Professor Catherine Christian and Jiang Li

Effects of Epilepsy on Neural Activity in Mice Fluctuate with Reproductive Cycle

Mice with epilepsy have altered patterns of neuron activity in the portion of the brain that controls the reproductive endocrine system, University of Illinois researchers report in a new study. Furthermore, the differences in neuron activity in female mice fluctuate across the reproductive cycle, the team found.

The study, which tracked hormone levels and activity in specific neurons that trigger the release of reproductive hormones in mice with epilepsy, demonstrates that the effects of epilepsy on other areas of the brain may not be as static as researchers have thought, said study leader Catherine Christian, a professor of molecular and integrative physiology at Illinois. The study was published in the journal eNeuro. Jiang Li, a graduate student at the University of Illinois, was the lead author of the study.

People with temporal lobe epilepsy – the most common type affecting adults – also have high rates of problems with their reproductive endocrine systems, though the connection is poorly understood.

Theory of Mind Impairment in Focal Versus Generalized Epilepsy

Theory of Mind (ToM) is a critical component of social cognition, and thus, its impairment may adversely affect social functioning and quality of life. Recent evidence has suggested that it is impaired in epilepsy. What is not clear, however, is whether it is related to particular types of epilepsy or other factors.

Researchers undertook this study to explore ToM in patients with focal versus those with generalized epilepsy, the particular pattern of ToM deficits, and the potential influence of antiepileptic medication load. The sample included 149 adults: 79 patients with epilepsy (34 with generalized epilepsy and 45 with focal epilepsy) and 70 healthy controls.

Theory of Mind tasks included:

  1. comprehension of hinting
  2. comprehension of sarcasm and metaphor
  3. comprehension of false beliefs and deception
  4. recognition of faux pas
  5. a visual ToM task in cartoon form

We found significant ToM impairment in the group with focal epilepsy relative to the performance of both the healthy group and the group with generalized epilepsy on all tasks, with the exception of faux pas, on which the group with generalized epilepsy also performed more poorly than the healthy group. Additionally, early age at seizure onset, but not antiepileptic drug (AED) load, was associated with ToM performance.

These findings suggest that focal temporal and frontal lobe, but not generalized, epilepsies were associated with impaired theory of mind. This may reflect the neuroanatomical abnormalities in the relevant neuronal networks and may have implications for differential cognitive-behavioral interventions based on epilepsy type.

Whole-Brain Connectome Maps Teach Artificial Intelligence to Predict Epilepsy Outcomes

Medical University of South Carolina (MUSC) neurologists have developed a new method based on artificial intelligence that may eventually help both patients and doctors weigh the pros and cons of using brain surgery to treat debilitating seizures caused by epilepsy. This study, which focused on mesial temporal lobe epilepsy (TLE), was published in the September 2018 issue of Epilepsia. Beyond the clinical implications of incorporating this analytical method into clinicians’ decision making processes, this work also highlights how artificial intelligence is driving change in the medical field.

Despite the increase in the number of epilepsy medications available, as many as one-third of patients are refractory, or non-responders, to the medication. Uncontrolled epilepsy has many dangers associated with seizures, including injury from falls, breathing problems, and even sudden death. Debilitating seizures from epilepsy also greatly reduce quality of life, as normal activities are impaired.

Epilepsy surgery is often recommended to patients who do not respond to medications. Many patients are hesitant to undergo brain surgery, in part, due to fear of operative risks and the fact that only about two-thirds of patients are seizure-free one year after surgery. To tackle this critical gap in the treatment of this epilepsy population, Dr. Leonardo Bonilha and his team in the Department of Neurology at MUSC looked to predict which patients are likely to have success in being seizure free after the surgery.

Neurology Department Chief Resident Dr. Gleichgerrcht explains that they tried “to incorporate advanced neuroimaging and computational techniques to anticipate surgical outcomes in treating seizures that occur with loss of consciousness in order to eventually enhance quality of life”. In order to do this, the team turned to a computational technique, called deep learning, due to the massive amount of data analysis required for this project.

Meta-analysis Shows General Pattern Of Cognitive Dysfunction In Frontal Lobe Epilepsy

Abstract
Frontal lobe epilepsy (FLE) is associated with cognitive problems, especially in areas related to frontal lobe functioning as executive functions, attention, and motor skills, but with impact on memory and psychosocial adaptation. Deficits are similar in both adults and children with FLE, although no studies have compared adult and pediatric performance in the same study. The aim of this research was to analyze the existing evidence concerning the cognition in adults and children with FLE. A random effect meta-analysis was used using Cohen’s d, and the confidence interval for each cognitive factor was calculated. The results in the meta-analysis show a general pattern of cognitive dysfunction in FLE, especially in functions related to the frontal lobe, with an influence of the duration and the age at onset of epilepsy, as well as the age of the sample used. In addition, researches in this type of epilepsy are heterogeneous, with too many different sampling and methodological characteristics, which is not a standard format for reporting clinical sample characterization, making it difficult to study FLE in depth.

Unusual Ictal Propagation Patterns Suggesting Poor Prognosis After Temporal Lobe Epilepsy Surgery

OBJECTIVE: The objective of this study was to investigate unusual ictal propagation patterns in patients with drug-resistant temporal lobe epilepsy (TLE) and reveal their electrophysiological, neuroimaging, and prognostic properties after surgery.

METHODS: Among 248 patients with TLE who underwent scalp video-electroencephalographic (EEG) monitoring, 24 patients with ‘switch of lateralization’ or ‘bilateral asynchrony’ in at least one of their seizures (9.3%) were analyzed retrospectively. The postoperative outcome was determined in 16 patients who had undergone epilepsy surgery.

RESULTS: All but 5 of the included patients had hippocampal sclerosis (HS) as their magnetic resonance imaging (MRI) findings. Twelve out of 16 patients (75%) who had surgery were seizure-free for at least 1?year. Nine out of 12 patients (75%) with good outcome had unilateral interictal EEG discharges in temporal regions whereas 3 out of 4 patients with poor outcome had bilateral temporal interictal spiking (p?=?0.018).

CONCLUSION: Unusual ictal propagation patterns are not always related to poor prognosis after surgery in patients with temporal lobe epilepsy. Patients with unilateral interictal spiking in the temporal region tend to have good outcome despite these unusual patterns. These patterns can also be seen in patients with temporal lobe epilepsy with other etiologies besides the well-known HS in MRI.

CURE Discovery: Transplanting Inhibitory Neurons Can Reduce Seizures

CURE Grantee Dr. Janice Naegele of Wesleyan University has been working on harnessing the brain’s own inhibitory power as a treatment to reduce excitability and “quiet” the overly excitable epileptic brain. As a promising first step, she and her team have successfully shown that transplantation of mouse inhibitory neurons into the mouse hippocampus – a brain structure that is often involved in epilepsy – can reduce the number of seizures in mice with temporal lobe epilepsy. (1)

Temporal lobe epilepsy is the most common form of epilepsy, with neuronal loss being one of its hallmark traits. (2,3) The loss of inhibitory neurons can be an important factor in the development or worsening of the disorder, (4) because the balance between excitatory and inhibitory neuronal activity is essential for proper brain function. Fewer inhibitory neurons can decrease inhibitory neurotransmission, in turn leading to excessive neuronal excitation, seizures, and epilepsy. One focus of Dr. Naegele’s epilepsy research has been to find a way to increase inhibition in the hyperexcitable epileptic brain. (5)

Dr. Naegele used her CURE grant to focus on transplanting both mouse and human inhibitory neurons into the hippocampus of mice with temporal lobe epilepsy. She hypothesized that these inhibitory neurons would wire up with existing neurons, increasing inhibitory transmission and decreasing the hyperexcitability that characterizes temporal lobe epilepsy. This type of treatment is called “regenerative medicine” because it uses healthy tissue to restore normal brain functioning. An advantage of regenerative medicine is that the transplanted cells can potentially replace lost or damaged inhibitory neurons and also integrate into the existing brain circuitry. This treatment would provide a cure for seizures by addressing the root cause, unlike standard antiepileptic drugs that simply treat the symptoms of seizures.

Indeed, as shown by advanced imaging techniques, the inhibitory neurons Dr. Naegele’s team transplanted into the brains of mice with temporal lobe epilepsy formed new, functional connections with excitatory neurons already present in the hippocampus, providing the increased inhibition that likely led to fewer seizures in these mice. (1)

Following the success of quieting seizures using the implantation of mouse inhibitory neurons, Dr. Naegele and her team are now focused on a means to quiet seizures by implanting human inhibitory neurons, pushing this research one step closer to being a viable treatment for people with epilepsy. As part of their strategy, they are keeping in mind important potential differences in neuronal generation and transmission between humans and mice. (6)

Dr. Naegele’s research brings an exciting possibility to the future of epilepsy treatment: the transplantation of a type of neuron that already exists in the human brain with the goal of stopping seizures. While work still remains, CURE applauds the progress Dr. Naegele has made thus far. We share Dr. Naegele’s hopes that her approach becomes a non-drug method of treating those affected by not only temporal lobe epilepsy, but other forms of epilepsy as well.

1 Henderson et al. Long-term seizure suppression and optogenetic analysis of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. J Neurosci 2014; 34(40):13492-13504.
2 Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Neurol 2002; 1(3):173-181.
3 Engel J Jr, Williamson PD, Weiser HG. Mesial temporal lobe epilepsy. In: Epilepsy: a comprehensive textbook (Engel J Jr, Pedley TA, eds) 1997: 2417-2426.
4 Kumar SS, Buckmaster PS. Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci 2006; 26(17):4613-4623.
5 Van Zandt MA, Naegele JR. GABAergic synapse dysfunction and repair in temporal lobe epilepsy. (2017) Synaptic Plasticity Thomas Heinbockel, IntechOpen; DOI: 10.5772/67218. Available from: https://www.intechopen.com/books/synaptic-plasticity/gabaergic-synapse-d….
6 Naegele JR. Controversial brain study has scientists rethinking neuron research. (2018) Available from: https://theconversation.com/controversial-brain-study-has-scientists-ret…

Associated and Predictive Factors of Quality of Life in Patients with Temporal Lobe Epilepsy

OBJECTIVE: Identifying the factors that are correlated with and predictive of reduced quality of life (QOL) is essential to optimize the treatment of epilepsy and the management of comorbidities.

METHODS: Researchers analyzed the independent associations between the Quality of Life in Epilepsy-31 (QOLIE-31) inventory and the demographic, clinical, psychiatric, and cognitive variables of 47 consecutive patients with temporal lobe epilepsy (TLE). Predictors of the correlated variables were analyzed by multiple linear regression analysis.

RESULTS: The QOLIE-31 total score was positively correlated with occupational status and Mini-Mental State Examination (MMSE) scores (r?=?0.290 and 0.295, respectively; P?<?0.05) and negatively correlated with the duration of seizures, adverse effects of antiepileptic drugs (AEDs), and the Pittsburgh Sleep Quality Inventory (PSQI), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS) scores (r?=?-0.357, 0.321, 0.328, -0.672, and -0.565, respectively; P?<?0.05; P?<?0.01 for the SAS and SDS). In the final multivariate regression model, anxiety, long durations of seizures, adverse effects of AEDs, and depression explained approximately 60.6% (adjusted R2?=?0.606, R coefficient?=?0.800) of the QOLIE-31 overall score variance.

CONCLUSION: Anxiety, long durations of seizures, adverse effects of antiepileptic drugs, and depression were significant predictors of quality of life, and these variables had relatively high prediction capacities for the overall QOLIE-31 in the regression model. Comorbid anxiety is the most powerful negative determinant of the QOLIE-31.

Research Reveals Underappreciated Role of Brainstem in Epilepsy

New research from Vanderbilt suggests that repeated seizures reduce brainstem connectivity, a possible contributor to unexplained neurocognitive problems in epilepsy patients.

The brainstem has been rarely studied in epilepsy because seizures typically originate in the temporal lobe or other areas of the cortex. Noting that people with temporal lobe epilepsy often lose consciousness even though the temporal lobe does not control wakefulness, Dario Englot, MD, PhD, surgical director of epilepsy at Vanderbilt University Medical Center, said he decided to focus on the region that does control wakefulness — the brainstem. He hypothesized that connectivity disruptions with the brainstem resulting from a history of seizures might play a role in diminished cognitive functions that are not related to the temporal lobe.

The research, published online May 30 in Neurology, is the first to investigate how epilepsy affects the ascending reticular activating system (ARAS) — circuitry that is responsible for regulating wakefulness — within the brainstem. Functional magnetic resonance imaging revealed that ARAS disruptions occurred, with decreases in circuitry being quantitatively associated with disease severity.

“Seizures do not start in areas deep below the surface of the brain called subcortical nuclei,” said Englot, the study’s lead author and assistant professor of Neurological Surgery, Radiology and Radiological Sciences and Biomedical Engineering. “So these areas are not often studied in epilepsy. But we think that problems develop in some deep subcortical circuits that may contribute to some of the unexplained global brain problems in temporal lobe epilepsy, including progressive neurocognitive problems and problems with arousal that can’t be explained by problems in the temporal lobe.”

Study: Increased Cardiac Stiffness is Associated with Autonomic Dysfunction in Patients with Temporal Lobe Epilepsy

Autonomic dysfunction is linked to sudden death regardless of the presence of structural heart disease. The pathway from autonomic dysfunction to sudden death is not fully understood, but myocardial sympathetic stimulation leading to arrhythmia and/or cardiac fibrosis might play a role. Our goal was to evaluate cardiac stiffness by echocardiography and its association with clinical, structural, and autonomic variables in people with epilepsy (PWE) compared to healthy controls.

A 12-lead electrocardiogram, treadmill testing, and transthoracic echocardiography from 30 patients with temporal lobe epilepsy (TLE) without any known cardiovascular disorders were compared to 30 individuals without epilepsy matched by sex, age, and body mass index. Distribution of cardiovascular risk factors was similar in both groups. PWE had a higher left ventricle stiffness, left ventricle filling pressure, and greater left atrial volume as well as markers of autonomic dysfunction such as impaired chronotropic index and percentage achieved of predicted peak heart rate at effort. In multiple regressions, autonomic dysfunction explained 52% of stiffness and carbamazepine treatment and polytherapy with antiepileptic drugs (AEDs) explained, additionally, 6% each.

Stiffness is increased in young patients with TLE and is related to autonomic dysfunction and to a lesser extent, carbamazepine use and polytherapy with AEDs.

Study: Phenotypic Spectrum in Families with Mesial Temporal Lobe Epilepsy Probands

Purpose: The traditional perception of mesial temporal lobe epilepsy (MTLE) as a predominantly acquired disorder is challenged due to emerging evidence of familial aggregation. In this study, we ascertained the extent of familial occurrence of epilepsy in MTLE patients, as well as phenotypic heterogeneity in affected relatives.

Methods: We identified and reevaluated patients with MTLE, treated at Epilepsy Department for a period of two years. All eligible putatively affected relatives were asked to participate in the study. In addition to comprehensive epilepsy interview, they underwent EEG and MRI studies.

Results: 52 patients with MTLE were included; nine of them (17%) had at least one family member with epilepsy. Subsequently, we analyzed nine probands with MTLE and a total of 15 relatives with seizures. Among affected relatives, spectrums of clinical manifestations were observed. Typical MTL seizures were described in five individuals, while other types of focal or generalized tonic-clonic seizures were reported in other ten relatives. A total of seven individuals had febrile seizures. Hippocampal sclerosis was found in three probands and none of the relatives. Two of affected family members had a traumatic brain injury in addition to febrile seizures, prior to the occurrence of their epilepsy.

Conclusion: We demonstrate that familiar occurrence of epilepsy and subsequently putative genetic background, accounts for a substantial proportion MTLE patients. In addition, we foreground the remarkable intra- and interfamilial phenotypic heterogeneity than usually described, displaying the complexity of the genotype-phenotype correlations.