Abstract
Miron G, Müller P, Hohmann L, Oltmanns F, Holtkamp M, Meisel C, Chien C. Ann Neurol. 2024;95(5):984–997. doi: 10.1002/ana.26893 Objective: In temporal lobe epilepsy (TLE), a taxonomy classifying patients into 3 cognitive phenotypes has been adopted: minimally, focally, or multidomain cognitively impaired (CI). We examined gray matter (GM) thickness patterns of cognitive phenotypes in drug-resistant TLE and assessed potential use for predicting postsurgical cognitive outcomes. Methods: TLE patients undergoing presurgical evaluation were categorized into cognitive phenotypes. Network edge weights and distances were calculated using type III analysis of variance F-statistics from comparisons of GM regions within each TLE cognitive phenotype and age- and sex-matched healthy participants. In resected patients, logistic regression models (LRMs) based on network analysis results were used for prediction of postsurgical cognitive outcome. Results: A total of 124 patients (63 females, mean age ± standard deviation [SD] = 36.0 ± 12.0 years) and 117 healthy controls (63 females, mean age ± SD = 36.1 ± 12.0 years) were analyzed. In the multidomain CI group (n = 66, 53.2%), 28 GM regions were significantly thinner compared to healthy controls. Focally impaired patients (n = 37, 29.8%) showed 13 regions, whereas minimally impaired patients (n = 21, 16.9%) had 2 significantly thinner GM regions. Regions affected in both multidomain and focally impaired patients included the anterior cingulate cortex, medial prefrontal cortex, medial temporal, and lateral temporal regions. In 69 (35 females, mean age ± SD = 33.6 ± 18.0 years) patients who underwent surgery, LRMs based on network-identified GM regions predicted postsurgical verbal memory worsening with a receiver operating curve area under the curve of 0.70 ± 0.15. Interpretation: A differential pattern of GM thickness can be found across different cognitive phenotypes in TLE. Including magnetic resonance imaging with clinical measures associated with cognitive profiles has potential in predicting postsurgical cognitive outcomes in drug-resistant TLE.
Commentary
While seizure is the first thing that comes to mind when we think about epilepsy, there is another battle that many patients face—cognitive impairment. And it is not just about cognition; mood and behavioral changes are common underdiagnosed comorbidities. Scientists have been hard at work trying to uncover how epilepsy impacts the brain, and this recent study by Miron and team takes a step forward. 1 They are shedding new light on the connection between epilepsy and cognitive function.
Gray Matter and Cognitive Changes
For years, researchers have tried to unlock the brain's secrets by examining its structure, such as gray and white matter volume, cerebrospinal fluid volume, gyral and sulcal pattern, subcortical structures, white matter tracts, and functional connectivity. Scientists have also studied serum biomarkers, animal models, and more to understand how these changes link to cognitive problems.
In this study, Miron's team focused on the brain's gray matter thinning in adults with drug-resistant temporal lobe epilepsy. They identified three groups of patients based on the severity of their cognitive impairment using the International Classification of Cognitive Disorders in Epilepsy criteria. Some had no detectable cognitive issues (however, they are called minimal impairment [MI], 17%), others had trouble in just one domain (focal impairment, 30%), while the most affected group (multidomain impairment, 53%) struggled in two or more cognitive areas.
The study revealed distinct gray matter thinning patterns associated with the severity of cognitive impairments independent of clinical factors, including age, sex, epilepsy duration, number of antiseizure medications, hemisphere of seizure onset, and hippocampal sclerosis. Interestingly, even the group without identified cognitive impairment (MI) had gray matter thinning in the auditory and primary visual cortices, tied to sensory processing, suggesting early structural changes even when neuropsychological tests were negative. Could this structural finding suggest early links to cognitive decline? Is this a golden opportunity for early intervention?
Moreover, the cortical thinning did not exclusively involve the temporal lobe—it spreads, especially into the frontal regions in patients with more severe impairments. The findings suggest that the pathologic network in temporal lobe epilepsy is widespread beyond lobar boundaries. But we still don't know if the changes in the brain cause the cognitive problems or if the cognitive decline somehow reshapes the brain. These intricate findings present an exciting challenge for future research.
What Happens to Cognition After Surgery?
Cognitive functions drop faster in patients with temporal lobe epilepsy than in healthy individuals. 2 Epilepsy surgery increases the chance of seizure control and can improve cognition in those who become seizure-free and those who stop antiseizure medication. 3 Conversely, 30% to 50% of patients experience memory decline post-surgery. 4
The big question is: how do we predict who is at risk? Miron's team proposed a predictive model based on specific gray matter thinning patterns to predict memory decline one year after surgery. Adding clinical factors to the model improved its accuracy, though it still needs validation.
While advanced imaging technologies are valuable for developing predictive models for cognitive outcomes, most hospitals don't have the resources. Alternatively, there are accessible tools using clinical factors to estimate memory risk.5,6 Factors such as resection of the language-dominant hemisphere and intact preoperative memory reliably predict memory decline after temporal lobe resection.6,7 Furthermore, less invasive surgical techniques such as stereotactic laser amygdalohippocampectomy and responsive neurostimulators offer new hope for preserving cognitive functions when used in appropriate patients.8,9
Cognitive Therapy
So, what can we do to treat patients living with epilepsy and cognitive impairments? The truth is that we still struggle with the basics and need more well-designed research to help us understand effective strategies to help patients improve and compensate for their cognitive deficits. Neuropsychological test methods and intervention strategies vary widely, as do cognitive impairment classification systems. As a result, there is a lack of a harmonized way to diagnose cognitive disorders in epilepsy, hindering large-scale research collaborations and impactful advancement in this area.
In an empirical sense, some experts suggest starting with psychoeducation to help patients understand their conditions and optimization of mood and seizure control as the first steps of cognitive treatment for patients with epilepsy. 10 Programs such as Coping Openly and Personally with Epilepsy (COPE) focus on coping skills and empowering patients and caregivers, providing valuable support. 11 Finally, using predictive tools based on individual patient factors to predict cognitive trajectory can guide decision-making and personalize cognitive treatment strategies.
The Road Ahead
This study shows the link between temporal lobe epilepsy, cognitive phenotypes, and associated cortical thinning patterns. Using this information, the author also proposed a predictive tool for postoperative cognitive outcomes. The more we learn, the closer we get to improving care for patients with epilepsy and cognitive impairment. Recognition and understanding of the cognitive aspects of epilepsy form a crucial foundation for treatment. Accurate predictive tools to anticipate cognitive outcomes and personalize intervention strategies can yield significant benefits. Future research using a standardized framework of cognitive classification, assessment, and intervention is critical for the comprehensive and effective treatment of patients with epilepsy and cognitive impairment.
