Abstract
In 1885, William Gowers proposed that epilepsy is a progressive disease, based on clinical evidence before any effective treatments were available. His long-standing hypothesis has been summarized with the statement “seizures beget seizures.” Whether this is the case and related questions about seizure-induced modification and damage of brain circuits are of fundamental importance for neurobiological understanding of epilepsy, development of effective treatment strategies, clinical management, and prognostication. Consensus about progression and seizure-induced damage has remained controversial. Here, we critically review these long-standing questions, incorporating perspectives about perceived inconsistencies in past studies, potential implications of recent longitudinal imaging and cognitive studies, and emphasize experimental and clinical gaps that have proved challenging. Answers to these questions are important for development of management strategies to achieve prompt effective acute control of seizures and prevention of their potential recurrence and long-term comorbidities.
From the article:
Consensus Points in 2025?
The long-standing controversies about progressive brain damage in chronic epilepsy remain difficult to conclusively resolve, but recent longitudinal human studies demonstrating progressive cortical thinning associated with continuing seizures and cognitive studies revealing progressive declines over decades associated with neuronal loss and decreased neurogenesis provide new context to critically reevaluate Gower's progression hypothesis and the significance of seizure-induced neuronal loss observed in the most sensitive experimental studies. We conclude with a summary of potential consensus points across experimental and clinical perspectives in 2025:
1.
Epilepsy is not progressive in all patients
The >60% of patients achieving seizure control do not have progressive courses or cognitive decline, but a subset of patients with TLE and other focal epilepsies experience progressive decline without apparent progressive initial insults. The decline may include increasing frequency of seizures over time, with or without functional or cognitive declines. Typical absence seizures and other “benign” childhood epilepsies do not invariably lead to progressive decline, but in a subset of absence and “benign” epilepsy patients, attention, cognitive, behavioral, and psychiatric issues may emerge in adolescence after seizures abate, perhaps reflecting initial etiology or a consequence of seizures.
2.
Damage is greater with longer versus shorter seizures
Damage in SE has increased urgency for rapid treatment, with intervention thresholds shifting from 30 min of unremitting seizures to 5 min. Whether a single seizure or repeated brief seizures lead to significant structural or functional changes in the human brain remains controversial, but the most sensitive histologic methods in experimental animals demonstrate subtle, but cumulative, neuronal death with repeated brief seizures accompanied by functional deficits.
3.
Progressive cortical thinning occurs with recurring seizures in human longitudinal imaging studies
Cortical thinning increases with duration of epilepsy, appears to be related to seizures, and progresses in postsurgical patients whose seizures continue compared to postsurgical patients who are seizure free. These observations are consistent with seizure-induced cumulative cortical damage.
4.
Neuropsychological studies across epilepsy patients over decades demonstrate a declining cognitive trajectory not seen in age-matched people without epilepsy
Recent human studies associating cognitive declines with decades of epilepsy, neuronal loss, and reduced neurogenesis, as well as animal studies showing seizure-induced neuronal loss, potentially implicate continuing underestimated seizures as a contributing factor, but primary progressive etiological and/or effects of other factors such as ASMs cannot be excluded.
5.
Studies of progression in humans are significantly limited by the inaccuracy of seizure counts over long periods
Continuous scalp EEG recordings reveal seizures not detected clinically, and depth EEG recordings demonstrate that electrographic seizures are more frequent than detected in scalp recordings or clinical records, and may not be recognized as a clinically apparent seizure. Patient, family, and medical historical records are inadequate for resolution of questions about relationships of seizure burden to imaging patterns of damage and cumulative cognitive deficits. The insensitivity and inaccuracy of human seizure counts is a major impediment to resolving questions about progressive impact of uncontrolled seizures, but experimental studies offer the potential to determine seizure counts more accurately.
6.
Across both experimental and human domains, it remains difficult to separate progression caused by underlying primary etiologies from progression secondary to recurring seizures
Experimental studies that induce focal seizures without initial pathologic alterations offer the potential to separate these confounding processes. Transgenic animals with epilepsy secondary to genetic or epigenetic defects do not typically provide this opportunity, or resolve the question of initial etiological or secondary seizure-induced contributions to progressive damage.
These points derived from recent clinical, imaging, cognitive studies, and previous experimental observations may serve as guidelines and provide potential directions for investigations to address cumulative adverse consequences of recurring seizures. Concerns about progressive damage remain compelling for the ∼35% of patients who do not achieve control with current therapies and for those who lack access to adequate treatment. The available data about progressive adverse long-term effects of epilepsy provides a compelling need for more effective acute interventions to prevent recurring seizures and their potential consequences.
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