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Updated: Jun 6, 2026
Quantitative Measurement of Intrathecally Synthesized Proteins in Mice
Published on: November 29, 2019
Intrathecal antibody synthesis - Reiber method revisited
John J Halperin1,2, Dane Granger3
1Department of Neurology, Atlantic Health Overlook Medical Center, Summit, NJ, 07901, USA. John.halperin@atlantichealth.org.
Insights
Linear models better quantify central nervous system inflammation than the Reiber hyperbolic model for diagnosing diseases like Lyme. New cutoffs improve accuracy for immunoglobulin G index and synthesis assessments.
Area of Science:
- Neurology
- Immunology
- Biostatistics
Background:
- Cerebrospinal fluid (CSF) immunoglobulin G (IgG) analysis aids in diagnosing central nervous system (CNS) inflammatory diseases.
- Common methods include qualitative oligoclonal bands (OCBs) and quantitative CSF:serum IgG:albumin ratios (e.g., IgG index).
- Laboratories in the US typically use linear models, while European labs often use Reiber's hyperbolic model.
Purpose of the Study:
- To compare the diagnostic accuracy of linear and Reiber hyperbolic models for assessing excess CSF IgG.
- To evaluate the performance of both models in relation to OCBs and Lyme-specific antibody indices (AI).
Main Methods:
- Compared linear and Reiber hyperbolic models using data from 1,872 CSF samples (1,365 with Lyme-specific data).
- Assessed correlations with OCBs using Receiver Operating Characteristic (ROC) analysis.
- Compared Lyme-specific antibody indices calculated by both methods.
Main Results:
- Linear regression showed a strong correlation (r=0.98) in normal samples and a robust correlation (r=0.95) in abnormal samples.
- Linear models demonstrated stronger associations with OCBs (ROC AUC 0.81) compared to the Reiber model (ROC AUC 0.74).
- Reiber model modification was applicable in only 14.7% of Lyme AI analyses, with minimal impact on diagnostic conclusions.
Conclusions:
- Linear models more accurately reflect intra-CNS inflammation and are recommended for diagnosing CNS inflammatory diseases.
- ROC-derived cutoffs for IgG index and IgG synthesis provide more accurate assessments of CSF immunoreactivity.
- The Reiber hyperbolic model, despite its complexity, functions linearly within the clinically relevant range.
Background:
CSF immunoglobulin (IgG) often informs diagnosis in CNS inflammatory disease- qualitatively (oligoclonal bands; OCBs), or quantitatively (CSF: serum IgG: albumin, e.g. IgG index). Most US laboratories estimate excess CSF IgG using linear models, most in Europe, Reiber's hyperbolic model - the latter often also incorporated into CSF pathogen-specific immunoreactivity calculations. We compared Reiber hyperbolic and linear approaches.
Methods:
Required data were available for 1,872 samples, Lyme-specific data for 1,365. We compared linear and Reiber's hyperbolic models to determine which better describes normal CSF: serum IgG/albumin, assessed correlations with OCBs using ROC analysis and compared Lyme-specific antibody indices (AI) by both methods.
Results:
On linear regression (CSF: serum albumin vs. CSF: serum IgG) in 890 normals, r 0.98; 0.86 on polynomial. In 982 abnormals r was 0.95 by both linear and polynomial regression. Linear regression slope was 74% greater in abnormals than normals. We tested the linearity of the Reiber hyperbolic model and found it to be essentially linear in the clinically relevant range. Dichotomizing the full dataset by OCBs, IgG index ROC AUC was 0.81, Reiber 0.74 (p<0.001). Linear models consistently demonstrated stronger associations with OCBs than the Reiber method. IgG index and IgG synthesis cutoffs from ROC analyses differed substantially from, and were more robust than, customary ones. On Lyme AI analysis, Reiber modification was potentially applicable in just 14.7% of samples, possibly changing the diagnostic conclusion in just 0.1%.
Conclusions:
Linear models more accurately reflect intra-CNS inflammation, including a novel linear regression model. Notably, we found that, despite its equation's complexity, the Reiber hyperbolic model is also linear in the clinically relevant range. In CNS inflammation, local antibody production and altered BBB/BCB permeability both contribute to excess CSF IgG. ROC-derived cutoffs for IgG index and IgG synthesis more accurately reflect CSF immunoreactivity. Reiber QLimit substitution in the Lyme-specific AI denominator did not improve accuracy.
