On 20 December 2011 Elisabeth Cats defended her thesis "Multifocal motor neuropathy in the Netherlands: immunology, genetics and treatment." Prof. Dr. Leonard van den Berg, University Medical Center Utrecht is her promotor and Dr. Ludo van der Pol, University Medical Center Utrecht her co-promotor. Prof. Dr. Nobuhiro Yuki was present at the defence.
Multifocal motor neuropathy (MMN) is a pure motor neuropathy with conduction block (CB) characterized by slowly progressive, asymmetrical weakness of limbs. It was first described approximately 20 years ago. MMN is an important mimic of motor neuron disease (MND), but is amenable to treatment and has a more favorable prognosis. The relative rarity of MMN has precluded detailed studies of the phenotype and the pathogenesis of MMN is incompletely understood.
Aims of this thesis were to document clinical phenotypes of MMN, to study the immune pathogenesis and genetics of MMN and to describe the correlates of outcome and response to intravenous immunoglobulin (IVIg).
PART I - CLINICAL FEATURES OF MMN
We performed a national study on MMN and identified 97 patients, which corresponds to a prevalence of at least 0.6 per 100.000 inhabitants. All participating patients were examined. We did not only confirm that MMN is more prevalent in men than women, but also showed that symptom onset was at a younger age in males. Clinical presentation and patterns of weakness were fairly homogeneous, with onset of weakness in the distal arm or distal leg, and occasionally in the upper arm. In one-third of patients the initial diagnosis was MND. Brisk, but not pathological, reflexes in weakened muscles were not uncommon. Ulnar, median, radial and tibial nerves were most commonly affected, with striking differences in weakness of muscles innervated by a common terminal nerve. Ninety-four percent of patients responded to IVIg therapy: non-responders had longer disease duration before the first treatment. Multivariate analysis showed that axon loss and longer disease duration without IVIg were independent determinants of more severe weakness and disability (chapter 2).
PART II- IMMUNE PATHOGENESIS OF MMN
Prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum from 88 MMN patients were investigated. Anti-ganglioside IgM antibodies in MMN had a surprisingly limited specificity (against GM1, and occasionally against GD1b and GM2) (chapter 3). Therefore, we investigated whether anti-ganglioside antibodies also showed limited clonality. Using light chain analysis of anti-GM1 IgM antibodies, we demonstrated that serum anti-GM1 IgM antibodies in the majority of patients with MMN have the same Ig light chain, suggesting that these antibodies are monoclonal. This is a further indication of the highly selective fine-specificity of these antibodies (chapter 4). The presence of anti-GM1 IgM antibodies was associated with a relatively poor outcome. Patients with anti-GM1 IgM antibodies had more disability, more axon loss and more severe weakness compared to patients without anti-GM1 IgM antibodies (chapter 3). These findings support the assumption that anti-ganglioside IgM antibodies play a role in MMN pathogenesis, but also suggest that a limited number of B-cell clones is activated, even in patients with longstanding disease.
Although it seems generally accepted that MMN is an inflammatory disorder, it is not clear whether MMN is a 'classic' autoimmune disease (AID). The male predominance is uncommon for AID, which tend to have a higher incidence in women. Since different AID often co-occur within patients and their families, we studied the prevalence of AID among MMN patients and their families. In a case-control study encompassing 81 MMN patients and 417 first-degree relatives, and 438 controls and 2377 first-degree relatives we found that AID are more common in MMN patients (11%) compared to controls (5%) (chapter 5). This finding might suggest that MMN is not only an inflammatory disorder, but may represent an AID sharing genetic risk factors with other AID.
Because of the importance of the complement system in the pathogenesis of experimental models for antibody-mediated neuropathy, we studied variation in the activity of the classical and lectin pathway of the complement system in MMN patients and controls. We found no difference in activity of both pathways between patients and controls, and complement activity was not associated with outcome of MMN (chapter 6).
PART III- GENETICS OF MMN
The human leukocyte antigen (HLA) locus is highly heterogeneous, and several HLA alleles have been found associated with AID. A case-control study showed that HLA-DRB1*15 is associated with MMN (chapter 7). Although this finding may support the hypothesis that MMN is a classic AID, we did not find increased frequencies of single nucleotide polymorphisms (SNPs) in genes that are common in a number of other AID (chapter 8).
PART IV- MMN TREATMENT
Treatment with IVIg is the only intervention known to improve muscle strength in MMN patients. It has been shown to postpone axonal degeneration. Maintenance treatment with IVIg every few weeks is necessary because the beneficial effects of IVIg infusions only last a few weeks. IVIg infusions are time-consuming and the frequent visits to the hospital may be burdensome for patients. In chapter 9 we compared the efficacy, safety and tolerability of the 10% ready-to-use liquid IVIg preparation with the less concentrated (5%) freeze-dried preparation in 20 patients with MMN and showed that the 10% IVIg preparation was well tolerated in patients with MMN. Muscle strength and disability scores remained stable. Infusion times were substantially reduced in 85% of patients. A cross-sectional descriptive study of 52 MMN patients receiving home-based IVIg treatment and 15 MMN patients receiving hospital-based IVIg treatment showed that IVIg treatment at home is time-saving and reduces the number of days missed at work. Home-treatment is safe when maximum infusion rates are respected and the presence of an anaphylactic kit at home is ensured. Home-based IVIg treatment is more convenient for most MMN patients (chapter 10). Despite its use, the mechanisms of IVIg that underlie its efficacy in MMN have not been studied in detail. Relevant effector mechanisms of IVIg include anti-idiotype effects, and modulation of B-cell and complement function, among others. In chapter 11 we compared the complement-activating properties of anti-GM1 IgM antibodies in sera from MMN patients and disease controls. We showed that anti-GM1 IgM antibodies in sera from patients with MMN efficiently activate complement in comparison with disease controls. The addition of IVIg reduced complement deposition significantly. IVIg infusions also reduced concentrations of crucial classical pathway components including C1q in sera of MMN patients. IVIg may thus exert both local and systemic effects on the classical route of the complement system, which may contribute to reduced complement deposition in nerves.
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