Why Seizures Break Through: Distinguishing Background Susceptibility From Proximal Precipitants in Patients With...

Breakthrough seizures are commonly described as unprovoked seizures that recur in patients with epilepsy who remain on antiseizure medication (ASM) after a sustained period of seizure freedom. These events are clinically important because they can disrupt previously stable seizure control and alter counseling, safety considerations, and treatment decisions. The literature often combines two conceptually different explanations: background factors that reflect a greater underlying propensity for recurrence and proximal exposures that may help explain why a seizure occurs at a particular time. This focused narrative review distinguishes these concepts and evaluates the strength of evidence supporting each. Breakthrough-specific studies suggest that greater prior seizure burden, difficulty achieving remission, neurological impairment, treatment history, and epilepsy etiology may reflect greater background susceptibility. In contrast, frequently cited precipitants such as medication nonadherence, sleep deprivation, psychological stress, infection, alcohol exposure, and pregnancy vary considerably in evidentiary strength. Nonadherence has relatively strong mechanistic and objective support, although inadequate medication exposure can complicate whether an event should be classified as a breakthrough seizure. Sleep deprivation and stress are commonly reported and biologically plausible, but their independent causal contributions remain uncertain. Heavy alcohol exposure appears more clinically relevant than modest intake. Pregnancy may alter ASM exposure in a medication-specific manner, but available evidence does not support treating pregnancy as a uniform independent cause of seizure worsening. Precipitants may also cluster, making attribution to a single exposure potentially misleading. Broader electrophysiological evidence further suggests that underlying seizure susceptibility may fluctuate over time. Distinguishing background susceptibility from proximal precipitants provides a practical framework for prognosis, counseling, medication management, and future research while emphasizing the difference between association and demonstrated causation.