By Robert McInnis, MD
Synopsis: A subset of people with head injury will develop post-traumatic epilepsy (PTE). This prospective cohort study demonstrated a 4.5-fold increased risk of dementia in those with PTE compared to people without head trauma or epilepsy, and that this risk exceeds that observed in people with head trauma or epilepsy alone.
Source: Schneider ALC, Law CA, Gottesman RF, et al. Posttraumatic epilepsy and dementia risk. JAMA Neurol 2024;81:346-353.
Head injury and epilepsy are conditions with serious public health consequences. A substantial proportion of those with head injury will develop post-traumatic epilepsy (PTE). Dementia has been independently linked with head injury and epilepsy, compounding the disability associated with these conditions. It remains unknown whether PTE confers additional risk of developing dementia, although a growing body of literature suggests that neurodegeneration plays an important role in the pathophysiology of this form of acquired epilepsy.
To address this knowledge gap, Schneider and colleagues conducted a prospective cohort study using data from the multicenter Atherosclerotic Risk in Communities (ARIC) study, which enrolled participants aged to 45 to 64 years between 1987 through 1989 from four study sites. From this population, 103 patients who were of self-reported Asian or American/Alaskan Indian or Black race were excluded because of small numbers and race/center aliasing at certain study sites, one patient was excluded because of having dementia at the study baseline, 1,957 patients with a first head injury occurring prior to the study baseline were excluded, and 1,073 patients with missing head injury data or data included in model covariates were excluded. The remaining 12,558 patients were included in the analysis.
The ARIC protocol involved a total of seven visits from 1987 to 2019, with assessments of whether participants had acquired a head injury, epilepsy, or dementia during the period of follow-up. Head injury was defined using data from three different sources: patient self-report during study visits, International Classification of Diseases (ICD)-9/10 codes from ARIC hospitalization data, and ICD 9/10 codes from outpatient/hospital-based linked Centers for Medicare and Medicaid Services (CMS) data. Epilepsy was defined using epilepsy or seizure-related ICD 9/10 codes from hospitalization and linked CMS data, with primary analyses employing a criterion of at least one or more encounters with an epilepsy or seizure-related code. PTE was defined as a diagnosis of seizure/epilepsy occurring seven or more days after diagnosis of a head injury. Dementia was defined using continuously collected ICD 9/10 codes or death certificate codes.
The study cohort was organized into four different exposure groups: a reference group composed of participants with no head injury and no seizure/epilepsy, those with head injury alone, those with seizure/epilepsy alone and no antecedent head injury (those with head injury after development of epilepsy were included in this group), and those with PTE (those with head injury followed by seizure/epilepsy). Analyses also were performed using head injury and seizure/epilepsy sequentially as reference groups to determine if PTE confers a higher risk for dementia than either exposure alone.
The cohort was composed of 12,558 participants with a mean age of 54.3 years at the study baseline, of which 57.7% were female and 28.2% were self-reported Black race. There was a median period of 25.4 years of follow-up. There were 1,811 subjects diagnosed with head injury, 640 subjects with seizure/epilepsy, and 145 subjects with PTE. There were 2,498 incident cases of dementia over 250,372 person-years. The cumulative dementia-free survival was lowest in the PTE group. After controlling for demographic factors, PTE was found to confer 4.85 times the risk of dementia, seizure/epilepsy alone to confer 2.81 times the risk of dementia, and head injury alone to confer 1.64 times the risk of dementia. The added risk of PTE was slightly attenuated after adding vascular comorbidities and apolipoprotein E e4 genotype to the statistical model; however, in all models, younger participants with PTE were at higher risk of dementia than older participants.
Secondary analyses demonstrated that the associated risk of dementia was similar for PTE occurring after a first vs. second head injury, and after mild vs. moderate, severe, or penetrating head injury. Earlier onset of PTE (fewer than three years) from incident head injury was associated with a greater risk of dementia than later onset of PTE (more than three years).
Commentary
This was a prospective observational study that sought to characterize whether there is added risk of dementia in those who develop PTE. The study revealed that PTE confers a 4.5-fold increased risk of dementia, and that this risk exceeds that observed in people with head trauma or epilepsy alone. These observations were strengthened by the prospective nature of the study, the large population, and long duration of follow-up.
Of special concern is that the relative risk of dementia in those with PTE was found to be higher in younger individuals when compared to older individuals. Although this may at least partially be explained by a higher prevalence of dementia in older individuals, it highlights a potentially devastating effect of PTE in younger people.
A weakness of this study is that the cohort was limited to participants from the Midwest and Southern United States, and, thus, the generalizability of these findings to other regions and populations is unclear and warrants further investigation. ICD codes were used to identify some cases of head trauma, epilepsy, and dementia and are imperfect surrogates for these conditions, but this approach likely mitigated the bias of attrition. Overall, this study adds to our understanding of the epidemiology of PTE and dementia, and underscores the need for further inquiry into the role of neurodegeneration of PTE, as well as the importance of public health measures to prevent head injury. For those already experiencing PTE, these findings also invite development of improved medical and surgical treatments for epilepsy, which may require tailored strategies in this population.
Robert McInnis, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.
A subset of people with head injury will develop post-traumatic epilepsy (PTE). This prospective cohort study demonstrated a 4.5-fold increased risk of dementia in those with PTE compared to people without head trauma or epilepsy, and that this risk exceeds that observed in people with head trauma or epilepsy alone.
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