First-Time Seizures May Signal Occult Cancer Risk, Large Danish Study Finds

Data from a large nationwide cohort study published in JAMA Neurology suggest that adults presenting with a first-time seizure face a markedly elevated short-term risk of cancer, particularly neurological malignancies, with more modest but persistent risk observed over long-term follow-up.¹

In the population-based analysis, investigators—led by researchers from Aarhus University including senior author Henrik Toft Sørensen, MD, DMSc—evaluated nearly 50,000 adults with incident seizures and found that cancer diagnoses were substantially more frequent within the first year after seizure onset compared with the general population, raising the possibility that seizures may serve as an early clinical signal of occult malignancy.

Marked Short-Term Risk, Especially for Neurological Cancers

The study included 49,894 adults (median age, 51.5 years; 41.4% women) identified from Danish national registries between 1996 and 2022, all without prior cancer diagnoses. Median follow-up was 5.7 years.

Within the first year after a first-time seizure, investigators observed 2022 cancers, including 1172 neurological and 850 nonneurological malignancies. This translated to an absolute cancer risk of 4.1% and a standardized incidence ratio (SIR) of 5.30 (95% CI, 5.07–5.54), indicating more than a fivefold increase relative to the general population. The signal was particularly pronounced for neurological cancers, where the absolute risk reached 2.4% with an SIR of 76.1 (95% CI, 71.8–80.6). Brain tumors drove much of this association, with an SIR approaching 99 within the first year.¹

Nonneurological cancers were also elevated, though to a lesser extent, with a 1-year SIR of 2.32 (95% CI, 2.17–2.48). The highest relative risks were seen in lung, bronchial, and tracheal cancers (SIR, 5.94), as well as metastatic or unspecified lymph node malignancies (SIR, 7.34). Notably, the incidence rates for both neurological and nonneurological cancers peaked within the first month following seizure diagnosis, suggesting a temporal relationship between seizure onset and cancer detection.¹

Risk Persists Beyond Initial Presentation

Although the magnitude of risk declined after the first year, it remained elevated over time. Between 1 and 5 years, the SIR for any cancer was 1.18 (95% CI, 1.12–1.25), and from 5 to 20 years, it increased slightly to 1.34 (95% CI, 1.28–1.40). Long-term risk was driven largely by nonneurological cancers, which accounted for the majority of malignancies beyond the first year. By 20 years, the cumulative absolute risk of any cancer reached 13.4%.

These findings suggest that while early cancers may be directly related to seizure-provoking lesions, longer-term associations could reflect shared risk factors such as age, systemic inflammation, or underlying comorbidities.

Clinical Yield and Diagnostic Implications

The study estimated that approximately 30 patients with a first-time seizure would need to be evaluated to identify 1 cancer diagnosis within the first year. For neurological cancers, this number increased to 43, and for nonneurological cancers, to 103. Interestingly, cancer risk was lower among patients with identifiable seizure risk factors, such as recent stroke, compared with those without known etiologies, suggesting that unexplained seizures may warrant heightened diagnostic scrutiny.

Additionally, among nonneurological cancers detected within the first year, metastatic disease was disproportionately represented, reinforcing the possibility that seizures may reflect advanced or disseminated malignancy at presentation.

Mechanistic Considerations and Context

Seizures are known to arise from structural and metabolic disruptions in the brain, including tumor-related processes such as peritumoral inflammation, mass effect, and altered neurotransmission. The authors noted that reverse causation—where undiagnosed cancers trigger seizures—likely explains much of the early risk signal. However, they also highlighted that increased medical surveillance following seizures may contribute to earlier cancer detection.¹

Importantly, the persistence of elevated risk beyond the first year suggests additional mechanisms may be involved, including systemic inflammation, immune dysregulation, or shared genetic predisposition.

Clinical Takeaways and Remaining Questions

These findings build on prior work linking epilepsy to increased cancer risk but uniquely isolate the impact of first-time seizures by excluding patients with established epilepsy diagnoses.

The authors concluded that “First-time seizures were associated with clearly elevated short-term relative risk of cancer and slightly elevated long-term risk, indicating they may be an early clinical sign of both neurological and nonneurological occult cancers.”¹

From a clinical perspective, the study supports consideration of broader diagnostic evaluation following unexplained first-time seizures, particularly in patients without clear provoking factors. However, investigators cautioned that routine extensive cancer screening may not be universally appropriate, citing risks of overdiagnosis, patient anxiety, and unclear impact on long-term outcomes.

REFERENCE
1. Pedersen L, Körmendiné Farkas D, Fuglsang K, et al. Risk of cancer in patients with first-time seizure. JAMA Neurol. Published online April 27, 2026. doi:10.1001/jamaneurol.2026.0894