1274_1275_Franciotta_JON_1820 30.09.2005 08:03 Uhr Seite 1274

J Neurol (2005) 252 : 1274–1275 DOI 10.1007/s00415-005-0820-1

LETTER TO THE EDITORS

Diego Franciotta Roberto Bergamaschi Maria Pia Amato Elisabetta Zardini Alessandra Persico Emilio Portaccio Francesco Lolli

Clinical correlations of CSF single IgG bands Received: 8 September 2004 Received in revised form: 6 December 2004 Accepted: 31 December 2004 Published online: 16 September 2005

Sirs: Oligoclonal IgG bands (OCBs) are a mainstay in the diagnosis of multiple sclerosis (MS), and an aid for laboratory diagnosis in other inflammatory or infectious neurological diseases. The last consensus report to deal with this topic classifies serum and CSF pairs, after isoelectric focusing (IEF) analysis, into five patterns [1]. The report does not include patterns composed of single CSF bands, and single CSF bands with additional, identical OCBs in serum and CSF. In recent years, laboratory sightings of these patterns have increased [2, 3]. In a previous letter, we showed that single CSF band patterns might be the “tip of the iceberg” of oligoclonal responses, and thus suggested “possi-

ble” intrathecal IgG synthesis [4]. Here we review the results of CSF examinations and assess the frequency and disease association of these patterns in a representative neurological setting. We retrospectively evaluated 3273 consecutive neurological patients who underwent lumbar puncture for diagnostic purposes in 1999–2002. Serum and CSF samples were analysed with IEF for OCB detection. IEF was performed in agarose gel. Proteins were transferred to nitrocellulose paper by capillarity, and stained with an IgG-specific peroxidase-based method [5]. The same amounts of IgG (0.3 µg) were loaded onto the gel. Results are summarised in the table. The single CSF band pattern was more frequent in definite MS [6] than in all the other neurological diseases, which included: viral encephalitis (n = 6), myelitis (n = 6), polyneuropathy (n = 5), acute demyelinating encephalomyelitis (n = 2), Alzheimer’s disease (n = 2), retrobulbar optic neuropathy (n = 2), and Guillain-Barrè syndrome (n = 1). The pattern characterised by a single CSF band with additional, identical OCBs in serum and CSF was found in patients with chronic (HIV-1 dementia, 4; neurosyphilis, 1), or acute (viral encephalitis, 5) CNS infectious diseases. The group of MS patients with the single CSF band

pattern showed an inverse female/ male ratio and a higher mean age at onset vs the MS group with CSF OCBs. These associations were significant irrespective of the distinction between relapsing-remitting and primary progressive forms. Single CSF bands were described early after IEF entered laboratory routine for OCB detection [7], and were initially associated with non-MS neurological diseases [3, 5]. More recently, a follow-up study showed that patients with single CSF bands who developed OCBs had prevalently MS, or clinically isolated syndromes due to demyelination [2]. Our data reinforce this observation, and imply that: a) the two patterns characterised by single CSF bands, and single CSF bands with additional, identical OCBs in serum and CSF, should be added to the five existing consensually categorized serum/CSF IEF patterns [1], and used for clinical and research purposes; b) in differential diagnostics, the single CSF band pattern might suggest, rather than exclude, MS, especially in males with late age at onset; c) the presence of single CSF band with additional, identical OCBs in serum and CSF inclines the diagnosis towards infectious CNS diseases. Limitations in the interpretation of our data include the facts that: a) the identification of single bands is highly technique-depen-

Table Demographic features and isoelectric focusing findings of patients with multiple sclerosis (MS), and other neurological diseases (ONDs) n (%)

– OCBs – SB

245a 203 (83) 27b (11)

ONDs – SB – SB plus

3028 24 (0.79) 10 (0.33)

JON 1820

MS

RR/PP 209/36 177/26 22/5 n. a. n. a. n. a.

female/male (ratio)

age (ys) ± SD (range)

age at onset (ys) ± SD (range)

DD (ys) ± SD (range)

EDSS ± SD (range)

PI ± SD (range)

156/89 (1.75) 134/69 (1.94) 12/15 (0.80)c

40.1 ± 11.8 (18–77) 39.3 ± 11.3 (18–74) 46.3 ± 13.7 (27–77)

32.4 ± 10.2 (18–77) 31.8 ± 10.0 (9–61) 36.8 ± 10.6 (22–72)d

7.3 ± 6.9 (1–35) 7.1 ± 6.6 (1–35) 8.9 ± 8.8 (2–35)

2.4 ± 1.9 (0–8) 2.4 ± 1.9 (0–8) 2.6 ± 2.1 (0–7)

0.6 ± 0.5 (0–3.5) 0.6 ± 0.5 (0–3.5) 0.5 ± 0.5 (0–2.2)

1468/1560 (0.94) 10/14 (0.71) 3/7 (0.43)

37.1 ± 15.3 (1–88) 39.7 ± 13.0 (16–60) 39.2 ± 14.5 (18–62)

n. a. n. a. n. a.

n. a. n. a. n. a.

n. a. n. a. n. a.

n. a. n. a. n. a.

RR relapsing-remitting; PP primary progressive; SD standard deviation; DD disease duration; EDSS expanded disability status scale; PI progression index (EDSS/DD); RR relapsing-remitting; PP primary progressive; OCBs CSF oligoclonal IgG bands; SB CSF-restricted single IgG band; SB plus CSF-restricted single IgG band in addition to OCBs equal in serum and CSF; n. a. not applicable; a OCB-negative patients (n = 15) were included; b P < 0.0001 (χ2 test); c P = 0.034 (Fisher’s exact test); d P = 0.016 (unpaired t test)

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dent; b) increases in the amount of IgG loaded onto the gel could cause the appearance of additional bands to appear, although the concomitant increase in polyclonal IgG background probably interferes; c) intrathecal IgG synthesis can only be excluded by non-IgG OCB searches. With regard to the third limitation, Goffette et al. found oligoclonal free kappa bands in 3 out of 4 MS patients with single CSF IgG bands [8]. CNS lymphomas should also be considered as sources of single CSF bands [9]. The high frequency of single CSF bands in MS here reported could depend on two factors. Firstly, within a context of increasing health awareness, lumbar puncture is now performed sooner after initial neurological symptoms appear, than it was in the past, and early-stage CSF samples could contain traces of a not-yet-oligoclonally organized, and in any case differing, humoral immune response. In infectious neurological diseases, a single CSF band with additional, identical OCBs in serum and CSF could similarly indicate an initial, probably ongoing, restriction of Bcell response within the CNS. Secondly, the diagnostic indications for lumbar puncture at the beginning of the “IEF era” were less specific than they are today, and, consequently, the chance of detecting single CSF bands in non-MS neurological diseases was higher. Although the associations here

reported require confirmation in other series, our findings indicate that a “grey zone” exists between certain absences (no CSF OCBs), and certain occurrences (two or more CSF OCBs) of intrathecal IgG synthesis. To regard single CSF bands as OCBs is an oversimplification. The immunological characteristics of many diseases that are associated with single CSF bands, with or without identical OCBs in serum and CSF, suggest that this “grey zone” can be the zone of “possible” intrathecal IgG synthesis. Confirmation of our data requires studies, preferably prospective, on other series. ■ Acknowledgement This work was supported by a grant from the ‘Ministero della Salute’(RC 2004).

References 1. Andersson M, Alvarez-Cermeño J, Bernardi G, et al. (1994) Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 57:897–902 2. Davies G, Keir G, Thompson EJ, Giovannoni G (2003) The clinical significance of an intrathecal monoclonal immunoglobulin band. A follow up study. Neurology 60:1163–1166 3. Franciotta D, Zardini E (1997) Single immunoglobulin band in cerebrospinal fluid isoelectric focusing. J Neurol Sci 146:93–94 4. Franciotta D, Zardini E, Lolli F (2004) The clinical significance of an intrathecal monoclonal immunoglobulin band: a follow-up study. Neurology 62:675

5. Walker RWH, Keir G, Johnson MH, Thompson EJ (1983) A rapid method for detecting oligoclonal IgG in unconcentrated CSF by agarose isoelectric focusing, transfer to cellulose nitrate, and immunoperoxidase staining. J Neuroimmunol 4:141–148 6. Poser CM, Paty DW, Scheinberg L, et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231 7. Kostulas VK (1985) Oligoclonal IgG bands in cerebrospinal fluid. Methodological and clinical aspects. Acta Neurol Scand 103(suppl.):1–112 8. Goffette S, Schluep M, Henry H, Duprez T, Sindic CJ (2004) Detection of oligoclonal free kappa chains in the absence of oligoclonal IgG in the CSF of patients with suspected multiple sclerosis. J Neurol Neurosurg Psychiatry 75: 308–310 9. Trip SA, Wroe SJ, Davies G, Giovannoni G (2003) Primary CNS mantle cell lymphoma associated with an isolated CSF monoclonal IgG band. Eur Neurol 49: 187–188 Dr. D. Franciotta (
) · E. Zardini Laboratory of Neuroimmunology Foundation “Neurological Institute C. Mondino”, via Mondino 2 27100 Pavia, Italy Tel.: +39-0382/380296 Fax: +39-0382/380286 E-Mail: [email protected] R. Bergamaschi · A. Persico Clinical Neurology IRCCS Foundation “Neurological Institute C. Mondino”, University of Pavia via Mondino 2 27100 Pavia, Italy M. P. Amato · E. Portaccio · F. Lolli Dept. of Neurological and Psychiatric Sciences University of Florence Viale Morgagni 85 50134 Florence, Italy