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ARTICLES: Gerard Davies, Geoff Keir, Edward J. Thompson, and Gavin Giovannoni The clinical significance of an intrathecal monoclonal immunoglobulin band: A follow-up study Neurology 2003; 60: 1163-1166 [Abstract] [Full text] [PDF]

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The clinical significance of an intrathecal monoclonal immunoglobulin band: A follow-up study

Ulrich Wurster, PhD   (28 October 2003)

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Gavin Giovannoni, Geoff Keir, PhD, Edward Thompson DSc   (28 October 2003)

The clinical significance of an intrathecal monoclonal immunoglobulin band: A follow-up study 28 October 2003
Ulrich Wurster, PhD, Medical School Hannover Neurochemical Laboratory -7217-,Med. Hochschule, Carl-Neuberg- Str. 1, 30625 Hannover, Germany Send Correspondence to journal: Re: The clinical significance of an intrathecal monoclonal immunoglobulin band: A follow-up study Wurster.Ulrich{at}mh-hannover.de Ulrich Wurster, PhD	With modern CSF analysis, oligoclonal bands can be demonstrated in the CSF of patients with clinical definite MS at a rate of > 95 % 1. This may be closer to 100 % if the cut-off was lowered to one band but there may be an impact on specificity. Davies et al. [2] have addressed this question, since the existing literature on the significance of a single band focuses on work conducted with agarose-electrophoresis which is of low resolution and sensitivity. However, some issues need clarification. What was the overall frequency of a single band in the whole population? Restriction to the 31 patients who consented to repeat lumbar puncture might introduce a bias towards patients with demyelinating diseases. How many bands were present in the follow-up CSFs and was the change to an oligoclonal pattern accompanied also by a quantitative increase in intrathecal IgG? Considering the unavoidable variance (VK?) between different gels, it is advisable to rerun the original (frozen) specimens along with the follow-up samples. Furthermore, faint bands might escape detection when CSF and sera are not diluted to exactly the same uniform IgG concentration. It is important to note that detection of total IgG is less sensitive than, for example, affinity immunoblotting. Sindic et al [3] have shown that the oligoclonal IgG does not coincide with the oligoclonal staining for various microbial antigens and negative staining for IgG does not rule out oligoclonal reactions against such antigens. Thus, what might appear as a single IgG band may still be oligoclonal. The interchangeable use of monoclonal and single band is confusing. The term monoclonal bands (plural) is already reserved for the type 5 pattern (IgG paraprotein) as defined in the European consensus. [1] Although a (truly) monoclonal IgG paraprotein will appear as a single band in agarose-electrophoresis, it is split up in 2-15 bands (own observations) in isoelectric focusing because of postsynthetic modifications. The number of bands alone does not allow differentiation between oligoclonal and monoclonal. Many patients with a single band and no obvious explanation for intrathecal IgG synthesis speak against a cut-off of one band. In order to retain high sensitivity and specificity, I suggest the use of two cut-off levels. Two-three bands are rated as borderline and four or more as definitely positive. [4] References 1. Anderson M, Alvarez-Cermeno J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 1994;57:897-902. 2. Davies G, Keir G, Thompson EJ, Giovannoni G. The clinical significance of an intrathecal monoclonal immunoglobulin band. Neurology 2003; 60:1163- 1166. 3. Sindic CJM, Monteyne P, Laterre EC. The intrathecal synthesis of virus specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol 1994;54:75- 80. 4. Wurster U. Isoelectric focusing on macro polyacrylamide gels with automated silver staining: A versatile method for demonstration of oligoclonal bands in the CSF by direct protein stain or IgG immunofixation, and the identification of beta-2-transferrin in CSF rhinorrhoea. Clin Chem 2003; 49:Supplement A 115.
Reply to Wurster 28 October 2003
Gavin Giovannoni, Institute of Neurology Queen Square, London WC1N 3BG, Geoff Keir, PhD, Edward Thompson DSc Send Correspondence to journal: Re: Reply to Wurster g.giovannoni{at}ion.ucl.ac.uk Gavin Giovannoni, et al.	We thank Dr. Wurster for his comments. The overall incidence is < 1% and the question of bias may have less to do with demyelination but more with follow-up to rule out CNS lymphoma which is noted in the print-out for these patients. All the patterns did not develop in the same way. Some became oligoclonal, some remained the same, and in others the original monoclonal bands disappeared. This suggests that no major bias was introduced. The increased number of bands was not counted, as we (and others) have not found any useful correlations. Likewise, quantification of the amounts of IgG is notoriously less sensitive and less specific than the “gold standard” of determining the presence of oligoclonal bands. The question of applying “exactly the same uniform IgG concentration” has been well described as not being problematic for this technique. [1] This accommodates a range of almost two logs, from 20 ng to 1200 ng of IgG. The point about microbial antigens being of different affinity has also been well described, however this point is irrelevant since it employs a different technique. [2] We agree that the number of bands alone does not allow differentiation between oligoclonal and monoclonal. Concerning the general point of the number of bands to diagnose local synthesis, there has been a recent international consensus meeting at which the work of Davies et al was considered [3] and work on single bands using the technique of Sindic. [4] The consensus was that 2 bands present in CSF but absent from serum were required and sufficient enough to make the diagnosis of local synthesis of IgG within the CNS. References 1. Keir G, Luxton RW, Thompson EJ. Isoelectric focusing of cerebrospinal fluid immunoglobulin G: An annotated update. Ann Clin Biochem 1990;27:436-443. 2. Moyle SP, Thompson EJ. Viral immunoblotting of measles-specific oligoclonal immunoglobulin G, kappa and lambda light chains in subacute sclerosing panencephalitis. Biochem. Soc. Trans. 1985;13:902-903. 3. Davies GR, Keir G, Thompson EJ, Giovannoni G. The clinical significance of an intrathecal monoclonal immunoglobulin band: a follow-up study. Neurology 2003;60:1163-1166. 4. Sindic CJM, Laterre EC. Oligoclonal free kappa and lambda bands in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. J Neuroimmunol 1991;33:63-72.