ALD, adrenoleukodystrophy; AT, ataxia telangiectasia; CNS, central nervous system; CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; MS, multiple sclerosis; SLE, systemic lupus erythematosus; SSPE, sub-acute sclerosing pan encephalitis.
A glimpse at the cerebrospinal fluid immunoglobulins in neurological conditions. Does it help the clinician?
Article first published online: 7 NOV 2012
© The Author. Developmental Medicine & Child Neurology © 2012 Mac Keith Press
Developmental Medicine & Child Neurology
Volume 55, Issue 1, pages 10–12, January 2013
How to Cite
LIM, M. (2013), A glimpse at the cerebrospinal fluid immunoglobulins in neurological conditions. Does it help the clinician?. Developmental Medicine & Child Neurology, 55: 10–12. doi: 10.1111/dmcn.12033
- Issue published online: 13 DEC 2012
- Article first published online: 7 NOV 2012
Cerebrospinal fluid (CSF) analysis is an important tool in the evaluation of neurological diseases. CSF biomarkers that are used to diagnose potentially treatable inflammatory disorders of the central nervous system (CNS) may be specific for a condition such as auto-antibodies in the autoimmune encephalitides, or may evaluate disease-specific mechanisms such as the upregulation of various aspects of the immune system when measuring neopterins and oligoclonal bands.1
Immunoglobulins (often IgG) that reflect local synthesis and/or breach in the blood–brain barrier can be detected in the serum and CSF, using qualitative (oligoclonal patterns) and quantitative (IgG Index) techniques. Measuring these bands in a paired serum and CSF sample by isoelectric focusing on agarose gels followed by immunoblotting2 is now the widely accepted criterion standard technique to qualitatively determine oligoclonal bands in a range of inflammatory and immune-mediated conditions such as multiple sclerosis.3 Although the method has been standardized and is commercially available, the technique and interpretation requires expertise and should be performed by laboratories with experience with CSF diagnostics.4 The qualitative analysis of these oligoclonal bands can be categorized into five patterns (Type 1–5).3,5 A more descriptive nomenclature of these patterns has been more widely used by clinicians. Table I summarizes some of the descriptive terms used for the different patterns and also the groups of neurological conditions commonly reported to be associated with the varied patterns.
|Pattern3,5||Alternative nomenclature5–7||Descriptive of bands observed||Interpretation||Conditions5–7|
|Type 1||Negative||No bands found in serum or CSF||Normal||Non-inflammatory conditions|
|Type 2||Intrathecal||CSF oligoclonal bands||Intrathecal production of IgG||Infection (encephalitis, meningitis, borrelia, HIV, SSPE, syphilis) Inflammation (MS, demyelination, neuro-sarcoid, Behcet syndrome, cerebral lupus) Paraneoplastic/neoplastic Neurodegeneration (AT, ALD)|
|Type 3||Greater||CSF oligoclonal bands as in Type 2 and additional identical bands in both CSF and serum as in Type 4||Intrathecal production but also ongoing systemic inflammation (may be independent inflammation in either components) Intrathecal production induced by systemic inflammation||Infection (encephalitis, meningitis) Inflammation (MS, demyelination) Paraneoplastic/neoplastic|
|Type 4||Equal/Mirror/Same||Identical oligoclonal bands in serum and CSF||Systemic inflammation with CNS inflammation as part of same disease Systemic inflammation causing secondary CNS inflammation||Infection (encephalitis, meningitis) Inflammation (MS, demyelination) Autoimmune (SLE, vasculitis) Paraneoplastic/neoplastic Guillain-Barré syndrome Peripheral neuropathy Vascular Neurodegenerative|
|Type 5||Monoclonal||Large monoclonal bands in serum and CSF||Abnormal clones of lymphocytes||Paraproteinaemia, myeloma|
Evaluation of these oligoclonal bands have centred on disease-specific conditions such as multiple sclerosis and a range of inflammatory conditions, often emphasizing the intrathecal production.5 Less has been reported on the other patterns and their relevance in the wider range of CNS disorders. Two studies using the aforementioned criterion standard technique report the range of neurological conditions where oligoclonal bands are identified in a paediatric6 and adult cohort.7 However, both these studies that reveal the range of neurological conditions whereby these bands could be found in the serum and CSF (see Table I) are based on cohorts from at least two decades ago.
Sinclair et al.8 evaluate the utility of measuring CSF oligoclonal bands in a contemporary cohort of children presenting with neurological conditions. This study provides valuable and important data on the presence of oligoclonal bands in a range of childhood-onset neurological conditions, not dissimilar to those previously reported.6,7 The authors found in their evaluation that the presence of CSF bands, both the ‘intrathecal’ and ‘mirrored’ pattern, were good predictors of CNS inflammation, irrespective of aetiology. What this study and the two older cohorts also emphasize is that the presence of oligoclonal bands in the CSF in either pattern can be used to diagnose inflammatory conditions but cannot be used to exclude them. Although a quantitative analysis of the IgG would have provided a more thorough analysis in this contemporary cohort, one might question the additional information it would yield. Despite numerous efforts and some early promise on the quantification of CSF with elaborate evaluations of disease-related data patterns,9 the quantitative analysis by measure of the IgG Index has proven to be less sensitive in detecting the majority of CNS inflammatory conditions when compared with the qualitative technique.3
In interpreting the data derived from this and the other two studies, it is important to recognize that these observed oligoclonal patterns reflect the differential involvement of the systemic and central (CNS) immune system; at one spectrum there is primary CNS inflammation (intrathecal or predominantly intrathecal pattern), and at the other a mixed (or secondary) CSF inflammation coexisting with (or as a result of) systemic inflammation (mirror pattern). Hence when evaluating the diagnostic accuracy of such an analysis that identifies an inflammatory mechanism, care needs to be given when CNS disorders are only classified according to their primary pathology. Immune and inflammatory mechanisms have been implicated in a broad range of neurodegenerative disorders,10 epilepsies,11 and even headache syndromes,12 and it is thus not surprising that oligoclonal bands are also identified in these conditions.6,7 As such, the specificity of this test needs to be evaluated against the inflammatory mechanism it detects, and not just an arbitrary diagnosis based on primary cause.
Finally, in looking ahead the authors acknowledge the difficulty in referencing this analysis of oligoclonal bands to a criterion standard (as CNS inflammation cannot be directly measured). They propose a prospective cohort evaluated over a longer period where putative inflammatory mechanisms of inflammation may be evaluated in this range for neurological conditions. This would allow for a more precise evaluation of the utility of measuring oligoclonal bands. Furthermore, the current analysis only affords the clinician a snapshot of an otherwise dynamic process, and therefore an evaluation of sequential samples may prove as, or more, informative. Hence in this cohort the oligoclonal band should be evaluated systematically and, when possible, sequentially to see if they would predict the natural history of disease or may indeed be used to evaluate disease progression and treatment response in neurological conditions where inflammation features.
- 5Cerebrospinal fluid. In: Hughes RAC, editor. Neurological Investigations. London: BMJ Publishing Group, 1997: 443–66..
- 8Clinical association of intrathecal and mirrored oligoclonal bands in paediatric neurology. Dev Med Child Neurol. DOI: 10.1111/j.1469-8749.2012.04443.x. [Epub ahead of print]., , , , .