The electrophysiological footprint of CACNA1A disorders

Abstract

Objectives: CACNA1A variants underlie three neurological disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). EEG is applied to study their episodic manifestations, but findings in the intervals did not gain attention up to date. Methods: We analyzed repeated EEG recordings performed between 1994 and 2019 in a large cohort of genetically confirmed CACNA1A patients. EEG findings were compared with those of CACNA1A-negative phenocopies. A review of the related literature was performed. Results: 85 EEG recordings from 38 patients (19 EA2, 14 FHM1, 5 SCA6) were analyzed. Baseline EEG was abnormal in 55% of cases (12 EA2, 9 FHM1). The most common finding was a lateralized intermittent slowing, mainly affecting the temporal region. Slowing was more pronounced after a recent attack but was consistently detected in the majority of patients also during the follow-up. Interictal epileptic discharges (IEDs) were detected in eight patients (7 EA2,1 FHM1). EEG abnormalities and especially IEDs were significantly associated with younger age at examination (16 ± 9 vs 43 ± 21 years in those without epileptic changes, p = 0.003) and with earlier onset of disease (1 (1–2) vs 12 (5–45) years, p = 0.0009). EEG findings in CACNA1A-negative phenocopies (n = 15) were largely unremarkable (p = 0.03 in the comparison with CACNA1A patients). Conclusions: EEG abnormalities between attacks are highly prevalent in episodic CACNA1A disorders and especially associated with younger age at examination and earlier disease onset. Our findings underpin an age-dependent effect of CACNA1A variants, with a more severe impairment when P/Q channel dysfunction manifests early in life.