Cerebrospinal fluid folate, and vitamin B₁₂ in anticonvulsant-induced megaloblastosis

Anticonvulsant therapy commonly leads to the development of subnormal serum folate levels, and in some individuals to a true megaloblastic anemia. In addition, the folate depletion has been suggested as a basis for a variety of neurologic and psychiatric defects in such patients. Since neuropsychiatric changes are not seen in most circumstances of folate deprivation by other pathophysiologic mechanisms, a study of cerebrospinal fluid B₁₂ and folate was performed in patients treated with anticonvulsants. Patients on long-term anticonvulsant therapy with no hematologic abnormality were found to have a lower mean cerebrospinal fluid (CSF) B₁₂ level (9.7 pg. per milliliter) than normal subjects (mean: 17.8 pg. per milliliter). Nine patients with anticonvulsant-associated megaloblastosis had the expected low serum and CSF folate levels but in addition had mean CSF B₁₂ levels of 3.7 pg. per milliliter. These CSF B₁₂ levels were similar to those seen in classical pernicious anemia (mean of 1.2 pg. per milliliter). However, the anticonvulsant-associated megaloblastosis patients had a dichotomy between these CSF B₁₂ values and their serum B₁₂ levels, since all had normal or high serum B₁₂ levels. Therapy with vitamin B₁₂ resulted in a reticulocyte response and partial repair of the anemia and improvement in mentation with no increase in seizure rate. These studies suggest that the neuropsychiatric syndromes ascribed to the folate deprivation during anticonvulsant therapy may in fact be secondary to B₁₂ depletion in the central nervous system (CNS) rather than a true folate deficiency.