The spectrum of lower motor neuron syndromes : classification, natural course and treatment

Abstract

This thesis focusses on patients with lower motor neuron syndromes. This relatively rare group of syndromes is clinically not well described and the pathogenesis is largely unknown. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) or motor axons and their surrounding myelin (multifocal motor neuropathy (MMN)) are affected, both leading to muscle atrophy and weakness. As MMN is a potentially treatable disorder, its differentiation from LMND is important. Evidence of motor conduction block on nerve conduction studies and a positive response to treatment with intravenous immunoglobulins (IVIg) are considered the most relevant criteria for the diagnosis of MMN. The improvement of the techniques to detect conduction block and new developments in DNA-proven hereditary LMND, have made some of the earlier classi.cations of lower motor neuron syndromes obsolete. Also little is known about the natural course and treatment of lower motor neuron syndromes. Aims The aims of this study were (1) to improve the classi.cation of patients with lower motor neuron syndromes using newest diagnostic methods, (2) to determine the natural course of these syndromes, and (3) to study treatment forms in MMN. Methods Patients were examined clinically at a regular basis, which consisted of the assessment of muscle atrophy and weakness, respiratory function and functional impairment. All patients underwent an extensive, standardized electrophysiological examination at least once. Results Based on the pattern of weakness in 49 patients with LMND, we identi.ed four subgroups. Except for one group with generalized weakness and respiratory insuf.- ciency, leading to death in one third of patients, the disease course in patients with IX LMND was slow, with minimal progression of muscle weakness and functional impairment over years. Also in patients with MMN we found evidence for a slowly progressive disease course. We propose a set of clinical, laboratory and electrophysiological criteria for the diagnosis of MMN, which has been verifed by follow-up and response to IVIg treatment in 37 patients with a lower motor neuron syndrome. Additionally, we studied the distribution of electrophysiological abnormalities in MMN, its correlation with weakness and the development of an optimal electrodiagnostic protocol for MMN. The results of a follow-up study on the efficacy of long-term (4-8 years) maintenance therapy in 11 patients with MMN, showed that IVIg maintenance treatment has a bene.cial long-term effect on muscle strength and upper limb disability, and thus seems rational, but may not prevent a slight decrease in muscle strength. Electrophysiologically, both improvement and worsening were found. In an open pilot-study with interferon-b1a (IFN-b1a, 3x/wk for 6 months) in nine patients with MMN, three patients showed an improvement on IFN-b1a which was more pronounced than on IVIg and which sustained itself for months after discontinuation of IFN-b1a. A controlled study is necessary to further investigate the effect of IFN-b1a treatment in patients with MMN. Conclusions Until we have identi.ed these possible underlying pathophysiological mechanisms it will prove difficult to consider the various lower motor neuron syndromes as separate diseases. Because diagnostic and therapeutic options may differ, it seems rational to consider them as a spectrum of syndromes, which can be distinguished from each other on the basis of the clinical presentation and the electrophysiological findings. For the individual patient distinction between the various syndromes is important as it enables the physician to provide adequate information over the disease course and to facilitate early treatment in MMN.