauterine hiccup can be the first symptom. Myoclonic and clonic seizures,
sometimes associated with apnea, have been described. Affected neonate may be irritable, jittery, obtunded, or even
becomes comatose. Electroencephalographic (EEG) recordings in the neonatal period manifest a discontinuous
background pattern and multifocal spikes or sharp waves. This syndrome is probably caused by impaired transport of
folate across the blood–brain barrier into the central nervous system. The transport defect can be overcome by
administration of folinic acid (an active form of folic acid), which bypasses the blocked folate transport mechanism. The
disorder of folinic acid-responsive seizures is lethal when no specific treatment is initiated. Folinic acid administration
should be considered in all cases of refractory neonatal seizures in which no other diagnosis is evident. The starting dose
of folinic acid is usually 2.5 mg twice per day, and can be gradually increased up to 8 mg/kg/day. Seizures commonly
cease within 24 h after folinic acid is initiated. Withdrawal of the treatment leads to seizure recurrence within a few days.
Oral folinic acid should be continued indefinitely (2.5–5 mg/kg/day). Most children require continuation of antiepileptic
medication as well. The prognosis is poor even with folinic acid therapy and seizure control42-43.
In patients with seizures not due to cerebral folate deficiency, folic acid (or its derivatives) supplementation is of
little or no benefit with respect to seizure control. However, folate deficiency is common in patients with epilepsy and may
have negative effects on other aspects of health and therefore, its correction is desirable. It has been observed that low dose
of folate supplementation may prevent carbamazepine-induced leukopenia or anemia in patients with epilepsy. In one
randomized clinical trial of carbamazepine-treated children44, white blood cell and polymorphonuclear cell counts were
significantly higher in patients who received folate supplementation and the incidence of neutropenia was cut almost in
half. Hemoglobin concentration dropped in carbamazepine-only treated children, but rose slightly in children who received
folate supplementation as well; these changes were also significant. These findings could be helpful if considered in the
management process of the patients who are prescribed carbamazepine, especially in patients who are at more risk for
carbamazepine- induced leukopenia (e.g., those with borderline low white blood cells, neutrophil, or monocyte counts at
baseline)45. While correction of folate deficiency is desirable, administration of large doses of folic acid can decrease blood
levels of phenytoin, phenobarbital, and carbamazepine, potentially interfering with seizure control46,21. The impact of
adding folic acid to a stable phenytoin regimen in an effort to correct folate deficiency is often underestimated. The mean
decrease in total serum phenytoin level after the addition of 1 mg oral folic acid is about 20% and after adding 5 mg of oral
folic acid might be as high as 40%. Pharmacokinetic studies of this interaction strongly suggest that folic acid is a cofactor
in the metabolism of phenytoin. Higher levels of folate appear to increase the affinity of metabolizing enzymes, thus
greatly increasing the efficiency of phenytoin degradation 46. Though evidence is lacking, the use of high dose folic acid
supplements in women with epilepsy before conception and during pregnancy is generally recommended to potentially
prevent some of the teratogenic effects of AEDs particularly neural tube defects.
Seizures occur in some infants with cerebral folate deficiency, a syndrome that also includes slow head growth,
psychomotor retardation, cerebellar ataxia, and other neurological abnormalities. This syndrome is caused by impaired
transport of folate across the blood-brain barrier into the central nervous system. The transport defect can be overcome by
administration of folinic acid (an active form of folic acid), which bypasses the blocked folate transport mechanism. There
are several case reports in which administration of folinic acid (2.5-20 mg twice daily in one study, 0.5-1.0 mg/kg body
weight per day in another) resulted in improvement or complete control of seizures in infants 41,53 . In patients with seizures
not due to cerebral folate deficiency, folic acid supplementation is of little or no benefit with respect to seizure control, and
may even exacerbate seizures in some instances. However, folate deficiency is common in patients with epilepsy and may
IJPR Volume 3 Issue 1 (2013) 3
Mohammad Asif Review Artticle
have negative effects on other aspects of health. Subnormal serum or erythrocyte folate concentrations have been observed
in patients with epilepsy in different studies54- 58. Low folate levels were found more frequently among inpatients than
outpatients, and in those with coexisting psychiatric illness than those without psychiatric illness. Folate deficiency is due
primarily to the use of anticonvulsant medications (e.g., phenytoin, valproate, carbamazepine, phenobarbital, and
primidone), which interfere with folic acid absorption59-61. While correction of folate deficiency is desirable, administration
of large doses of folic acid can decrease blood levels of phenytoin, phenobarbital, and carbamazepine 62-65, potentially
interfering with seizure control. An increase in seizure frequency has been seen in some 66, but not all67-69, studies in which
highdose folic acid (5 mg three times per day) was given to drug-treated epileptic patients. In addition to interfering with
anticonvulsant medication, high-dose folic acid itself may be epileptogenic. Intravenous administration of 14.4 mg folic
acid induced a tonic-clonic seizure in one epileptic patient, although other patients experienced no adverse effects from 75
mg folic acid given intravenously70. One woman with epilepsy had an increase in seizure frequency and severity after
receiving 0.8 mg folic acid per day, which was prescribed because she was planning to become pregnant71. A cause-effect
relationship in this case is uncertain. Based on these observations, modest doses of folic acid should be used to treat folate
deficiency in epileptic patients. The pregnant epileptic women taking anticonvulsant drugs found that a folic acid dose of
100-1,000 mcg/day was sufficient to prevent folate deficiency and did not impair seizure control72. Folic acid has also been
used to treat phenytoin-induced gingival hyperplasia. The use of a 0.1-percent folic acid mouth rinse for six months
significantly reduced the severity of this condition, whereas a placebo was ineffective. Patients used 5 mL of the mouth
rinse twice daily, spitting it out after rinsing for two minutes (should not be swallowed, 10 mg/day of folic acid). Oral,
rather than topical, administration of folic acid (3-4 mg/day) produced little or no improvement in phenytoin-induced
3.3 Vitamin D: Some antiepileptic drugs may have negative effects on bone mineral density through a variety of
mechanisms including inducing the hepatic cytochrome P450 system (CYP450) which promotes the metabolism of 25-
hydroxyvitamin D (25-OHD) to less biologically active analogues, resulting in decreased bone mineralization, decreased
intestinal calcium absorption, increased calcium mobilization from the skeleton to maintain eucalcemia, and decreased
bone density75,76. Valproate can also decrease bone mineral density with an unclear mechanism. Patients with epilepsy who
take enzyme inducing drugs or valproate should maintain a balanced diet rich in calcium and vitamin D; many
practitioners recommend supplementation with calcium and vitamin D daily. Evidence suggests that vitamin D might have
some antiepileptic effects.
It was observed that administration of 1,25-dihydroxyvitamin D3 resulted in the elevation of hippocampal seizure
threshold levels in rats77. In addition, it was observed that the frequency of epileptic seizures significantly decreased in
patients taking vitamin D as add-on-drug compared with patients taking placebo in addition to their antiepileptic drugs78.
Patients taking anticonvulsants are at increased risk of developing vitamin D deficiency, apparently because these
drugs induce liver enzymes that inactivate vitamin D48,79. Rickets, osteomalacia, and low bone mineral content78,80 have
been reported in drug treated epileptic patients. In patients with osteomalacia resulting from the use of phenytoin and
phenobarbital, the amount of vitamin D3 needed to achieve positive calcium balance was approximately 975 IU/day 81. In
patients with low 25-hydroxyvitamin D levels who were taking phenytoin, carbamazepine, and phenobarbitone, either
alone or in combination, the amount of vitamin D3 required to maintain a normal serum 25-hydroxyvitamin D
concentration (15 ng/mL or greater) ranged from 400 to 4,000 IU/day, with 72 percent of patients requiring 2,400 IU/day
3.4 Vitamin E: Vitamin E deficiency has been reported in patients with epilepsy, though its clinical significance remains
uncertain. This deficiency has been attributed to antiepileptic therapy83.The antiepileptic effect of vitamin E is
contradictory. In one animal study84, the anticonvulsant effects of alpha-tocopherol (vitamin E) in animal seizure models.
However, a placebo-controlled, cross-over trial85 with vitamin E as add-on therapy in patients with uncontrolled epilepsy
demonstrated no efficacy with regard to seizure control.Erythrocyte or plasma vitamin E concentrations were lower in
children with epilepsy than in healthy controls. Vitamin E levels were lower in children receiving multi-drug therapy than
in children receiving single-drug therapy86,87. In some studies, vitamin E supplementation reduced seizure frequency.
Twenty-four children (ages 6-17 years) with treatment-resistant epilepsy were randomly assigned to receive, in
double-blind fashion, 400 IU/day alpha-tocopheryl acetate or placebo for three months. Of the 12 patients given vitamin E,
10 had a greater-than-60-percent reduction in seizure frequency (of that 10, six had a 90-100% reduction). None of the
patients in the placebo group had a greater-than-60-percent reduction in seizure frequency (p<0.05 for the difference in
response rate between groups). Vitamin E treatment had no effect on plasma levels of anticonvulsant medications. Thirty-
five epileptic children and adults were randomly assigned to receive, in double-blind fashion, 250 IU/day vitamin E or
placebo for three months. Anticonvulsants were continued as previously. Of the 12 adults receiving vitamin E, eight had a
decrease in seizure frequency, two had an increase, and two were unchanged. Of the children receiving vitamin E, two had
a reduction in seizure frequency. No changes were seen in the children and adults receiving placebo88,89. The
supplementation with vitamin E reduced mean seizure frequency in a group of severely mentally handicapped patients
with treatment resistance epilepsy. However, information was omitted regarding the dosage regimen and the response in
IJPR Volume 3 Issue 1 (2013) 4
Mohammad Asif Review Article
the placebo group90. In a study of severely handicapped epileptic patients (ages 4-23 years) receiving anticonvulsants,
supplementation with 100 IU/day alpha-tocopheryl acetate for one month had no effect on seizure frequency83. The
teenagers and adults with uncontrolled epilepsy were randomly assigned to receive, in double-blind fashion, 600 IU/day
vitamin E or placebo for three months. The mean seizure frequency decreased by 25.7 percent during the placebo period
and by 13.8 percent during the vitamin E period compared with baseline85. Although the research on efficacy is conflicting,
vitamin E is relatively safe and may be considered for adjunctive treatment in epileptic patients, particularly children.
3.5 Vitamin K: The incidence of vitamin K deficiency is increased in neonates of mothers receiving enzyme-inducing
antiepilepltic drugs and vitamin K1 treatment decreases the frequency of vitamin K deficiency in these neonates 91. It is
widespread clinical practice to administer vitamin K to pregnant women and then to their newborns. This is certainly
appropriate for women taking enzyme-inducing drugs; it is not known whether women taking other drugs require this
regimen, but it seems prudent to follow it until more is known. Fourteen pregnant epileptic women received 20 mg/day
vitamin K1 for two weeks before delivery. No hemorrhages occurred in the babies and prothrombin times were all normal
at birth. This study suggested that vitamin K1 should be given routinely to drug-treated epileptic women near the end of
Manganese deficiency has been reported in patients with epilepsy, though it does not appear to correlate with
seizure frequency or the type, dose, or plasma levels of AEDs93.
Linolenic acid prevents kainate-induced seizures and neuronal death and has neuroprotective effects94,95,
supplementation with fish oil, providing omega-3 fatty acids, reduced seizure frequency, but the beneficial effect was not
sustained thereafter. Health care professionals caring for patients with epilepsy, especially children with intractable
epilepsy, should be aware of these nutritional recommendations and educate families to provide an adequate diet and/or
consider vitamin/mineral supplementation. Given the high probability of any patient not eating a well-balanced diet,
routine vitamin supplementation with modest doses can be considered reasonable96-100. Of course, cost–benefit ratio should
always be considered and over consumption of vitamin supplements should be avoided. The pyridoxine, folic acid, and
biotin supplementation is necessary in patients with pyridoxin, cerebral folate deficiency, or biotinidase deficiency,
respectively, there is no evidence to support their use in other circumstances, to control the seizures. In addition, though
evidence is lacking, the use of high dose of folic acid supplements in women with epilepsy before conception and during
pregnancy, supplementation with vitamin D in patients taking enzyme-inducing antiepileptic drugs and valproate, and
finally, vitamin K in pregnant women taking antiepileptic drugs and their newborns are recommended 101-105. The relation
between other nutrients (e.g., vitamin E and Omega-3 fatty acids and seizures) should be investigated further before
asserting any recommendations. On the other hand, unnecessary and excessive vitamin and mineral supplementation may
actually be harmful (106-108). For many people with epilepsy a healthy, balanced diet is the best, but many patients have
nutritional deficiencies. In one recent study, at least 30% of children with intractable epilepsy had intakes below the
recommended dietary allowance for vitamins D, E, and K, folate, calcium, and linoleic acid109-112.
A number of different dietary modifications, nutritional supplements, and hormones may help prevent seizures or
improve other aspects of health in patients with epilepsy. Supplementation with specific nutrients should also be
considered for the prevention and treatment of nutritional deficiencies resulting from anticonvulsant drugs. In most cases,
nutritional therapy is not a substitute for anticonvulsant medications. However, in selected cases, depending on the
effectiveness of the interventions, dosage reductions or discontinuation of medications may be possible. Because much of
the research on epilepsy management with diet, nutrients, and hormones is preliminary.
1. Nuytten D, Van Hees J, Meulemans A, Carton H. Magnesium deficiency as a cause of acute intractable seizures. J
2. Afzal S, Kalra G, Kazmi SH, Siddiqui MA. A study of serum and cerebrospinal fluid magnesium in convulsive
disorders. J Assoc Physicians India 1985;33:161-163.
3. Steidl L, Tolde I, Svomova V. Metabolism of magnesium and zinc in patients treated with antiepileptic drugs and with
magnesium lactate. Magnesium 1987;6:284-295.
4. Dupont CL, Tanaka Y. Blood manganese levels in children with convulsive disorder. Biochem Med 1985;33:246-255.
5. Grant EC. Epilepsy and manganese. Lancet 2004;363:572.
6. Pennetta R, Masi G, Perniola T, Ferrannini E. Electroclinical evaluation of the anti-epileptic action of taurine. Acta
Neurol (Napoli) 1977;32:316-322.
7. Pfeiffer CC, LaMola S. Zinc and manganese in the schizophrenias. J Orthomolecular Psychiatry 1983;12:215-234.
8. Mantovani J, DeVivo DC. Effects of taurine on seizures and growth hormone release in epileptic patients. Arch Neurol
IJPR Volume 3 Issue 1 (2013) 5
Mohammad Asif Review Artticle
9. Keyser A, De Bruijn SF. (1991) Epileptic manifestations and vitamin B1 deficiency. Eur Neurol 31:121–125.
10. Botez MI, Botez T, Ross-Chouinard A, Lalonde R. Thiamine and folate treatment of chronic epileptic patients: a
controlled study with the Wechsler IQ scale. Epilepsy Res 1993; 16:157-163.
11. Gascon G, Patterson B, Yearwood K, Slotnick H. N,N dimethylglycine and epilepsy. Epilepsia 1989;30:90-93.
12. Mikati MA, Trevathan E, Krishnamoorthy KS, Lombroso CT. (1991) Pyridoxine-dependent epilepsy: EEG
investigations and long-term follow-up. Electroencephalogr Clin Neurophysiol 78:215–221.
13. Nabbout R, Soufflet C, Plouin P, Dulac O. (1999) Pyridoxine dependent epilepsy: a suggestive electroclinical pattern.
Arch Dis Child Fetal Neonatal Ed 81:F125–129.
14. Kroll JS. Pyridoxine for neonatal seizures: an unexpected danger. Dev Med Child Neurol 1985;27:377-379.
15. Coker SB. Postneonatal vitamin B6-dependent epilepsy. Pediatrics 1992;90:221-223.
16. Gospe SM Jr. (2006) Pyridoxine-dependent seizures: new genetic and biochemical clues to help with diagnosis and
treatment. Curr Opin Neurol 19:148–153.
17. Rajesh R, Girija AS. (2003) Pyridoxine-dependent seizures: a review. Indian Pediatr 40:633–638.
18. Bennett CL, Huynh HM, Chance PF, Glass IA, Gospe SM Jr. (2005) Genetic heterogeneity for autosomal recessive
pyridoxine-dependent seizures. Neurogenetics 6:143–149.
19. Kuo MF, Wang HS. Pyridoxal phosphate-responsive epilepsy with resistance to pyridoxine. Pediatr Neurol
20. Wang HS, Kuo MF, Chou ML, et al. Pyridoxal phosphate is better than pyridoxine for controlling idiopathic
intractable epilepsy. Arch Dis Child 2005;90:512-515.
21. Gaby AR. (2007) Natural approaches to epilepsy. Altern Med Rev 12:9–24.
22. Hansson O, Hagberg B. Effect of pyridoxine treatment in children with epilepsy. Acta Soc Med Ups 1968;73:35-43.
23. Hansson O, Sillanpaa M. Letter: Pyridoxine and serum concentration of phenytoin and phenobarbitone. Lancet
24. Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. (1983) Sensory neuropathy from
pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 309:445–448.
25. Coursin DB. Convulsive seizures in infants with pyridoxine-deficient diet. J Am Med Assoc 1954;154:406-408.
26. Molony CJ, Parmelee AH. Convulsions in young infants as a result of pyridoxine (vitamin B6) deficiency. J Am Med
27. Johnson GM. Powdered goat’s milk: pyridoxine deficiency and status epilepticus. Clin Pediatr (Phila) 1982;21:494-
28. Davis RE, Reed PA, Smith BK. Serum pyridoxal, folate, and vitamin B12 levels in institutionalized epileptics.
29. Meeuwisse G, Gamstorp I, Tryding N. Effect of phenytoin on the tryptophan load test. Acta Paediatr Scand
30. Crowell GF, Roach ES. Pyridoxine-dependent seizures. Am Fam Physician 1983;27:183-187.
31. Robins MM. Pyridoxine dependency convulsions in a newborn. JAMA 1966;195:491-493.
32. Clarke TA, Saunders BS, Feldman B. Pyridoxinedependent seizures requiring high doses of pyridoxine for control.
Am J Dis Child 1979;133:963-965.
33. Goutieres F, Aicardi J. Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable
epilepsy in infants. Ann Neurol 1985;17:117-120.
34. Bankier A, Turner M, Hopkins IJ. Pyridoxine dependent seizures–a wider clinical spectrum. Arch Dis Child
35. Hagberg B, Hamfelt, Hansson O. Tryptophan load tests and pyridoxal-5-phosphate levels in epileptic children. II.
Cryptogenic epilepsy. Acta Paediatr Scand 1966;55:371-384.
36. Hagberg B, Hamfelt A, Hansson O. Epileptic children with disturbed tryptophan metabolism treated with vitamin B6.
37. Ernsting W, Ferwerda TP. Vitamin B6 in treatment of epilepsy. J Am Med Assoc 1952;148:1540.
38. Fois A, Borgheresi S, Luti L. Frequency of relative pyridoxine dependency in epileptic children. Helv Paediatr Acta
39. Fox JT, Tullidge GM. Pyridoxine (vitamin B6) in epilepsy. A clinical trial. Lancet 1946;2:345.
IJPR Volume 3 Issue 1 (2013) 6
Mohammad Asif Review Article
40. Heeley AF, Piesowicz AT, McCubbing DG. The biochemical and clinical effect of pyridoxine in children with brain
disorders. Clin Sci 1968;35:381-389.
41. Torres OA, Miller VS, Buist NM, Hyland K. Folinic acid-responsive neonatal seizures. J Child Neurol 1999;14:529-
42. Nicolai J, van Kranen-Mastenbroek VH, Wevers RA, Hurkx WA, Vles JS. (2006) Folinic acid-responsive seizures
initially responsive to pyridoxine. Pediatr Neurol 34:164–167.
43. Djukic A. (2007) Folate-responsive neurologic diseases. Pediatr neurol 37:387–397.
44. Asadi-Pooya AA, Ghetmiri E. (2006) Folic acid supplementation reduces the development of some blood cell
abnormalities in children receiving carbamazepine. Epilepsy Behav 8:228–231.
45. Asadi-Pooya AA, Hossein-Zade A. (2005) What do nurses and physicians think about the need for specific dietary
restrictions in the patients with epilepsy? Epilepsy Behav 6:604–606.
46. Steinweg DL, Bentley ML. (2005) Seizures following reduction in phenytoin level after orally administered folic acid.
47. Joshi S, al-Essa MA, Archibald A, Ozand PT. (1999) Biotinidase deficiency: a treatable genetic disorder in the Saudi
population. East Mediterr Health J 5:1213–1217.
48. Krause KH, Berlit P, Bonjour JP. Impaired biotin status in anticonvulsant therapy. Ann Neurol 1982;12:485-486.
49. Mock DM, Dyken ME. Biotin catabolism is accelerated in adults receiving long-term therapy with anticonvulsants.
50. Mock DM, Mock NI, Nelson RP, Lombard KA. Disturbances in biotin metabolism in children undergoing long-term
anticonvulsant therapy. J Pediatr Gastroenterol Nutr 1998;26:245-250.
51. Said HM, Redha R, Nylander W. Biotin transport in the human intestine: inhibition by anticonvulsant drugs. Am J
Clin Nutr 1989;49:127-131.
52. Wolf B, Grier RE, Allen RJ, et al. Phenotypic variation in biotinidase deficiency. J Pediatr 1983;103:233-237.
53. Ramaekers VT, Rothenberg SP, Sequeira JM, et al. Autoantibodies to folate receptors in the cerebral folate deficiency
syndrome. N Engl J Med 2005;352:1985-1991.
54. Reynolds EH, Preece J, Johnson AL. Folate metabolism in epileptic and psychiatric patients. J Neurol Neurosurg
55. del Ser Quijano T, Bermejo Pareja F, Munoz-Garcia D, Portera Sanchez A. Psychological disturbances and folic acid
in chronic epileptic outpatients. Epilepsia 1983;24:588-596.
56. Snaith RP, Mehta S, Raby AH. Serum folate and vitamin B12 in epileptics with and without mental illness. Br J
57. Trimble MR, Corbett JA, Donaldson D. Folic acid and mental symptoms in children with epilepsy. J Neurol
Neurosurg Psychiatry 1980;43:1030-1034.
58. Enneking-Ivey O, Bailey LB, Gawley L, et al. Folic acid and vitamin D status of young children receiving minimal
anticonvulsant drug therapy. Int J Vitam Nutr Res 1981;51:349-352.
59. Deb S, Cowie VA, Richens A. Folate metabolism and problem behaviour in mentally handicapped epileptics. J Ment
Defic Res 1987;31:163-168.
60. Apeland T, Mansoor MA, Strandjord RE, et al. Folate, homocysteine and methionine loading in patients on
carbamazepine. Acta Neurol Scand 2001;103:294-299.
61. Hendel J, Dam M, Gram L, et al. The effects of carbamazepine and valproate on folate metabolism in man. Acta
Neurol Scand 1984;69:226-231.
62. Mattson RH, Gallagher BB, Reynolds EH, Glass D. Folate therapy in epilepsy. A controlled study. Arch Neurol
63. Seligmann H, Potasman I, Weller B, et al. Phenytoinfolic acid interaction: a lesson to be learned. Clin
64. Furlanut M, Benetello P, Avogaro A, Dainese R. Effects of folic acid on phenytoin kinetics in healthy subjects. Clin
Pharmacol Ther 1978;24:294-297.
65. O’Hare J, O’Driscoll D, Duggan B, Callaghan N. Increase in seizure frequency following folic acid. J Ir Med Assoc
66. Reynolds EH. Effects of folic acid on the mental state and fit-frequency of drug-treated epileptic patients. Lancet
67. Ralston AJ, Snaith RP, Hinley JB. Effects of folic acid on fit-frequency and behaviour in epileptics on anticonvulsants.
IJPR Volume 3 Issue 1 (2013) 7
Mohammad Asif Review Artticle
68. Grant RH, Stores OP. Folic acid in folate-deficient patients with epilepsy. Br Med J 1970;4:644-648.
69. Gibberd FB, Nicholls A, Wright MG. The influence of folic acid on the frequency of epileptic attacks. Eur J Clin
70. Ch’ien LT, Krumdieck CL, Scott CW Jr, Butterworth CE Jr. Harmful effect of megadoses of vitamins:
electroencephalogram abnormalities and seizures induced by intravenous folate in drug-treated epileptics. Am J Clin
71. Guidolin L, Vignoli A, Canger R. Worsening in seizure frequency and severity in relation to folic acid administration.
Eur J Neurol 1998;5:301-303.
72. Hiilesmaa VK, Teramo K, Granstrom ML, Bardy AH. Serum folate concentrations during pregnancy in women with
epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome. Br Med J (Clin Res Ed)
73. Drew HJ, Vogel RI, Molofsky W, et al. Effect of folate on phenytoin hyperplasia. J Clin Periodontol 1987;14:350-356.
74. Brown RS, Di Stanislao PT, Beaver WT, Bottomley WK. The administration of folic acid to institutionalized epileptic
adults with phenytoininduced gingival hyperplasia. A double-blind, randomized, placebo-controlled, parallel study.
Oral Surg Oral Med Oral Pathol 1991;71:565-568.
75. Pack AM, Morrell MJ. (2001) Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and
therapeutic implications. CNS Drugs 15:633–642.
76. Mintzer S, Boppana P, Toguri J, DeSantis A. (2006) Vitamin D levels and bone turnover in epilepsy patients taking
carbamazepine or oxcarbazepine. Epilepsia 47:510–515.
77. Siegel A, Malkowitz L, Moskovits MJ, Christakos S. (1984) Administration of 1,25-dihydroxyvitamin D3 results in
the elevation of hippocampal seizure threshold levels in rats. Brain Res 298:125–129.
78. Christiansen C, Rodbro P, Sjç O. (1974) ‘‘Anticonvulsant action’’ of vitamin D in epileptic patients? A controlled pilot
study. Br Med J 2:258–259.
79. Bouillon R, Reynaert J, Claes JH, et al. The effect of anticonvulsant therapy on serum levels of 25-hydroxy-vitamin
D, calcium, and parathyroid hormone. J Clin Endocrinol Metab 1975;41:1130-1135.
80. Silver J. Letter: Vitamin D therapy for children on anticonvulsants. N Engl J Med 1975;293:1106.
81. Peterson P, Gray P, Tolman KG. Calcium balance in drug-induced osteomalacia: response to vitamin D. Clin
Pharmacol Ther 1976;19:63-67.
82. Collins N, Maher J, Cole M, et al. A prospective study to evaluate the dose of vitamin D required to correct low 25-
hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic drug-
induced osteomalacia. Q J Med 1991;78:113-122.
83. Higashi A, Tamari H, Ikeda T, Ohtani Y, Matsukura M, Miyoshino S, Matsuda I. (1980) Serum vitamin E
concentration in patients with severe multiple handicaps treated with anticonvulsants. Pediatr Pharmacol (New York)
84. Levy SL, Burnham WM, Hwang PA. (1990) An evaluation of the anticonvulsant effects of vitamin E. Epilepsy Res
85. Raju GB, Behari M, Prasad K, Ahuja GK. (1994) Randomized, double-blind, placebo-controlled, clinical trial of D-
alpha-tocopherol (vitamin E) as add-on therapy in uncontrolled epilepsy. Epilepsia 35:368–372.
86. Tamai H, Wakamiya E, Mino M, Iwakoshi M. Alphatocopherol and fatty acid levels in red blood cells in patients
treated with antiepileptic drugs. J Nutr Sci Vitaminol (Tokyo) 1988;34:627-631.
87. Ogunmekan AO. Vitamin E deficiency and seizures in animals and man. Can J Neurol Sci 1979;6:43-45.
88. Ogunmekan AO, Hwang PA. A randomized, doubleblind, placebo-controlled, clinical trial of d-alphatocopheryl
acetate (vitamin E), as add-on therapy, for epilepsy in children. Epilepsia 1989;30:84-89.
89. Sullivan C, Capaldi N, Mack G, Buchanan N. Seizures and natural vitamin E. Med J Aust 1990;152:613-614.
90. Hom AC, Weaver RC, Alderson JJ. Efficacy of dalpha tocopheryl acetate as adjunctive antiepileptic agent in patients
with refractory epilepsy and profound developmental disability: a prospective, randomized, double-blind, placebo-
controlled trial. Epilepsia 1991;32:S62.
91. Cornelissen M, Steegers-Theunissen R, Koll E L, Eskes T, Motohara K, Monnens L. (1993) Supplementation of
vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet
Gynecol 168(3 Pt 1):884–888.
92. Deblay MF, Vert P, Andre M, Marchal F. Transplacental vitamin K prevents haemorrhagic disease of infant of
epileptic mother. Lancet1982;1:1247.
IJPR Volume 3 Issue 1 (2013) 8
Mohammad Asif Review Article
93. Carl GF, Keen CL, Gallagher BB, Clegg MS, Littleton WH, Flannery DB, Hurley LS. (1986) Association of low
blood manganese concentrations with epilepsy. Neurology 36:1584–1587.
94. Lauritzen I, Blondeau N, Heurteaux C, Widmann C, Romey G, Lazdunski M. (2000) Polyunsaturated fatty acids are
potent neuroprotectors. EMBO J 19:1784–1793.
95. Yuen AW, Sander JW, Fluegel D, Patsalos PN, Bell GS, Johnson T, Koepp MJ. (2005) Omega-3 fatty acid
supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav 7: 253–258.
96. Alan R. Gaby. Natural Approaches to Epilepsy. Alternative Medicine Review, 12, (1), 2007: 9-24.
97. Ali A. Asadi-Pooya, Scott Mintzer, and Michael R. Sperling. Nutritional supplements, foods, and epilepsy: Is there a
relationship? Epilepsia, 49(11):1819–1827, 2008.
98. Anderson GD. (2004) Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology
99. Asadi-Pooya AA, Ghafari A. (2004) Do patients with epilepsy think they need specific dietary restrictions? Epilepsy
100.Asadi-Pooya AA, Ghetmiri E. (2007) Allergy and idiopathic generalized epilepsy: a case-control study. J Pediatr
101.Asadi-Pooya AA, Sperling MR. (2007) Do foods precipitate seizures? A cross-cultural comparison. Epilepsy Behav
102.Camfield PR, Camfield CS, Dooley JM, Gordon K, Jollymore S, Weaver DF. (1992) Aspartame exacerbates EEG
spike-wave discharge in children with generalized absence epilepsy: a double-blind controlled study. Neurology
103.Christiansen C, Rodbro P, Lund M. Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled
therapeutic trial. Br Med J 1973;4:695-701.
104.Gissel T, Poulsen CS, Vestergaard P. (2007) Adverse effects of antiepileptic drugs on bone mineral density in children.
Expert Opin Drug Saf 6:267–278.
105.Hewitt NJ, Lecluyse EL, Ferguson SS. (2007) Induction of hepatic cytochrome P450 enzymes: methods, mechanisms,
recommendations, and in vitro-in vivo correlations. Xenobiotica 37:1196–1224.
106.Kumandas S, Koklu E, Gms H, Koklu S, Kurtoglu S, Karakukcu M, Keskin M. (2006) Effect of carbamezapine and
valproic acid on bone mineral density, IGF-I and IGFBP-3. J Pediatr Endocrinol Metab 19:529–534.
107.Raju GB, Behari M, Prasad K, Ahuja GK. 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.
108.Rapuri PB, Gallagher JC, Nawaz Z. (2007) Caffeine decreases vitamin D receptor protein expression and
1,25(OH)2D3 stimulated alkaline phosphatase activity in human osteoblast cells. J Steroid Biochem Mol Biol
109.Schlanger S, Shinitzky M, Yam D. Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy
patients. Epilepsia 2002;43:103-104.
110.Vaddadi KS. The use of gamma-linolenic acid and linoleic acid to differentiate between temporal lobe epilepsy and
schizophrenia. Prostaglandins Med 1981; 6:375-379.
111. Verrotti A, Greco R, Morgese G, Chiarelli F. Carnitine deficiency and hyperammonemia in children receiving valproic
acid with and without other anticonvulsant drugs. Int J Clin Lab Res 1999;29:36-40.
112.Volpe SL, Schall JI, Gallagher PR, Stallings VA, Bergqvist AG. (2007) Nutrient intake of children with intractable
epilepsy compared with healthy children. J Am Diet Assoc 107:1014 -1018.
IJPR Volume 3 Issue 1 (2013) 9