Machine Learning Approaches for Imaging-Based Prognostication of the Outcome of Surgery for Mesial Temporal Lobe Epilepsy

Article found in Wiley Online Library

Summary

Objectives: Around 30% of patients undergoing surgical resection for drug-resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG-PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques (logistic regression, support vector machines, random forests and artificial neural networks) applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice.

Results: In the study cohort, 24/82 (28.3%) who underwent an ATLR for drug resistant MTLE did not achieve an Engel Class I (i.e. free of disabling seizures) outcome at a minimum of 2 years post-operative follow-up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70-80% and area under curve (AUC) of receiver operating characteristic of 0.75-0.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to 0.59-0.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance.

Significance: Collectively, these results indicate that ‘acceptable’ to ‘good’ patient specific prognostication for drug resistant mesial temporal lobe epilepsy surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.

Neuroregenerative Gene Therapy Treats Temporal Lobe Epilepsy in Rat Model

Article, news provided by NeuExcell Therapeutics

A research team led by Professor Gong Chen of Jinan University, also the scientific founder of NeuExcell Therapeutics Group, published an article in the latest issue of Progress in Neurobiology, using neuroregenerative gene therapy to treat temporal lobe epilepsy (TLE) in rats. Chen’s team developed a new technology to convert hippocampal astrocytes directly into inhibitory interneurons and effectively reduced epileptic seizures, raising new hope for patients suffering from refractory TLE.

In recent years, Chen’s team has developed a novel neuroregenerative gene therapy that offers a potential new approach to treat a variety of neurological disorders. Neuroregenerative gene therapy is a new technology that uses viral vectors to deliver neural transcription factors to glial cells in the brain and directly convert glial cells into functional neurons in situ. Based on this innovation, Chen’s team has published a series of research articles demonstrating effective brain repair in both ischemic stroke and Huntington’s disease animal models.

“In this work, we used adeno-associated virus (AAV) as the gene delivery vector to overexpress a neural transcription factor NeuroD1 specifically in hippocampal astrocytes of TLE rats. NeuroD1 significantly downregulates glial gene expression but upregulates neuronal gene expression, and ultimately converts astrocytes into neurons”, said Dr. Jiajun Zheng, the first author of this work, explaining the principle of this work.

“Our electrophysiological and behavioral analyses demonstrated that the neuroregenerative gene therapy not only inhibited spontaneous recurrent seizures but also rescued the cognitive impairment and mood abnormalities of the epileptic animals. Different from traditional anti-epileptic drugs or surgery treatment, neuroregenerative gene therapy directly regenerates new neurons in the epileptic region to restore the balance between excitation and inhibition in neural networks. This novel technology may lead to a new path toward an effective treatment of drug-resistant epilepsy”, the co-corresponding author Jiandong Yu gave an additional note.

Glucocorticoid Modulation of Synaptic Plasticity in the Human Temporal Cortex of Epilepsy Patients: Does Chronic Stress Contribute to memory Impairment?

Abstract originally published in Epilepsia

Objective: Memory impairment is common in patients with temporal lobe epilepsy and seriously affects life quality. Chronic stress is a recognized cofactor in epilepsy and can also impair memory function. Furthermore, increased cortisol levels have been reported in epilepsy patients. Animal models have suggested that aggravating effects of stress on memory and synaptic plasticity were mediated via glucocorticoids. The aim of this study was, therefore, to investigate the effect of glucocorticoid receptor (GR) modulation on synaptic plasticity in the human cortex of epilepsy patients.

Methods: We performed field potential recordings in acute slices from the temporal neocortex of patients who underwent surgery for drug-resistant temporal lobe epilepsy. Synaptic plasticity was investigated by a theta-burst stimulation (TBS) protocol for induction of long-term potentiation (LTP) in the presence of GR modulators.

Results: LTP was impaired in temporal cortex from epilepsy patients. Pretreatment of the slices with the GR antagonist mifepristone (RU486) improved LTP induction, suggesting that LTP impairment was due to baseline GR activation in the human cortex. The highly potent GR agonist dexamethasone additionally weakened synaptic strength in an activity-dependent manner when applied after TBS.

Significance: Our results show a direct negative glucocorticoid effect on synaptic potentiation in the human cortex and imply chronic activation of glucocorticoid receptors. Chronic stress may therefore contribute to memory impairment in patients with temporal lobe epilepsy. Furthermore, the activity-dependent acute inhibitory effect of dexamethasone suggests a mechanism of synaptic downscaling by which postictally increased cortisol levels may prevent pathologic plasticity upon seizures.

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Epilepsy Surgery May Improve Overall Brain Health in Some Patients

Article, originally published in Neurology

Epilepsy surgery may be associated with improvements to overall brain health, a study led by University of Liverpool researchers has found.

The study, published in Neurology, the medical journal of the American Academy of Neurology, used advanced magnetic resonance imaging (MRI) techniques to inform its findings.

Corresponding author Dr. Christophe de Bezenac said: “Many clinicians remain hesitant in referring patients with refractory temporal lobe epilepsy (TLE) for surgery despite the known safety and efficacy. Here we provide imaging evidence to suggest that it may improve overall brain health.”

To determine whether surgery in patients with mesial temporal lobe epilepsy (mTLE) is associated with reduced brain-predicted age as a neural marker overall brain health, the researchers compared brain-predicted and chronological age difference in patients before and after surgery to healthy controls.

Christophe de Bezenac said: “MRI analysis of brain-predicted and chronological age difference (BrainAGE) is thought to provide a surrogate marker of overall brain health. We have shown that BrainAGE is greater in patients with refractory TLE by at least seven years compared to healthy controls and that this difference is reduced after epilepsy surgery. Our findings are in line with other work suggesting that earlier surgery may benefit patients with refractory TLE.”

Christophe de Bezenac said: “MRI analysis of brain-predicted and chronological age difference (BrainAGE) is thought to provide a surrogate marker of overall brain health. We have shown that BrainAGE is greater in patients with refractory TLE by at least seven years compared to healthy controls and that this difference is reduced after epilepsy surgery. Our findings are in line with other work suggesting that earlier surgery may benefit patients with refractory TLE.”

Seizure and social Outcomes in Patients with Non-Surgically Treated Temporal Lobe Epilepsy

Abstract published in PubMed.gov 

Objectives: To investigate the seizure outcome with medical treatment in patients with temporal lobe epilepsy (TLE) and its associated factors. We also investigated the social outcome of the patients.

Methods: This was a retrospective study of a prospectively built electronic database of patients with epilepsy. All patients with a diagnosis of TLE were studied at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2019. In a phone call to the patients, at least 24 months after their diagnosis at our center, we investigated their current seizure control and social status.

Results: Two hundred and twenty-two patients were studied; 101 patients (45.5%) were seizure-free. A lower number of the prescribed drugs was the only factor with a significant association with the seizure-free outcome (Odds Ratio: 1.460; p = 0.001). At the time of the phone call, 76 patients (37.6%) reported having a college education, 103 patients (51%) were employed, 146 patients (72.3%) were married, and 81 patients (40%) reported driving a motor vehicle. The employment status, college education, and driving a motor vehicle were significantly associated with a seizure-free outcome status. The social achievements of the patients, who were partially responsive to medical therapy, were significantly worse than those who were seizure-free.

Conclusion: Many patients with temporal lobe epilepsy may suffer from drug-resistant seizures. Ongoing seizures in these patients may affect their social lives substantially. Seizure reduction (not freedom) is not good enough to help the patients with TLE enjoy a healthy life with satisfactory social achievements.

Understanding Long-Term Changes in Patient Identity 15–20 Years After Surgery for Temporal Lobe Epilepsy

Abstract, originally published in Epilepsia

Objective: Following epilepsy surgery, patients can experience complex psychosocial changes. We recently described a longer-term adjustment and reframing (“meaning-making”) process 15–20 years following surgery for temporal lobe epilepsy, which could involve an ongoing sense of being a “different” person for some patients. Here, we quantitatively examine identity at long-term follow-up and how this relates to meaning-making and postoperative seizure outcome.

Methods: Eighty-seven participants were included: 39 who underwent anterior temporal lobectomy (ATL) 15–20 years ago (59% female; median age = 49.2 years, interquartile range [IQR] = 10; median follow-up = 18.4 years, IQR = 4.4) and 48 surgically naïve focal epilepsy patients (56% female; median age = 34.5 years, IQR = 19). We captured the approach to meaning-making by coding for key narrative features identified in our previous qualitative work. Nonparametric tests and correspondence analysis were then used to explore relationships between a quantitative measure of identity and meaning-making, as well as seizure outcome, mood, and health-related quality of life (HRQOL).

Results: Patients 15–20 years post-ATL demonstrated a shift toward increasing identity commitment and exploration compared to the surgically naïve cohort, with this shift significantly linked to seizure outcome. Examining the relationship between identity and meaning-making also revealed three groups: (1) those who embraced self-change (29%), (2) those who continued to struggle with this process (60.5%), and (3) those who showed minimal engagement (10.5%). Those who “embraced change” were significantly younger at regular seizure onset and demonstrated a trend toward higher HRQOL.

Significance: Findings suggest that anterior temporal lobectomy patients show a more developed identity profile compared to surgically naïve controls; however, the majority still struggled with postoperative identity change at long-term follow-up. Approximately one-third of patients demonstrated positive psychological growth following surgery, reflected in the ability to embrace change. Findings highlight the importance of understanding the impact of surgery on patient identity to maximize the psychosocial benefits.

Anxiety Symptoms Are the Strongest Predictor of Quality of Life in Temporal Lobe Epilepsy

Abstract, originally published in Seizure

Purpose: It is established that the severity of depressive and anxiety symptoms is associated with poorer quality of life (QOL) in persons with drug-resistant epilepsy. We aimed to verify the presence of subsyndromic depressive episodes (SDEs) and subsyndromic anxiety episodes (SAEs) in persons with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) compared to healthy controls and to determine the impact of depressive and anxiety symptoms on patients’ QOL.

Methods: We prospectively evaluated 35 persons with TLE-HS and 90 healthy controls. QOL was assessed by the Epilepsy Surgery Inventory (ESI) and QOL in Epilepsy Inventory-31 (QOLIE-31). The Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-X) were used to assess symptoms, and SDEs and SAEs diagnosis were made considering the total scores of BDI (<9) and STAI-Trait (<49), respectively.

Results: Persons with TLE-HS had higher symptoms on BDI, STAI-S, and STAI-T. They have 3.011 greater odds of presenting SDEs and 7.056 times odds, SAEs. The depressive and anxiety symptoms, added in the model with epilepsy-related factors, accounted for a significant increase in the variance in several aspects of QOL. Anxiety-trait symptoms are the most critical individual determinant of the QOL.

Conclusion: Our results demonstrated that persons with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) had greater odds of presenting subsyndromic depressive episodes and subsyndromic anxiety episodes than healthy controls. Besides, there was a relationship between anxiety and depressive symptoms and worse quality of life in TLE-HS. It is essential to be aware of psychiatric symptoms, even though these symptoms do not meet the criteria to be considered a “disorder.”

Cognitive and Behavioral Profiles of Pediatric Surgical Candidates With Frontal and Temporal Lobe Epilepsy

Abstract, originally published in Epilepsy & Behavior

Background: We aimed to prospectively analyze memory and executive and social cognitive functioning in patients with drug-resistant frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE) with focal lesions and isolate the impact of intellectual ability on specific deficits.

Methods: A neuropsychological evaluation was performed in 23 children with FLE, 22 children with TLE, and 36 healthy pediatric controls (HCs). Patients in the epilepsy groups had a range of lesions, including low-grade epilepsy-associated tumors (LEAT), focal cortical dysplasia (FCD) type II, and mesial temporal sclerosis (MS).

Results: There were no significant differences between children with FLE and TLE regarding memory, executive, or social cognitive functioning. General Ability Index (GAI) was a predictor of memory, executive function, and social cognition scores and was influenced by age at onset, duration of epilepsy, and number of antiepileptic drugs (AEDs) prescribed at the time of assessment. Working Memory Index scores of patients with TLE, which measure verbal mnesic processing, were significantly lower than those of HCs and patients with TLE. The greatest differences in both clinical groups compared to HCs were recorded in cognitive executive functions, and patients with FLE had lower scores in this domain. Regarding behavioral executive functions, patients with TLE presented impaired emotional control and impulse inhibition and patients with FLE exhibited decreased flexibility.

Conclusion: Consistent with previous research, our findings provide further detailed evidence of small differences in cognitive performance among children with frontal lobe epilepsy and temporal lobe epilepsy. These differences emerge on analysis of the factors with which deficits are associated.

Deep Brain Stimulation Prevents Epileptic Seizures in Mouse Model

Summary, originally published in EurekAlert!

Scientists led by neurobiologist Prof. Dr. Carola Haas, head of the research group at the Department of Neurosurgery at Medical Center – University of Freiburg and the BrainLinks-BrainTools research center, have investigated a new therapeutic approach to prevent epileptic seizures in temporal lobe epilepsy. They showed in mice that low-frequency stimulation of specific brain areas could completely stop epileptic activity. Instead of using electric current, the researchers stimulated the cells with light. To do this, they had previously introduced a light-sensitive molecule into the cells that allows particularly precise stimulation. They published the results in December 2020 in the scientific journal elife.

“As soon as we stimulated the brain region with a frequency of one hertz, the epileptic seizures disappeared. This effect was stable over several weeks,” Haas says. Habituation, which can occur with drug therapy, did not take place. The brain region was stimulated for one hour daily.

Epilepsy Research News: January 2021

This month’s research news includes announcements about CURE Epilepsy’s Frontiers in Research seminar series, and an announcement from the CDC about an incidence and etiology funding opportunity.

We also share that the NINDS Clinical Trials Methodology Course is accepting applications, and that the deadline to apply to the National Science Foundation Enabling Discovery Through Genomics (EDGE) Program is March 16.

These news items are summarized below.

Research Highlights

CURE Epilepsy’s Frontiers in Research Seminar Series has gone virtual!

As part of our on-going commitment to supporting the research community through these difficult times, we are conducting our research seminar series virtually with the topics below. Mark your calendars!

The virtual Frontiers in Research Seminar Series is sponsored by the Nussenbaum-Vogelstein Family.

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CDC Epilepsy Incidence and Etiology Funding Opportunity Announcement
Projects are intended to inform incidence and social determinants of epilepsy including risk factors and protective factors that affect epilepsy incidence. Information about epilepsy incidence will provide invaluable information to help better guide interventions or services for preventing epilepsy, treating and rehabilitating people with epilepsy, and minimizing their health disparities and adverse outcomes.

Click here for details. Search opportunity number by RFA-DP-21-004 and SIP 21-007.

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NINDS Clinical Trials Methodology Course-Application Deadline February 28
The NINDS Clinical Trials Methodology Course (CTMC) is accepting applications for the 2021 cohort. The overarching goal of the CTMC is to help investigators develop scientifically rigorous, yet practical clinical trial protocols. The focus is on investigators who have not previously designed their own prospective, interventional clinical trials.

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National Science Foundation Enabling Discovery Through Genomics (EDGE) Program-Application Deadline March 16
The goal of the EDGE program is to provide support for genomic research and associated theory, approaches, tools, and infrastructure development to address the mechanistic basis of complex traits in diverse organisms within the context (environmental, developmental, social, and/or genomic) in which they function.

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