Pharmacologic reversal of cortical hyperexcitability in patients with ALS

Objective: To reverse the profile of abnormal intracortical excitability in patients with ALS by administering drugs that promote GABAergic transmissi on. Background: Transcranial magnetic stimulation (TMS) has revealed abnorm alities of cortical inhibition in ALS, a reduction of the silent period, an d the absence of intracortical inhibition normally occurring in response to paired TMS. Impaired inhibitory transmission could play a role in the phys iopathology of this illness, Methods: Using paired TMS with conditioning st imuli from 1-to-6-msec-interstimulus intervals, we investigated 16 patients with ALS. The protocol included: (1) the "drug-free" profile of paired TMS ; (2) paired TRIS 30 minutes after the intake of diazepam (3.5 mg); (3) pai red TMS after 3 weeks' treatment with gabapentin (GBP) (600 mg/day) or rilu zole (50 mg/twice a day). Results: Intracortical inhibition is lost in pati ents with ALS, and this abnormal profile is reversed by diazepam or sustain ed treatment with GBP. We also noted that motor-evoked potential amplitudes to single stimuli increased (p < 0.01) after diazepam and GBP. Conclusions : The demonstration of pharmacologic reversal of hyperexcitability in patie nts with ALS makes a potentially significant contribution toward understand ing the pathophysiology of a disease that has so far eluded an effective cu re.