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Multifocal motor neuropathy: a trial of therapeutic complement inhibition, and investigation of serological factors

Fitzpatrick, Amanda (2012) Multifocal motor neuropathy: a trial of therapeutic complement inhibition, and investigation of serological factors. MSc(R) thesis, University of Glasgow.

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Abstract

Immune-mediated neuropathies cause inflammation of the peripheral nerve, with disruption of the axon, myelin sheath or both. In the acute setting, immune-mediated neuropathy can lead to respiratory muscle weakness, in the group of Guillain-Barré syndrome (GBS). In the chronic setting, immune-mediated neuropathies, which can be sensorimotor (CIDP, MADSAM), sensory predominant (anti-MAG neuropathy, others) and purely motor (MMN), cause permanent and progressive disability and impairment in activities of daily living. Anti-gangliosides antibodies have been detected with varying frequencies in the immune-mediated neuropathies, with the highest prevalence being anti-GQ1b antibodies in Miller-Fisher syndrome and anti-GM1 antibodies in MMN and AMAN (axonal variant of GBS). There is evidence that the inflammatory potential of these antibodies is reliant upon complement activation, and the resultant formation of the MAC (membrane attack complex). In experimental models of anti-ganglioside mediated neuropathy, inhibition of the complement cascade results in the complete prevention of inflammatory damage, and preserved nerve function. Multifocal motor neuropathy is a chronic, progressive purely motor neuropathy which causes weakness and wasting. IgM anti-GM1 antibodies are found in between 50 – 80% of affected cases. The only current treatment for MMN is high dose IVIg (intravenous immunoglobulin). The response rate to IVIg is around 80%, and cases who are antibody negative can also respond to this treatment. However, the effect is temporary, and further doses are usually re-administered at around 4 weekly intervals. Since it is a human blood product which is pooled from donated blood products, it is in short supply and does carry some important side effects. The main focus of this study was to test a novel therapy for immune-mediated neuropathy. The treatment tested was the first complement inhibitor licensed for human use, eculizumab. In this study it has been tested in the treatment of MMN, in patients who may also be receiving treatment with IVIg. The aim was to collect safety information regarding the concurrent use of these biological products, and to test for any neutralising effect between them. Any beneficial effect of complement inhibition in MMN was investigated by various outcome measures, clinical, functional and electrophysiological. The results of the clinical trial showed that eculizumab treatment was associated with a higher rate of adverse events, in patients who were or were not receiving IVIg. Most adverse events were mild to moderate in severity, none were unexpected, and more occurred during the induction phase of treatment than during the maintenance phase. The most common adverse event was headache, which 69% of patients experienced at any time. Two thirds of all headaches occurred in the induction phase. IVIg did lower the serum concentration of eculizumab, however eculizumab activity was not compromised. There were significant changes to subjective scores overall, and some objective scores also displayed significant improvement. However repeated IVIg doses were still required by those who were regularly using it prior to the study, albeit perhaps at slightly longer intervals. Electrophysiology showed small significant improvement in two parameters in keeping with improved nerve conduction. Overall it was felt that complement inhibition was associated with some potential benefits in MMN however did not substitute the therapeutic mechanism of action of IVIg. Aspects of the study design meant that evidence of efficacy could not be concluded from this study, and further trials are necessary to elucidate this. In addition, this thesis presents a laboratory-based study in which further information about the binding characteristics of the IgM GM1 antibody were sought using different methods than the standard ELISA technique. Using a combinatorial glycolipid microarray, MMN sera were screened against a large range of glycolipid pairs, to test for novel epitopes in the ‘antibody negative’ MMN patients without anti-GM1 antibody. It was found that in patients who did not have an antibody to GM1 or any other single ganglioside on ELISA or microarray, there was presence of an antibody to the glycolipid pair, GM1:GalC. It was shown that the IgM GM1 antibody in MMN is also inhibited from binding to GM1 in a solid phase and live membrane due to the local presence of GD1a. These findings lead to greater understanding of the pathogenesis of MMN and possibility of a more sensitive diagnostic test.

Item Type: Thesis (MSc(R))
Qualification Level: Masters
Keywords: multifocal motor neuropathy, MMN, neuropathy, conduction block, complement, eculizumab, ganglioside
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Supervisor's Name: Willison, Professor H.W.
Date of Award: 2012
Depositing User: Dr Amanda Fitzpatrick
Unique ID: glathesis:2012-3220
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 01 Mar 2012
Last Modified: 10 Dec 2012 14:05
URI: http://theses.gla.ac.uk/id/eprint/3220

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