Natural Approaches to Epilepsy_0

Alternative Medicine Review Voiume 12, Number 1 2007

Natural Approaches to EpilepsyAlan R. Gaby, MD

Abstract

This article reviews research on the use of diet, nutritional

supplements, and hormones in the treatment of epiiepsy.

Potentially beneficial dietary interventions include identifying

and treating blood glucose dysregulation, identifying and

avoiding allergenic foods, and avoiding suspected triggering

agents such as alcohol, aspartame, and monosodium

glutamate. The ketogenic diet may be considered for severe,

treatment-resistant cases. The Atkins diet (very low in

carbohydrates) is a less restrictive type of ketogenic diet that

may be effective in some cases. Nutrients that may reduce

seizure frequency include vitamin B6. magnesium, vitamin E,

manganese, taurine, dimethylglycine, and omega-3 fatty acids.

Administration of thiamine may improve cognitive function in

patients with epiiepsy, Supplementation with folic acid, vitamin

B6, biotin, vitamin D, and L-carnitine may be needed to prevent

or treat deficiencies resulting from the use of anticonvulsant

drugs. Vitamin K l has been recommended near the end of

pregnancy for women taking anticonvulsants. Melatonin may

reduce seizure frequency in some cases, and progesterone

may be useful for women with cyclic exacerbations of seizures.

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.

{Altern Med Rev 2007:12(l);9-24)

IntroductionEpilepsy is a disorder of brain electrical activity

that results in recurrent seizures. The type of seizure de-pends on the portion of the brain affected. While thereare many different causes of seizures, including brainrumor, head injury, stroke, and alcohol withdrawal, thediscussion in this article is limited mainly to cases inwhich the cause is tdiopathic (primary epilepsy).

Conventional treatment of epilepsy consistsprimarily of anticonvulsant medications. Akhoughthe.se drugs often control or reduce the frequency of sei-zures, some patients show little or no improvement.

A number of dietary modifications, nutritionalsupplements, and hormones have been found to be ben-eficial for some patients with epilepsy.

Potentially useful dietary interventions includemeasures to stabilize blood glucose levels, identifica-tion and avoidance of allergenic foods, and avoidanceof potential inciting agents (such as ethanol and aspar-tame). Tbe ketogenic diet has been successful for manypatients, but because of its highly restrictive nature andpotential to cause significant adverse effects, its use isrestricted to severe cases that tail to respond to othertreatments. A less restrictive version of tbe ketogenicdiet, the Atkins diet, has sbown promise and deservesfurther study.

Several different nutrients (and two bormones)may also be beneficial in selected patients witb epilep-sy. Tbe fact tbat nutritional factors are involved in tberegulation of electrical activity in tbe brain is Indicated

Alan R. Gaby, MD - Private practice 17 yeais, specializing In nutritional medicine;past-president, American Holistic Medical Association; contnbuting editor.Alternative Medicine Review: auttiof. Preventing and Reversing Osteoporosis (Prima.1994) and 7?ie Doctoi's Guide to Vitamin 86 (Rodale Press. 1984); co-auUior.The Patients Book of Natural Healing (Prima. 1999}; publistied numerousscientific papers in the field of nutritional medicine; contributing medical editor,The Townsend Letter for Doctors and Patients since 1985,Correspondence address: 301 Dorwood Drive, Carlisle, PA 17013

Page 9

Alternative Medicine Review Volume 12, Number 1 2007

bv the fact that severe deficiency of thiamine, mag-n' .sium, or vitamin B6 can cause seizures. A subnor-mal concentration of each of rhese nutrients has beenFound to be common in patients with epilepsy. Whilethe severity of these deficiencies is probably not greatenougb in most cases to cause seizures in otherwisehealthy people, marginal status with respect to any ofthese nutrients could conceivably exacerbate a seizuredisorder due to another cause.

In addition, some patients with epilepsymight have a higber-than-normal requirement forone or more nutrients that play a role in brain elec-trical activity. That phenomenon has been clearlydemonstrated in the case of vitamin B6-dependentepilepsy, a condition in which intractable seizures canbe completely controlled by administration of largedoses of vitamin B6. The existence of this relativelynire syndrome raises the possibility that more subtleterms of nutrient dependency occur more commonly.While mildly or moderately increased requirementsfor vitamin B6 or other nutrients may not by them-selves be sufficient to cause seizures, a failure to meetthese increased requirements could aggravate an ex-isting seizure disorder.

Some studies have found tbat supplemen-tation witb individual nutrients reduced seizure fre-quency or improved other aspects of health in patientswith epilepsy, but other studies have failed to confirmthose findings. Administration of combinations ofn jtrients might be more effective than supplementingwitb a single nutrient, but that possibility has largelybeen unexplored. Nutrient supplementation may alsobe necessary to prevent or reverse the effects of cer-tain deficiencies that frequently result from the use ofanticonvulsant drugs. The potential benefits of nutri-ent supplementation in patients with epilepsy mustbe weighed against reports that large doses of certainnutrients (such as vitamin B6 and foUc acid) can in-terfete with the effects of anticonvulsants.

Because there are many different types of ep-ilepsy, a nutritional intervention that is helpful for onepatient may not be beneficial for another. Some stud-ies did not specify the types of epilepsy being treated,so it is difficult to generalize results. Nevertheless,natural approaches to the treatment of epilepsy showpromise and should be considered as part of the over-all treatment of epilepsy.

Dietary FactorsHypoglycemia/Hyperinsulinemia

Seizures are a known manifestation of hypo-glycemia.''^ In patients with epilepsy, hypoglycemiamight decrease the threshold for seizure development.In one study of 92 patients with epilepsy, 56.4 percentwere found to have a subnormal fasting blood glucoseconcentration.'

In addition, transient EEG abnormalities havebeen observed in some patients during a glucose toler-ance test. Tliese abnormalities occurred, not when theblood glucose level was at its lowest point, but at a timethat insulin levels would have been expected to be ele-vated."* These EEG changes were hypothesized to resultfrom insulin-induced transport of water and electro-lytes into the brain, leading to cerebral hyperosmolality.While the observed EEG changes were not necessarilyof the type associated with seizures, these findings raisethe possibility that hyperinsulinemia could trigger sei-zures in patients with epilepsy.

Thus, hypoglycemia and hyperinsulinemiamight each contribute to the pathogenesis of epilepsyin some cases. Patients with epilepsy who have evidenceof these abnormalities might benefit from nutritionalinterventions, such as avoiding refined sugar, caffeine,and alcohol; eating frequently; consuming adequateamounts of protein; and supplementing with chromi-um, other trace minerals, magnesium, and B vitamins.

In case reports, specific foods were implicatedin epilepsy causation;' the avoidance of symptom-evok-ing foods resulted in a reduction in seizure frequencyor elimination of seizures/'' In a study of 63 childrenwitli epilepsy, identification and avoidance of allergenicfoods was frequently successful for patients who hadother symptoms suggestive of allergy, but not for chil-dren who had epilepsy alone.

For four weeks, 63 children with epilepsy un-derwent an elimination diet consisting of lamb, chicken,potato, rice, banana, apple, cabbage, sprouts, cauliflower,broccoli, cucumber, celery, carrots, parsnips, water, salt,pepper, pure herbs, calcium, and vitamins. Of 18 chil-dren who had epilepsy alone, none improved. The other45 children with epilepsy also had recurrent migraines,abdominal symptoms, or hyperkinetic behavior. Of

Page 10


those children, 55.6 percent stopped having seizuresand an additional 24.4 percent had fewer seizures dur-ing diet therapy (a total of 80 percent with complete orpartial resolution of seizures). Headaches, abdominalpains, and hyperkinetic behavior resolved in all patientswhose seizures resolved, as well as in some patients whocontinued to have seizures. Symptoms were evoked by42 different foods, and seizures occurred after ingescionof 31 different foods. Most children reacted to severalfoods. Both generalized epilepsy (including myoclonicseizure.s and petit nial) and partial epilepsy improved onthe diet. In double-blind, placebo-controlled food chal-lenges, symptoms recurred in 15 of 16 children, includ-ing seizures in eight cases, after ingestion of offendingfoods; whereas, no symptoms recurred when placebowas given.**

The prevalence of celiac disease has been foundto be higher in patients with epilepsy than in controls(1/44 versus 1/244, respectively).'' Seizures have im-proved in patients with celiac disease who consumeda gluten-free diet,'" but only when the diet was startedsoon after the onset of epilepsy." Most epileptic pa-tients with celiac disease did not have gastrointestinalsymptoms at the time of presentation, so testing for ce-liac disease should be considered even in the absence ofsuch symptoms. Some patients with epilepsy and celiacdisease have also been found to have cerebral calcifica-tions,'^''' tliie significance of which is not clear.

Dietary Inciting FactorsIn some cases, epileptic seizures have been trig-

gered by excessive alcohol intake.'^Two case reports indicate ingestion of mono-

sodium glutamate appeared to trigger or exacerbate sei-zures in children."'

Grand mal seizures have occurred after con-sumption of aspartame by people who had no priorhistory of epilepsy.'' ' Ingestion of a drink containingaspartame (40 mg/kg body weight) also exacerbatedEEG spike-wave discharges in children with a historyof absence seizures.'''

However, in trials funded by the NutraSweetCompany (the manufacturer of aspartame), adminis-tration of aspartame (34 mg/kg/day for two weeks or asingle dose of 50 mg/kg) did not provoke seizures in pa-tients with epilepsy or in people who reported a history

of aspartame-induced seizures."""' A potential limita-tion of these trials is that aspartame was administered incapsules, rather than in soft drinks or other aspartame-containing foods or beverages. As aspartame in com-mercial products is said to undergo chemical changes onexposure to high temperatures or after storage for morethan two months, these degradation products may bepartly responsible tor the reported adverse eflects of as-partame." Therefore, symptoms that occur after inges-tion of aspartame-containing commercial products orhot drinks to which aspartame has been added may notbe reproducible by challenging with aspartame in cap-sules. Based on the available evidence, aspartame shouldbe considered a potential trigger for seizures and shouldbe excluded during an elimination diet.

Ketogenic DietTlie ketogenic diet has been used since 1921

to control seizures in children who do not respond toanticonvulsant medications.^'^' The diet is calorie-re-stricted and provides a ratio of fat to (carbohydrate +protein) ranging from 2:1 to 5:1. The proportion of to-tal energy derived from fat ranges from 82-92 percent.Consuniing a ketogenic diet produces a state of keto-sis, which helps control seizures through an unknownmechanism. Fluid intake is restricted to maintain urinespecific gravity at 1.020-1.025, since fluid intake dilutesblood ketoncs.

In different studies, 40-70 percent of patientsfollowing the diet experienced at least a 50-percent re-duction in seizure frequency, and 10-33 percent becameseizure-free. In many cases, medications could be dis-continued or the dosages decreased. Two children withacquired epileptic aphasia were also successfully treatedwith this diet.'^ According to some research, myoclonicepilepsy responds best to the ketogenic diet.^^ However,another study found that the response to the diet didnot vary significantly according to seizure type."'' Thediet is most effective in children ages 2-5 years, althoughpatients of other ages have also benefited.^"

To be effective, the diet must be followed strict-ly; if the patient discontinues it, seizures are likely toreturn within hours. Typically, treatment is initiated inthe hospital, starting with a 36-hour water fast to in-duce ketosis; however, some investigators have foundthat it is not necessary to begin the diet with a fast.

Page 11


Tbe ketogenic diet is usually followed for abouttwo years, after which the proportion of fat is reducedgradually over 6-9 months to that of a regular diet. Af-ter a patient lias been on the diet for two years, seizuresaic less likely to recur on resumption of a normal diet.In some cases, the diet regimen is repeated if seizuresrecur.

There are some drawbacks to the ketogenicdiet. Supplementation with multivitamins, calcium, andiron is necessary to prevent nutritional deficiencies. Iniiiidition, the ketogenic diet is unpalatable and is diffi-cult for parents to administer.

Ketogenic Diet for AdultsWhile most ketogenic diet studies have been

conducted in children, one trial investigated its effect inI 1 adults (ages 19-45 years; median, 32.2 years) withn-fractory epilepsy, At eight months of follow-up, threepatients li.id a 90-percent reduction in seizure frequen-cy compared with baseline, three patients had a 50- to89-percent decrease, and one patient had a less-than-50-percent decrease. All types of seizures responded tothe diet. Common adverse effects included constipadon,menstrual irregularities, and increases in triglyceridelevels and cholesterol/HDL ratios."

Ketogenic Diet with Medium-chainTriglycerides

The triglycerides of ocranoic and decanoic ac-ids (medium-chain triglycerides; MCTs) are more ke-togenic than long-chain triglycerides present in dietaryfats. Diets containing large proportions of MCTs (usu-ally provided by supplementing with MCT oil) are alsoeasier to prepare, more palatable, better tolerated, andrequire less carbohydrate and protein restriction thanstandard ketogenic diets.

Tlie MCT ketogenic diet, which provides 50-70 percent ot total energy in the form of MCTs, hasbeen used as an alternative to the classic ketogenicdiet."'^'' In one study, adherence to this diet resultedin improvement or complete control of seizures in 44percent oi 50 children with drug-resistant epilepsy.''(Children who have had a positive response to this dietmay be able to taper off the diet after 3-4 years withoutexperiencing a recurrence of seizures. While the MCTdiet is frequently well tolerated, some patients abandonit because of gastrointestinal intolerance.

Ketogenic Diet: Adverse EffectsThe ketogenic diet has caused a number of ad-

verse effects, some serious. Initiation of the diet can re-sult in vomiting, hypoglycemia, or dehydration. In onestudy, serious adverse events (severe hypoproteinemia,Fanconi's renal tubular acidosis, or marked abnormali-ties on liver function tests) occurred in five of 52 chil-dren on a ketogenic diet.^" Other potential side effectsinclude increased bruising or other minor bleeding (inassociation with a prolonged bleeding time), constipa-tion, and diarrhea."'""'

Long-term problems include moderate growthretardation, renal stones (5-8% of cases), gallstones,acidosis or metabolic problems (particularly during ill-ness), recurrent infections, hypercholesterolemia, hy-peruricemia, vitamin deficiency, and feeding problems.Prolonged ketosis may raise the serum level of pheno-barbitone, which can result in alopecia, renal stones, andgrowth retardation.'^

Tlie ketogenic diet and anticonvulsant drugsboth have an adverse effect on bone density, which canbe partially reversed with vitamin D supplementation.Carnitine deficiency may also occur with the ketogenicdiet, particularly in patients taking valproic acid. L-car-nitine supplementation is recommended for patientswho have low serum carnitine levels."

Patients on the ketogenic diet must be moni-tored closely by a practitioner experienced in its use.

Atkins DietThe Atkins diet is a low-carbohydrate, high-

fot diet used by millions of people for weight reduction,.Like the ketogenic diet, the Atkins diet can induce astate of ketosis, but it has fewer restrictions on caloriesand protein. In addition, the Atkins diet does not re-quire fluid restriction and does not need to be startedin the hospital.

According to one study, the Atkins diet maybe an effective alternative to the ketogenic diet in somechildren with intractable epilepsy. Twenty children(ages 3-18 years) with intractable epilepsy, with at leastthree seizures per week, who had been treated with atleast two anticonvulsants, followed a modified Atkinsdiet (nature of the modification not specified) over asix-month period. Carbohydrates were limited to 10g/day for the first month and consumption of fats was

Page 12

Alternative Medicine Revievi/ Volume 12, Number 1 2007

encouraged. All children received vitamin and calciumsupplements. At six months, 13 patients (65%) hadmore than 50-percent improvement and seven patients(35%) had more than 90-pei-cent improvement (fourwere seizure-free). Small increases were seen in serumcholesterol and blood urea nitrogen levels during thestudy.''"

In another study, two adults (ages 42 and 52)with epilepsy showed no improvement on tbe Atkinsdiet/ ' Table 1 weighs the evidence for various dietary/metabolic interventions.

increased xanthurenic acid excrecion following a tryp-tcphan load).^' However, other factors may be involvedas well, since there does not appear to be a strong rela-tionship between low vitamin B6 levels and use of anyspecific anticonvulsant medication.

Vitamin B6 supplementation is clearly benefi-cial in cases of vitamin B6-dependent seizures. Somestudies have demonstrated improvements in patientswith non-vitamin B6-depenclent epilepsy as well, al-though the research has produced conflicting results.

Table 1, Dietary or Metabolic Factors Associated with Epilepsy

Dietary or Metabolic Factors

Reactive hypoglycemia/hypertnsulinemiaFood allergy

Reaction to aspartame

Reaction to monosodium glutamateKetogenic diet

Atkins {very low carbohydrate) diet

Evidence

Clinical observations and lab findings

Case reports and uncontrolled clinical trialCase reportsCase reports

Multiple uncontrolled clinical trials

Uncontrolled clinical trial

Nutritional SupplementsVitamin B6

Experimentally-induced vitamin B6 deficiencyresulted in seizures in rats"" and swine.''' In the early1950s, numerous infants in the United Stares devel-oped convulsions traced to the use of a formula that wasdeficient in pyridoxine.''^''" Seizures also occurred in aninfant fed exclusively on powdered goat's milk, whichhad undetectable levels of the vitamin. The seizures re-solved after supplementation with vitamin B6.'"'

Vitamin B6 deficiency has been found in a highproportion of patients with epilepsy. Of 62 drug-treat-ed epileptic patients, 55 percent had a subnormal bloodlevel ot pyridoxal phosphate (PLP).''^ In a study of 68institutionalised patients with severe epilepsy, 37 per-cent had a reduced serum concentration of pyridoxal.'*'Low levels of vitamin B6 may be due in part to treat-ment with phenytoin, which has been associated withlaboratory evidence of reduced vitamin B6 status (i.e..

Vitamin B6-dependent SeizuresVitamin B6-dependent epilepsy is a rare inher-

ited disorder that usually presents with intractable sei-zures in the first six months of life. The seizures can becompletely controlled by administration of large dosesof vitamin B6,^-''^ but if the condition is not treatedpromptly irreversible neurological damage may occur.

The diagnosis of vitamin B6 dependency canbe established hy intravenous administration of pyri-doxlne, which results in cessation of seizures withinminutes. Intravenous administration of vitamin B6 toinfants afirer a long period of convulsions has been fol-lowed in some cases by acute hypotonia; in one case as-sisted ventilation was required.^'' For that reason, resus-citation equipment should be available during a trial ofintravenous vitamin B6.

Most patients can subsequently be maintainedon 25-50 mg/day oral pyridoxine, although one childrequired 200 mg/day.'^' Long-term supplementation isnecessary; discontinuation of pyridoxine after several

Page 13


years of good seizure control has resulted in death fromstatus epilepticus.

Some patients with vitamin B6-dependent sei-zures present with an atypical picture, including lateronset (up to 19 months of age),'' • ' a seizure-free periodbefore administration of pyridoxine, a long remissionafter withdrawal of pyridoxine, and an atypical seizuret)'pe. Because the spectrum of vitamin B6-dependentseizures is broader than initially thought, it has beenrecommended that a trial of vitamin B6 be consideredin all infants and young children with intractable epi-lepsy.'-''

It is also recommended that women who havea child with vitamin B6 dependency receive vitamin B6supplements during subsequent pregnancies.

Vitamin B6 for Non-vitamin B6-dependentEpilepsy

Vitamin B6 supplementation has been report-ed to be beneficial in some, but not all, studies of pa-tients with non-vitamin B6-dependent epilepsy.

Twenty-six children with epilepsy received 160mg/day pyridoxine. Ot the 19 patients with laboratoryevidence of vitamin B6 deficiency (i.e., increased uri-nary excretion ot xanthurenic acid following a trypto-phan load), nine had complete or partial amelioration ofseizures, and some ol these patients were able to discon-tinue anticonvulsant medication. Of tbe seven patientsvv'ith a normal tryptophan load test, none responded topyridoxine.'''^

Of three children (ages 3-8 years) with epilepsyassociated with impaired intellectual development, pro-gressive emotional disturbances, and abnormal EEGs,all excreted elevated amounts of xanthurenic acid aftera tryptophan load. After administration of 60-160 mgpyridoxine daily, tryptophan metabolism became nor-mal and substantial clinical improvement occurred.*""

Pyridoxine (20 mg, 3-6 times daily) was givenfor an unspecified length of time to 14 epileptic patients,ages 2-17 years. All patients had petit mal and one alsohad grand mal epilepsy. Seizures ceased in five patientsand became less frequent in three others.*"'

Fifty-six epileptic children received 160-200mg pyridoxine daily tor at least six weeks. Signiticantclinical improvement was seen in five cases.*"'

A 23-year-old man with recurrent seizurespresented with status epilepticus, which resolved imme-diately following intravenous administration ot 60 mgPLP. Prior to treatment, his serum pyridoxine concen-tration was markedly decreased (80% below the lowerlimit of normal).*^*

Pyridoxine was given intravenously to infantsand children with acute, recurrent seizures due primar-ily to acute infections. A dose of 30 or 50 mg/kg/daywas administered in 100-250 mL of 10-percent glucoseover 2-4 hours and given for a few days. Anti-epilepticdrugs were used as appropriate. Ihe treatment was rated"very etFective" (i.e., duration and frequency of seizuresdecreased by more than 75 percent afrer 24 hours) in62.5 percent ot patients receiving pyridoxine comparedwith 26 percent of control patients (p<0.001); bothdoses of pyridoxine were equally etFective. Aside fromtransient Hushing, no adverse effects were seen.^

In other studies, pyridoxine in doses of 20-100mg/day orally* - or 300 mg/day parenterally''^ pro-duced no clinical improvement in patients with varioustypes of epilepsy.

Pyridoxine versus Pyridoxal PhosphateWliile most patients with vitamin B6-depen-

dent seizures can be effectively treated with pyridoxine,some patients have only responded to PLP, the biologi-cally active form of vitamin B6.''"'''' The average effectiveoral dose in six patients with PLP-responsive seizureswas 30 mg/kg/day (range, 7-38 mg/kg/day), whichwas significantly higher than the average effective pyri-doxine dose (18 mg/kg/day) in pyridoxine respond-ers.™ Because of superior efficacy in certain cases, PLPshould be considered for first-line treatment of patientsin whom a clinical trial of vitamin B6 is indicated. PLPshould also be considered for patients with suspectedvitamin B6-responsive seizures that are unresponsive topyridoxine.

Vitamin B6 in Clinical PracticeVitamin B6 should be tried in all infants and

young children with intractable epilepsy. For childrenand adults whose seizures are well controlled on medi-cation, moderate doses of vitamin B6 (such as 10-50mg/day) may be considered to prevent possible drug-induced vitamin B6 deficiency. Although larger doses

Page 14

Alternative Medicine Review Volume 12. Number 1 2007

might be appropriate in selected cases, high-dose vita-min B6 appears to interfere with some anticonvulsantmedications. In one study, supplementation with 80-200 mg/day pyridoxine reduced serum phenytoin andphcnoharbitone levels in epileptic children. ' In addi-tion, long-term administration of 500 mg/day or moreof pyridoxine has resulted in neurotoxicity in someadults/~ which could presumably occur at lower dosesin children.

One practitioner found that supplementationwith 600 mg/day vitamin B6 reversed phenytoin-in-duced gingival hypcrplasia in several patients; however,such high doses are probably excessive for most patientswith epilepsy/' Lower doses might be effective for phe-nytoin-induced gingival hyperplasia, particularly whenused in combination with a folic acid mouth rinse (seebelow).

Patients being treated with vitamin B6 shouldprobably also receive a magnesium supplement, in viewof evidence that these nutrients work together and an-ecdotal reports that vitamin B6 supplementation in-creases the requirement for magnesium.

MagnesiumSevere magnesium depletion can cause sei-

zures^'"'"' or increase susceptibility to seizure-inducingstimuli. *• Intravenously infused magnesium exerted ananticonvulsant effect against experimentally-inducedepileptic foci in cats and dogs.^^ In humans, parenter-ally administered magnesium is an effective treatmentfor the seizures ot neonatal tetany"** and eclampsia andpossibly for those associated with ethanol withdrawaland acute intermittent porphyria."''

Magnesium concentrations in serum and ce-rebrospinal fluid (CSF) were significantly lower in 40patients with grand mal epilepsy than in controls.^'"^Serum and CSF magnesium levels fell with increasingduration and frequency ot seizures. Oral administra-tion of magnesium has been associated in some caseswith an improvement in EEG findings and a reductionin seizure frequency.**^

Vitamin EErythrocyte or plasma vitamin E concentra-

tions were lower in children with epilepsy than inhealthy controls. Vitamin E levels were lower in childrenreceiving multi-drug therapy than in children receiving

single-drug therapy. ^** In some studies, vitamin E sup-plementation reduced seizure frequency, although noimprovement was seen in other studies.

Twenty-four children (ages 6-17 years) withtreatment-resistant epilepsy were randomly assigned toreceive, in double-blind fashion, 400 lU/day d-alpha-tocopheryl acetate or placebo for three months. Of the12 patients given vitamin E, 10 had a greater-than-60-percent reduction in seizure frequency (of that 10, sixhad a 90-100% reduction). None of the patients in theplacebo group had a greater-than-60-percent reductionin seizure frequency (p<0.05 for the difference in re-sponse rate between groups). Vitamin E treatment hadno effect on plasma levels of anticonvulsant medica-tions.'*'

Thirty-five epileptic children and adults wererandomly assigned to receive, in double-blind fashion,250 lU/day vitamin E or placebo for three months.Anticonvulsants were continued as previously. Of the12 adults receiving vitamin E, eight had a decrease inseizure frequency, two had an increase, and two wereunchanged. Of the six children receiving vitamin E, twohad a reduction in seizure frequency and four had nochange. No changes were seen in the children and adultsreceiving placebo/"

In a double-blind stLidy published as an ab-stract, supplementation with vitamin E reduced meanseizure frequency by 32 percent (p=0.03) in a group ofseverely mentally handicapped patients with treatment-resistance epilepsy. However, information was omittedregarding the dosage regimen and the response in theplacebo group.^'

In a study of 10 severely handicapped epilep-tic patients (ages 4-23 years) receiving anticonvulsants,supplementation with 100 IU/day dl-alpha-tocopherylacetate for one month had no effect on seizure frequen-cy.««

Forty-three teenagers and adults with uncon-trolled epilepsy were randomly assigned to receive, indouble-blind fashion, 600 IU/day vitamin E or pla-cebo for three months. After a one-week washout pe-riod, each patient received the alternate treatment foran additional three months. Anticonvulsant medica-tions were continued as previously. Tlie mean seizurefrequency decreased by 25.7 percent during the placeboperiod and by 13.8 percent during the vitamin E periodcompared with baseline."^

Page 15


Although the research on efficacy is conflicting,vitamin E is relatively safe and may be considered foradjunctive treatmenr in epilepric patients, particularlychildren.

ManganeseIn rats, manganese deficiency increased sus-

ceptibility to electroshock-induced convulsions. In ad-dition, hydralazine-induced seizures in rats were pre-vented by prior administration of manganese.™

In humans vi'itb epilepsy, whole-blood man-ganese levels were significanrly lower by 20-41 percentthan in controls.'" * Manganese concentrations in epi-leptic patients did not correlate with seizure frequencyor the type, dose, or plasma levels of anticonvulsanrmedication. Concentrations of other minerals, suchas zinc and copper, were generally normal, suggestingthat the association between manganese deficiency andepilepsy was not due to general malnutrition. Patientswhose epilepsy was a result ot trauma had significantlyhigher blood manganese concentrations than patientswith no history of trauma,''- which suggests that man-ganese deficiency is a primary contributing factor, ratherthan a consequence, of epilepsy or its treatment.

One group of practitioners stated that unspeci-fied doses of manganese were helpful in controlling epi-leptic seizures.''^ In a case report, a 12-year-old boy withpoorly controlled epilepsy and a low blood manganeselevel experienced fewer seizures after treatment with 20mg manganese daily. A dose of 10 mg/day was tried ini-tially tor three weeks, but was not effective.'"

TatfrineTaurine acts as a modulator of membrane ex-

citability in the central nervous system by inhibiting therelease of other neurotransmitters and decreasing mitO'chondri;il release of calcium.^" Taurine concentrationshave been found to be elevated in serum, but decreasedin the brain, of some patients with epilepsy. In contrast,serum concentrations of most other amino acids werelower in patients with epilepsy than in healthy controls.Taurine administration partially corrected these low se-rum amino acid concentrations.^''"*^

Taurine has been administered orally or intra-\'enousiy at a wide range of doses (200 mg/day to 21 g/day) for varying periods of time to patients with severe.

intractable epilepsy. In some studies, a significant reduc-tion in seizure frequency was observed,'"^'"^ whereas nobenefit was seen in others.""* According to one report,taurine was effective against partial epilepsy but bad lit-tle effect on generalized epilepsy. Tlie beneficial effectsof taurine frequently diminished or disappeared after afew weeks of treatment. One possible explanation forthe loss of efficacy is that high-dose taurine caused ami-no acid imbalances, as suggested by the appearance ofgeneralized aminoaciduria in a patient during treatmentdaily with 2.0-2.5 g taurine. It hvis been suggested thatthe optimal dose of taurine to treat epilepsy might be intbe range of 100-500 mg/day, and in one report a loss ofantiseizure activity was seen in some patients when thedose was increased above 1.5 g/day. While additionalstudies are needed to determine taurine's optimal dos-age range, no specific dosage regimen has been shown toproduce long-lasting improvement of epilepsy.

DimethylglycineDimethylglycine, a metabolite of betaine, dem'

onstrated anticonvulsant activity in mice in one study,""but not in another.""

In a case report, a 22-year-old mentally handi-capped man with mixed complex, partial, and grand malseizures had been having 16-18 generalized seizures perweek, despite therapeutic levels of pbenobarbital andcarbamazepine. His mother began giving him 90 mgdimethylglycine twice daily because of a suggestion itmight improve his stamina. Within one week his seizurefrequency dropped to three per week. Two attempts towithdraw dimethylglycine resulted in a dramatic in-

crease in seizures.In follow-up studies, administration of di-

methylglycine to 24 epileptic patients in doses of 300-810 mg/day for up to 30 days did not produce any im-provement."^'" It was suggested that the one patientwho benefited from dimethylglycine may have had anisolated metabolic defect that was overcome by treat-ment with this compound.

ThiamineSevere thiamine deficiency can cause seizures

in both alcoholic and non-alcoholic patients; these sei-zures are reversible with tbiamine supplementation. Low

Page 16


thiamine status was found in 25 percent of 620 epilep-tic patients attending an outpatient cUnic in one study,and in 31 percent of 72 patients in another study. ''*' ^In a placebo-controlled trial, supplementation of epilep-tic patients with 50 mg thiamine daily for six monthswas associated with significant improvements in testsof both verbal and non-verbal IQ." ' Thus, suboptimalthiamine status may be a factor in che impaired cogni-tive function seen in some patients with epilepsy.

Folic AcidSeizures occur in some infants with cerebral

tolate deficiency, a syndrome that also includes slowliead growth, psychomotor retardation, cerebellar atax-ia, and other neurological abnormalities. This syndromeis caused by impaired transport ot folate across theblood-brain barrier into the central nervous system. Tlietransport defect can be overcome by administration offolinic acid (an active form of folic acid), which bypassesthe blocked folate transport mechanism. Tliere are sev-eral case reports in which administration of tolinic acid(2.5-20 mg twice daily in one study, 0.5-1.0 mg/kg bodyweight per day in another) resulted in improvement orcomplete control ot seizures in infants.'"'"'^

In patients with seizures not due to cerebralfolate deficiency, folic acid supplementation is of littleor no benefit with respect to seizure control, and mayeven exacerbate seizures in some instances (see below).However, folate deficiency is common in patients withepilepsy and may have negative effects on other as-pects of health. Subnormal serum or erythrocyte folateconcentrations have been observed in 19-88 percentot patients with epilepsy in different smdies.'*^''*''"^''"Low folate levels were found more frequently amonginpatients than outpatients, and in those with coexist-ing psychiatric illness than those without psychiatricillness. Folate deficiency is due primarily to tbe use ofanticonvulsant medications (e.g., phenytoin, valproate,carbamazepine, phenobarbital, and primidone), whichinterfere with folic acid absorption.'^^'^^

While correction of folate deficiency is de-sirable, administration of large doses of tbiic acid candecrease blood levels of phenytoin, phenobarbital, .indcarbamazepine,'^''^^^ potentially interfering with seizurecontrol. An increase in seizure trequency has been seenin some,130 but not all,'^' ' " studies in which high-

dose folic acid (5 mg three times per day) was given todrug-treated epileptic patients. In addition to interfer-ing with anticonvulsant medication, high-dose folic aciditself may be epileptogenic. Intravenous .administrationo^ 14.4 mg tolic acid induced a tonic-clonic seizure inone epileptic patient, although other patients expe-rienced no adverse effects from 75 mg folic acid givenintravenously."'^ One woman with epilepsy had an in-crease in seizure frequency and severity after receiving0.8 mg folic acid per day, which was prescribed becauseshe was planning to become pregnant.''^ A cause-effectrelationship in this case is uncertain.

Based on these observations, modest doses offolic acid should be used to treat folate deficiency inepileptic patients. A study of pregnant epileptic womentaking anticonvulsant drugs found that a folic acid doseof 100-1,000 meg/day was sufficient to prevent folatedeficiency and did not impair seizure control.''^

Folic acid has also been used to treat phenytoin-induced gingival hyperplasia. In a small double-blindstudy, use of a 0.1-percent folic acid mouth rinse for sixmonths significantly reduced the severity of this condi-tion, whereas a placebo was ineffective. Patients used 5mL of the mouth rinse twice daily, spitting it out afterrinsing for two minutes (this solution should not beswallowed, as doing so would provide 10 mg/day offolic acid). Oral, rather than topical, administration offolic acid (3-4 mg/day) produced little or no improve-ment in phenytoin-induced gingival hyper

BiotinSerum biotin levels were below normal in 74

percent of 264 epileptic patients on long-term anticon-vulsant therapy."'' Low biotin levels appear to resultfrom an acceleration ot biotin catabolism by phenytoin,carbamazepine, and phenobarbital.'*'"''" In addition,carbamazepine and primidone may inhibit intestinalabsorption of biotin.'**^ Interestingly, dermatitis andataxia, side effects of many anticonvulsants, are also ob-served in patients with an inborn error of biotin-depen-dent enzymes.

There is no evidence that biotin supplementa-tion interferes with the effect of anticonvulsants. To thecontrary, correction of biotin deficiency might reduceseizure frequency, as suggested by the face that biotin-responsive seizures have occurred in some patients withinborn errors of biotin metabolism.'''*

Page 17


Vitamin DPatients taking anticonvulsants are at increased

risk of developing vitamin D deficiency, apparently be-cause these drugs induce liver enzymes that inactivatevitamin D.'"' '^' Rickets/"' osteomalacia,''' and lowbone mineral content'""* have been reported in drug-treated epileptic patients. The frequency with whichthese disorders occurred has varied widely in differentstudies, in part because of difi^erences in sun exposure.

In patients with osteomalacia resulting fromrhe use of phenytoin and phenobarbiral, the amount ofvitamin D3 needed to achieve positive calcium balancewas approximately 975 IU/day.'"*'* In patients with low25-hydroxyvitamin D levels who were taking phenyt-om, carbamasepine, and phenobarbitone, either aloneor in combination, the amount of vitamin D3 requiredto maintain a normal serum 25-hydroxyvitamin D con-ct-ntration (15 ng/mL or greater) ranged from 400 to4,000 IU/day, with 72 percent of patients requiring2,400 IU/day or more.'-"

Essential Fatty Acidshive severely mentally handicapped patients

(ages 12-26 years) with more than 3-4 grand mal sei-zures per month received a daily supplement provid-ing 900 mg eicosapentaenoic acid (EPA), 2.3 g doco-sahcxaenoic acid (DHA). and 50 mg alpha-linolenicacid. All five patients experienced a marked reductionin both frequency and severity of grand mal seizures."^ 'In a double-blind study that included 57 adults (meanage, 39 years), supplementation with fish oil (providing1 g/day EPA and 0.7 g/day DHA) reduced seizure fre-quency during the first six weeks of treatment, but thebeneficial effect was not sustained thereafter.'^^

In contrast co the possible beneficial effect ofomega-3 fatty acids, the omega-6 fatty acids in eveningprimrose oil may have deleterious effects in some pa-tients with epilepsy. Tliere are several case reports inwhich administration of evening primrose oil appearedto exacerbate or unmask temporal lobe epilepsy.'^''^^

CarnitineTreatment of children with valproic acid,

particularly in combination with other anticonvulsantdrugs, reduced total and free carnitine concentrationsand increased plasma ammonia concentrations (a

manifestation of carnitine deficiency). Carnitine levelsin patients taking anticonvulsants other than valproicacid were normal.''*'''^'' A consensus statement by apanel of pediatric neurologists concluded that L-car-nitine supplementation is indicated for patients withsymptomatic valproic acid-associated hyperammone-mia, multiple risk factors for valproic acid hepatotox-icity, or renal-associated syndromes; infants and youngchildren taking valpi'oic acid; patients with epilepsyusing the ketogenic diet who have low serum carnitinelevels; patients receiving dialysis; and premature infantsreceiving total parenteral nutrition. Tlie panel recom-mended an oral L-carnitine dosage of 100 mg/kg/day,to a maximum of 2 g/day. Intravenous L-carnitine wasrecommended for valproic acid-induced hepatotoxicity,overdose, and other acute metabolic crises associatedwith carnitine deficiency.""

Vitamin KA hemorrhagic diathesis associated with

low prothrombin levels occurs in about 27 percent ofinfants of mothers receiving anticonvulsant medica-tion. Fourteen pregnant epileptic women received 20mg/day vitamin K.1 for two weeks before delivery. Nohemorrhages occurred in the babies and prothrombintimes were all normal at birth. The authors of this studysuggested that vitamin Kl should be given routinelyto drug-treated epileptic women near the end of preg-nancy.158

HormonesMelatonin

In one study, 3 mg melatonin was given eachnight for three months to six children (ages 2-15 years)with severe, intractable seizures. Tlie mean seizure fre-quency decreased from 3.6 per day at baseline to 1.5per day during treatment (58% reduction; p<0.05).'''''Melatonin has also been used in doses of 2-10 mg be-fore bedtime to treat sleep disturbances in children withepilepsy. Melatonin treatment was associated with anincrease in seizure frequency in some patients and a de-crease in others. "'' "'

Because melatonin appears to have unpredict-able effects on seizure frequency, it should be used withcaution in patients with epilepsy.

Page 18

Aiternative Medicine Review Voiume 12, Number 1 2007

ProgesteroneAccording to one study, progesterone may be

beneficial for women who have seizure exacerbations atspecific times during the menstrual cycle. Twenty-fivewomen with cyclic exacerbation of complex partial orsecondary generalized motor seizures of temporal originreceived progesterone lozenges (200 mg 3 times per day).Women with perimenstrual exacerbations received treat-ment on days 23 to 25 ot each cycle; women who hadexacerbations during the entire luteal phase were treat-ed from days 15 to 25 of each menstrual cycle. In bothgroups of women, progesterone was tapered after day 25and discontinued by day 28. Progesterone was well toler-ated by 23 of the 25 women. Two women experiencedasthenia and emotional depression, which resolved with-in one day of discontinuing treatment. Eighteen women(72%) experienced a decline in seizure frequency duringthe three-month treatment period, compared with rhethree months prior to therapy (p<0.01). Among the 23women who continued treatment, the average frequen-cy of complex partial seizures declined by 54 percent(p<0.01) and the frequency of secondary generalizedmotor seizures declined by 58 percent

ConclusionA number of different dietary modifications,

nutritional supplements, and hormones may help pre-vent seizures or improve other aspects of health in pa-tients with epilepsy. Table 2 summarizes the strengthof the evidence for potential nutrient and hormoneinterventions. Supplementation with specific nu-trients should also be considered for the preventionand treatmetit of nutritional deficiencies resultingfrom anticonvulsant drugs. In most cases, nutritionaltherapy is not a substitute for anticonvulsant medica-tions. However, in selected cases, depending on theeffectiveness of the interventions, dosage reductionsor discontinuation of medications may be possible.

Because much of the research on epilepsymanagement with diet, nutrients, and hormones ispreliminary, there are few clear guidelines on whenand how to use the various interventions described inthis article. However, consideration of basic aspects ofnutrition and metabolism should aid the clinician inevaluating this research and making rational cUnicaldecisions.

Table 2. Nutrient and Hormone Interventions in Epilepsy

Nutrient

Vitamin B6

Magnesium

Vitamin E

IVlanganese

Taurine

Dimethylgiycine

Thiamine (to improve cognitive function)

Folic acid

Biotin

Vitamin D

Omega-3 fatty acids

L-Carnitine (to prevent valproate toxicity)

Vitamin K (to prevent drug-induced deficiency)

Melatonin

Progesterone

Evidence ^

Case reports, uncontroiled clinical trials|


Double-blind trials


Uncontrolled trials

Case report, negative follow-up studies





Uncontrolled and double-blind trials

Clinical observations and lab findings J

Uncontrolled trial |

Uncontrolled trial J

Uncontrolled trial |

Page 19


For example, hypoglycemia should be consid-

ered a potential triggering factor in patients who develop

seizures in rhe late morning or late afternoon or when

a meal is missed. Food allergy might be a contributing

factor in epileptic patients who have other manifesta-

tions of possible allergy, such as migraines, asthma, or a

history of recurrent ear infections in childhood. A trial

of manganese supplementation would seem appropriate

for patients with low whole-blood manganese concen-

trations. An empirical trial with vitainin E would seem

reasonable for many patients with epilepsy, particularly

children. Supplementation with magnesium (200-600

mg per day) and modest doses of vitamin B6 (such as

10 mg per day) for general nutritional support would

also be reasonable for many patients, in light oi evidence

tliar a large proportion of the population has subopti-

mal intakes of these nutrients. "* '" ^ Larger doses of vita-

min B6 could be considered for patients whose epilepsy

is not adequately controlled by other treatments.

References1, Motiami M. Manniicci E, BrcsL-lii A, Marchionni N.

Seizures as rhe only clinic;il manifcscinon of reactivehypoglycemia: a case report. J Endocriwl Invest2005)28:940-941.

2- Liu YX, Lu BX, Liu L, et al. Clinical analysis of 73 casesof hypoglycemia with brain dysfunctions. Di Yijun YiDa Xuc Xue BM 2005:25:1585-1586,1588. [Article inChinese]

3. Tyson GNJr, Otis L.Joyce T E A study of blood sugarofepilcptics.A»j;ML'<I.Sa 1935;i90:164-169.

4. Hudsperh WJ, Peterson LW. Soli DE, Trimble BA.Neurohiology of the hypoglycemia syndrome. J HolistMcJ 1981;3:6O-71.

5. CraytonJW, Stone T. Stein G. Epilepsy precipitatedby food sensitivicy: report of a case with double-hlindplacebo-controlled assessment. CIIM Elcitwciiccphaio^r1981;12:192-198.

6. Rfichelc KL. Ekiem J, Scott H. Gluten, milk proteinsand autism: dietary intervention effects on behavior andpeptide secretion. / Appl Nutr 1990:42:1-11.

7. Schmidt K, Brajkovich WR, Asch M. Clinical ecologytreatment approach for juvenile offenders. Intj BiosocRes 1981:2:15-20.

8. Egger J, Carter CM, SoothillJF, Wilson J.Oligoantigenic diet treatment of children with epilepsyand migraine.7PL\iw(rl989;l 14:51-58.

J. Cronin CC. Jackson LM, Feighery C, et al. Coeliacdisease and epilepsy 0M1998;91:3O3-3O8.

10. Pratesi R, Modelli IC, Martins RC, et al. Celiac diseaseand epilepsy: favorable outcome in a child with difficultto control seizures. Ada Neural Scand 2003;108:290-293.

11. Gobbi G, Bouquet F, Greco L, et al. Coeliac disease,epilepsy, and cerebral calcifications. The Italian WorkingGroup on Coeliac Disease and Epilepsy. Lancet1992:340:439-443.

12. Hernandez MA, Colina G, Ortigosa L. Epilepsy,cerebral calcifications and clinical or subclinical coeliacdisease. Course and follow up with gluten-free diet.Seizure 1998;7:49-54.

13. Piattclla L, Zamponi N, Cardinali C, et al. Hndocranialcalcifications, infantile celiac disease, and epilepsy. CbihisNervSyst I99r,9:l72'l75.

14. Ventura A, Bouquet F, Sartorelli C, et al. Coeliacdisea.se, folic acid deficiency and epilepsy with cerebralcalcifications. Acta Paediatr Scand 1991:80:559-562.

15. Wolf P, Okujava N. Possibilities of non-pharmacologicalconservative treatment of epilepsy. Seizure 1999:8:45-52.

16. Shovic A, Bart RD, Stalcup AM.'We think yourson has Lennox-Gasrauc syndrome' - a case study ofmonosodium glutamates possible effect on a child.J AmD/cfAssof 1997:97:793-794.

17. Wurtman RJ. Aspartame: possible effect on seizuresusceptibility. Lancet 1985:2:1060.

18. Walton RG. Seizure and mania after high intake ofasparrame. PsychosoiHatic:^ 1986;27:218,220.

19. Camfield PR, Camfield CS, Dooley JM, et al.Aspartame exacerbates HHG spike-wave discharge inchildren with generalized absence epilepsy: a double-blind controlled study. Neurology 1992:42:1000-1003.

20. Shaywitz BA, Anderson GM, Novotny EJ, et al.Aspartame has no effect on seizures or epileptiformdischarges in epileptic children. Ann Neurol1994:35:98-103.

21. Rowan AJ, Shaywitz BA.Tuchman L, et al. Asparrameand seizure susceptibility: results of a clinical study inreportedly sensitive individuals. Epikpsia 1995:36:270-275.

22. Roberts HJ. Aspartame and headache. Neurology1995:45:1631.

23. Kinsman SL, Vining EP, Quaskey SA, et al. Efficacyof the ketogenic diet for intractable seizure disorders:review of 58 cases. f>;i7'.s,,) 1992:33:1132-1136.

24. Hemingway C, Freeman JM, Pillas DJ, Pyzik PL. 'Tlieketogenic diet: a 3- to 6-year follow-up of 150 childrenenrolled prospecrively. Pediatrics. 2001;108:898'905.

25. Vining EP. Clinical efficacy of the ketogenic diet.Epikpiy Rei 1999:37:181-190.

26. Gasch AT. Use of the traditional ketogenic diet fortreatment of intractable epilepsy. / Am Diet Associ990;90:1433-1434.

27. Tallian KB, Nahata MC, Tsao CY. Role of theketogenic diet in children with intractable seizures. AwnP/.iarj»aa.((3erl998;32:349-361.

28. Katyal NG, Koehler AN, McGhee B, et al. Theketogenic diet in refractory epilepsy: the experience ofChildren's Hospital of Pittsburgh. Clin Pediatr (Phila)2000:39:153-159.

Page 20


29. Hassan AM, Kcenc DL, Whiting SE, et al. Ketogenicdicr in the treatment ot refractory epilepsy in childhood.PfMatrNeuwl 1999;21:548'552.

30. Frteraan JM, Vining EP, Pilbs DJ, et al. The efficacyof the ketogenic diet-1998: a prospective evaluation ofintervention in 150 diildren. PeiiuUria. 1998;102:I358-1363.

31. Vining EP, Freeman JM. BLiJ[.iban-GiI K, et al. Amulticencer study of the efficicy of the ketogenic diet.Arch Nciiwl 1998:55:1433-1437.

32. Bergqvist ACi, Brooks-Kayal AR. Ketogenic diet in thetreatment of acquired epileptic aphasia. Ann Ncurol1997;42:505.

33. Sirven J, Whcdon B, Caplan D, ct al. The ketogenic dietfor intractable epilepsy in adults: preliminary results.Epilcpsia 1999:40:1721-1726.

34. Trauner DA. Medium-chain triglyceride (MCT) dietin intractable seizure disorders. Neurology 1985:35:237-238.

35. Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhoodepilepsy. Neurology 1971:21:1097-1103.

36. Gordon N. Medium-chain tH^lycerides in a ketogenicdiet. Dev Mai ChiU Ncuroi 1977; 19:535-538.

37. Sills MA. Forsythe Wl, Haidukewych D, et al. Themedium chain triglyceride diet and intractable epilepsy.Arch Dh Child 1986:61:1168-1172.

38. Ballaban-Gil K. Callalian C, O'Dell C, et al.Complication.s of the ketogenic diet. Epilepsia1998:39:744 748.

39. Berry-Kravis E, Booth G, Taylor A, Valentino LA.Bruising and the ketogenic diet; evidence for diet-induced changes in platelet fiuiction. Ann Ncurol2001:49:98-103.

40. Edelstein SF, Chisholm M. Management of intractablechildhood seizures using the non-MCT oil ketogenicdiet in 20 patients.7 Am Diet Asioc 1996;96:1181-1182.

41. De Vivo DC, Bohan TP, Coulter DL, etal. L-carnitinesupplementation in childhood epilepsy: currentperspectives. E}ulcp<.ia 1998;39:1216'1225.

42. KossofFEH, McGrogaii JR, BiumI RM, et al. Amodified Atkins diet is etFective for the treatment ofintractable pediatric epilepsy. Upilepsia 2006;47:421-424.

43. Kossoff EH, Krauss GL. McGrogan JR. Freeman JM.Efficacy of the Arkins diet as therapy for intractableepilepsy. Neurology 2003:61:17894791.

44. No authors listed. Central nervous system changes indeficiency of vitamin B6 and other B-complex vitamins.NHfrRn'1975;33:21-23.

45. Wintrobe MM. Follis RH Jr, Miller MH, et al.Pyridoxine deficiency in swine^Johns Hopkim Med Bull1943:72:1-25.

46. Coursin DB. Convulsive seizures in infantsvk-ith pyridoxine-deficient diet. / Am Meii Assoc1954:154:406-408.

47. Molony CJ, Parmelee AH. Convulsions in young infantsas a result of pyridoxine (vitamin B6) deficiency.J AmMcd Aiioc 1954:154:405-406.

48. Johnson GM. Powdered goat's milk: pyridoxinedeficiency and status epilepticus. Clin Pediatr (Phila)1982:21:494-495.

49. Tanuira T, Aiso K.Johnston KE, et al. Homocysteine,folate, vitamin B-12 and vitamin B-6 in patientsreceiving antiepileptic drug monotherapy. Epilcpiy Rei2000;4d:7-15.

50. Davis RE, Reed PA, Smith BK. Serum pyridoxal, folate,and vitamin B12 levels in institutionalized epileptics.£>.7fpii.i 1975:16:463-468.

51. Meeuwisse G, Gamstorp L Tryding N. Effect ofphenytoin on the tryptophan load test. Ada Paediatr

52. Crowell GF, Roach F-S. Pyridoxine-dependent seizures.Am Fam Physician 1983:27:183-187.

53. Robins MM. Pyridoxine dependency convulsions in anewborn.7AM/\ 1966:195:491-493.

54. Kroll JS. Pyridoxine for neonatal seizures: anunexpected danger. Dev Med Child Neurol1985:27:377-379.

55. Clarke TA, Saunders BS, Feldman B. Pyridoxine-dependent seizures requiring high doses of pyridoxinefor control. AmJ DU Child 1979:133:963-965.

56. Coker SB. Postneonatal vitamin B6-dependent epilepsy.Pediatrics 1992:90:221-223.

57. Goutieres F, Aicardi J. At)'pical presentations ofpyridoxine-dependent seizures: a treatable causeof intractable epilepsy in infants. Ann Neurol1985:17:117-120.

58. Bankier A, Turner M. Hopkins IJ. Pyridoxinedependent seizures - a wider clinical spectrum. ArchDisC/j("W 1983:58:415-418.

59. Hagberg B, Hamfelt, Hansson O. Tryptophan loadtests and pyridoxaI-5-phosphate levels in epilepticchildren. II. Cryptogenic epilepsy. Ada Paediatr Samd1966:55:371-384.

60. Hagberg B, Hamfelt A, Hansson O. Epileptic childrenwith disturbed tryptophan metabolism treated vfithvitamin B6. Lancet 1964:39:145.

61. Ernsting W, Ferwerda TP. Vitamin B6 in treatment ofepilepsy.J Am Med Assoc 1952:148:1540.

62. Hansson O, Hagberg B. Effect of pyridoxinetreatment in children with epilepsy. Acta Soc Mcd Ups1968;73:35-43.

63. Nakagawa E, Tanaka T. Ohno M, et al. Efficacyof pyridoxal phosphate in treating an adultwith intractable status epilepticus. Neurology1997:48:1468-1469.

64. Jiao FY, Gao DY. Takuma Y, et al. Randomized,controlled trial of high-dose intravenous pyridoxinein the treatment of recurrent seizures in children.Pediatr Neurol 1997:17:54-57.

65. Fox JT, TuUidge GM. Pyridoxine (vitamin B6) inepilepsy. A clinical trial. Lancet 1946;2:345.

Page 21

Alternative Medicine Review Volume 12, Nunnber 1 2007

66. Hceley AF, Piesowicz AT, McCubbing DG. The 84.biochemical and clinical cftect of pyridoxine inchildren with biain disorders. C7IH Sci 1968;35:381- 85.389.

67. Fois A. Borghcresi S, Luti L. Frequency of relarivepyridoxine dependency in epileptic children. HehPaaiiatr Act.i 1966;21:486-492. 86.

68. Clayton PT, Surtees RA, DeVile C, et ill. Neonatalepileptic encephaloparhy. Lancet 2O03;361:1614.

69. Kuo MF, Wang HS. Pyridoxal phospliate-responsive 87.epilepsy with resistance to pyridoxine. Pt\iiatr Neurol2002:26:146-147.

70. Wang HS, Kuo MF, Chou ML, er al. Pyridoxalphosphate i.s better than pyridoxine for controllingidiopathic intractable epilepsy Arch Dii Child2005:90:512-515. 88.

71. Hansson O, Sillanpaa M. Letter: Pyridoxineand serum concentration oi phenytoin andphenobarbitone. Lancet 1976;1:256.

72. Schaumburg H, Kaplan J, Windebank A, et al. 89.Sensory neuropathy from pyridoxine abuse. A newmegavitamin syndrome. N EnglJ Med 1983:309:445-448.

73. Toll N. To the Editor.J Orthomolecular Psychiatry1982:11:42. 90.

74. Arnold JD, Oldfield RK. Pollard AC, Silink M.Primary hyponiagnesaemia: case report. Aust PaediatrJ 1983:19:45-46. 91.

75. Nuytten D, Van Hees J, Meulemans A, Carton H.Magnesium deliciency as a cause of acute intractable 92.seizures. J Ncurol 199'l;238:262-264.

76. Grccnbcrg DM, Tufts EV. Effect of a diet low inmagnesium on the rat. Proc Soc Exp Biol Med 1934- 93.5;32t674-675.

77. Borges LF, Guccr G. Effect of magnesium on epilepticfoci. K;'i/t'ps(^ 1978:19:81-91.

78. Turner TL, Cockburn F, Forfar JO. Magnesium 94.therapy in neonatal tetany. Lancet 1977:1:283-284.

79. Sadch M, Blatt I, Martonovits G, et al. Treatmentof porphyric convulsions with magnesium sulfate. 95.E^^r/qtsia 1991:32:712-715.

80. Govil MK, Mangal BD, Alam SM, et al. Serum andcerebrospinal fluid calcium and magnesium levels in 96.cases of idiopathic grand mal epilepsy and inducedconvulsions.J Assoc Physicians India 1981:29:695- 97.699.

SI. Afzal S, Kaira G, Kazmi SH, Siddiqui MA. Astudy of serum and cerebrospinal fluid magnesium 98.in convulsive disorders. J Asioc Physicians. India1985;33:16M63.

82. Steidl L, Tolde I, Svomova V. Metabolism ofmagnesium and zinc in patients treated withantiepileptic drugs and with magnesium lactate.Magnesium 1987:6:284-295. 99.

83. Tamai H, Wakamiya B, Mino M, Iwakoshi M. Alpha-tocopherol and fatty acid levels in red blood cells inpatients treated with antiepileptic drugs. J Nutr SciVitiwiinol (Tokyo) 1988:34:627-631.

Ogunmekan AO. Vitamin E deficiency and seizuresin animals and man. CanJ Neurol Sci 1979:6:43-45.Ogunmekan AO, Hwang PA. A randomized, double-blind, placebo-controlled, clinical trial of d-alpha-tocopheryi acetate (vitamin E), as add-on therapy, forepilepsy in children. Epilepsia 1989;30:84-89.Sullivan C, Capaldi N, Mack G, Buchanan N.Seizures and natural vitamin E. Med } Ami1990;] 52:613-614.Hom AC, Weaver RC, Alderson JJ. Efficacy of d-alpha tocopheryl acetate as adjunctive antiepilepticagent in patients with refractory epilepsy andprofound developmental disability: a prospective,randomized, double-blind, placebo-controlled trial.Epikpsia 1991:32:S62.Higa.shi A, Tamari H, Ikeda T, et al. Serum vitaminE concentration in patients with severe multiplehandicaps treated with anticonvulsants. PediatrPharmacol (New York) 1980:1:129-134.Raju GB, Behari M, Prasad K, Ahuja GK.Randomized, double-blind, placebo-controlled,clinical trial of D-alpha-tocopherol (vitamin E) asadd-on therapy in uncontrolled epilepsy. Epilepsia1994:35:368-372.Hurley LS, WooUey DE, Rosenthai F, Timiras PS.Influence oi manganese on susceptibility of rats toconvulsions. ^ » i j Physioi 1963;204:493-496.Sampson P. Low manganese level may trigger epilepsy.jAMA 1977:238:1805.Carl GF, Keen CL, Gallagher BB, et al. Associationof low blood manganese concentrations with epilepsy.Neurology 1986:36:1584-1587.Sohler A, Pfeiffer CC. A direct method for thedetermination of manganese in whole blood:patients with seizure activity have low blood levels. /Orthomolecuhn Psychiatry 1979:8:275-280.Papavasilious PS, Kutt H. Miller ST, et al. Seizuredisorders and trace metals: manganese tissue levels intreated epileptics. Neurology 1979:29:1466-1473.Dupont CL, Tanaka Y. Blood manganese levels inchildren with convulsive di.sorder. Biochcm Med1985:33:246-255.Grant EC. Epilepsy and manganese. Lancet2004:363:572.PfeiJfer CC, LaMola S. Zinc and manganese inthe schizophrenias.^ Orthomolecular Psychiatry1983:12:215-234.Kuriyama K, Muramatsu M, Nakagawa K,Kakita K. Modulating role of taurine on release ofneurotransmitters and calcium tran.sport in excitabletissues. In: Barbeau A, Huxtable RJ, eds. Taurine andNeurological Disorders. New York, NY: Raven Press:1978:201-216.Monaco F, Mutani R, Durelli L, Delsedime M. Freeamino acids in serum of patients with epilepsy:significant increase in taurine. Epilcpsta 1975;16:245-249.

Page 22


100. Mutani R, Monaco F, Durelli L, Delsedime M.Levels of free amino acids in serum and cerebrospinalfluid after administration of taurine to epileptic andnormal subjects. £/>i/cpsi<J 1975;16;765-769.

101. Van Gelder NM, Sherwin AL. Sacks C, AndermanF. Biochemical observations following administrationof taurine to patients with epilepsy. Braitt Res1975;94:297-306.

102. Goodman HO, Connolly BM, McLean W, ResnickM. Taurine transport in epilepsy. C7/M Chem1980:26:414-419.

103. Betgamini L, Mutani R, Delsedime M, Durelli L.First clinical experience on the antiepileptic action oftaurine. Eur Neurol 1974;ll;261-269.

104. Pennetta R, Masi G, Perniola T, Ferrannini E.Electroclinical evaluation of the anti-epileptic actionof taurine. AcM Neurol (Napoli) 1977:32:316-322.[Article in Italian]

105. Takaliashi R, Nakane Y. C'linical trial of tautine inepilepsy. In: Barbeau A, Huxtable RJ, eds. Taurine andNeurological Disorders. New York, NY: Raven Press;1978:375-385.

106. Konig P, Kriechbaum G, Presslich O, et al. Orally-administered taurine in therapy-resistant epilepsy{author's tran.s!). Wias Kliu Wochcnschr 1977;89:111-113. [Article in German]

107. Barbeau A, Donaldson J. Zinc, taurine, and epilepsy.Arch Neurol 1974;30;52-58.

108. Mantovani J, DeVivo DC. Effects of taurine onseizures and growth hormone release in epilepticpaticnta. Arch Neurol 1979;36:672-674.

109. Freed WJ. Prevention of .strychnine-induced seizuresand death by the N-methylated glycine derivativesbetaine, dimethyiglycine and sarcosine. PharmacolBitKhcm Behav 1985;22:641-643.

110. Haidukewych D, Rodin EA. N,N-dimethylglycineshows no anticonvuLsant potential. Ann Neurol1984;l5:405.

111. Roach HS, Carlin L. N,N-dimethylglycine forepilepsy. N EH^ /_/ Med 1982;307:1081 -1082.

112. Roach ES, Gibson P. Failure of N,N-dimethylglydnein epilepsy. Ann Neurol 1983:14:347.

1 I 3. Gascon G, Patterson B, Yearwood K, SlotnickH. N,N dimethyiglycine and epilepsy. Bpilcpsta1989;30:90'93,

114. Keyser A, De Bruijn SF. Epileptic manifestations andvitamin Bl deficiency. Eur Neurol 1991:31:121-125.

115. Botez MI, Botes T. Ross-Chouinard A, Lalonde R.lliiamine and folate treatment of chronic epilepticpatients: a controlled study with the Wechsler IQscale. Epilepsy Res 1993;16:157-163.

116. Torres OA. Miller VS, Buist NM, Hyland K. FoUnicacid-responsive neonatal seizures.J Child Neurol1999:14:529-532.

117. Ramaekers VT. Rothcnberg SP, SequeiraJM,et ;il. Autoantibodies to folate receptors in thecerebral folate deficiency syndrome. N EriglJ Med2005:352:1985-1991.

118. Reynolds EH, PreeceJ, Johnson AL. Folacemetabolism in epileptic and psychiatric patients. /Neurol Neurosurg Psychiatry 1971:34:726-732.

119. del Set Quijano T, Bermejo Pareja F, Munoz-GarciaD. Portera Sanchez A. Psychological disturbances andfolic acid in chronic epileptic outpatients. EpHcpsiaI983;24:588-596,

120. Snaith RP, Mehta S, Raby AH. Serum folate andvitamin B12 in epileptics with and without mentalillness. BrJ Psychiatry 197O;116:179.183.

121. Trimble MR, Corbett JA, Donaldson D, Folic acidand mental symptoms in children with epilepsy. /Neurol Neiirosurg Psychiatry 1980:43:1030-1034.

122. Enneking-Ivey O, Bailey LB, Gawley L, et ai. Folicacid and vitamin D status of young children receivingminimal anticonvulsant drug therapy, hitj VitamNiitrRci 1981:51:349-352.

123. Deb S. Cowie VA. Richens A. Fotate metabolismand problem behaviour in mentally handicappedepilepticsj Mcnt Dejic Ra 1987;31:163-168.

124. Apeland T, Mansoor MA, Srrandjord RE, et al.Folate, homocysteine and methionine loading inpatients on carbamazepine. Acto Neurol Scand2001:103:294-299.

125. Hendel J, Dam M, Gram L, et al. The effects ofcarbamazepine and valproate on folate metabolism inman. Arid Neurol Samd 1984:69:226-231.

126. Mattson RH, Gallagher BB. Rcynold.s EH, Glass D.Folate therapy in epilepsy. A conttolled study. ArchNcHroM 973:29:78-81.

127. Seligmann H, Potasman I, Weller B. et al. Phenytoin-folic acid interaction: a lesson to be learned. ClinNcurophnrmacol 1999;22:26S-272.

128. Furlanut M, Beneteilo P, Avogaro A, Dainese R.Effects of folic acid on phenytoin kinetics in healthysubjects. Oitt Pharmacol Iher 1978;24:294-297,

129. O'Hare J, O'Driscoll D, Duggan B, Callaghan N.Increase in seizure frequency following folic acid.J hMed Assoc 1979;72:241-242.

130. Reynolds EH. Effects of folic acid on the mental stateand fit-frequency of drug-treated epileptic patients.L.iHcct 1967:1:1086-1088.

131. Ralston AJ, Snaith RP. HinleyJB. Effects of folicacid on fit-frequency and behaviour in epileptics onanticonvulsants. Lancet 1970:1:867-868.

132. Grant RH. Stores OP. Folic acid in foIate-deHcientpatients with epilepsy. Br Med ] 1970:4:644-648.

133. Gibberd FB. Nicholls A, Wright MG. I h e influenceof folic acid on the frequency of epileptic attacks. EurJClin Pharmacol 1981;19:57-60.

134. Ch'ien LT. Krumdieck CL. Scott CW Jr, ButterworchCE Jr. Harmful effect of megadoses of vitamins:electroencephalogram abnormalities and seizuresinduced by intravenous folate in drug-treatedepileptics. AIM J Clin Nutr 1975;28:51-58.

135. Guidolin L, Vignoli A, Canger R. Worsening inseizure frequency and severitj' in relation to folic acidadministration. EurJ Neurol 1998:5:301-303.

Page 23


136. Hiilesmaa VK, Teramo K, Granstrom ML, Bardy 151.AH. Serum folace concentrations during pregnancyin women with epilepsy: relation to antiepilepticdrug concenrrations, number of seizures, and fetal 152.outcome. Br Med j (Clin Res Ed) 1983;287:577-579.

1 37. Drew HJ, Vogcl Rl, Molofsky W, et al. Effect offoLite on phenytoin hyperplasia.J Clin Periodontol1987;14:350-356. 153.

138. Brown RS, Di Stanislao PT, Beaver WT,Bottomley WK. ll ic administration of folic acid toinstitutionalized epileptic adults with phcnytoin-induced gingival hyperplasia. A douhle-blind, 154.randomized, placebo-con trolled, parallel study. OralStag Oral Med Oral Pathol 1991:71:565-568.

139. Krause KH, Berlit R Bonjour JP. Impaired biotinstatus in anticonvulsant therapy. Ann Neurol 155.1982;12:485-486.

140. Mock DM, Dyken ME. Biotin carabolism isaccelerated in adults receiving long-term therapy witll 156.anticonvulsants. Neurology 1997:49:1444-1447.

141. Mock DM, Mock NI, Nelson RP, Lombard KA.Di.sturbances in biorin metabolism in childrenundergoing long-term anticonvulsant thcrapy.JPediatr Gastroenterol Nutr 1998;26:245-250. 157.

142. Said HM, Redha R, Nylander W. Biotin transportin rhf buman intestine: Inhibition by anticonvulsantdrugs. Am } C/iH Nutr 1989;49:127-131. 158.

143. Wolf B, Grier RE, Allen RJ, et al. Phenocypicvariation in biotinidase deficiency.^ Pediatr1983;lO3:233-237.

144. Krause KH, Berlit P, Bonjour JP. et al. Vitamin status 159.in patients on chronic anticonvulsant therapy. /"(_/Vitam Nutr Res 1982;52:375-385.

145. Bouillon R, Reynaert J, ClaesJH, et al. Tlie effect 160.of anticonvulsant therapy on serum levels of 25-liydroxy-vitamin D, calcium, and parathyroid 161.hormone.j Clin EHi ocrmoi Ale((ji)1975;41:1130-1135.

146. Silver J. Letter: Vitamin D therapy for children on 162.anticonvulsants. N Englj Med 1975;293:1106.

147. No authors listed. Osteomalacia and anticonvulsantdrugs. NH(rRn'1971;29:38-41. 163.

148. Christiansen C, Rodbro P, Lund M. Incidence ofanticonvulsanr osteomalacia and effect of vitamin D:controlled therapeutic trial. Be McdJ 1973:4:695- 164.701.

149. Peter.son P, Gray P, Tolman KG. Calcium balance in 165.drug-induced osteomalacia: response to vitamin D.CUn PharmiKol Vser 1976:19:63-67.

150. Collins N, Maher J, Cole M, et al. A prospectivestudy to evaluate the dose of vitamin D required tocorrect low 25-hydroxyvitamin D levels, calcium, andalkaline phosphatase in patients at risk of developingantiepileptic drug-induced osteomalacia, QJ Med1991;78:113-122.

Schlanger S, Shinirzky M, Yam D. Diet enriched withomega-3 fatty acids alleviates convulsion symptoms inepilepsy patients. Epilepsia 2002;43:103-104.Yuen AW, Sander JW, Fluegel D, et al. Omega-3 fatty acid supplementation in patients withchronic epilepsy: a randomized trial. Epilepsy Behav2005:7:253-258.Vaddadi KS, Gilleard CJ, Mindham RH, Butler R.A controlled trial of prostaglandin El precursor inchronic neuroleptic resistant schizophrenic patients.Psychopharniacology (Rerl) l986;88:362-367.Vaddadi KS. The use of gamma-linolenic acid andlinclcic acid to differentiate between temporal lobeepilepsy and schizophrenia. Prostagiaiidnn Med1981:6:375-379.Holmaii CP, Bell AFJ. A trial of evening primroseoil in the treatment of chronic schizophrenia./Orthomoleaitar Psychiatry 1983:12:302-304.Verrotti A, Greco R, Morgesc G, Chiarelli F.Carnitine deficiency and hyperammonemia inchildren receiving valproic acid with and withoutother anticonvulsant drugs. IntJ Clin Lab Rci1999;29:36-40.Opala G, Winter S, Vance C, et al. Tlie effect ofvalproic acid on plasma carnitine levels. AmJ DisCfciW 1991:145:999-1001.Deblay MF, Vert P, Andre M, Marchal F.Transplacental vitamin K prevents hacmorrhagicdisease of infant of epileptic mother. Lancet1982:1:1247.Peled N, Shorer Z, Peled E, Pillar G. Melatonin effecton seizures in children with severe neurologic deficitdisorders. Epilepsia 2001:42:1208-1210.Jones C, Huyton M, Hindley D. Melatonin andepilepsy. Arch Dis Child 2005:90:1203.Sheldon SH. Pro-convuLsant effects of oralmelatonin in neurologically disabled children. Lancet1998:351:1254.Fauteck J, Schmidt H, Lcrchl A, ct al. Melatonin inepilepsy: first results of replacement therapy and firstclinical results. Biol Signals Recept 1999:8:105-110.Herzog AG. Progesterone therapy in women witbcomplex partial and secondary generalized seizures.Neurology 1995:45:1660-1662.Gaby AR. Ihe Doctor's Guide to Vitamin B6. Emmaus,PA: Rodale Press; 1984.Gaby AR. Magnesium. New Canaan, CT: KeatsPublishing: 1994.

Page 24

Documents

Natural Approaches to Epilepsy_0