The effects of 4-aminopyridine on motor evoked potentials in multiple sclerosis

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Abstract

In order to study the effects of 4-aminopyridine (4-AP) on impulse conduction in multiple sclerosis (MS), we studied motor-evoked potentials (MEPs) in the upper (U/E) and lower extremities (L/E) of six MS patients with stable spastic paraparesis before and after intravenous administration of 4-AP. As a result, we found a significant increase in mean amplitudes in U/E and L/E (P=0.008) and a significant decrease in the variability of onset latencies in L/E (P=0.017) without any significant changes in mean and shortest onset latencies. In four limbs of three patients in whom there were no detectable MEP responses before 4-AP administration, definite responses were elicited after 4-AP administration. 4-AP seems to have its therapeutic effects by improving impulse conductivity in demyelinated nerve fibers or by enhancing central or peripheral synaptic transmission, which thus results in coordinated contractions of more muscle fibers in MS.

Introduction

4-Aminopyridine (4-AP) can improve neural impulse conduction. 4-AP relieves conduction block in demyelinated nerve fibers by blocking potassium channels on the paranodal axon membranes in vitro [11]and enhances synaptic transmission by increasing transmitter release [4]. In a therapeutic trial of 4-AP for multiple sclerosis (MS), 4-AP has proved to be effective in relieving motor and visual symptoms of patients with MS 1, 13, 14, and these reports included neurophysiological analyses of the therapeutic effects of 4-AP on MS, such as visual-evoked potentials, eye movement registrations and isokinetic dynamometry, as well as clinical observations of patients' neurological status.

Motor-evoked potentials (MEPs) with transcranial magnetic stimulation is a feasible and objective measure to assess the conductivity of the human motor pathways [3]. In MS, delayed central motor conduction time (CMCT) and increased onset latency variability were reported 2, 5, 6. Also, MEP wave forms were abnormally dispersed 2, 5, 6and MEP amplitudes are significantly lower in the patients than in normal subjects 2, 7. We predicted that treatment of MS patients with 4-AP would improve the MEP abnormalities. Therefore, we recorded MEPs in upper extremities (U/E) and lower extremities (L/E) of patients with clinically stable spastic paraparesis due to MS before and after intravenous administration of 4-AP.

Section snippets

Patients

Six patients with definite MS using Poser's criteria [10]were studied (Table 1). All of the patients had stable neurologic symptoms of MS, mainly spastic paraparesis and had not shown a relapse of MS for the last six months. With the exception of Patient KA, the muscle power of U/E in the patients was normal. Two patients reported that some neurologic symptoms were temperature-sensitive. None of the patients had evidence of radiculoneuropathy or a history of epilepsy or inflammatory

MEP responses

MEP responses of U/E and L/E in the MS patients, recorded before and after 4-AP administration, are shown in Fig. 1. Mean amplitudes of MEPs in both U/E and L/E increased significantly 1 h after 4-AP administration in the majority of subjects, compared to those recorded before 4-AP administration (P=0.008). The percentage increments in mean amplitudes after 4-AP administration compared with pre-treatment values varied in individual cases (19.8∼2211.6%). In four limbs of three patients in whom

Discussion

The suppression of the leakage of impulse currents in the demyelinated nerve fibers by 4-AP is important in considering its therapeutic mechanism in MS [11], but 4-AP also enhances the excitability of motor neurons in the central nervous system, and facilitates neuromuscular transmission by inducing the release of acetylcholine from nerve terminals [4]. Since each of these mechanisms may possibly be involved in the therapeutic effects of 4-AP on MEPs in MS, in the present study, we evaluated

Acknowledgements

We thank Dr Shozo Tobimatsu of Department of Clinical Neurophysiology, Neurological Institute, Faculty of Medicine, Kyushu University, for reviewing the manuscript, Dr Kiyomi Takayanagi of the Institute of Health Sciences, Hiroshima University School of Medicine, for technical assistance, and Dr Tetsuya Nagata of the Department of Neurology, Tohoku University School of Medicine, for data processing.

References (15)

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