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Enhanced brain motor activity in patients with MS after a single dose of 3,4-diaminopyridine

From the Sections of Clinical Neurology (Drs. Mainero, Inghilleri, Conte, Lenzi, Frasca, and Pozzilli) and Neuroradiology (Drs. Pantano and Bozzao), Department of Neurological Sciences, University of Rome "La Sapienza," Italy.

Address correspondence and reprint requests to Dr. C. Mainero (c/o Carlo Pozzilli), Department of Neurologic Sciences, University of Rome "La Sapienza," Viale dell’Università, 30, I-00185, Rome, Italy; e-mail: caterina.mainero{at}uniroma1.it

Background: 3,4-Diaminopyridine (3,4-DAP), a potassium (K⁺) channel blocker, improves fatigue and motor function in multiple sclerosis (MS). Although it was thought to do so by restoring conduction to demyelinated axons, recent experimental data show that aminopyridines administered at clinical doses potentiate synaptic transmission.

Objective: To investigate motor cerebral activity with fMRI and transcranial magnetic stimulation (TMS) after a single oral dose of 3,4-DAP in patients with MS.

Methods: Twelve right-handed women (mean ± SD age 40.9 ± 9.3 years) underwent fMRI on two separate occasions (under 3,4-DAP and under placebo) during a simple motor task with the right hand. FMRI data were analyzed with SPM99. After fMRI, patients underwent single-pulse TMS to test motor threshold, amplitude, and latency of motor evoked potentials, central conduction time, and the cortical silent period; paired-pulse TMS to investigate intracortical inhibition (ICI) and intracortical facilitation (ICF); and quantitative electromyography during maximal voluntary contraction.

Results: FMRI motor-evoked brain activation was greater under 3,4-DAP than under placebo in the ipsilateral sensorimotor cortex and supplementary motor area (p < 0.05). 3,4-DAP decreased ICI and increased ICF; central motor conduction time and muscular fatigability did not change.

Conclusion: 3,4-DAP may modulate brain motor activity in patients with MS, probably by enhancing excitatory synaptic transmission.

Received August 14, 2003. Accepted in final form February 3, 2004.

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