Folates epilepsy

Folate supplements will rectify the megaloblastic anemia of vitamin Bj2 deficiency but may hasten the development of the (irreversible) nerve damage found in B,2 deficiency. There is also antagonism between fohc acid and the anticonvulsants used in the treatment of epilepsy. 

One unwanted side-effect of phenytoin is its anti-folate activity. A programme of synthetic chemistry to manipulate the structure of the anti-folate compound pyri-methium to try to replace that property with anticonvulsant activity resulted in the synthesis of lamotrigine. It proved to be an effective AED in partial and generalised epilepsy but experience has found it also to be of value in absence seizures. 

Pregnancy the exact cause of malformations is difficult to establish as epilepsy itself may cause foetal malformations (neural tube, clef palate...). Folate supplementation is considered to have a preventive effect. 

Compared with healthy controls, 51 patients with epilepsy taking a variety of antiepileptic drugs (mostly carbamaze-pine) had higher mean plasma concentrations of homocysteine (130). This effect, which could be related to reductions in the concentrations of folate and vitamin B6, was likely to be drug-induced, but a causative role of the underlying disease could not be excluded. Although homocysteine is an experimental convulsant and a risk factor for atherosclerosis, the clinical relevance of these findings is uncertain. 

Gidal BE, Tamura T, Hammer A, Vuong A. Blood homocysteine, folate and vitamin B12 concentrations in patients with epilepsy receiving lamotrigine or sodium valproate for initial monotherapy. Epilepsy Res 2005 64 161-6. 

Oxidized folate is not only metabolically dead buyt may even be neurotoxic. For example, a patient with epilepsy who has not had a convulsion in years because dilantin has produced complete control, can be thrown into an immediate convulsion with a megadose of folic acid, because folic acid and dilantin compete for absorption at the brain cell surface, and too much oxidized folic acid will block the ability of the brain cell to take up dilantin, similar to the competition between dilantin and folic acid for uptake by the gutcell (22). 

Antiepileptics. Large doses of vitamin B6 can reduce serum levels of phenytoin and phenobarbital, and thus cause loss of control of epilepsy. Vitamin B6 in excess of 10 mg a day should be avoided. The antiepileptics phenytoin, phenobarbital and primidone can cause folate deficiency (resulting in... 

Drugs. Antiepilepsy drugs, particularly phenytoin, primidone and phenobarbital, occasionally cause a macrocytic anaemia that responds to folic acid. This may be due to enzyme induction by the antiepileptics increasing the need for folic acid to perform hydroxylation reactions (see Epilepsy) but other factors such as reduced absorption may be involved. Administration of folic acid causes a recurrence of seizures in some patients. Some anti-malarials, e.g. pyrimethamine, may interfere with conversion of folates to the active tetrahydrofolic acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megaloblastic anaemia especially when used long-term for leukaemia, rheumatoid arthritis or psoriasis. 

A small fraction of epileptics treated with anticonvulsants dilantin, phenytoin, diphenylhydantoin) develop folate deficiency. Epilepsy is not a rare disease. Hence, there is an awareness of the possibility of the occurrence of megaloblastic anemia in epileptics treated with the aforementioned anticonvulsant. Supplementing epileptics with folate can alleviate the deficiency however, the supplements may also result in an increase in Ihe seizure rate. Thus, physicians must be prepared to halt folate supplementation of epileptics beuig treated for anemia. 

Folic acid can alter the metabolism of phenytoin. In one case folic acid 5 mg/day reduced the serum phenytoin concentration to below the target range, and a breakthrough seizure occurred (25). The Km of phenytoin metabolism was significantly reduced, suggesting competitive inhibition of metabohsm. In another series folic acid reduced the serum concentrations of phenytoin (37). Furthermore, the administration of fohc acid to treat folate deficiency can reduce the beneficial effects of anticonvulsants (38). Rare but serious cases in which this epileptogenic effect of fohc acid has been very pronounced have been reported (39). However, fohc acid is well tolerated by many other patients with epilepsy who require fohc acid. 

The treatment of folate deficiency in patients receiving anticonvulsant drugs is not without difiiculties. Chanarin (C3) described an epileptic patient who had developed a megaloblastic anemia due to folate deficiency. Treatment with folic acid apparently precipitated convulsions. Up to this time the patient had been free of seizures while on phenobarbital for 4 years. There have since been a number of reports of treatment with folic acid precipitating seizures in patients with epilepsy (D6, R3, W8). 

The antiseizure drugs introduced after 1990 have teratogenic effects in animals but whether such effects occur in humans is uncertain. One consideration for a woman with epilepsy who wishes to become pregnant is a trial period without antiseizure medication monotherapy with careful attention to drug levels is another alternative. Polytherapy with toxic levels should be avoided. Folate supplementation (0.4 mg/day) is recommended for all women of childbearing age to reduce the likelihood of neural tube defects, and this is appropriate for epileptic women as well. 

Botez, M.I., Botez, T., Ross-Chouinard, A., and Lalonde, R. (1993). Thiamine and folate treatment of chronic epQeptic patients a controlled study with the Wechsler IQ scale. Epilepsy Res. 16 157-163. 

Folate has been extensively studied in epilepsy since the first report in 1952. Most studies on patients with unselected AEDs demonstrate low levels of serum folate compared with healthy control subjects. Studies in patients on monotherapy have revealed that some AEDs are associated with a low folate status (Table 30.1). It appears that AEDs with inducer effects on liver enzymes are most likely to cause low folate levels (Apeland et al. 2003 Kishi et al. 1997). On the other hand, valproate (VPA) has little effect on total folate concentrations in adult patients, but appears to decrease the folate status in children (Verrotti et al. 2000). The reason for this difference is unclear. 

Folate deficiency is most likely to occur in patients on long-lasting AED therapy. Furthermore, folate concentrations are inversely related to the number of prescribed AEDs. Patients on combinations of two or more AEDs tend to have lower folate levels than patients on monotherapy. Combinations of AEDs may have synergistic effects on folate absorption and/or metabolism. Moreover, the dietary intake of B vitamins tends to decrease with an increasing number of AEDs. Patients on combination therapy tend to a have more severe epilepsy, often associated with other neurological deficits and may even need to live in institutions. 

A few studies have examined the folate concentrations in the spinal fluid of patients with epilepsy. 5-MTHF is the main form of folate in both blood and cerebrospinal fluid. The CSF concentrations of 5-MTHF are usually about three times higher than serum concentrations. In the choroid plexus, there is an active transport mechanism which tends to keep cerebrospinal folate concentrations stable despite variable serum coneentrations (Figure 30.1) (Ramaekers et al. 2002). 

The risk of foetal malformation is increased in women with epilepsy compared with the general population. Minor dysmorphic features are most frequent, but more severe forms such as facial clefts and neural tube defects are not uncommon. The two major forms of neural tube defects are (i) anence-phaly, a lethal malformation, and (ii) spina bifida—a closure defect in the spinal eolumn that may lead to paralysis of the lower limbs. The rates of malformations are about 3% with CBZ and lamotrigine (LTG), 7% with VPA, and 15% with combinations of two or more AEDs. It is probable that AEDs have several different teratogenic mechanisms. Low folate levels appear to be associated with increased risks of foetal malformations in women on AEDs. Furthermore, it has been suggested that maternal C677T MTHFR polymorphism or some abnormality related to methionine synthetase increase the risk of foetal malformation in patients on AEDs (Mills et al. 1995). 

In a few studies, the protective effect of folic acid among pregnant women on AEDs has been assessed. A possible but small reduction in congenital malformations with folic acid supplements has been reported (Hill et al. 2010). It appears that most of the teratogenic effects of AEDs are via other mechanism than low folate. Despite the modest protective effect of folate supplements, it is still recommended in women with epilepsy. 

Folate deficiency usually takes 3-5 years to evolve in patients with epilepsy. Therefore, prophylactic B vitamin supplements may be recommended for patients at risk. As long as physiological doses are used, vitamin therapy should be safe. 

Antagonism between folic acid and the anticonvulsants used in the treatment of epilepsy is part of their mechanism of action about 2% of the population have (drug-controlled) epilepsy. Relatively large supplements of folic acid (in excess of 1000 Jg/day) may antagonize the beneficial effects of the anticonvulsants and lead to an increase in the frequency of epileptic attacks. If enrichment of a food such as bread with folate is to provide 400 Jlg/day to those who eat little bread, those who eat a relatively large amount may well have an intake in excess of 1000 Jg/day. 

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