‘Hippocampal innate inflammatory gliosis only’ in pharmacoresistant temporal lobe epilepsy

Abstract

Drug-resistant mesial temporal lobe epilepsy is a devastating disease with seizure onset in the hippocampal formation. A fraction of hippocampi samples from epilepsy-surgical procedures reveals a peculiar histological pattern referred to as ‘gliosis only’ with unresolved pathogenesis and enigmatic sequelae. Here, we hypothesize that ‘gliosis only’ represents a particular syndrome defined by distinct clinical and molecular characteristics. We curated an in-depth multiparameter integration of systematic clinical, neuropsychological as well as neuropathological analysis from a consecutive cohort of 627 patients, who underwent hippocampectomy for drug-resistant temporal lobe epilepsy. All patients underwent either classic anterior temporal lobectomy or selective amygdalohippocampectomy. Based on their neuropathological exam patients with hippocampus sclerosis and ‘gliosis only’ were characterized and compared within the whole-cohort and within a subset of matched-pairs. Integrated transcriptional analysis was performed to address molecular differences between both groups. ‘Gliosis only’ revealed demographics, clinical and neuropsychological outcome fundamentally different from HS. ‘Gliosis only’ patients have a significantly later seizure onset (16.3 yr. vs. 12.2 yr., p = 0.005) and worse neuropsychological outcome after surgery compared to patients with HS. Epilepsy was less amendable by surgery in ‘gliosis only’ patients resulting in a significantly worse rate of seizure freedom after surgery in this subgroup (43% vs 68%, p = 0.0001, OR = 2.8, CI 1.7-4.7). This finding remained significant after multivariate and matched pairs analysis. The ‘gliosis only’ group demonstrated pronounced astrogliosis and lack of significant neuronal degeneration in contrast to characteristic segmental neuron loss and fibrillary astrogliosis in HS. RNA sequencing of ‘gliosis only’ patients deciphered a distinct transcriptional program that resembles an innate inflammatory response of reactive astrocytes. Our data indicates a new temporal lobe epilepsy syndrome for which we suggest the term ‘Innate inflammatory gliosis only’ (I2GO). Innate inflammatory ‘gliosis only’ is characterized by a diffuse gliosis pattern lacking restricted hippocampal focality and is poorly controllable by surgery. Thus, innate inflammatory ‘gliosis only’ patients need to be clearly identified by presurgical examination paradigms of pharmacoresistant temporal lobe epilepsy patients, surgical treatment of this subgroup should be considered with great precaution. Innate inflammatory ‘gliosis only’ requires innovative pharmacotreatment strategies.

Postoperative seizure and memory outcome of temporal lobe epilepsy with hippocampal sclerosis: A systematic review

“…After full text screening, 15 cohort studies with 2485 patients were included in the meta-analysis of seizure outcomes. [14][15][16]18,20,[41][42][43][44][45][46][47][48][49][50] Seven articles including six cohorts with detailed information of postoperative memory outcome were included. 14,[17][18][19][20]50,51 Eight studies were conducted from four datasets , 16,18,19,44,46,[51][52][53] and only the larger cohort study reporting seizure outcomes was included.…”

“…Inconsistent postoperative seizure and cognitive outcomes among different subtypes were reported. [14][15][16][17][18][19][20] Therefore, we performed a systematic review and meta-analysis to consider the total body of evidence and comprehensively assess postoperative seizure and memory outcome in different HS subtypes.…”

Global trends in research of glutamate in epilepsy during past two decades: A bibliometric analysis

“…Finally, six possible research directions were identified as follows ( Figure 8A ): “mechanism of excitotoxicity induced by glutamate and neuroprotection by glutamate transporters,” “the modulating mechanism of synaptic transmission by glutamate receptors,” “AEDs,” “animal models study of epileptogenesis in TLE,” “autoimmune diseases associated with seizures and epilepsy,” and “ in vivo studies.” The common keywords with the most occurrences were “epilepsy,” “glutamate,” “TLE,” “hippocampus,” and “seizures.” TLE is one of the most common types of DRE ( Engel et al, 2012 ). The sclerotic hippocampus is key in generating and maintaining temporal lobe seizures ( Grote et al, 2022 ). The hippocampus is an important region for studying the pathological mechanisms of epilepsy.…”

“…TLE is one of the most common types of DRE (Engel et al, 2012). The sclerotic hippocampus is key in generating and maintaining temporal lobe seizures (Grote et al, 2022). The hippocampus is an important region for studying the pathological mechanisms of epilepsy.…”

Neuropathological Insights into Unexpected Cognitive Decline in Epilepsy

“…Thus, these alterations represent disease modifiers with respect to network function rather than primary epileptogenic alterations. In contrast, LE-like and "gliosis only" alterations may constitute seizure foci and harm neuronal network function, 54,55 manifesting as poor neuropsychological performance.…”