Los Angeles—A correlation between the duration of antiepileptic drug (AED) therapy and folate levels suggests that patients receiving chronic AED therapy may develop hyperhomocysteinemia as folate stores are depleted. High levels of homocysteine are known to be epileptogenic and may predispose patients to premature arteriosclerosis. Early intervention by folate supplementation may prevent these complications, according to researchers from the Medical College of Ohio, Toledo. They speculate that since folate depletion is very common with AEDs, other complications associated with folate deficiency (ie, cognitive deficits, peripheral neuropathy, and myelopathy) may be underestimated.

"The reason we did the study is because there is a fairly large amount of literature that antiepileptics [including phenytoin, primidone, phenobarbital, carbamazepine, and valproate] affect folate levels, and there are neural tube defects that occur in the offspring of women with epilepsy [that] may be related to folate deficiency. So, we wanted to look at that association, as it has tremendous implications for public health," explained Imran A. Ali, MD. Folate supplementation reduces the incidence of neural tube defects in high-risk groups by 60%, he added.

Folate is a cofactor required for conversion of homocysteine to methionine; deficiency of folate results in elevated levels of homocysteine. "There is considerable evidence to suggest that homocystinemia may develop even when the serum and red blood cell folate levels are within normal limits. So, an elevation of homocysteine may be indicative of tissue depletion of folic acid," he said.

STUDY SPECIFICS

"We wanted to look at that particular association between folate and homocysteine—specifically in patients receiving chronic AED therapy. What we found was that there was an inverse correlation between the folate levels and the homocysteine. So, even though your total folate levels may be within normal limits, the homocysteine levels may increase as the folate levels drop, even within their normal range," said Dr. Ali.

In order to establish an association between long-term antiepileptic therapy, folate deficiency, and elevated homocysteine levels, the researchers studied individuals who had been on long-term multiple-drug therapy and who had received AEDs for more than six months.

Thirty-six patients (18 male; mean age, 39.8) and 19 controls (12 female; mean age, 41.5) were evaluated. Mean duration of antiepileptic therapy was 9.04 years (range, 7 months to 28 years). There were six patients on monotherapy, 21 on two AEDs, and nine on three AEDs. There were 22 patients on carbamezapine (four on monotherapy) and ten on phenytoin and divalproex sodium each (one each on monotherapy). Fewer patients were on phenobarbital, primidone, lamotrigine, topiramate, gabapentin, and tiagabine in combination.

No clear association was noted between any specific AED and homocysteine or folate levels in the smaller subgroups. Mean homocysteine levels in the patients were 10.76 µmol/L and 9.15 µmol/L in the control group. An evaluation of the link between homocysteine level and age indicated that homocysteine level in patients younger than 41 was 9.09 µmol/L; and in those older than 41 it was 12.43 µmol/L. Homocysteine levels correlated with age but not with gender, number of AEDs, or duration of therapy.

The mean folate levels were 10.15 ng/ml in the group receiving AEDs and 12.83 ng/ml in the control group. This difference was statistically significant, said Dr. Ali. Folate levels were lower in men (mean 10.44 ng/ml) than in women (mean 15.3 ng/ml). Interestingly, folate levels correlated with duration of therapy, which is a very significant finding.

"There is a very clear indication now that there is, over a period of time, depletion in patients receiving antiepileptic drug therapy. What is the time to depletion? Presently, we do not know the answer. We looked at patients who had been on chronic therapy for more than six months. The next logical step is to look at folate and homocysteine levels longitudinally in patients with epilepsy. Certainly this association between AEDs and folate depletion is a strong one and has implications for development of vascular disease by increasing homocysteine levels as well as for producing neural tube defects in the offspring of women with epilepsy who are receiving AEDs," said Dr. Ali.

ASSOCIATION WITH AGE

Although the mechanism by which antiepileptic drugs cause folate deficiency is unknown, the researchers theorize that there is interference with intestinal absorption of folate and with metabolism of folate coenzymes and induction of liver enzymes.

The consequences of elevated homocysteine have been documented— hyperhomocysteinemia is now well identified as a risk factor for premature arteriosclerosis, which may be compounded by adverse effects of these drugs on lipoprotein metabolism. Recently, elevated lipoprotein (a) levels as well as increased carotid wall thickness have been reported in medicated patients with epilepsy. This suggests that individuals with epilepsy are more likely to develop vascular disease, an association that requires further study, Dr. Ali said. "Elevated homocysteine levels are associated with increased risk of atherosclerosis, cardiac disease, and stroke. Are we, with the use of AEDs, producing a state of increased risk of cerebrovascular disease? Some of the older AEDs, such as carbamezapine, also affect the lipid profiles. Are these people at an increased risk of stroke if they are maintained on AED therapy for a period of time?" asked Dr. Ali.

This study suggested that the elderly who are taking AEDs may be at greater risk of developing hyperhomocysteinemia. Due to the presence of other risk factors for the development of vascular disease in the elderly and the possible deleterious effects of AEDs on lipoprotein and homocysteine metabolism, the researchers recommend that greater caution be exercised by clinicians considering these drugs for this age group. The effect of newer AEDs on lipoprotein and folate metabolism is presently unknown, and further study is warranted as the effect may have a significant impact on clinical practice.

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