Valproic acid, divalproex sodium, and sodium valproate are closely related drugs used to control (prevent) seizures in people with epilepsy.
Several controlled studies have shown that long-term anticonvulsant treatment decreases blood levels of biotin.1 , 2 , 3 , 4 In children, a deficiency of biotin can lead to withdrawn behavior and a delay in mental development. Adults with low biotin levels might experience a loss of appetite, feelings of discomfort or uneasiness, mental depression, or hallucinations. To avoid side effects, individuals taking anticonvulsants should supplement with biotin either alone or as part of a multivitamin.
In various studies of children treated with valproic acid for epilepsy compared with control groups, serum zinc levels remained normal5 , 6 or decreased,7 serum copper levels remained normal8 , 9 or decreased,10 and red blood cell zinc levels were decreased.11 The importance of these changes and how frequently they occur remain unclear.
Anticonvulsant drugs can occasionally cause birth defects when taken by pregnant women, and their toxicity might be related to low blood levels of vitamin A. One controlled study showed that taking multiple anticonvulsant drugs results in dramatic changes in the way the body utilizes vitamin A.12 Further controlled research is needed to determine whether supplemental vitamin A might prevent birth defects in children born to women on multiple anticonvulsant therapy. Other research suggests that ingestion of large amounts of vitamin A may promote the development of birth defects, although the studies are conflicting.
Anemia is an uncommon side effect experienced by people taking anticonvulsant drugs. Though the cause may be folic acid deficiency in many cases, a deficiency of vitamin B12 may also be a factor in some cases. Deficiencies of folic acid and vitamin B12 can lead to nerve and mental problems. One study revealed that individuals on long-term anticonvulsant therapy had dramatically lower levels of vitamin B12 in their cerebrospinal fluid (the fluid that bathes the brain) when compared with people who were not taking seizure medications. Improvement in mental status and nerve function was observed in a majority of symptomatic individuals after taking 30 mcg of vitamin B12 daily for a few days.13 Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12.14 Despite these contradictory findings, people taking anticonvulsant drugs for several months or years might prevent nerve and mental problems by supplementing with vitamin B12.
Preliminary research has linked anticonvulsant therapy with possible depletion of vitamin B6 in children.15 One preliminary study found that a combination of 10–50 mg per 2.2 pounds of body weight of vitamin B6 plus valproic acid was more effective than valproic acid or vitamin B6 alone at treating children with recurrent seizures.16 On the other hand, supplementation with large amounts of vitamin B6 (80–200 mg per day) has been reported to reduce blood levels of some anticonvulsant drugs, which could theoretically trigger seizures. People taking anticonvulsant drugs should discuss with their doctor whether supplementing with vitamin B6 is advisable.
Anemia is an uncommon side effect experienced by people taking anticonvulsant drugs. Though the cause may be folic acid deficiency in many cases, a deficiency of vitamin B12 may also be a factor in some cases. Deficiencies of folic acid and vitamin B12 can lead to nerve and mental problems. One study revealed that individuals on long-term anticonvulsant therapy had dramatically lower levels of vitamin B12 in their cerebrospinal fluid (the fluid that bathes the brain) when compared with people who were not taking seizure medications. Improvement in mental status and nerve function was observed in a majority of symptomatic individuals after taking 30 mcg of vitamin B12 daily for a few days.17 Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12.18 Despite these contradictory findings, people taking anticonvulsant drugs for several months or years might prevent nerve and mental problems by supplementing with vitamin B12.
Individuals on long-term multiple anticonvulsant therapy may develop below-normal blood levels of calcium, which may be related to drug-induced vitamin D deficiency.19 Two infants born to women taking high doses of phenytoin and phenobarbital while pregnant developed jitteriness and tetany (a syndrome characterized by muscle twitches), cramps, and spasms that can be caused by calcium deficiency during the first two weeks of life.20 Controlled research is needed to determine whether pregnant women who are taking anticonvulsant medications should supplement with additional amounts of calcium and vitamin D.
Two studies showed that individuals taking phenytoin and phenobarbital had lower blood vitamin E levels than those who received no treatment for seizures.22 , 23 It is not known whether this same interaction occurs with valproic acid. Though the consequences of lower blood levels of vitamin E are unknown, people taking multiple anticonvulsant drugs should probably supplement with 100 to 200 IU of vitamin E daily to prevent a deficiency.
On the basis of the biochemical actions of valproic acid, it has been suggested that people taking valproic acid should make sure they have adequate intakes of vitamin E and selenium.24 The importance of supplementation with either nutrient has not yet been tested, however.
Several studies have shown that multiple anticonvulsant therapy reduces blood levels of folic acid and dramatically increases homocysteine levels.25 , 26 , 27 Homocysteine, a potential marker for folic acid deficiency, is a compound used experimentally to induce seizures and is associated with atherosclerosis.
One preliminary study showed that pregnant women who use anticonvulsant drugs without folic acid supplementation have an increased risk of having a child with birth defects, such as heart defects, cleft lip and palate, neural tube defects, and skeletal abnormalities. However, supplementation with folic acid greatly reduces the risk.28 Consequently, some healthcare practitioners recommend that women taking multiple anticonvulsant drugs supplement with 5 mg of folic acid daily, for three months prior to conception and during the first trimester, to prevent folic acid deficiency-induced birth defects.29 Other practitioners suggest that 1 mg or less of folic acid each day is sufficient to prevent deficiency during pregnancy.30
One well-controlled study showed that adding folic acid to multiple anticonvulsant therapy resulted in reduced seizure frequency.31 In addition, three infants with seizures who were unresponsive to medication experienced immediate relief following supplementation with the active form of folic acid.32
Despite the apparent beneficial effects, some studies have indicated that as little as 0.8 mg of folic acid taken daily can increase the frequency and/or severity of seizures.33 , 34 , 35 , 36 However, a recent controlled study showed that both healthy and epileptic women taking less than 1 mg of folic acid per day had no increased risk for seizures.37 Until more is known about the risks and benefits of folic acid, individuals taking multiple anticonvulsant drugs should consult with their healthcare practitioner before supplementing with folic acid. In addition, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss folic acid supplementation with their practitioner.
Valproic acid causes depletion of carnitine in children,38 and blood carnitine levels are often low in people taking valproic acid for long periods of time. While there have been several case reports of valproic acid-related carnitine deficiency causing abdominal pain in children, there is controversy about the need for carnitine supplements in children taking valproic acid.39 , 40 , 41
Complete disappearance of severe valproic acid-induced abdominal pain was achieved in one child with intractable epilepsy immediately following the introduction of 300 mg per day of L-carnitine.42 Carnitine supplementation (50 mg per 2.2 pounds of body weight) has protected children from valproic acid-induced increases in blood ammonia levels in some research,43 though other published work has questioned whether the depletion of carnitine and the increase in blood ammonia levels (both caused by valproic acid) are actually related to each other.44 This last report found that the depletion of carnitine was significantly more severe when epileptics were taking valproic acid together with other anti-seizure medications. A double-blind, crossover study found that carnitine supplementation (100 mg per 2.2 pounds of body weight) was no more effective than placebo in improving the sense of well-being in children treated with valproic acid.45 To date, the question of whether carnitine supplementation is beneficial for people taking valproic acid remains unresolved.46 However, a panel of pediatric neurologists and experts on L-carnitine supplementation strongly recommended oral L-carnitine supplementation for all infants and children taking valproic acid, as well as for adults with carnitine deficiency syndromes, people with valproic acid-induced liver and kidney toxicity, people on kidney dialysis, and premature infants on total parenteral nutrition (intravenous feeding). The panel recommended an amount of 100 mg per 2.2 pounds of body weight per day, up to a maximum of 2 grams per day.47
Though research results vary, long-term use of anticonvulsant drugs appears to interfere with vitamin D activity, which might lead to softening of bones (osteomalacia). One study showed that blood levels of vitamin D in males taking anticonvulsants were lower than those found in men who were not taking seizure medication.48 In a controlled study, bone strength improved in children taking anticonvulsant drugs who were supplemented with the activated form of vitamin D and 500 mg per day of calcium for nine months.49 Some research suggests that differences in exposure to sunlight—which normally increases blood levels of vitamin D—might explain why some studies have failed to find a beneficial effect of vitamin D supplementation. In one controlled study, blood vitamin D levels in children taking anticonvulsants were dramatically lower in winter months than in summer months.50 Another study of 450 people in Florida taking anticonvulsants found that few had drug-induced bone disease.51 Consequently, people taking anticonvulsant drugs who do not receive adequate sunlight should supplement with 400 IU of vitamin D each day to help prevent osteomalacia.
Some studies have shown that babies born to women taking anticonvulsant drugs have low blood levels of vitamin K, which might cause bleeding in the infant.52 Though some researchers recommend vitamin K supplementation prior to delivery,53 , 54 not all agree that supplementation for women taking anticonvulsant drugs is necessary.55 Until more information is available, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss vitamin K supplementation with their healthcare practitioner.
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10. Kaji M, Ito M, Okuno T, et al. Serum copper and zinc levels in epileptic children with valproate treatment. Epilepsia 1992;33:555–7.
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20. Friis B, Sardemann H. Neonatal hypocalcaemia after intrauterine exposure to anticonvulsant drugs. Arch Dis Child 1977;52:239–41.
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22. Higashi A, Tamari H, Ikeda T, et al. Serum vitamin E concentration in patients with severe multiple handicaps treated with anticonvulsants. Pediatr Pharmacol (New York) 1980;1:129–34.
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