Abstract
Seizure Freedom Score: A New Simple Method to Predict Success of Epilepsy Surgery
Gracia CG, Yardi R, Kattan MW, Nair D, Gupta A, Najm I, Bingaman W, Gonzalez-Martinez J, Jehi L. Epilepsia 2014;56(3):359–365.
OBJECTIVE: We aim to develop a new scale that predicts seizure outcomes after resective epilepsy surgery. METHODS: We retrospectively reviewed patients who underwent surgery for medically refractory epilepsy at our center between 1999 and 2012. Four predictive outcome indicators were selected: preoperative seizure frequency, history of generalized tonic–clonic seizures, brain magnetic resonance imaging (MRI), and epilepsy duration. A score of 0 or 1 was given if the indicator was associated with poor or good outcome, respectively. A seizure freedom score (SFS) was calculated by adding these four categories (total score ranged from 0 to 4). A modified SFS (m-SFS) was then calculated with two additional outcome indicators: invasive electroencephalography (EEG) evaluation (IEI) (performed or not performed) and lobe of resection (temporal vs. extratemporal), for a score ranging from 0 to 6. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom in the overall group. Statistical significance was tested using the log-rank test and comparison of 95% confidence intervals (CIs). RESULTS: The study population included 466 patients with 244 (52%) male. Seizure freedom rates were directly correlated with the SFS score: at 10 years, 36.9% of patients with SFS of 0 were seizure-free, as opposed to 45% for SFS = 1, 60% for SFS = 2, 72% for SFS 3 or above (p = 0.002). When calculated including the IEI and the localization, the score's performance improved: 24% of patients with a m-SFS of 0 were seizure-free at 10 years, as opposed to 38–59% for m-SFS = 1–3, and 75–79% for m-SFS of 4–6 (p < 0.001). SIGNIFICANCE: An easily measurable seizure freedom score could be a reliable tool to synthesize multiple seizure outcome predictors into a single simple score to predict postoperative seizure freedom. This tool will help with patient and family counseling and estimation of surgical candidacy at both early (SFS) and advanced (m-SFS) stages of a surgical evaluation.
Development and Validation of Nomograms to Provide Individualised Predictions of Seizure Outcomes after Epilepsy Surgery: A Retrospective Analysis
Jehi L, Yardi R, Chagin K, Tassi L, Lo Russo G, Worrell G, Hu W, Cendes F, Morita M, Bartolomei F, Chauvel P, Najm I, Gonzalez-Martinez J, Bingaman W, Kattan MW. Lancet Neurol 2015;14:283–290.
BACKGROUND: Half of patients who have resective brain surgery for drug-resistant epilepsy have recurrent postoperative seizures. Although several single predictors of seizure outcome have been identified, no validated method incorporates a patient's complex clinical characteristics into an instrument to predict an individual's postsurgery seizure outcome. METHODS: We developed nomograms to predict complete seizure freedom from seizures and Engel score of 1 (eventual freedom from seizures allowing for some initial postoperative seizures, or seizures occurring only with physiological stress such as drug withdrawal) at 2 years and 5 years after surgery on the basis of sex, seizure frequency, secondary seizure generalisation, type of surgery, pathological cause, age at epilepsy onset, age at surgery, epilepsy duration at time of surgery, and surgical side. We designed the models from a development cohort of patients who had resective surgery at the Cleveland Clinic (Cleveland, OH, USA) between 1996 and 2011. We then tested the nomograms in an external validation cohort operated on over a similar period in four epilepsy surgery centers, in Brazil, France, Italy, and the USA. We assessed performance of the nomogram by calculating concordance statistics and assessing the calibration of predicted freedom from seizures with the reported freedom from seizures and Engel score of 1. FINDINGS: The development cohort included 846 patients and the validation cohort included 604 patients. Variables included in the nomograms were sex, seizure frequency, secondary seizure generalisation, type of surgery, and pathological cause. In the development cohort, the baseline risk of complete freedom from seizures was 0·57 at 2 years and 0·40 at 5 years. The baseline risk of Engel score of 1 was 0·69 at 2 years and 0·62 at 5 years. In the validation cohort, the models had a concordance statistic of 0·60 for complete freedom from seizures and 0·61 for Engel score of 1. Calibration curves showed adequate calibration (judged by eye) of predicted and reported freedom from seizures, throughout the range of seizure outcomes. INTERPRETATION: If validated in prospective cohorts, these nomograms could be used to predict seizure outcomes in patients who have been judged eligible for epilepsy surgery.
Commentary
It is well demonstrated that resective epilepsy surgery for both medically resistant mesial temporal lobe and neocortical focal-onset epilepsies are superior over medical therapies (1–3), with rare complications at experienced epilepsy surgery centers (4, 5). The term “medically resistant” is defined here as persistent disabling seizures despite at least two appropriate antiepileptic drug trials at maximal tolerated doses. Favorable postresective seizure outcomes have significantly improved for these medically resistant focal-onset epilepsy categories over the last 2 decades (6). Such outcome statistics are well known to nearly every epilepsy neurosurgeon and epileptologist performing these surgeries and following these patients. Epilepsy specialists strive to integrate and interpret the many factors for predicting the probability of prolonged seizure freedom for a given potential candidate. However, a large proportion of patients do not fall into straightforward categories regarding postresective outcomes. Therefore, it has been challenging to synthesize with patient specificity, conflicting diagnostic indicators, particularly in complex scenarios for predicting postresective seizure control.
Some of the “straightforward” favorable predictive factors include duration of active epilepsy for no longer than 5 years, younger age on presentation, rare secondarily generalized seizures, unilateral hippocampal sclerosis for temporal lobe epilepsy, characteristic predominantly unilateral EEG signatures, and concordant multimodal diagnostic data—including lateralizing neuropsychologic findings. In the case of medically resistant mesial temporal epilepsy, favorable outcomes in relation to the extent of resected temporal lobe tissue (e.g., standard [en bloc] resection versus selective [tailored] amygdalohippocampectomy) have been studied for decades (7). A resurgence of this latter factor has been particularly valuable with the advent of minimally invasive surgical techniques such as MRI-guided laser ablation. However, referrals to epilepsy centers for resective epilepsy surgery remain extraordinarily underutilized for both straightforward as well as more challenging patients (8, 9). In either case, a large proportion of patients with medically resistant focal-onset epilepsy who are finally referred to epilepsy centers have already endured uncontrolled seizures for over 2 decades with resulting irreversible negative sequelae (10).
The Cleveland Clinic studies authored by Jehi et al. and Gracia et al. present assessment scales constructed as nomograms or simple predictive scores, respectively. These organized scales adjust for patient complexity, in an attempt to improve predicting postresective outcomes for both medically resistant mesial temporal lobe, and neocortical focal-onset epilepsies. Jehi and colleagues predicted surgical outcome derived from 846 patients prior to presenting to the Cleveland Clinic (Cleveland, OH). Hemispherectomies, multi-lobar resections, and reoperations were excluded from the study cohort. These retrospective data were validated with data collected from an additional 604 patients prior to referring to two epilepsy centers in Western Europe, a center in Brazil, and the Mayo Clinic in the United States. The study described by Gracia et al. included 466 patients from the Cleveland Clinic, with 177 having undergone temporal lobe resections, and 289 having had extratemporal resections.
Jehi et al. used a strategy that capitalized on organized scales or nomograms, where a set of validated classic outcome measures were used to predict favorable seizure control (Engel Class = 1) for a given individual. The authors generated an instrument to sort patient-specific diagnostic data, accounting for any conflicting results, into a comprehensive validated risk assessment outcome measure. Gracia et al. similarly demonstrated an easily calculated predictor score, called a seizure freedom score (SFS), determined prior to the presurgical evaluation. Well-established predictor indicators were used, similar to Jehi et al., for calculating an overall SFS. A simple strategy of using binary or dichotomous values for each outcome measure was performed. Additionally, a surrogate measure for sorting patient complexity was included as a so-called “modified SFS.” Specifically, two more indicators were included indicating whether or not invasive electrocorticography was performed, and whether the resection was temporal versus extratemporal. Gracia et al. found that the SFS was a useful and easily calculated indicator for counseling patients at various stages of the presurgical evaluation.
Limitations of both studies included relying on classic prognostic indicators prior to an in-depth presurgical evaluation. It is noteworthy that multimodality diagnostic neuroimaging procedures, with the exception of easily accessible MRI studies, were not factored into the calculations. For example, ictal SPECT, MEG, PET, long-term video-EEG monitoring, and other specialized imaging modalities, such as diffusion tensor imaging (DTI) and fMRI, were excluded as prognostic indicators. In addition, the predictor measures in both studies admittedly did not include quality of life, mood, and psychosocial functioning. Lastly, the predictor statistics for both studies did not incorporate potential surgical comorbidities. Gracia et al. admitted their results were not externally validated. Both studies require prospective validation.
Further development of these scales will likely contribute to counseling prospective surgical patients with improved clarity on a case-by-case basis regarding potential for seizure freedom following resective surgery. Such nomograms are envisioned to be employed during an initial clinic visit, prior to a formal presurgical evaluation. Realistic unbiased outcome scores can be useful to patients and providers for convincing patients to further pursue a presurgical evaluation. Additional well-designed studies must include an interpretative safeguard to prevent inappropriately discouraging complex patients and their providers from considering epilepsy surgery. Such assessment tools can be readily converted to, and deployed as, easily accessible computer-based algorithms. Furthermore, more evolved algorithms can utilize a level of complexity score to facilitate allocation of diagnostic resources, perhaps activating patient referrals to specially equipped epilepsy centers. Moreover, such instruments can generate value-based presurgical evaluation cost-to-outcome analyses, particularly in an era of healthcare reform. Following further development and validation, these simple but powerful tools can be utilized by nonspecialist healthcare providers for convincing both patients and providers themselves to seek referrals to qualified surgical epilepsy centers. Overall, these two studies lay the foundation for further developing novel assessment instruments for circumventing underutilization of well-proven resective surgery for medically resistant focal-onset epilepsy.