Clinical assessments were combined with threshold-tracking transcranial magnetic stimulation and peripheral nerve excitability techniques in 11 genetically characterized MJD patients and results compared to 40 age-matched healthy controls. The International Cooperative Ataxia Rating Scale (ICARS) was used to quantify the severity of ataxia in MJD patients.
Clinical severity varied, ranging from presymptomatic in 2 patients to severe as reflected by the broad spectrum in ICARS score (range 0–59, median 27). Short-interval intracortical inhibition (SICI) was significantly reduced in presymptomatic (5.3 ± 0.5%) and symptomatic MJD patients (-1.3±1.4%) compared to healthy controls (10.3 ± 0.7%, P < 0.0001), evident prior to clinical onset of ataxia and related to worsening severity (R = −0.67, P < 0.05). SICI reduction was accompanied by decreases in resting motor threshold and cortical silent period in pre-symptomatic patients and inversely related to severity of clinical ataxia. CMCT was also significantly prolonged in all MJD patients (symptomatic MJD 7.5 ± 0.4 ms; pre-symptomatic MJD 6.2 ± 0.5 ms controls 5.3 ± 0.2 ms, P < 0.0005) and a feature of neurodegeneration related to clinical severity (R = 0.72, P = 0.01). Markers of peripheral motor neurodegeneration and excitability were not associated with cortical hyperexcitability or ataxia.
Simultaneous investigation of clinical status, central and peripheral nerve excitability has established that cortical dysfunction is evident in patients with MJD and precedes the development of cerebellar symptoms, ataxia and peripheral neurodegeneration. Taken together this indicates that cortical dysfunction may be an early feature that may herald widespread neurodegeneration in MJD.