Sharper Minds: Cognitive Recovery After Epilepsy Surgery in Children

Abstract

Long-Term Neuropsychological Trajectories in Children With Epilepsy: Does Surgery Halt Decline?

Eriksson MH, Prentice F, Piper RJ, Wagstyl K, Adler S, Chari A, Booth J, Moeller F, Das K, Eltze C, Cooray G, Perez Caballero A, Menzies L, McTague A, Shavel-Jessop S, Tisdall MM, Cross JH, Martin Sanfilippo P, Baldeweg T. Brain. 2024;147(8):2791–2802. doi: 10.1093/brain/awae121.

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery may alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990–2018). We extracted patient information and neuropsychological functioning—obtained from intelligence quotient (IQ) tests (domains: full-scale IQ, verbal IQ, performance IQ, working memory, and processing speed) and tests of academic attainment (reading, spelling, and numeracy)—and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery (median age at surgery = 11.9 years, interquartile range = [7.8,15.0]) and neuropsychology assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all p-values ≤ .001; eg, βFSIQ = −1.9, SEFSIQ = 0.3, pFSIQ < 0.001). Children lost on average 1 to 4 points per year, depending on the domain considered; 27% to 43% declined by 10 or more points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46% to 60%) scored 1 or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (full-scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all p-values > .128). However, children who became seizure-free through surgery showed higher postoperative neuropsychological performance (eg, rrb-FSIQ = 0.37, p < .001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (eg, βFSIQ = 0.9, SEFSIQ = 0.3, pFSIQ = 0.004). Children who had discontinued antiseizure medication (ASM) treatment at 1-year follow-up showed an 8-to-13-point advantage in postoperative working memory, processing speed, and numeracy, and greater improvements in verbal IQ, working memory, reading, and spelling (all p-values < .034) over the postoperative period compared to children who were seizure-free and still receiving ASMs. In conclusion, by providing seizure freedom and the opportunity for ASM cessation, epilepsy surgery may not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible, or potentially prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.

Commentary

People with drug-resistant epilepsy (DRE) experience numerous deleterious effects of recurrent seizures, including risk of injury, social stigma, antiseizure medication (ASM) side effects, and higher rates of premature death. ¹ The harmful effects of DRE also include neuropsychological deficits that interfere with an individual's school or work, as well as general activities of daily living.^2,3 Neurocognitive deficits often colocalize with regions of seizure onset, but distal brain network disruption and associated cognitive impairments are also common. We now have class I evidence that temporal lobe and extratemporal epilepsy surgery leads to substantially improved seizure outcomes compared to ASMs alone, with many patients achieving complete seizure freedom. However, this level of evidence does not exist for postoperative neuropsychological outcomes. It may seem intuitive that seizure cessation after surgery would halt the neurocognitive decline, however, the intervention itself may cause network disruptions. Overall, what is the likelihood that successful surgery halts or even reverses cognitive decline in DRE, and what are the contributions of seizure cessation versus ASM discontinuation in determining neuropsychological outcomes? These questions are particularly important in the pediatric population, where neurocognitive development is still underway, and they are explored in the presently highlighted study.

Eriksson et al ⁴ present a retrospective study examining neuropsychological function in children who underwent resection or disconnection epilepsy surgery at their center. In total, a cohort of 500 individuals was included over an 18-year period, all of whom had neurocognitive testing either before or after surgery, with many patients tested at multiple time points. Postoperative evaluations were recorded anywhere from days after surgery to 16 years later, with serial evaluations performed on many individuals. The median age of epilepsy onset and surgery was approximately 3 and 12 years, respectively. Two-thirds of individuals had a focal lesion on magnetic resonance imaging, and approximately one-half of patients had surgery within their temporal lobe. The authors specifically focused on a subset of neuropsychological tests from their typical batteries that were common across individuals, such as verbal and performance intelligence quotient (IQ), as well as academic attainment tests in spelling, reading, and numeracy. Notably, significant declines in all 8 neurocognitive domains examined were seen before surgery, both cross-sectionally and longitudinally, with most children scoring more than 1 standard deviation below the mean on the 5 IQ domains. After surgery, approximately two-thirds of children achieved seizure freedom, and improvement or decline in neuropsychological performance was defined as a 10-point difference in IQ score compared to the preoperative baseline. Patients who became seizure-free demonstrated improved performance in full-scale IQ, verbal IQ, working memory, and reading after resection or disconnection, while those with persistent seizures showed either a continued decline or plateau in these measures. In addition to seizure outcomes predicting neuropsychological trajectory after surgery, focal resection and low-grade brain tumor pathology portended more favorable cognitive outcomes. Furthermore, seizure-free children off ASMs experienced greater neuropsychological improvements than those still on ASMs at the time of evaluation, suggesting that both seizure and medication burdens contribute to deleterious cognitive effects in epilepsy.

This work by Eriksson et al ⁴ represents an elegant longitudinal study in a large cohort demonstrating the potential neurocognitive benefits of successful epilepsy surgery in children. Critically, not only did the authors find that surgical intervention may halt neuropsychological decline, but it may also allow progressive recovery of various cognitive functions, such as full-scale IQ, working memory, and reading ability. Of note, consensus guidelines endorse early surgical referral of children with DRE, as reaffirmed recently by the International League Against Epilepsy (ILAE). ⁵ These ILAE recommendations even advise surgical evaluation in individuals with medically controlled epilepsy with an accessible focal lesion. Nevertheless, prior work by the present authors and others has shown that surgery continues to be dramatically underutilized in children, and surgical referrals are substantially delayed until several years after drug resistance.^6,7 The presently highlighted results further suggest that surgical referral should be considered early in DRE to promote cognitive preservation, but that it is also “not too late” for those who have already experienced profound neuropsychological decline, as larger increases in postoperative neuropsychological scores were noted in individuals with more profound deficits before surgery.

One limitation of the study is that it was performed retrospectively, and therefore the timing of the pre- and postoperative neuropsychological evaluations was not standardized across patients. Nonetheless, this presented an opportunity to relate cognitive changes to the duration of time after surgery across the large cohort. Notably, while cognitive benefits were not yet observed in most patients at the initial 1-year (median) postoperative evaluation, clear improvements were present in subsequent evaluations performed in patients achieving approximately 3 years or more years of seizure freedom. This is consistent with another recent study demonstrating progressive postoperative improvements in various neurocognitive domains over the first 5 years of postoperative seizure freedom after pediatric epilepsy surgery. ⁸ It is possible that some of the discordance in prior studies shows neuropsychological improvement versus decline after epilepsy surgery is related to postoperative cognitive evaluations being performed too early, when the temporary cognitive “hit” of a major neurosurgical procedure has not yet abated, and the potential “benefit” of long-term seizure freedom has not yet been realized. Future prospective studies of long-term, progressive neurocognitive changes after epilepsy surgery will be worthwhile, with a particular focus on the differential effects of seizure outcome and ASM discontinuation. It will also be worthwhile to pursue longitudinal neuroimaging studies to understand brain network alterations that relate to cognitive changes after surgical interventions. For instance, there is some evidence that broad neurocognitive deficits in focal epilepsy may relate to abnormal connectivity from subcortical arousal structures with widespread neocortical projections, and that seizure freedom after epilepsy surgery may lead to improvement in some of these functional connections. ⁹

Finally, it is worthwhile to note that the field of epilepsy surgery is moving toward greater use of minimally invasive therapies such as neuromodulation and laser ablation, with a focus on network-based approaches. ¹⁰ Much of this shift is in adult epilepsy surgery and is driven in part by a growing desire to reduce deleterious neurocognitive side effects of large resections and disconnections, perhaps at a cost of somewhat lower seizure freedom rates. The results of Eriksson et al ⁴ suggest, however, that striving for seizure freedom is a critical goal to optimize neurocognitive outcomes, particularly in children with a developing brain and higher potential for recovery. Overall, the highlighted work further supports important messaging about surgery in DRE: refer early, refer often, and strive for seizure freedom whenever possible.