Altered cortical excitability in patients with Charcot-Marie-Tooth disease

Abstract

Objective: Charcot-Marie-Tooth (CMT) disease is the most common hereditary motor and sensory peripheral neuropathy. There have been no transcranial magnetic stimulation (TMS) investigations to understand physiologic abnormalities in central as well as peripheral motor pathways in CMT patients in different genetic subtypes. In this study, we investigate the motor cortical excitability using TMS and their relationship with clinical severities in CMT patients with different genetic subtypes. Methods: Fifty-eight patients (mean age 36.3 year-old) with genetically confirmed CMT and 30 age-gender-matched control subjects (mean age 37.71 year-old) were enrolled for this study. Clinical severities were evaluated by age at onset, disease duration, MRC motor power, functional disability score (FDS) and CMT neuropathy scale (CMTNS). We measured TMS indices to investigate motor cortical excitability in CMT patients and controls. Subtype of CMT were genetically confirmed as CMT1A with PMP22 mutation (15/58, 25.9%), CMT1B with MPZ mutation (8/58, 13.8%), CMT2A with MFN2 mutation (20/58, 34.4%) and CMTX with Cx32 mutation (15/58, 25.9%). TMS indices were measured for resting motor threshold (RMT), motor evoked potential (MEP), cortical silent period (CSP), central motor conduction time (CMCT), intracortical inhibition (ICI) and intracortical facilitation (ICF) at different stimulus intensities in first dorsal interosseus (FDI) and tibialis anterior (TA) muscles. Results: In CMT patients, RMT increased, CMCT and MEP latencies prolonged, ICI decreased and MEP amplitude decreased in FDI and TA muscles compared to control subjects. Patients with CMT1B showed more prolonged CMCT and MEP latencies at all TMS stimulus intensities than other CMT subtypes in FDI and TA muscles. Increased RMT in FDI muscles was correlated with more severe FDS, CMTNS and longer disease duration and increased RMT in TA was related to more severe motor weakness. Attenuated ICI in FDI and decreased MEP amplitudes in TA muscles were correlated more severe motor weakness in CMT patients. Attenuated ICI in FDI and decreased MEP amplitudes in TA muscles were correlated more severe motor weakness in CMT patients. Conclusion: This study using TMS demonstrated physiologic changes in corticospinal tracts of central motor pathway in addition to peripheral nerve abnormalities in CMT patients, most prominently in CMT IB. Alterations in TMS indices for central motor cortical excitability were correlated with functional disability and clinical severity in CMT patients. TMS investigation in CMT patients suggests pathophysiologic abnormalities in central as well as peripheral motor pathways possibly associated with pathological involvement in both CNS and PNS as well as functional compensation after long standing motor weakness.;유전운동감각신경병 혹은 샤르코-마리-투스병은 운동신경 및 감각신경이 특정한 유전자 돌연변이에 의해 손상되는 질환을 말한다. 이전에 알려진, 샤르코-마리-투스병은 말초신경에서 이상소견이 있었는데 축삭형인 샤르코-마리-투스병 아형에서도 중추신경계에 변화가 있는 것으로도 알려져 왔다. 본 연구의 목적은 샤르코-마리-투스병으로 진단된 환자에서의 중추운동신경과 말초운동신경과 관련된 전기생리학적 근원을 알아내고자 시행되었다. 연구참여 대상자는 14세에서 67세 사이의 샤르코-마리-투스병 환자 58명과 연령, 성별이 비슷한 정상인 30명을 이화여자대학교 부속 목동병원 신경과에서 모집하였다. 신경생리검사를 위해 경두개자기자극과 신경전도검사 등이 수행되었다. 정상인과 환자의 데이터를 분석하기 위해 SPSS 버전12로 분석하였다. 경두개자기자극 대뇌운동피질의 활성도 측정 결과, 환자군에서 정상인에 비해 운동역치가 증가하고 운동유발전위는 감소하였으며, 중추운동전도시간, 운동유발전위잠시는 증가하였고 피질간억제는 감소하였다. 특히, 샤르코-마리-투스병, CMT1B그룹에서 중추운동전도시간이 증가하고 피질간의 억제가 감소하는 경향이 가장 뚜렷하였다. 본 연구의 결과를 종합하면, 샤르코-마리-투스병 환자에서 유의한 기능적 연결성의 변화를 관찰하였다. 특히 대뇌운동피질 활성도의 변화는 피질과 피질간의 억제가 감소되어 피질과 피질간의 상호조절작용의 변화가 있었으며 중추운동신경의 침범이 운동마비나 말초신경병, 일상생활 기능장애의 정도와 같은 임상적 심각도와도 유의한 관련이 있었다.