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Re: Relation of anti-ganglioside antibodies and childhood Guillain-Barré syndrome: More work is needed

Dear Editor,

We read with interest the recent article in Arch Dis Child (January 2007) by Schessl et al1 on ‘Prospective study on anti-ganglioside antibodies in childhood Guillain-Barré syndrome’. Since Ilyas et al2 first reported the clinical–serological association between Anti-ganglioside antibodies and Guillain-Barré syndrome 20 years ago, a number of publications have reported its strong association; prevalence ranging from 15% to 47%.3 The authors concluded serologic evidence of recent infection with Campylobacter jejuni (C. jejuni) is correlated significantly with raised antiganglioside antibodies. If raised titers of antibodies really occurred, how could the study by Schessl et al1 unable to show worse outcome on the clinical course? Why there is discrepancy between applying pathological principles and failure to predict clinical outcomes. We believe there are important potential limitations to the above assertion.

Lack of attempt to define criteria for evidence of recent C jejuni- The authors need to point the nature of the antibodies (IgG, IgM or IgA) realizing that IgG may represent a past infection while IgM & IgA identify more recent ones. The criteria for the diagnosis of recent C. jejuni positivity should be particularly stringent to exclude any false positive serologic results. High optical density for IgM antibodies to C. jejuni may be found in patients with both salmonella and shigella enteritis, and therefore their presence alone should not be regarded as specific for C. jejuni infection. Similarly, patients with elevated levels of a single IgG or IgA antibody class but without a history of recent diarrheal illness should also be excluded in order to minimize the number of false positive results. Lacunae in outcome of GBS- Secondly, Schessl et al did not find worse clinical outcome in patients with positive IgG-GM1antibodies. Experimental studies4 showed an antagonizing effect of IVIG on anti-ganglioside antibody mediated neuromuscular transmission blockage. In this study most patients received IVIG, which could have negated effect of anti- ganglioside antibodies on clinical outcome. Therefore fallaciously study does not support the hypothesis that raised anti-ganglioside antibodies are associated with worse clinical outcome. Small number of patients- Finally, a major flaw in the study design, also mentioned by the authors, was the small sample size. The number of patients with positive antibodies was four only, and the authors do not report a difference in clinical outcome. With such small sample size the possibility of type II error cannot be excluded.

Schessl and colleagues are to be congratulated for performing a practical clinical study that is the first of its kind on anti-ganglioside antibodies in childhood Guillain-Barré syndrome. Clinicians should interpret this study with caution as there are important shortcomings in the study. Hopefully, other centres will continue to address this issue, and maybe in time we will have the perfect study with long follow-up and pertinent clinical outcome parameters to satisfy our colleagues in evidence-based medicine.

References:

1. J Schessl, M Koga, K Funakoshi, J Kirschner, W Muellges, A Weishaupt, et al. Prospective study on anti-ganglioside antibodies in childhood Guillain-Barre syndrome. Arch Dis Child 2007;92: 48 - 52.

2. Ilyas AA, Willison HJ, Quarles RH, Jungalwala FB, Cornblath DR, Trapp BD, et al. Serum antibodies to gangliosides in Guillain–Barré syndrome. Ann Neurol 1988;23: 440–7.

3. Wilson HJ, Yuki N. Peripheral neuropathies and anti-glycolipid antibodies. Brain 2002;125:2591-625.

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Re: Reply to Dr. Jitendra K. Sahu and Dr. Kalra Veena

Dear Editor,

We thank Dr. Sahu and Dr. Veena from New Delhi, India for their interest in our study (1) and their critical comments. They point out that our study has some methodological flaws and that its conclusions cannot be generalized. We want to comment to this as follows:

Our study has been performed prospectively in a cohort of German, Swiss and Austrian children. It was our aim to investigate the frequency of Campylobacter jejuni infections and anti-ganglioside antibodies and their correlation in that population. Stool cultures from the multicenter study were investigated in one German lab, and Campylobacter serology was performed in parallel in Germany and in the labs of Dr. Yuki, Japan. Dr. Jitendra claimed that we lacked definite criteria for recent C. jejuni infection. However, we have reported such criteria as documented in our reference 13 (2). Dr. Koga tested three classes of Igs (IgG, IgM, and IgA) of anti-C. jejuni Ab and jugded "positive serology for recent C. jejuni infection" if two or more classes of Abs are detected. With these criteria, based on the results of C. jejuni-isolated patients there is a high sensitivity (91%) and specificity (97%) of the serological tests. Anti-ganglioside antibodies were also investigated by the team of Dr. Yuki who is one of the most renowned researchers in this field.

Although we admit that false-positive and false-negative results may be possible, we believe that our conclusion that Campylobacter jejuni aetiology and the presence of anti-ganglioside antibodies are rare in children from highly-developed Western countries is correct. This is supported by reports from other authors (3). This contrasts to results from other countries (China, South America, Turkey and South Africa), as we have discussed in our paper (4-7). Despite the small number of cases with C. jejuni aetiology in our series, we were able to show a correlation between this aetiology and anti-ganglioside antibodies which has repeatedly been described in adults.

Dr. Sahu is correct when he remarks that from this small number of C. jejuni- and antibody-positive patients we cannot draw firm prognostic conclusions. This would need much larger numbers of affected patients. However, reports from other countries also show that the prognosis in C. jejuni-associated GBS and AMAN might be much better in children than in adults (6,7).

References:

1. J Schessl, M Koga, K Funakoshi, J Kirschner, W Muellges, A Weishaupt, R Gold, and R Korinthenberg. Prospective study on anti- ganglioside antibodies in childhood Guillain–Barré syndrome. Arch Dis Child 2007; 92: 48-52.

2. Koga M, Gilbert M, Li J, et al. Antecedent infections in Fisher syndrome: a common pathogenesis of molecular mimicry. Neurology 2005;64:1605-11.

3. Asbury A. New concepts of Guillain-Barré syndrome. J Child Neurol 2000;15:183-91.

4. Wu HS, Liu TC, Lu ZL, et al. A prospective clinical and electrophysiologic survey of acute flaccid paralysis in Chinese children. Neurology 1997;49:1723-5.

5. Goddard EA, Lastovica AJ, Argent AC. Campylobacter 0:41 isolation in Guillain-Barré syndrome. Arch Dis Child 1997;76: 526-8.

6. Paradiso G, Tripoli J, Galicchio S, et al. Epidemiological, clinical, and electrodiagnostic findings in childhood Guillain-Barré syndrome: a reappraisal. Ann Neurol 1999;46:701-7.