Author Affiliations: Divisions of Infectious Diseases (Mr Renuart and Dr Shah), Emergency Medicine (Dr Mistry), General Pediatrics (Drs Boswinkel and Shah), and Neurology (Dr Avery) and the Neuro-Ophthalmology Service (Drs Avery and Liu), The Children's Hospital of Philadelphia, and Departments of Pediatrics (Drs Licht and Shah), Neurology (Drs Licht and Liu), Ophthalmology (Dr Liu), Anesthesiology and Critical Care (Dr Huh), and Biostatistics and Epidemiology (Drs Avery and Shah), University of Pennsylvania School of Medicine, Philadelphia; and the Department of Pediatric Emergency Medicine, Virtua-West Jersey Hospital, Voorhees, New Jersey (Dr Seiden). Dr Avery is now with the Departments of Pediatrics and Neurology, Children's National Medical Center, Washington, DC.
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.
Correspondence: Dr Shah, Division of Infectious Diseases, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Room 1526 (North Campus), Philadelphia, PA 19104 (firstname.lastname@example.org).
Author Contributions:Study concept and design: Mistry, Avery, Licht, Seiden, Huh, Boswinkel, Liu, and Shah. Acquisition of data: Mistry, Avery, Huh, and Boswinkel. Analysis and interpretation of data: Renuart, Mistry, Licht, Huh, Liu, and Shah. Drafting of the manuscript: Renuart, Mistry, Licht, Huh, Liu, and Shah. Critical revision of the manuscript for important intellectual content: Mistry, Avery, Licht, Seiden, Huh, Boswinkel, Liu, and Shah. Statistical analysis: Renuart and Shah. Obtained funding: Shah. Administrative, technical, and material support: Boswinkel. Study supervision: Mistry, Avery, Licht, Huh, Liu, and Shah.
Financial Disclosure: None reported.
Funding/Support: Dr Avery received support from the National Institutes of Health (National Institutes of Health/National Eye Institute Loan Repayment Program; 1T32NS061779-01 Neurologic Clinical Epidemiology Training Program, principal investigator, Laura Balcer, MD). Dr Shah received support from National Institute of Allergy and Infectious Diseases grant K01 AI73729 and the Robert Wood Johnson Foundation under its Physician Faculty Scholar Program. Dr Licht is supported by National Institute of Neurological Disorders and Stroke grant NS-052380, a grant from the DANA Foundation, and a gift from the June and Steve Wolfson Fund for Neurological Research. Dr Huh received support from National Institute of Neurological Disorders and Stroke grant NS053651.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Renuart AJ, Mistry RD, Avery RA, Licht DJ, Seiden JA, Huh JW, Boswinkel JP, Liu GT, Shah SS. Reference Range for Cerebrospinal Fluid Protein Concentration in Children and Adolescents. Arch Pediatr Adolesc Med. 2011;165(7):671-673. doi:10.1001/archpediatrics.2011.89