I read with profound interest the insightful report by Smith et al. detailing the diagnostic challenges in the neuropsychology of epilepsy.1 I sincerely congratulate the authors for their masterful delineation of the constellation of non-seizure-related factors, ranging from neurodevelopmental trajectories to psychosocial disparities, that shape the neurocognitive presentation of patients. As a clinical neuropsychologist, I deeply appreciate this multifactorial conceptualization, which captures the clinical realities I face daily when interpreting complex test data and setting expectations for patient care. Building humbly upon this robust framework, I look toward emerging basic science literature to better understand the limits of cognitive recovery I frequently observe. While I do not investigate molecular pathways in my clinical practice, I am captivated by recent translational research concerning behavioral epigenetics. Basic science models increasingly suggest that chronic epileptogenesis and prolonged chronological delay before surgical intervention (surgical latency) may induce pathological epigenetic alterations.2 Specifically, chronic excitotoxic stress may lead to aberrant DNA methylation at the promoter regions of critical neuroplasticity genes, such as the brain-derived neurotrophic factor (BDNF).3 Some researchers in molecular neuroscience have begun describing such persistent, stress-induced chromatin remodeling as an “epigenetic lock” that suppresses the transcriptional machinery necessary for synaptic repair.4 Reading this literature, I wonder if this “epigenetic lock” concept could offer basic scientists a complementary molecular explanation for a pervasive clinical paradox I observe: why certain patients, despite achieving complete seizure freedom (Engel Class I) following a successful neurosurgical resection, fail to demonstrate the anticipated trajectory of cognitive recovery.5 If the surviving, structurally intact cortical networks remain transcriptionally paralyzed by a hypermethylated state,2 it might explain why fixing the anatomical “hardware” through excellent surgical technique does not necessarily reboot the epigenetic “software” required to regain lost cognitive ground. As a neuropsychologist, I cannot test molecular hypotheses, but I believe my discipline can provide the rigorous phenotypic data that translational researchers need to explore them. To capture the clinical footprint of this potential molecular burden,6, 7 I advocate for the systematic, longitudinal application of standardized taxonomies, specifically the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) elegantly described by Hermann et al.8 By mapping patients' cognitive phenotypes at regular intervals post-surgery, I can help look beyond localized, test-specific variance. If translational researchers wish to investigate the correlation between surgical latency, accumulated epigenetic load,6 and cognitive outcomes, longitudinal IC-CoDE phenotyping could potentially serve as a robust, non-invasive clinical anchor for their molecular studies. I offer this perspective as a collaborative reflection, hoping it might encourage multidisciplinary partnerships that bridge our neuropsychological observations with the molecular realities of the post-surgical brain. The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Cristian Blanco‐Inostroza (Mon,) studied this question.