Seize the Day or Let It Slip Away? The Dilemma of Epilepsy Surgery in Older Adults

Abstract

Role of Comorbidities in Epilepsy Surgery Outcomes of Older Adults

Tsai C, Taylor S, Thompson N, Vegh D, Bingaman W, Jehi L, Punia V. Epilepsia. 2024. doi:10.1111/epi.18103, PMID: 39283622.

We lack knowledge about prognostic factors of resective epilepsy surgery (RES) in older adults (≥60 years), especially the role of comorbidities, which are a major consideration in managing the care of people with epilepsy (PWE). We analyzed a single-center cohort of 94 older adults (median age = 63.5 years, 52% females) who underwent RES between 2000 and 2021 with at least 6 months of post-surgical follow-up. Three-fourths of the study cohort had lesional magnetic resonance imaging and underwent temporal lobectomy. Fifty-four (57%) PWE remained seizure-free during a median follow-up of 3.5 years. Cox proportional hazard multivariable analysis showed that aura (hazard ratio [HR] = .52, 95% confidence interval [CI] = .27–1.00), single ictal electroencephalographic pattern (HR = .33, 95% CI = .17–.660), and Elixhauser Comorbidity Index (HR = 1.05, 95% CI = 1.00–1.10) were independently associated with seizure recurrence at last follow-up. A sensitivity analysis using the Charlson Combined Score (HR = 1.38, 95% CI = 1.03–1.84, p = .027) confirmed the association of comorbidities with worse seizure outcome. Our findings provide a framework for a better informed discussion about RES prognosis in older adults. More extensive, multicenter cohort studies are needed to validate our findings and reduce hesitancy in pursuing RES in suitable older adults.

Commentary

With the advancement in surgical techniques and peri-operative care, epilepsy surgery for drug-resistant epilepsy (DRE) in older adults has gained traction in the 21st century. ¹ Recent studies have demonstrated that many older adults can achieve seizure freedom comparable to younger adults.^1,2 Despite these promising results, concerns surrounding comorbidities and surgical risks continue to impede the widespread application of resective epilepsy surgery (RES) in older adults, even though it is regarded as the gold standard treatment for DRE. Although one in four new epilepsy diagnoses occur in those above 65, ³ older adults have historically been marginalized in epilepsy care. Today, this demographic represents the fastest-growing segment of people with epilepsy (PWE), yet they account for a mere fraction of those undergoing surgical interventions. ¹ The complexities that accompany aging necessitate a deeper understanding of factors that influence surgical outcomes in this demographic.

Tsai et al ⁴ study deftly address this critical gap, offering valuable insights into the role of comorbidities and other prognostic factors in shaping post-surgical success in older adults. Conducted at Cleveland Clinic, this single-center retrospective study is the largest of its kind, encompassing 94 adults over 60 who underwent RES between 2000 and 2021.

The study's principal contribution and novelty lies in its focus on the impact of comorbidities on RES outcomes in PWE, a critical but largely overlooked domain. The authors found that a higher burden of comorbidities, quantified by the Elixhauser and Charlson Comorbidity Scores (CCS), was significantly correlated with poorer seizure outcomes. Specifically, for each one-point increase in CCS, the rate of seizure recurrence increased by 38%. Similarly, the predicted probability of seizure freedom one year after surgery was 43% lower in individuals with higher Elixhauser scores than those with lower scores. Previous studies with smaller cohorts had not established such an association between comorbidities and outcomes and reported comparable outcomes among older and younger adults, ¹ likely due to insufficient statistical power. These new findings underscore the significance of evaluating comorbidity burden when considering RES in older PWE. These results could facilitate greater referrals for healthy older adults with lower comorbidity burden while fostering more personalized deliberations for those with a higher comorbidity load.

In addition to examining comorbidities, the study also addresses surgical complications, a central concern in the evaluation of older adults for RES. Tsai et al ⁴ reported a 10% rate of major complications, including subdural hygromas, hydrocephalus, infarctions, cerebrospinal fluid leaks, intracranial hemorrhage, and infections. While a higher comorbidity burden in epilepsy is known to be associated with higher in-hospital mortality, ⁵ none of the patients in the study experienced major cardiovascular complications, peri-operative mortality, or surgery-related deaths within two years post-surgery. These findings align with prior literature, which has shown that surgical complications in RES, regardless of age, range from 1.2% to 12.9%, ⁶ while peri-operative mortality remains rare, with temporal lobe epilepsy showing a 0.4% mortality rate and extratemporal lobe epilepsy a 1.2% rate. ⁶ These reassuring outcomes dispel fears about high mortality and severe complications in older adults undergoing RES, offering much-needed assurance to both clinicians and patients.

While the study excels in delineating the various factors that influence surgery outcomes in older adults, it does fall short in one key area: direct comparison with younger adults. A systematic review reported epilepsy surgery complication rate to be 2.8 times higher in older compared to younger adults. ⁷ Thus, although the overall complication rate in older adults remains relatively low, it is still likely higher than in younger patients.

Furthermore, comorbidities increase frailty in older PWE, and it is frailty—rather than age—that is more closely associated with higher mortality. In fact, mortality rates as high as 20% have been observed in frail older PWE undergoing surgery. ⁸ For older adults with high comorbidity burdens and advanced frailty, nonresection, minimally invasive procedures such as laser ablation or neuromodulation, including Vagus Nerve Stimulation and Responsive Neurostimulation (RNS), may offer a more appropriate solution to DRE. A study comparing RNS outcomes in older and younger adults demonstrated comparable efficacy (older = 76% vs. younger = 50% median seizure reduction) along with similar tolerability and surgical complications, despite a higher CCS in the older group. ⁹ Moreover, reducing the anti-seizure medication (ASM) burden in high-risk older adults through these less invasive procedures ⁹ can mitigate complications associated with ASM use, such as increased frailty, cardiovascular complications, and osteoporosis-related fractures. ⁸

Beyond comorbidities, the authors identified the presence of auras and a localizable ictal electroencephalogram pattern as significant prognostic factors associated with a lower risk of seizure recurrence unique to this older cohort. Seventy-eight percent had a localizable ictal pattern, and 64% reported an aura. In addition, 77% had temporal lobe epilepsy, and 80% had unilateral lesional magnetic resonance imaging, two of the most established favorable factors influencing seizure freedom after RES. ¹⁰ This high prevalence of known favorable prognostic factors likely suggests a potential selection bias. Older adults with these favorable characteristics were more likely referred for surgery, skewing the sample toward better prognostic outlooks. Despite this, the reported seizure freedom rate of 57% was lower than the pooled 70.1% reported in a systematic review of older adults over 50 who had undergone RES. ⁷ The lower rate of seizure freedom in Tsai et al ⁴ cohort is likely attributable to the older age threshold (above 60) and possibly a higher comorbidity burden in the current sample.

Although Tsai et al ⁴ study provides a wealth of valuable insights, several limitations must be acknowledged. The single-center, retrospective nature of the study may introduce selection biases and limit the generalizability of the findings. The cohort, drawn from a tertiary care center, may not be representative of the broader population, as such centers typically serve patients with more advanced diseases and comorbidities. Additionally, the 20-year study period encompasses changes in clinical practice that are not accounted for in the analysis, potentially confounding the results. Finally, despite being the largest reported cohort of older adults undergoing RES, the sample size remains relatively small compared to other epilepsy surgery studies, potentially underestimating the strength of some associations.

In conclusion, Tsai et al ⁴ have made a significant contribution by underscoring the critical role that comorbidities play in determining surgical outcomes for older adults. Their work serves as a clarion call for more nuanced discussions between patients and providers regarding surgical options, including both RES and less invasive procedures. By offering comprehensive data on seizure outcomes, comorbidities, and surgical complications, this research provides an essential foundation for improving the utilization of surgery in this rapidly expanding demographic. However, larger prospective multicenter studies are essential to validate these findings, refine surgical decision-making protocols, and alleviate hesitation in recommending surgery for suitable older adults. By marking a significant advancement in how to optimize surgical outcomes in older PWE, Tsai et al ⁴ work paves the way for more informed decisions about epilepsy surgery, ultimately guiding more older individuals toward the possibility of a seizure-free life.