Diagnostic Value of Oligoclonal Bands in Children: A Nationwide Population-Based Cohort Study

Cerebrospinal fluid oligoclonal bands (OCB) are commonly obtained in patients when there is a concern for multiple sclerosis (MS). OCBs are positive in 98% of adults with MS,¹ but previous data suggests that OCB results may be age-dependent in children, with an earlier age of MS onset (2 Additionally, 25% of children with central nervous system (CNS) infections or immune-mediated CNS diseases will test positive for OCBs.³

The goal of the current study was to clarify the diagnostic utility of OCBs in children with suspected demyelinating disease (defined as MS, acute disseminated encephalomyelitis, neuromyelitis optica, optic neuritis and transverse myelitis) in a nationwide population-based setting. All children less than 18 years of age in the Danish National Patient Register from 1994-2017 with OCB testing were reviewed (2055 patients,median age 15 years).

The rate of OCB positivity was found to be age dependent. In children aged 12-17, 68% with ADS diagnoses demonstrated positive OCB. Although OCB were not sensitive for ADS, they showed high positive (0.89) and negative (0.87) predictive value in differentiating ADS compared with infection or immune-mediated CNS diseases. In contrast, just 24% of children

Other diagnoses associated with OCB positivity included CNS infection, malignancy, static encephalopathy and other CNS immune-mediated disorders. 

There are several limitations to this manuscript. The authors used ADS as an aggregate of MS, ADEM and neuromyelitis optica, however a recent study found that while the agreement between a diagnostic code in the National Patient Register and a correct medical-record-validated diagnosis was excellent for pediatric MS, it was only acceptable for pediatric optic neuritis and transverse myelitis, and unacceptable for ADEM.⁴ Furthermore, the diagnostic criteria in the fields of autoimmune encephalitis and ADS evolved over the course of the study, with the introduction of new biomarkers and MRI criteria. This study also did not examine anti-myelin oligodendrocyte glycoprotein antibodies, which are present at disease onset in 18-35% of children with ADS, most of whom do not have CSF OCBs.

Overall however this was an interesting retrospective review looking at a large, nationwide cohort of pediatric patients that had OCB testing. This study supports the diagnostic utility of OCBs in children aged 12-17 presenting with symptoms of MS but cautions against the use of OCBs as a way of differentiating CNS disease in children

1. Reiber, H., Ungefehr, S., Jacobi, C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler. 1998; 4: 111–117.
2. Chabas, D., Ness, J., Belman, A. et al. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology. 2010; 74: 399–405
3. Sinclair, A.J., Wienholt, L., Tantsis, E., Brilot, F., and Dale, R.C. Clinical association of intrathecal and mirrored oligoclonal bands in paediatric neurology. Dev Med Child Neurol. 2013; 55: 71–75
4. Boesen, M. S., Magyari, M., Born, A. P., & Thygesen, L. C. (2018). Pediatric acquired demyelinating syndromes: a nationwide validation study of the Danish National Patient Register. Clinical epidemiology, 10, 391.

Commentary- Daniel Freedman, MD, (Nationwide Children’s Hospital)

Abstract

Objective: We evaluated the diagnostic value of cerebrospinal fluid oligoclonal bands in individuals less than 18 years of age. Methods: In a nationwide population-based setting, we retrieved data on 2055 children's oligoclonal band examination, including concordant cerebrospinal fluid biomarkers, during 1994 to 2017. Case ascertainment was by review of medical records and diagnostic codes. We used Fisher's exact test to explore distribution differences of oligoclonal band positivity in acquired demyelinating syndromes (ADS) before and after age 12 years and calculated the sensitivity, specificity, positive predictive value, and negative predictive value of oligoclonal bands to distinguish ADS from the other diagnostic groups. Results: Median age at oligoclonal band examination was 15.2 years (range = 1.8 to 18.0), and 10% had presence of cerebrospinal fluid oligoclonal bands. Oligoclonal band positivity was the highest in ADS (52%), but it was age dependent: 21% in children with ADS before age 12 years and 68% in children aged 12 through 17 years (P < 0.0001) owing to the higher incidence of multiple sclerosis in the latter. Cerebrospinal fluid oligoclonal bands were not predictive of ADS before age 12 years compared with the other diagnostic groups. However, cerebrospinal fluid oligoclonal bands in children aged 12 through 17 years were highly predictive of ADS compared with central nervous system infections and non–ADS immune-mediated central nervous system diseases (positive predictive value: 0.89; 95% confidence interval = 0.82 to 0.94; P < 0.0001), but negative oligoclonal bands were not discriminatory (negative predictive value: P = 0.17). Conclusions: In a clinical setting, cerebrospinal fluid oligoclonal band examination may be of higher yield in children aged 12 through 17 years if there is clinical suspicion of multiple sclerosis, and in such circumstances a positive test supports a diagnosis of multiple sclerosis.

Pediatric Neurology 2019: 97, 56-63