First-Time Seizure Linked to Increased Risk of Systemic and Neurological Cancer

The Diagnostic Weight of New-Onset Seizures

New-onset seizures in adults frequently serve as the presenting symptom for primary central nervous system neoplasms, such as meningiomas or glioblastomas [1, 2]. While the immediate clinical priority is often stabilizing the patient and initiating antiseizure medications, the underlying etiology remains a critical diagnostic challenge [3]. Beyond primary brain tumors, seizures can arise from metabolic derangements, autoimmune limbic encephalitis, or metastatic disease [4, 5]. Current guidelines emphasize neuroimaging for atypical presentations, yet the long-term systemic implications of an initial seizure event are not fully defined [6]. A large-scale population study now provides specific data on the temporal relationship between first-time seizures and the subsequent diagnosis of both neurological and nonneurological cancers, offering clinicians a clearer timeline of oncological risk.

Large-Scale Registry Analysis of Adult Seizure Patients

The researchers conducted a population-based cohort study utilizing comprehensive data from nationwide Danish medical registries spanning from January 1996 through December 2022. This longitudinal design allowed for a robust assessment of the temporal relationship between seizure onset and subsequent malignancy. The study cohort included 49,894 adults who received a first-time hospital diagnosis of a seizure. To ensure the findings reflected seizures as a potential early indicator of occult disease, the inclusion criteria required that all participants be at least 18 years of age and have no preceding history of cancer. The demographic profile of the cohort showed a median age of 51.5 years at the time of seizure diagnosis (interquartile range, 35.6 to 67.8 years), and 20,648 participants (41.4%) were women. The analysis tracked patients from their initial seizure until a cancer diagnosis, emigration, death, or the study conclusion on December 31, 2022. The researchers excluded nonmelanoma skin cancer from the primary outcomes. To capture both immediate and long-term risks, the follow-up structure categorized outcomes into specific intervals: within one year, from one to less than five years, and from five to 20 years after the first seizure. This granular approach provides clinicians with specific data regarding the duration of elevated risk following a first-time seizure event, helping to define the window for heightened diagnostic vigilance.

Acute Cancer Risk Following Initial Seizure

The study identified a significant clustering of cancer diagnoses immediately following the index seizure event. Within the first 12 months of follow-up, the researchers observed a total of 1,172 neurological and 850 nonneurological cancers. For clinicians managing these patients, the data translate to an absolute risk for any cancer of 4.1% during the first year. When compared to the general Danish population, this represents a standardized incidence ratio of 5.30 (95% CI, 5.07-5.54). The standardized incidence ratio, a metric comparing the observed number of cancer cases in the seizure group to the expected number in the general population, indicates that adults presenting with a first-time seizure are more than five times as likely to be diagnosed with a malignancy within a year than their peers. The risk was most pronounced for malignancies of the central nervous system. Within the first year, the absolute risk for neurological cancers was 2.4%. This corresponds to a standardized incidence ratio of 76.1 (95% CI, 71.8-80.6), representing a 76-fold increase in relative risk compared to the general population. These data suggest that a first-time seizure is frequently the sentinel clinical event for an underlying primary or secondary brain tumor, reinforcing the necessity of immediate and thorough neuroimaging in the acute diagnostic workup. Beyond intracranial pathology, the findings also demonstrated a heightened risk for systemic malignancies. The absolute risk for nonneurological cancers within one year was 1.7%. While lower than the risk for neurological cancers, this still represented a standardized incidence ratio of 2.32 (95% CI, 2.17-2.48). The observation of 850 nonneurological cancers in the first year suggests that seizures may serve as a paraneoplastic phenomenon or an early indicator of metastatic disease from primary sites outside the nervous system. This elevated short-term risk for systemic cancer highlights the importance of considering a broader diagnostic assessment in patients whose initial seizure cannot be clearly attributed to a primary neurological lesion.

Long-Term Surveillance and Systemic Malignancy

While the most acute risk of malignancy occurs within the first year following a first-time seizure, the Danish cohort data demonstrate that a persistent, albeit lower, relative risk remains for decades. In the intermediate follow-up period, defined as one to less than five years after the index seizure, the researchers observed 87 neurological and 1,226 nonneurological cancers. During this interval, the absolute risk for any cancer was 3.5%, which corresponds to a standardized incidence ratio of 1.18 (95% CI, 1.12-1.25). This indicates that even after the initial diagnostic window, patients with a history of seizure remain at an 18% higher risk of cancer than the general population. Specifically, the absolute risk for neurological cancers was 0.2% with a standardized incidence ratio of 1.85 (95% CI, 1.48-2.28), while the absolute risk for nonneurological cancers was 3.3% with a standardized incidence ratio of 1.15 (95% CI, 1.09-1.22). The long-term data extending from 5 to 20 years after the initial seizure reveal a significant cumulative burden of disease, particularly regarding systemic malignancies. During this late follow-up period, the study identified 112 neurological and 2,120 nonneurological cancers. The absolute risk for any cancer reached 13.4%, with a standardized incidence ratio of 1.34 (95% CI, 1.28-1.40). This sustained elevation in relative risk suggests that a first-time seizure may be a very early marker of physiological vulnerability or occult oncogenic processes. For neurological malignancies, the absolute risk was 0.7% with a standardized incidence ratio of 1.46 (95% CI, 1.20-1.75). Most notably, the absolute risk for nonneurological cancers rose to 12.8%, representing a standardized incidence ratio of 1.33 (95% CI, 1.28-1.39). These findings underscore that the clinical significance of a first-time seizure extends far beyond the immediate postictal period, necessitating a high index of suspicion for both primary brain tumors and systemic cancers throughout the patient's life.

Clinical Implications for Diagnostic Workup

The association between first-time seizures and occult malignancy necessitates a reassessment of how clinicians approach the initial diagnostic workup. By evaluating absolute risks and standardized incidence ratios across multiple categories, the study provides a comprehensive map of oncological vulnerability over a 20-year longitudinal window. The findings indicate that first-time seizures are associated with a clearly elevated short-term relative risk of cancer and a slightly elevated long-term risk, suggesting that a seizure may serve as an early clinical sign of both neurological and nonneurological occult cancers. For the practicing physician, this means that a first-time seizure in an adult should not only trigger an investigation into primary brain pathology but also prompt consideration of broader diagnostic assessments. Because the data show a standardized incidence ratio of 5.30 (95% CI, 5.07-5.54) for any cancer within the first year, the clinical priority must include screening for systemic malignancies that may be presenting paraneoplastically or via early metastatic involvement. Furthermore, the persistence of an elevated risk for decades, demonstrated by a standardized incidence ratio of 1.34 (95% CI, 1.28-1.40) between 5 and 20 years, suggests that these patients require vigilant, long-term surveillance that extends beyond the standard neurological follow-up. Routine primary care visits should incorporate age-appropriate cancer screenings and a thorough review of systems to detect any delayed oncological developments.

References

1. Khan MF, Patel S, Alnasser AA, et al. Predicting epilepsy in patients diagnosed with intracranial meningiomas: A systematic review and meta-analysis of clinical and anatomical risk factors.. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2025. doi:10.1016/j.jocn.2025.111451

2. Wen PY, Weller M, Lee EQ, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-Oncology. 2020. doi:10.1093/neuonc/noaa106

3. Avila EK, Tobochnik S, Inati SK, et al. Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management. Neuro-Oncology. 2023. doi:10.1093/neuonc/noad154

4. Radja GK, Cavanna AE. Treatment of VGKC complex antibody-associated limbic encephalitis: a systematic review.. The Journal of neuropsychiatry and clinical neurosciences. 2013. doi:10.1176/appi.neuropsych.13020022

5. Vilstrup H, Amodio P, Bajaj JS, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014. doi:10.1002/hep.27210

6. Evans RW, Burch R, Frishberg B, et al. Neuroimaging for Migraine: The American Headache Society Systematic Review and Evidence‐Based Guideline. Headache The Journal of Head and Face Pain. 2019. doi:10.1111/head.13720