Idiopathic Generalized Epilepsy: Misunderstandings, Challenges, and Opportunities

Abstract

The idiopathic generalized epilepsies (IGE) make up a fifth of all epilepsies, but <1% of epilepsy research. This skew reflects misperceptions: diagnosis is straightforward, pathophysiology is understood, seizures are easily controlled, epilepsy is outgrown, morbidity and mortality are low, and surgical interventions are impossible. Emerging evidence reveals that patients with IGE may go undiagnosed or misdiagnosed with focal epilepsy if EEG or semiology have asymmetric or focal features. Genetic, electrophysiologic, and neuroimaging studies provide insights into pathophysiology, including overlaps and differences from focal epilepsies. IGE can begin in adulthood and patients have chronic and drug-resistant seizures. Neuromodulatory interventions for drug-resistant IGE are emerging. Rates of psychiatric and other comorbidities, including sudden unexpected death in epilepsy, parallel those in focal epilepsy. IGE is an understudied spectrum for which our diagnostic sensitivity and specificity, scientific understanding, and therapies remain inadequate.

Figure 1. Classification of Genetic Generalized Epilepsies

Figure 2. EEG Findings in IGE and IGE Mimics

(A) Symmetric and synchronous generalized epileptiform discharges. (B) Asymmetric or focal EEG features in patients with IGE based on their clinical history and other EEGs with symmetrical and synchronous generalized discharges. (C) Focal slow, focal spikes, and asymmetric generalized discharges in patient with a right frontal lesion and secondary bilateral synchrony.

Figure 3. Structural and Functional Changes in IGE Cohorts

(A) Cortical thickness and subcortical volume reductions in IGE (n = 289), relative to controls (n = 1,075), affected predominantly bilateral precentral cortical regions (P_FDR < 9 × 10⁻¹⁰) and the thalamus (P_FDR < 3 × 10⁻⁶). Negative log₁₀-transformed FDR-corrected p values are shown. (B) Patient-specific functional disease epicenters identified by keeping brain regions whose connectivity profiles significantly correlated with the patient's atrophy map (P_spin < 0.05). In IGE, bilateral frontocentral areas (including sensorimotor cortices) and amygdala were disease epicenters (modified from reference 19).

Figure 4. Altered Structural Connectivity in Juvenile Myoclonic Epilepsy (JME)

(A) The anterior presupplementary motor area (SMA) cluster showed reduced connectivity to frontopolar region (B) and increased connectivity to medial central region (C) and descending motor pathways (D). The posterior SMA cluster showed reduced connectivity to the central region (E) but increased connectivity to the temporal (F) and occipital (G) cortices. (H) Functional connectivity (fMRI) between prefrontal cortex and SMA correlated with the structural connectivity on diffusion tensor imaging (DTI). (I) SMA connectivity correlated with disease activity. From Vollmar et al. with permission.