Reference Range for Cerebrospinal Fluid Protein Concentration in Children and Adolescents FREE

Elevated cerebrospinal fluid (CSF) protein concentration measured during diagnostic lumbar puncture (LP) can indicate a pathologic central nervous system process. Interpretation of CSF protein concentration requires established reference values. However, evidence-based, standardized assessments of CSF protein concentration do not exist. Ethical considerations prohibit subjecting healthy children to invasive procedures solely for research purposes. Consequently, normative values in children must be determined from diagnostic LPs.

Limitations of prior studies of CSF protein concentration in children include small sample sizes, varying inclusion and exclusion criteria, and presentation of mean and standard deviation rather than ranges.^1- 6 The objective of this study was to determine age-specific reference values for CSF protein concentration.

This was a secondary analysis of a prospective cohort study performed at The Children's Hospital of Philadelphia. Subjects aged 1 to 18 years undergoing diagnostic LP were eligible. Consent from the parent and assent from the child were obtained following institutional review board approval. Subjects were screened for enrollment between January 15, 2007, and February 28, 2009, as described previously.⁷

Subjects were not approached for enrollment in the primary study of CSF opening pressure measurements if they were medically unstable or had a brain tumor.⁷ Enrolled subjects with conditions that had the potential to alter CSF protein concentration (eg, meningitis, demyelinating disease) and those with CSF pleocytosis (>10 white blood cells/mm³) or traumatic LP (>500 red blood cells/mm³) were excluded. When a patient received multiple LPs, only results of the first LP were included.

Initially, 1066 patients with LP were screened for enrollment and 439 were enrolled⁷; of these, 210 subjects remained in the study (Table).

The median patient age was 11.1 years (interquartile range, 5.2-14.5 years); 68 (32%) were black. The Table presents CSF protein concentrations among children in the reference group. There was an age-related increase in CSF protein concentration (eFigure). In linear regression, CSF protein concentration increased by 0.97 mg/dL (95% confidence interval, 0.75-1.18 mg/dL; P < .001) for each 1-year increase in age. Comparisons across different age categories suggested that a cutoff of age 10 years was most clinically applicable (Table).

We prospectively examined CSF protein concentrations in children and adolescents to establish clinically useful reference values. These findings are important because a variety of infectious and noninfectious conditions may cause elevations in CSF protein concentrations in the absence of CSF pleocytosis.

The median and 90th percentile CSF protein concentrations in our study were higher than the values reported by Wong et al.⁶ Our larger sample size may have resulted in a greater distribution of older children, which could account for these differences. The CSF protein values for children aged 1 to 9 years were comparable with a prior report.¹ It is unclear why children aged 10 to 18 years in our study had higher values than those reported by Biou et al¹ (median, 22 mg/dL; 95th percentile, 41 mg/dL).

The CSF protein concentration increased nearly 1 mg/dL for each additional year of age. The CSF protein concentration was significantly lower for subjects younger than 10 years compared with older subjects, suggesting that age 10 years may be an accurate and practical cutoff.

Children with unrecognized conditions associated with elevated CSF protein concentration may have been included despite our systematic exclusions. This limitation would cause us to overestimate the upper range of normal values. However, subjects with medical indications for LP may be a more clinically appropriate reference population than children without an indication for LP.

Our study quantifies the age-related increase in CSF protein concentration between 1 and 18 years of age. The 90th percentile values of 30 mg/dL (ages 1-9 years) and 45 mg/dL (ages 10-18 years) represent reference values to be used to guide the interpretation of CSF protein concentration.