Difficulties in establishing reference intervals for special fluids: the example of 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluids

Abstract

Biochemical measurements in "special fluids" are complicated with the problem of reference intervals. Reference intervals are difficult to establish for these types of samples since they are usually only collected in patients with clinical suspicion of disease. Determination of neurotransmitter metabolites in cerebrospinal fluid illustrates this difficulty. This paper will review the factors and circumstances that have been identified or are suspected to modify the concentration of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid. In addition to obvious parameters such as age-related variation that can affect the concentration of 5-HIAA and HVA in cerebrospinal fluid, a variety of other factors can explain the wide range of "control" group sizes reported in the literature. Reference intervals must take into account the purpose of cerebrospinal fluid examinations, whether they be prospective studies to explore physio-pathologic relationships or for diagnostic purposes. In the latter case, certain neurological disorders cannot be excluded if a single measured value is within the reference interval.

Cerebrospinal fluid levels of catecholamines and its metabolites in Parkinson's disease: effect of l‐DOPA treatment and changes in levodopa‐induced dyskinesia

“…). There is a large inter‐individual variation in CSF HVA levels (Parkinson study group ) – some of the variation may be due to gradient effects in CSF obtained in the first or later fractions (Dhondt ). In our study, the same fraction of CSF was used when comparing control and PD CSF.…”

Revisiting the serotonin–aggression relation in humans: A meta-analysis.

“…The failure to clarify the ambiguous relation between 5-HIAA and aggression may be in part due to difficulties in establishing reference levels of CSF 5-HIAA. CSF 5-HIAA has been shown to be moderated by age (e.g., Hedner, Lundell, Breese, Mueller, & Hedner, 1986; Seifert, Foxx, & Butler, 1980; Takeuchi et al, 2000), gender (e.g., Blennow et al, 1993; Hagenfeldt, Bjerkenstedt, Edman, Sedvall, & Wiesel, 1984), height and weight (e.g., Blennow et al, 1993; Hartikainen et al, 1991; Strömbom et al, 1996), physical activity (Eklundh, Gunnarsson, & Nordin, 2001; Nordin, Lindstöm, & Wieselgren, 1996), season (e.g., Brewerton, Berrettini, Nurnberger, & Linnoila, 1988; Hartikainen et al, 1991), atmospheric pressure (Eklundh, Fernström, & Nordin, 1994; Nordin, Swedin, & Zachau, 1992), and intraspinal pressure (Eklundh & Nordin, 2001), along with several psychiatric and neurological conditions (for a review of CSF 5-HIAA moderators, see Dhondt, 2004). One of the most serious confounding influences associated with measuring CSF 5-HIAA may be an inverse relation between CSF5-HIAA levels and stress associated with the lumbar puncture procedure itself (Hill et al, 1999).…”

The Anaesthetic Biobank of Cerebrospinal fluid: a unique repository for neuroscientific biomarker research

“…Most CSF biomarker studies have included patients with neurological symptoms as reference (in retrospect after excluding a CNS disease), have used very small control groups or included patients undergoing spinal anaesthesia (9,10,18,(23)(24)(25)(26)(27). Even studies designed to establish reference ranges for CSF neurotransmitters included symptomatic patients (28,29) or consisted of a small cohort with healthy volunteers (30).…”

“…To assist with interpretation of new findings, investigators ultimately depend on the availability of sufficiently large databases containing the results of assays of biomaterials (CSF, blood and urine), and concomitantly assessed clinical features and personal characteristics, of a range of patients and healthy controls. Due to the attendant risks of a LP, such as infection, neurological injury and post-dural puncture headache (PDPH) (31), it is difficult to obtain CSF from healthy controls because of the ethical considerations involved (9,27).…”