Altered paired associative stimulation‐induced plasticity in NMDAR encephalitis

OBJECTIVE: To determine whether neurophysiological mechanisms indicating cortical excitability, long‐term potentiation (LTP)‐like plasticity, GABAergic and glutamatergic function are altered in patients with anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis and whether they can be helpful as markers of diagnostic assessment, disease progression, and potentially therapy response. METHODS: Neurophysiological characterizations of patients with NMDAR encephalitis (n = 34, mean age: 28 ± 11 years; 30 females) and age/gender‐matched healthy controls (n = 27, 28.5 ± 10 years; 25 females) were performed using transcranial magnetic stimulation‐derived protocols including resting motor threshold, recruitment curve, intracortical facilitation, short intracortical inhibition, and cortical silent period. Paired associative stimulation (PAS) was applied to assess LTP‐like mechanisms which are mediated through NMDAR. Moreover, resting state functional connectivity was determined using functional magnetic resonance imaging. RESULTS: PAS‐induced plasticity differed significantly between groups (P = 0.0056). Cortical excitability, as assessed via motor‐evoked potentials after PAS, decreased in patients, whereas it increased in controls indicating malfunctioning of NMDAR in encephalitis patients. Lower PAS‐induced plasticity significantly correlated with the modified Rankin Scale (mRS) (r = −0.41; P = 0.0031) and was correlated with lower functional connectivity within the motor network in NMDAR encephalitis patients (P < 0.001, uncorrected). Other neurophysiological parameters were not significantly different between groups. Follow‐up assessments were available in six patients and demonstrated parallel improvement of PAS‐induced plasticity and mRS. INTERPRETATION: Assessment of PAS‐induced plasticity may help to determine NMDAR dysfunction and disease severity in NMDAR encephalitis, and might even aid as a sensitive, noninvasive, and well‐tolerated “electrophysiological biomarker” to monitor therapy response in the future. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT01865578