ENHANCING NEUROIMAGING GENETICS THROUGH META-ANALYSIS (ENIGMA): GENOME-WIDE ASSOCIATION META-ANALYSIS OF CORTICAL THICKNESS AND SURFACE AREA

Abstract

There is paucity of studies on predictors of seizures in Wilson disease with neurological manifestation (WDNM), and none has evaluated the role of copper (Cu) induced oxidative stress, proinflammatory and excitotoxicity in the genesis of seizure.To report frequency, refractoriness, and outcome of seizure in WDNM. We also evaluate role of Cu induced oxidative stress, excitotoxicity and cytokines in predicting seizures.The diagnosis of WDNM was based on clinical, MRI, KF ring and 24 h urinary Cu. Detailed clinical examination including severity of WD, occurrence of seizure, seizure semiology, antiepileptic drug (AED) and breakthrough seizures were noted. Cranial MRI and electroencephalography findings were noted. Serum free-Cu, oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), glutamate and cytokines (interleukin 6, 8 and 10 and tumour necrosis factor α) were measured by atomic absorption spectrophotometer, spectrophotometer, fluorometer and flow cytometer respectively, and correlated with seizures. Patients were treated with zinc with or without penicillamine, and those with epilepsy received second-generation antiepileptic drugs (AEDs).Out of 110 patients with WDNM, 16(14.5%) had seizures; focal in 11(68.7%) and generalized in 5(31.3%). Patients with seizure had higher serum free-Cu (35.87 ± 1.34 vs 31.72 ± 0.68; P = 0.02), severe dystonia (P = 0.04), and more frequent cortical (100% vs 6.4%; P < 0.01) and subcortical (81.3% vs 20.2%; P < 0.01) lesions on MRI compared to those without seizure. Oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), cytokines and glutamate were elevated in WDNM compared to controls. On multivariate logistic regression analysis, cortical involvement (OR = 105.49; 95%CI = 8.74–1272.39; P < 0.01) and number of MRI lesions (OR = 1.99; 95% CI = 1.11–3.57; P = 0.02) were independent predictors of seizure. The seizures were controlled with single and dual AEDs in seven patients each, and two patients needed three AEDs. All the patients had seizure remission for a median follow up of 66(24–180) months.About one-sixth WDNM patients have seizures especially in those with cortical and extensive MRI lesions. Seizures are easily controlled by AEDs.