Association of Normative and Non-Normative Brain Networks With Cognitive Function in Patients With Temporal Lobe Epilepsy.

BACKGROUND AND OBJECTIVES: Despite their temporal lobe pathology, a significant subgroup of patients with temporal lobe epilepsy (TLE) is able to maintain normative cognitive functioning. In this study, we identify patients with TLE with intact vs impaired neurocognitive profiles and interrogate for the presence of both normative and highly individual intrinsic connectivity networks (ICNs)-all toward understanding the transition from impaired to intact neurocognitive status. METHODS: This retrospective cross-sectional study included patients with TLE and matched healthy controls (HCs) from the Thomas Jefferson Comprehensive Epilepsy Center. Functional MRI data were decomposed using independent component analysis to obtain individualized ICNs. In this article, we calculated the degree of match between individualized ICNs and canonical ICNs (e.g., 17 resting-state networks by Yeo et al.) and divided each participant's ICNs into normative or non-normative status based on the degree of match. RESULTS: 100 patients with TLE (mean age 42.0 [SD: 13.7] years, 47 women) and 92 HCs were included in this study. We found that the individualized networks matched to the canonical networks less well in the cognitively impaired (n = 24) compared with the cognitively intact (n = 63) patients with TLE by 2-way mixed-measures analysis of variance (impaired vs intact mean difference [MD] -0.165 [-0.317, -0.013], p = 0.028). The cognitively impaired patients showed significant abnormalities in the profiles of both normative (impaired vs intact MD -0.537 [-0.998, -0.076], p = 0.017, intact vs HC MD -0.221 [-0.536, 0.924], p = 0.220, and impaired vs HC MD -0.759 [-1.200, -0.319], p < 0.001) and non-normative networks (impaired vs intact MD 0.484 [0.030, 0.937], p = 0.033, intact vs HC MD 0.369 [0.059, 0.678], p = 0.014, and impaired vs HC MD 0.853 [0.419, 1.286], p < 0.001) while the intact patients showed abnormalities only in non-normative networks. At the same time, we found that normative networks held a strong, positive association with the neuropsychological measures, with this association negative in non-normative networks. DISCUSSION: Our data demonstrated that significant cognitive deficits are associated with the status of both canonical and highly individual ICNs, making clear that the transition from intact to impaired cognitive status is not simply the result of disruption to normative brain networks.

Mechanical pain sensitivity is associated with hippocampal structural integrity.

ABSTRACT: Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage-ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity-the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.

Psychiatric comorbid disorders and impulsivity in patients with drug-resistant temporal and extra-temporal focal epilepsies.

PURPOSE: To analyze patients with drug-resistant focal epilepsy from temporal (TLE) and extra-temporal origin (ETE) and to compare the prevalence of psychiatric comorbid disorders and impulsivity between them and a control group. METHODS: Consecutively studied patients with TLE and ETE confirmed with Video-EEG were included. Standardized psychiatric assessment was conducted using the Structured Clinical Interview for Axis I and II diagnosis of DSM-IV (SCID I-II), the Barrat-11 scale for impulsivity, and Beck inventory for depression. Parametric and nonparametric tests were performed. RESULTS: Seventy-three patients with temporal lobe epilepsy (TLE), 21 extra-temporal epilepsy (ETE) and 58 healthy control subjects were included. Both groups of patients showed a high frequency of Axis I comorbid psychiatric disorders: Depression was the most frequent disorder followed by Anxiety Disorders. Furthermore, Axis II (Personality disorders) were also diagnosed, similarly in both groups of patients (p > 0.05). In addition, both TLE and ETE groups presented higher impulsivity scores compared with the control group (p < 0.01). ETE showed a tendency to a higher impulsivity in the motor factor (p = 0.05). Among patients with TLE, a left laterality of the epileptogenic zone, and the presence of comorbid psychiatric disorders (depression), were found as independent factors associated with higher impulsivity (p < 0.05). CONCLUSION: Comorbid depression associated with higher impulsivity are important issues to consider in behavioral and clinical evaluation of patients with drug-resistant focal epilepsies, with the aim to set up a prompt treatment.

Chinese Verbal Fluency Deficiency in Temporal Lobe Epilepsy with and without Hippocampal Sclerosis: A Multiscale Study.

To test a Chinese character version of the phonemic verbal fluency task in patients with temporal lobe epilepsy (TLE) and assess the verbal fluency deficiency pattern in TLE with and without hippocampal sclerosis, a cross-sectional study was conducted including 30 patients with TLE and hippocampal sclerosis (TLE-HS), 28 patients with TLE and without hippocampal sclerosis (TLE-NHS), and 29 demographically matched healthy controls (HC). Both sexes were enrolled. Participants finished a Chinese character verbal fluency (VFC) task during functional MRI. The activation/deactivation maps, functional connectivity, degree centrality, and community features of the left frontal and temporal regions were compared. A neural network classification model was applied to differentiate TLE-HS and TLE-NHS using functional statistics. The VFC scores were correlated with semantic fluency in HC while correlated with phonemic fluency in TLE-NHS. Activation and deactivation deficiency was observed in TLE-HS and TLE-NHS (p < 0.001, k ≥ 10). Functional connectivity, degree centrality, and community features of anterior inferior temporal gyri were impaired in TLE-HS and retained or even enhanced in TLE-NHS (p < 0.05, FDR-corrected). The functional connectivity was correlated with phonemic fluency (p < 0.05, FDR-corrected). The neural network classification reached an area under the curve of 0.90 in diagnosing hippocampal sclerosis. The VFC task is a Chinese phonemic verbal fluency task suitable for clinical application in TLE. During the VFC task, functional connectivity of phonemic circuits was impaired in TLE-HS and was enhanced in TLE-NHS, representing a compensative phonemic searching strategy applied by patients with TLE-NHS.

Slow wave sleep is associated with forgetting in patients with temporal lobe epilepsy.

While time spent in slow wave sleep (SWS) after learning promotes memory consolidation in the healthy brain, it is unclear if the same benefit is obtained in patients with temporal lobe epilepsy (TLE). Interictal epileptiform discharges (IEDs) are potentiated during SWS and thus may disrupt memory consolidation processes thought to depend on hippocampal-neocortical interactions. Here, we explored the relationship between SWS, IEDs, and overnight forgetting in patients with TLE. Nineteen patients with TLE studied object-scene pairs and memory was tested across a day of wakefulness (6 hrs) and across a night of sleep (16 hrs) while undergoing continuous scalp EEG monitoring. We found that time spent in SWS after learning was related to greater forgetting overnight. Longer duration in SWS and number of IEDs were each associated with greater forgetting, although the number of IEDs did not mediate the relationship between SWS and memory. Further research, particularly with intracranial recordings, is required to identify the mechanisms by which SWS and IEDs can be pathological to sleep-dependent memory consolidation in patients with TLE.

[Memory impairments in temporal lobe epilepsy].

Temporal lobe epilepsy is known to present with various cognitive impairments, among which memory deficits are frequently reported by patients. Memory deficits can be classified into two types: classical hippocampal amnesia, which is characterized by abnormalities detected in neuropsychological assessments, and atypical memory deficits, such as accelerated long-term amnesia and autobiographical memory impairment, which cannot be identified using standard testing methods. These deficits are believed to arise from a complex interplay among structural brain abnormalities, interictal epileptic discharges, pharmacological factors, and psychological states. While fundamental treatments are limited, there are opportunities for interventions such as environmental adjustments and rehabilitation. This review article aims to provide a comprehensive overview of the types, underlying pathophysiology, and intervention methods for memory disorders observed in patients with temporal lobe epilepsy.

Features of attention network impairment in patients with temporal lobe epilepsy: Evidence from eye-tracking and electroencephalogram.

AIM: To explore multiple features of attention impairments in patients with temporal lobe epilepsy (TLE). METHODS: A total of 93 patients diagnosed with TLE at Xiangya Hospital during May 2022 and December 2022 and 85 healthy controls were included in this study. Participants were asked to complete neuropsychological scales and attention network test (ANT) with recording of eye-tracking and electroencephalogram. RESULTS: All means of evaluation showed impaired attention functions in TLE patients. ANT results showed impaired orienting (p < 0.001) and executive control (p = 0.041) networks. Longer mean first saccade time (p = 0.046) and more total saccadic counts (p = 0.035) were found in eye-tracking results, indicating abnormal alerting and orienting networks. Both alerting, orienting and executive control networks were abnormal, manifesting as decreased amplitudes (N1 & P3, p < 0.001) and extended latency (P3, p = 0.002). The energy of theta, alpha and beta were all sensitive to the changes of alerting and executive control network with time, but only beta power was sensitive to the changes of orienting network. CONCLUSION: Our findings are helpful for early identification of patients with TLE combined with attention impairments, which have strong clinical guiding significance for long-term monitoring and intervention.

Connectome-based prediction of cognitive performance in patients with temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) patients often exhibit varying degrees of cognitive impairments. This study aims to predict cognitive performance in TLE patients by applying a connectome-based predictive model (CPM) to whole-brain resting-state functional connectivity (RSFC) data. METHODS: A CPM was established and leave-one-out cross-validation was employed to decode the cognitive performance of patients with TLE based on the whole-brain RSFC. RESULTS: Our findings indicate that cognitive performance in TLE can be predicted through the internal and network connections of the parietal lobe, limbic lobe, and cerebellum systems. These systems play crucial roles in cognitive control, emotion processing, and social perception and communication, respectively. In the subgroup analysis, CPM successfully predicted TLE patients with and without focal to bilateral tonic-clonic seizures (FBCTS). Additionally, significant differences were noted between the two TLE patient groups and the normal control group. CONCLUSION: This data-driven approach provides evidence for the potential of predicting brain features based on the inherent resting-state brain network organization. Our study offers an initial step towards an individualized prediction of cognitive performance in TLE patients, which may be beneficial for diagnosis, prognosis, and treatment planning.

Association of synaptic density and cognitive performance in temporal lobe epilepsy: Humans and animals PET imaging study with [18F]SynVesT-1.

AIM: Cognitive impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE), yet the underlying mechanisms remain unknown. This study explored the putative association between in vivo synaptic loss and cognitive outcomes in TLE patients by PET imaging of synaptic vesicle glycoprotein 2A (SV2A). METHODS: We enrolled 16 TLE patients and 10 cognitively normal controls. All participants underwent SV2A PET imaging using [18F]SynVesT-1 and cognitive assessment. Lithium chloride-pilocarpine-induced rats with status epilepticus (n = 20) and controls (n = 6) rats received levetiracetam (LEV, specifically binds to SV2A), valproic acid (VPA), or saline for 14 days. Then, synaptic density was quantified by [18F]SynVesT-1 micro-PET/CT. The novel object recognition and Morris water maze tests evaluated TLE-related cognitive function. SV2A expression was examined and confirmed by immunohistochemistry. RESULTS: Temporal lobe epilepsy patients showed significantly reduced synaptic density in hippocampus, which was associated with cognitive performance. In the rat model of TLE, the expression of SV2A and synaptic density decreased consistently in a wider range of brain regions, including the entorhinal cortex, insula, hippocampus, amygdala, thalamus, and cortex. We treated TLE animal models with LEV or VPA to explore whether synaptic loss contributes to cognitive deficits. It was found that LEV significantly exerted protective effects against brain synaptic deficits and cognitive impairment. CONCLUSION: This is the first study to link synaptic loss to cognitive deficits in TLE, suggesting [18F]SynVesT-1 PET could be a promising biomarker for monitoring synaptic loss and cognitive dysfunction. LEV might help reverse synaptic deficits and ameliorate learning and memory impairments in TLE patients.

Neurocognition in Pediatric Temporal Lobe Tumor-Related Epilepsy.

Tumor-related epilepsy is a common and understudied neurological comorbidity among pediatric temporal lobe tumor patients that poses risk for neurocognitive impairment (NCI). Forty-one youth with either TLT+ (n = 23) or nonneoplastic temporal lobe epilepsy (n = 18) ages 6-20 years completed routine neuropsychological evaluations. Rates of NCI were similar across groups; however, NCI was more common in nonneoplastic participants on a task of phonemic fluency, p = .047. Younger age of seizure onset and greater number of antiseizure medications were associated with NCI among TLT+ participants only. Preliminary findings suggest separate prognostic models of cognitive outcomes between TLT+ and nonneoplastic epilepsy populations may be needed.

Bilateral glymphatic dysfunction and its association with disease duration in unilateral temporal lobe epilepsy patients with hippocampal sclerosis.

OBJECTIVE: In this study, the diffusion tensor imaging along perivascular space analysis (DTI-ALPS) technique was utilized to evaluate the functional changes in the glymphatic system of the bilateral hemispheres in patients with unilateral temporal lobe epilepsy (TLE) accompanied by hippocampal sclerosis (HS). The aim was to gain insights into the alterations in the glymphatic system function in TLE patients. METHODS: A total of 61 unilateral TLE patients with HS and 53 healthy controls (HCs) from the Department of Neurosurgery at Xiangya Hospital were included in the study. All subjects underwent DTI using the same 3 T MR Scanner, and the DTI-ALPS index was calculated. Differences in the DTI-ALPS index between TLE patients and HCs were evaluated, along with the correlation between the DTI-ALPS index of TLE and clinical features of epilepsy. These features included age, age of onset, seizure duration, and neuropsychological scores. RESULTS: Compared to the bilateral means of the HCs, both the ipsilateral and contralateral DTI-ALPS index of the TLE patients were significantly decreased (TLE ipsilateral 1.41 ± 0.172 vs. HC bilateral mean: 1.49 ± 0.116, p = 0.006; TLE contralateral: 1.42 ± 0.158 vs. HC bilateral mean: 1.49 ± 0.116, p = 0.015). The ipsilateral DTI-ALPS index in TLE patients showed a significant negative correlation with disease duration (r = -0.352, p = 0.005). CONCLUSIONS: The present study suggests the presence of bilateral dysfunctions in the glymphatic system and also highlight a laterality feature in these dysfunctions. Additionally, the study found a significant negative correlation between the ipsilateral DTI-ALPS index and disease duration, underscoring the significance of early effective interventions and indicating potential for the development of innovative treatments targeting the glymphatic system.

Differential relational memory impairment in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is typically associated with pathology of the hippocampus, a key structure involved in relational memory, including episodic, semantic, and spatial memory processes. While it is widely accepted that TLE-associated hippocampal alterations underlie memory deficits, it remains unclear whether impairments relate to a specific cognitive domain or multiple ones. METHODS: We administered a recently validated task paradigm to evaluate episodic, semantic, and spatial memory in 24 pharmacoresistant TLE patients and 50 age- and sex-matched healthy controls. We carried out two-way analyses of variance to identify memory deficits in individuals with TLE relative to controls across different relational memory domains, and used partial least squares correlation to identify factors contributing to variations in relational memory performance across both cohorts. RESULTS: Compared to controls, TLE patients showed marked impairments in episodic and spatial memory, with mixed findings in semantic memory. Even when additionally controlling for age, sex, and overall cognitive function, between-group differences persisted along episodic and spatial domains. Moreover, age, diagnostic group, and hippocampal volume were all associated with relational memory behavioral phenotypes. SIGNIFICANCE: Our behavioral findings show graded deficits across relational memory domains in people with TLE, which provides further insights into the complex pattern of cognitive impairment in the condition.

Evaluating the prevalence and risk factors for depression in patients with temporal lobe epilepsy with hippocampal sclerosis: A cross-sectional multicenter study.

BACKGROUND: Epilepsy frequently accompanies Major Depressive Disorder (MDD). Notably, people with temporal lobe epilepsy and hippocampal sclerosis may face an increased susceptibility to MDD, as evidence indicates the involvement of the limbic system in the development of emotional symptoms. OBJECTIVES: To determine the prevalence and predictors of depression in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and compare them to those of other epilepsy types. METHODS: A sample of 293 epilepsy patients, including 159 non-TLE-HS and 134 TLE-HS, were recruited from three hospitals. Of these, 215 completed a two-section electronic survey. The first section collected demographic and epilepsy data, while the second used the Arabic version of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). RESULTS: Of 215 patients, 104 (48%) had TLE-HS-38 with right TLE-HS (37%), 56 with left TLE-HS (54%), and 10 with bilateral TLE-HS (10%). The prevalence and severity of depression was assessed with an NDDI-E score of 15 or higher identified 35 patients (16%) with MDD. Valproic acid and lamotrigine were associated with higher NDDI-E scores. No such associations were found for levetiracetam or carbamazepine. Polytherapy in TLE-HS showed a significant correlation with daily poor concentration. CONCLUSION: We explored the differences in depression prevalence between TLE-HS and other epilepsy types and concluded they are minimal but slightly higher in TLE-HS. Predictors of depression such as seizure frequency and disease duration influenced MDD prevalence in TLE-HS. Lamotrigine and valproate were linked to higher NDDI-E scores.

Postsurgical Outcomes of Mesial Temporal Lobe Epilepsy due to Hippocampal Sclerosis Associated with Calcified Neurocysticercosis.

The aim of this study was to analyze postsurgical outcomes for individuals with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who underwent anterior temporal lobectomy, based on the presence of calcified neurocysticercosis (cNCC). A retrospective cross-sectional study was conducted on 89 patients with MTLE-HS who underwent anterior temporal lobectomy between January 2012 and December 2020 at a basic epilepsy surgery center located in Lima, Peru. We collected sociodemographic, clinical, and diagnostic information. The postsurgical results were analyzed using bivariate analysis according to the Engel classification. We included 89 individuals with a median age of 28 years (interquartile range [IQR]: 24-37), and more than half (55.1%) were male. Seventeen (19.1%) were diagnosed with cNCC. A greater number of patients with cNCC had lived in rural areas of Peru during their early life compared with those without cNCC (12 [70.6%] versus 26 [36.1%]; P = 0.010). Patients with cNCC exhibited a greater median frequency of focal to bilateral tonic-clonic seizures per month (1 [IQR: 0-2] versus 0 [0-0.5]; P = 0.009). Conversely, a lower proportion of patients with cNCC reported a history of an initial precipitating injury in comparison to the group without cNCC (4 [23.5%] versus 42 [58.3%]; P = 0.014). At the 1-year follow-up, most patients (82.4%) with cNCC were categorized as Engel IA. Similarly, at the 2-year follow-up, nine (75.0%) were classified as Engel IA. Our findings suggest that most patients diagnosed with cNCC exhibit favorable postsurgical outcomes, comparable to those without cNCC. Additionally, it can be postulated that cNCC may play a role as an initial precipitating injury.

Lettre to editor: Case report of an ictal asystole as debut in new onset epilepsy.

The case report describes a 65-year-old man with arterial hypertension and a metallic aortic valve who presented to the emergency room for a loss of consciousness event and memory impairment. The electroencephalographic recording showed right temporal epileptiform activity followed by a 9 s asystole with quick consciousness recovery. The patient was diagnosed with right temporal epilepsy with asystole and was prescribed levetiracetam to prevent new events. A pacemaker was indicated in the follow-up for the long duration of the asystole, preventing major morbidity. Ictal asystole (IA) is a rare phenomenon of epilepsy that leads to syncope. It is observed in focal epilepsy, especially in left temporal epilepsy. Underlying cardiac pathology may facilitate IA, especially when the onset of the epilepsy is new. Knowledge of focal temporal semiology is key, concerning our case report, the memory impairment points to temporal pathology, and ictal vomiting in the non-dominant hemisphere. Anti-seizures drugs must be initiated in all patients, and there is a recommendation to avoid those with negative inotropic and arrhythmogenic effects (such as phenytoin, carbamazepine, and lacosamide). There is a discussion about pacemaker indication, however, it is highly recommended in non-controlled epilepsy and in ictal asystoles that last for more than 6 s to reduce morbidity.

Clinical utility and safety of a trapezoid-shaped electrode placement for evaluating the mesio-basal temporal lobe during epilepsy surgery.

A trapezoid-shaped electrode (TSE) is used for detecting epileptogenicity in patients with temporal lobe epilepsy (TLE). However, the utility and safety associated with TSE placement have not been reported. In this study, we evaluated the safety and usefulness of TSE by analyzing the seizure detection, surgical outcomes and complications in patients with TLE who underwent intracranial electrodes (ICE) placement. Between April 2000 and August 2019, 50 patients with TLE who underwent 51 ICE placement procedures were examined. A TSE with eight contacts covering the parahippocampal gyrus and basal temporal lobe was used. Among the 37 patients who underwent TSE placement, 26 and 11 patients were diagnosed with mesial TLE (mTLE) and extra-mTLE, respectively. The 14 remaining patients without TSE placement were diagnosed with extra-mTLE. Seizure freedom was achieved in 73% (19/26) of mTLE patients detected by TSE and 50% (14/24) of extra-mTLE patients.Good seizure outcomes (Engel class I and II) were observed in 81% (21/26) patients with mTLE and 67% (16/24) patients with extra-mTLE. Radiographic complications were observed in 20% (10/50) patients who underwent ICE placement. Although 6% (3/50) patients showed transient neurological deficits, none were permanent. The electrodes responsible for the occurrence of complications included nine grid electrodes and one TSE. The complication rate after TSE placement was 3% (1/37). More than 64 electrode contacts and male sex, not TSE placement, were identified as significant risk factors for developing complications. This study demonstrated the usefulness and safety of TSE for evaluating mTLE in patients undergoing ICE placement.

[Surgical treatment of focal drug-resistant epilepsy associated with temporal lobe encephalocele]. / Khirurgicheskoe lechenie patsientov so strukturnoi fokal'noi farmakorezistentnoi epilepsiei, assotsiirovannoi s visochnymi entsefalotsele.

BACKGROUND: In recent years, temporal lobe encephalocele has become more common in patients with focal drug-resistant epilepsy. Despite available experience, there are still no clear recommendations for choosing the extent of surgery in these patients. OBJECTIVE: To evaluate the effectiveness of diagnosis and surgical treatment of focal drug-resistant epilepsy associated with temporal lobe encephalocele. MATERIAL AND METHODS: The study included 21 patients with focal temporal lobe epilepsy and temporal lobe encephalocele. All patients underwent continuous video-EEG monitoring and MRI of the brain. There were 12 (57.4%) selective encephalocele resections and 9 (42.6%) anterior temporal lobectomies. The median follow-up period was 31 months. RESULTS: The overall effectiveness of surgical treatment with postoperative Engel class I was 76% (16 cases). Selective encephalocele resection was followed by postoperative Engel class I in 10 patients (83%). There were 6 (67%) patients with similar outcomes after temporal lobectomy. Mean volume of resected tissue adjacent to encephalocele was 8.3 cm3. CONCLUSION: Surgery is a highly effective treatment for patients with epileptic seizures following temporal lobe encephalocele. In our sample, favorable postoperative outcomes were achieved in 76% of patients (Engel class I). There were no significant differences in effectiveness between selective resection and temporal lobectomy. Further research is necessary for a clear protocol of surgical treatment of focal drug-resistant epilepsy associated with encephalocele.