Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

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Precipitation and inhibition of seizures and epileptic discharges by sensory stimuli are receiving increasing attention because they provide insight into natural seizure generation in human epilepsies and can identify potential nonpharmacological therapies. We aimed to investigate modulation (provocation or inhibition) of epileptiform discharges (EDs) in mesial temporal lobe epilepsy (MTLE) versus idiopathic generalized epilepsy (IGE) by olfactory stimulation (OS) compared with standard provocation methods. The underlying hypothesis was that any response would be more likely to occur in MTLE, considering the anatomical connections of the temporal lobe to the olfactory system. This multicenter, international study recruited patients with either MTLE or IGE who were systematically compared for responses to OS using an EEG/video-EEG protocol including a 30-min baseline, twice 3-min olfactory stimulation with ylang-ylang, hyperventilation, and intermittent photic stimulation. The 95% confidence interval (CI) for the baseline EDs in each patient was calculated, and modulation was assumed when the number of EDs during any 3-min test period was outside this CI. A total of 134 subjects (55 with MTLE, 53 with IGE, and 26 healthy controls) were included. Epileptiform discharges were inhibited during OS in about half the patients with both MTLE and IGE, whereas following OS, provocation was seen in 29.1% of patients with MTLE and inhibition in 28.3% of patients with IGE. Olfactory stimulation was less provocative than standard activation methods. The frequent subclinical modulation of epileptic activity in both MTLE and IGE is in striking contrast with the rarity of reports of olfactory seizure precipitation and arrest. Inhibition during OS can be explained by nonspecific arousal. The delayed responses seem to be related to processing of olfactory stimuli in the temporal lobe, thalamus, and frontal cortex.