Cerebrospinal fluid folates

Levels of folate in both the blood and the cerebrospinal fluid have been very low. The anemia is correctable with injections of folate, or with the administration of large oral doses, but the concentration in the CSF is still low, suggesting that a distinct carrier system mediates folate uptake into the brain and that this system is the same as that facilitating intestinal transport. 

Fig. 6.3.2a-c Chromatogram of 5MTHF using electrochemical detection, a Standard, 100 nM b control cerebrospinal fluid (CSF) c CSF from a patient with cerebral folate deficiency (CFD)... 

Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N (2002) Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydro-folate in cerebrospinal fluid a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 33 301-308... 

Blau N, Bonafe L, Krageloh-Mann I, Thony B, Kierat L, Hausler M, Ramaekers VT (2003) Cerebrospinal fluid pterins and folates in Aicardi-Goutieres syndrome a new phenotype. Neurology 61 642-648... 

Sulfadiazine achieves therapeutic concentrations in cerebrospinal fluid and in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Pyrimethamine, an antiprotozoal agent, is a potent inhibitor of dihydrofolate reductase. The combination of sulfadiazine and pyrimethamine is synergistic because these drugs block sequential steps in the folate synthetic pathway blockade (Figure 46-2). The dosage of sulfadiazine is 1 g four times daily, with pyrimethamine given as a 75 mg loading dose followed by a 25 mg once-daily dose. Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression. 

Cerebrospinal fluid contains a folate binder which appears identical to that present in serum except that it is unsaturated. Similar binders have been found in bile and urine but have not been well characterized (C6). 

Patients with folate deficiency and organic mental changes, polyneuropathy, and depression have been found to have a reduced cerebrospinal fluid level of 5-hydroxyindoleacetic acid. Following treatment with the vitamin the 5-hydroxyindoleacetic acid level was found to return to normal in those patients who showed improvement in their neuropsychiatric signs. However, patients who were folate deficient with neuropsychiatric symptoms which were not responsive to treatment with folic acid showed no change in their level of cerebrospinal 5-hydroxyindoleacetic acid (BIT). 

Normally, there is an active transport of folate across the blood-brain barrier. The concentration of 5-methyl tetrahydrofolate (5-MTHF) in the cerebrospinal fluid is three times higher than in the serum. The epithelial cells of the choroid plexus, which produce cerebrospinal fluid, have folate receptors, which are part of an active transport system (Figure 30.1). 

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). 

Folate plays an important role in the development and function of the central nervous system. The high folate levels in cerebrospinal fluid give an indication of its importance. An insufficient folate status during the early weeks of gestation leads to problems with the development of the neural tube. Peri-conceptual folic acid reduces the rate of neural tube defects in the general population, and is the reason for the mandatory folic acid fortification of cereals in the US and Canada. 

Clinical observations suggest that pyridoxine supplements have no effects on seizure frequency. Like folate, vitamin Bg has a specialized transport system into the cerebrospinal fluid. 

Low cerebrospinal fluid (CSF) levels of vitamin B12 and folate in dementia patients with normal serum levels have been demonstrated in a number of studies. Hence, CSF vitamin B and folate may be more sensitive indicators of their deficiencies at tissue level. This can be due to formation of inactive vitamin analogues at tissue level which are not detected by current analytical methods and disturbed transport of vitamin across the blood-brain barrier. 

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