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Seizures beget seizures

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Summary

The impact of seizures goes beyond episodic manifestations of these repetitive events. Recurrent seizures trigger a cascade of cellular, network, structural, and systemic changes in the brain that contribute to cumulative disease burden and potentially progression. Therefore, seizure freedom with minimal or no adverse events (AEs) should be the key goal of epilepsy treatment.1

Main points

The concept that ‘seizures beget seizures’ was first proposed as early as 1885.2 As scientific knowledge has evolved since then, it has become clear that seizures trigger a cascade of cellular, network, and systemic alterations, resulting in chronic changes in the brain that ultimately lead to not only further seizures but also cognitive and psychiatric comorbidities that add significant burden to patients, caregivers and society.1

Multilevel impact of recurrent seizures in epilepsy1

Cellular and molecular effects
↓
ROS
Neuroinflammation
Blood-brain barrier dysfunction
Receptor/channel alterations
Network reorganisation
↓
Hyperexcitability
Hub connectivity changes
Aberrant sprouting
Structural brain changes
↓
Accelerated cortical thinning
Cognitive association
Ventricular-brain ratio change (SE)
Individual and societal burden
↓
Mortality/SUDEP risk
Injury
Psychiatric comorbidity
QoL
DALYs/economic burden

Recurrent seizures trigger cellular pathophysiological changes and network remodeling in the brain

Seizures result in:

Reactive oxygen species generation and accumulation, increasing metabolic strain on neurons and eventually leading to neuron death1

Neuroinflammation that contributes to hyperexcitability and reinforces epileptogenic networks1

Remodeling of neural circuits that increase the frequency and reduce the threshold for further seizures1

Seizures accelerate structural brain changes that impact cognition

Many people with epilepsy experience progressive cortical thinning beyond normal aging, suggesting progressive atrophy and neurodegeneration over time.1 This process is associated with cognitive decline and psychiatric comorbidities, such as depression.2

76.8% (N=146/190) of patients with focal epilepsy had accelerated cortical thinning1

Seizure frequency and drug resistance have been associated with structural changes in the brain that resemble premature aging.3,4

Cellular, synaptic, and structural changes create a positive feedback loop that increases the likelihood of further seizures and contributes to the progression of epilepsy and its comorbidities.1

The self-reinforcing seizure cascade1

The positive feedback loop of persistent seizures translates to substantially increased clinical and societal burden

Epilepsy imposes a significant burden both on individuals, caregivers, healthcare systems, and society, particularly among those with uncontrolled epilepsy.1 The burden extends beyond seizures themselves and impacts every aspect of patients’ lives.

Mortality
Patients with epilepsy face an increased mortality risk that is directly attributable to seizures. Patients with uncontrolled seizures have a 40-fold higher mortality risk compared with those in remission.1,5 SUDEP is the most common cause of epilepsy-related death, with a rate up to 9.3 per 1000 patients.5,6 Lack of seizure freedom for 1–5 years carries a significantly increased SUDEP risk.6,7
Injuries
Seizures frequently result in physical injuries, most commonly fractures, craniocerebral trauma, and soft tissue injuries, representing a significant burden on patients.¹⁰ People with under-treated epilepsy have an 8–16-fold higher risk of epilepsy-related injuries and typically experience more severe outcomes compared with those receiving evidence-based treatment.¹
Psychiatric
comorbidities
People with uncontrolled seizures commonly experience psychological, social, and cognitive dysfunction. Patients with epilepsy experiencing seizures have a 4-fold higher incidence of major depressive symptoms versus those who are seizure-free.¹
QoL and
daily living
People with epilepsy have significantly lower QoL scores across physical and mental domains compared with the normal population.¹ Patients with seizures experience greater socioeconomic barriers and limitations in daily activities than seizure-free patients, meaning patients rate seizure freedom as one of the most important goals of treatment.¹
Financial
burden
Direct costs of epilepsy, including hospitalisations and ASMs, account for only a third of the overall financial burden, whereas the majority of the financial impact is in indirect costs such as lost productivity.² Seizure freedom is associated with reduced costs compared with active epilepsy.¹

“The numerous downstream processes triggered by recurrent seizures that contribute to disease progression, neurological impairment, and worsening comorbidities underscore the need for early and effective treatment to eliminate seizures.”1

CONCLUSIONS

  • Seizures act as catalysts for cellular, network, and structural changes that increase seizure susceptibility and reinforce epileptogenic processes.1
  • The burden of ongoing seizures on patients, healthcare systems and society is multifaceted and remains high.1
  • Early and sustained seizure freedom remains central, not only for symptom control but to potentially limit cumulative neurological and systemic burden.1

Abbreviations
AE, adverse event; DALY, disability-adjusted life years; QoL, quality of life; ROS, reactive oxygen species; SE, status epilepticus; SUDEP, sudden unexpected death in epilepsy

  1. Walker MC, et Epilepsia Open. 2025;10(6):1762-1773.
  2. Ioannou P, et Brain Behav. 2022;12(9):e2589.
  3. Verma G, et al. Epilepsy Behav Rep. 2022;18:100530.
  4. Pardoe HR, et Epilepsy Res. 2017;133:28-32.
  5. Lhatoo SD, Sander Epilepsia. 2005;46(Suppl 11):36-39.
  6. Whitney R, Donner Curr Treat Options Neurol. 2019;21(2):7.
  7. Harden C, et Neurology. 2017;88:1674–1680.
  8. Mühlenfeld N, et Chin J Traumatol. 2022;25(5):272-276.

MAT-UKI-0422-P | August 2026