Epilepsy After Traumatic Brain Injury: A Triple Threat to the Brain—Carpe Diem or Carpe Dementia?

Abstract

Increasing Risk of Dementia Among Patients With Subsequent Epilepsy Within 2 Years Post-Traumatic Brain Injury: A Population-Based Case-Control Study

Chu SF, Liao KH, Wei L. J Multidiscip Healthc. 2024;17:1447–1457. doi:10.2147/JMDH.S452086. PMID: 38577293; PMCID: PMC10992670.

Background: Although the association between neurodegenerative diseases, such as dementia, and traumatic brain injury (TBI) has long been known, the association between dementia and TBI with epilepsy has been controversial. Aim: This data-driven population-based study is designed to investigate the association between dementia and epilepsy after TBI within a 2-year period. Methods: This case-control cohort study was conducted using the Longitudinal Health Insurance Database 2000 (LHID2000). We included 784 individuals ambulatory or hospitalized for TBI with epilepsy from 2001 to 2011, compared with 2992 patients with TBI without epilepsy who were matched for characteristics including sex, age, and healthcare resource use index date. Every participant was followed up for 5 years to ascertain any dementia development. Data were stratified and analyzed using the Cox proportional hazards regression. Results: Through the 5-year follow-up period, 39 patients (5.21%) with TBI with epilepsy and 55 (1.53%) with TBI without epilepsy developed dementia. TBI with epilepsy was independently associated with a >3.03 times risk of dementia after correcting for age, sex, and comorbidities. Conclusion: These findings suggest an increased risk of dementia in patients with TBI with epilepsy. Our research recommends that individuals with TBI and epilepsy be monitored more intensively.

Commentary

Post-traumatic epilepsy (PTE) has been documented since antiquity, with early references found in the works of Hippocrates, who linked head injuries to seizure disorders. ¹ In the nineteenth century, John Hughlings Jackson's work brought considerable scientific attention to the connection between traumatic brain injury (TBI) and epilepsy. ² Since then, numerous contemporary studies have significantly advanced our comprehension of PTE's mechanisms, risk factors, prevention strategies, and, most importantly, its dire consequences, one of which is dementia. ³

The well-established association between TBI and dementia reveals up to a 4-fold augmented risk of dementia in TBI. ⁴ Similarly, the increased risk of dementia in epilepsy is also irrefutable.^5–7 Consequently, it is only logical that PTE is also a risk factor for dementia. ³ However, the extent to which PTE increases the risk of dementia remains an understudied entity.

In a perceptive study, Chu et al ⁸ meticulously aimed to elucidate the compounded risk of dementia in individuals with PTE, addressing a critical gap in existing research. This Taiwan population-based case-control study utilized data from the Longitudinal Health Insurance Database. The study encompassed 784 individuals with PTE and 2992 age and sex-matched individuals with TBI but without epilepsy.

The primary focus of the study was to examine the association between PTE and the subsequent risk of dementia within the ensuing 5 years. The authors found that people with PTE have a 3-fold higher risk of developing dementia compared to those with TBI without epilepsy after adjusting for age, sex, income, location, and comorbidities. Specifically, 5.21% of people with PTE developed dementia compared to 1.53% of TBI without epilepsy during the 5-year follow-up period. These results align with previous studies, which have demonstrated worse short-term cognitive outcomes and a several-fold increase in long-term dementia risk in PTE, significantly higher than the risk associated with TBI or epilepsy alone.^3,9,10 While some studies have demonstrated that worse cognitive outcomes in PTE relate to the severity of trauma rather than epilepsy, ⁹ others have shown a similar dementia risk in PTE across varying severity levels of brain injury. ³ However, the authors could not resolve this existing controversy because they did not delve into the severity of TBI.

Overall, these findings underscore the necessity to prevent both brain trauma and PTE after brain trauma. Further research should delve into the biological mechanisms underpinning the increased dementia risk in PTE, such as neuroinflammation, amyloid accumulation, and hippocampal damage. Understanding these mechanisms could facilitate the development of targeted therapeutic strategies. Extending follow-up periods beyond 5 years could provide a deeper understanding of the long-term risks and progression of dementia in this patient cohort. Longitudinal studies could also help identify critical periods for intervention. Developing and testing interventions aimed at reducing the risk of epilepsy after TBI could indirectly diminish the subsequent risk of dementia. This could include pharmacological treatments, lifestyle modifications, and enhanced monitoring of TBI patients.

Age is a pivotal factor in investigating the relationship between PTE and dementia. This study expands the existing literature by examining various age groups. Authors discovered that in PTE, the risk of developing dementia increased by 14.37-fold in the 18–64 age group and 3.41-fold in the 65–74 age group. They found no increased risk in individuals over 75. These findings aren’t entirely surprising, as previous studies have also shown a higher dementia risk in younger individuals with PTE compared to older individuals. ³ This contradicts the overall dementia risk in people with epilepsy, which is most prevalent in older adults. ⁷ This pattern is likely due to higher baseline prevalence and incidence of dementia in older individuals, making it less probable for PTE to add a measurable increase in dementia risk for this age group. ³ Regardless, these age-specific findings identify a potentially vulnerable population, ie, younger people with PTE, highlighting the necessity for targeted monitoring and interventions for younger individuals with PTE.

Perhaps the most significant contribution of this study is the investigation of sex-specific risks of dementia in PTE, a previously uncharted territory. While both brain trauma and PTE are more common in men, ¹¹ no sex-specific increased dementia risk in PTE has been demonstrated in previous studies. The authors found an ∼18-fold higher dementia risk in males aged 18–64 and a 6-fold higher dementia risk in males aged 65–74, with no increased risk in males above 75. No increased risk was observed in females with TBI or epilepsy. Given these differential impacts, future studies should focus on understanding the sex-specific mechanisms and risk factors that could potentially lead to tailored prevention and management strategies for males and females with PTE.

The authors also noted a significantly higher prevalence of stroke among people with PTE compared to TBI patients without epilepsy, suggesting that comorbid conditions might play a role in increasing dementia risk. Since stroke is a well-known risk factor for dementia, ⁶ the higher stroke prevalence may also explain the increased dementia risk in PTE.

While the study's strengths include its large sample size and nationally represented population-based data, notable limitations include reliance on diagnosis codes from government claims data, which may result in reduced diagnostic accuracy and the primarily Chinese study population, limiting the generalizability of results to other ethnic groups. Additionally, there was insufficient information on the severity of TBI, epilepsy, or dementia. The study also did not explore the subtypes of these conditions, which could influence the study results. The study's retrospective nature may introduce biases related to the completeness and accuracy of recorded data. These limitations suggest the need for further research with more comprehensive data, including diverse populations and detailed patient information, to better understand the relationship between TBI, epilepsy, and dementia. Integrating data on other potential risk factors such as diet, alcohol use, and smoking into the analysis could refine the understanding of how these factors interact with TBI and epilepsy to influence dementia risk.

While providing critical insights into the relationship between PTE and subsequent dementia risk, Chu et al's ⁸ study also paved new avenues for further research. By identifying a more than 3-fold increase in dementia risk among people with PTE, especially in younger males, the study underscores the need for intensive monitoring and intervention strategies in this particularly vulnerable group. Neuropsychiatric evaluations may be routinely considered in this patient population. Future research should investigate the underlying mechanisms, long-term risks, and potential interventions to mitigate this compounded risk. These findings also highlight the necessity for further research into the genetic and environmental risk factors influencing dementia development in PTE. Identifying risk factors and effective management strategies is crucial for reducing dementia risk and improving outcomes in this population.

Early and aggressive intervention for PTE has the potential to reduce the risk of cognitive decline and the overall burden of dementia. In essence, PTE presents a triple threat to the brain, emphasizing the need for intensive monitoring and intervention- a call to “Carpe Diem or Carpe Dementia.”