Biogenic amines and pterins in cerebrospinal fluid: some pitfalls with interpretation

The quantification of neurotransmitters or their metabolites in cerebrospinal fluid (CSF) can provide valuable clues for the detection of (often treatable) genetic disorders or their biosynthesis or salvage pathways. These analyses are technically demanding since the concentrations to be assessed are in the nanomolar range. To date, only a few laboratories worldwide offer these analyses. Since some metabolites are unstable at room temperature and sensitive to light or oxygen, special preparation of sampling tubes is helpful and the samples should be immediately frozen at the bedside. Furthermore, due to a craniocaudal gradient, a sampling protocol with numbered tubes should be adhered to. In addition to the technical difficulties, interpretation of the biochemical findings in lumbar CSF is much more complex than the interpretation of results in urine or blood. This article will focus on some pitfalls associated with the interpretation of analyses of dopamine, serotonin and pterin metabolites, and examines clinical data from pediatric patients to further illustrate those pitfalls. A mainstay for the interpretation of cerebrospinal fluid (CSF) results is a valid reference range for each metabolite. While appearing simple in practice , this is a challenge and has provoked some debate. First, there is a craniocaudal gradient from ventricular to lumbar CSF to take into account substances that are produced mainly in the brain, such as the dopamine and serotonin metabolites. The concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in CSF have been shown to be an overall estimate of dopamine and serotonin turnover, respectively. Unfortunaelty, more subtle imbalances between some receptor subpopulations or supersensitivity of receptors, which may also cause significant clinical problems, cannot be mirrored reliably in lumbar CSF. In addition to the craniocaudal gradient, a marked, nonlinear, age-dependency has to be considered, which is especially pronounced during the first year of life. The establishment of age-related reference ranges is therefore essential. For several reasons, the reference ranges given by different laboratories refer to different sampling protocols and different age groups. Bräutigam and colleagues have investigated this issue in a study enrolling 12 laboratories from six countries [1], and they found that the technical quality of analyses was comparable for most of the laboratories (nine of 12), whereas the age-related reference ranges and sampling protocols differed, sometimes substantially. However, clinical practice teaches us that the reference ranges are not the only criteria for the interpretation of CSF metabolites, as will be illustrated by some …