Lamotrigine use and potential for adverse cardiac effects: A retrospective evaluation in a Veteran population.

OBJECTIVE: To identify the impact of lamotrigine (LTG) on cardiac rhythm and conduction abnormalities for Veterans, an especially vulnerable population. BACKGROUND: In October 2020 the US Food and Drug Administration (FDA) added a new warning to the label of lamotrigine (Lamictal™) regarding its potential to cause cardiac rhythm and conduction abnormalities [1]. This warning came following in vitro data which suggested Class IB antiarrhythmic effects occurring at clinically achievable concentrations of lamotrigine [2]. However, it is unclear whether the in vitro findings will result in adverse clinical outcomes. Our objective was to assess for evidence for adverse clinical outcomes in a vulnerable population and examine for subtler signs of an association between lamotrigine and cardiac rhythm disturbances. METHODS: A retrospective chart review was conducted using records between 10-01-2017 and 07-06-2021, identifying patients at the William S. Middleton Memorial Veterans Hospital who were prescribed lamotrigine. Data collected included: dates of lamotrigine initiation or discontinuation, lamotrigine dosing over the time of the prescription and maximum lamotrigine dose, any cardiac-related ICD-10-CM codes or a history of a cardiology appointment, EKGs with any abnormalities or changes, any concomitantly prescribed medications with known potential to cause cardiac abnormalities, any cardiac deaths. This retrospective chart review was approved by the University of Wisconsin-Madison Institutional Review Board. RESULTS: Two hundred and thirty-three (189 male) patients with a lamotrigine prescription and 41.2 % (n = 96) of these patients had an EKG performed while prescribed lamotrigine. The average age of patients was 64.3 ± 13.0 (range 29 to 90) years and mean maximum lamotrigine daily dose was 250.8 ± 148.2 mg (range 25 to 800 mg). Nearly half (47.9 %, 46/96) of the patients were prescribed a concomitant sodium channel blocking medication in addition to lamotrigine. Eighty-four of the patients (87.5 %, 84/96) had a cardiac diagnosis, while 12 (12.5 %, 12/96) did not. A total of 12 deaths occurred within the review period, with two cardiac deaths from congestive heart failure. Four cases did not have information on cause of death. No LTG-associated cardiac adverse effects were noted as part of clinical care, though rash was noted in 5 cases. A total of 7 (7.3 %, 7/96) patients were found to have EKG abnormalities potentially related to lamotrigine, including 7.1 % (6/84) of those with a cardiac diagnosis and 8.3 % (1/12) of those without a cardiac diagnosis. CONCLUSIONS: While recent FDA warnings have suggested caution regarding cardiac complications associated with lamotrigine based on in vitro studies, the clinical implications are uncertain. Despite selecting a particularly vulnerable population, this retrospective chart review did not identify any deaths due to cardiac rhythm or conduction causes, nor demonstrate unambiguous cardiac complications related to lamotrigine. Even using permissive criteria (including any prolonged PR or QTc) to examine for subtle effects, only a low incidence (<10 %) of potential complications was found. Broader implications of this study are limited by the number of patients included and the retrospective nature of the study. Therefore, further studies are warranted to evaluate a link between cardiac complications and the use of lamotrigine, including the role of concomitant medications such as other sodium channel blocking agents and psychotropic medications.

A machine learning approach to seizure detection in a rat model of post-traumatic epilepsy.

Epilepsy is a common neurologic condition frequently investigated using rodent models, with seizures identified by electroencephalography (EEG). Given technological advances, large datasets of EEG are widespread and amenable to machine learning approaches for identification of seizures. While such approaches have been explored for human EEGs, machine learning approaches to identifying seizures in rodent EEG are limited. We utilized a predesigned deep convolutional neural network (DCNN), GoogLeNet, to classify images for seizure identification. Training images were generated through multiplexing spectral content (scalograms), kurtosis, and entropy for two-second EEG segments. Over 2200 h of EEG data were scored for the presence of seizures, with 95.6% of seizures identified by the DCNN and a false positive rate of 34.2% (1.52/h), as compared to visual scoring. Multiplexed images were superior to scalograms alone (scalogram-kurtosis-entropy 0.956 ± 0.010, scalogram 0.890 ± 0.028, t(7) = 3.54, p < 0.01) and a DCNN trained specifically for the individual animal was superior to using DCNNs across animals (intra-animal 0.960 ± 0.0094, inter-animal 0.811 ± 0.015, t(30) = 5.54, p < 0.01). For this dataset the DCNN approach is superior to a previously described algorithm utilizing longer local line lengths, calculated from wavelet-decomposition of EEG, to identify seizures. We demonstrate the novel use of a predesigned DCNN constructed to classify images, utilizing multiplexed images of EEG spectral content, kurtosis, and entropy, to rapidly and objectively identifies seizures in a large dataset of rat EEG with high sensitivity.

The Effective Use of Laser Ablation to Treat Mesial Temporal Lobe Epilepsy in the Setting of Implanted Responsive Neurostimulation.

BACKGROUND: Up to 16% of patients with responsive neurostimulation (RNS) implants for bilateral temporal epilepsy are found to have seizures originating mainly from just 1 lobe. OBJECTIVE: To describe the first use of laser interstitial thermal therapy (LITT) in a patient with a bilateral RNS implant to ablate the predominant temporal lobe and help control seizures. METHODS: A 55-year-old woman treated for temporal lobe epilepsy with conflicting information regarding lateralization underwent RNS implantation. She was then discovered to have seizures with electrographic onset nearly all from the right amygdala and hippocampus. She was offered LITT to ablate the affected region in the right temporal lobe, followed by reimplantation of the RNS lead in the remnant of the right hippocampal tail. RESULTS: Despite the positioning of the RNS ferrule on the operative side and the depth electrode in the contralateral lobe, we observed no significant artifact and obtained stable LITT temperature mapping using magnetic resonance. Laser ablation and RNS device replacement proceeded without complications. The patient has remained seizure-free for 6 months since the ablation in the setting of weaning antiseizure medications and regaining ambulation. CONCLUSION: LITT ablation can safely and effectively be performed in a patient with a concurrent RNS implant. Maintenance of the RNS device after ablation allows for continual detection and management of seizures.

Rescue Treatments for Seizure Clusters.

Treatment of seizure clusters endeavors to prevent additional seizures and avoid progression to conditions such as prolonged seizures and status epilepticus. Rescue therapies are key components of seizure action plans (SAPs) for individuals with seizure clusters. Three rescue therapies are approved in the United States for the treatment of seizure clusters: diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Diazepam rectal gel is an effective rescue therapy for seizure clusters, though adults and adolescents may have social reservations regarding its administration. Intranasal delivery of midazolam or diazepam is a promising alternative to rectal administration because these formulations offer easy, socially acceptable administration exhibit a rapid onset, and allow for the possibility of self-administration. Off-label benzodiazepines, such as orally disintegrating lorazepam and intranasal use of an intravenous (IV) formulation of midazolam via nasal atomizer, are less well characterized regarding bioavailability and tolerability compared with approved agents.

Levetiracetam-associated irritability and potential role of vitamin B6 use in veterans with epilepsy.

OBJECTIVES: Levetiracetam, a commonly prescribed antiseizure medication (ASM), may cause irritability, depression, and anger. The mechanisms underlying these behavioral effects and individual risk factors remain unknown. Mitigation strategies are limited, including discontinuation, supplementation with vitamin B6, or switching to an alternative ASM. Several retrospective studies and anecdotal reports, primarily in pediatric populations, suggest vitamin B6 supplementation may be helpful in reducing levetiracetam-associated irritability. Although data in adult patients is limited, and no data is available for Veterans. The objective of this project was to describe our preliminarily experience with vitamin B6 supplementation for alleviating levetiracetam-associated irritability in male Veterans with epilepsy. METHODS: Retrospective chart reviews were completed for patients who had an active prescription for levetiracetam from the William S. Middleton Memorial Veterans Hospital from January 1, 2015 to June 1, 2020. A total of 26 charts were screened. Patients were excluded if not using vitamin B6 supplementation or if deceased at end of data collection. Baseline characteristics were compared, including age, sex, comorbidities, and concomitant medications. Charts were then reviewed to identify any clinical description of irritability, including subjective assessment of change in symptoms across multiple visits, and scores from standardized instruments including the patient health questionnaire (PHQ-9), generalized anxiety disorder questionnaire (GAD-7), and/or irritability in adult patients with epilepsy (I-EPI) questionnaire. These symptoms and scores were then compared pre- and post-B6 supplementation. RESULTS: Of 22 patients, data was available for 20 (91%). For patients with data available, 9 (45%) showed improved irritability following supplementation with vitamin B6 and 11 (55%) showed no improvement. CONCLUSIONS: This project suggests that vitamin B6 supplementation may have a role in mitigating levetiracetam-associated irritability in a male Veteran population. These results support future prospective controlled studies to assess further the efficacy of this approach and characteristics associated with successful treatment in veterans.

Epilepsy and aging.

The intersection of epilepsy and aging has broad, significant implications. Substantial increases in seizures occur both in the elderly population, who are at a higher risk of developing new-onset epilepsy, and in those with chronic epilepsy who become aged. There are notable gaps in our understanding of aging and epilepsy at the basic and practical levels, which have important consequences. We are in the early stages of understanding the complex relationships between epilepsy and other age-related brain diseases such as stroke, dementia, traumatic brain injury (TBI), and cancer. Furthermore, the clinician must recognize that the presentation and treatment of epilepsy in the elderly are different from those of younger populations. Given the developing awareness of the problem and the capabilities of contemporary, multidisciplinary approaches to advance understanding about the biology of aging and epilepsy, it is reasonable to expect that we will unravel some of the intricacies of epilepsy in the elderly; it is also reasonable to expect that these gains will lead to further improvements in our understanding and treatment of epilepsy for all age groups.

Genetic Background Influences Acute Response to TBI in Kindling-Susceptible, Kindling-Resistant, and Outbred Rats.

We hypothesized that the acute response to traumatic brain injury (TBI) shares mechanisms with brain plasticity in the kindling model. Utilizing two unique, complementary strains of inbred rats, selected to be either susceptible or resistant to seizure-induced plasticity evoked by kindling of the perforant path, we examined acute electrophysiological alterations and differences in brain-derived neurotrophic factor (BDNF) protein concentrations after a moderate-to-severe brain injury. At baseline, limited strain-dependent differences in acute electrophysiological activity were found, and no differences in BDNF. Following injury, pronounced strain-dependent differences in electrophysiologic activity were noted at 0.5 min. However, the divergence is transient, with diminished differences at 5 min after injury and no differences at 10 and 15 min after injury. Strain-specific differences in BDNF protein concentration were noted 4 h after injury. A simple risk score model generated by machine learning and based solely on post-injury electrophysiologic activity at the 0.5-min timepoint distinguished perforant path kindling susceptible (PPKS) rats from non-plasticity-susceptible strains. The findings demonstrate that genetic background which affects brain circuit plasticity also affects acute response to TBI. An improved understanding of the effect of genetic background on the cellular, molecular, and circuit plasticity mechanisms activated in response to TBI and their timecourse is key in developing much-needed novel therapeutic approaches.

Magnetoencephalography: Clinical and Research Practices.

Magnetoencephalography (MEG) is a neurophysiological technique that detects the magnetic fields associated with brain activity. Synthetic aperture magnetometry (SAM), a MEG magnetic source imaging technique, can be used to construct both detailed maps of global brain activity as well as virtual electrode signals, which provide information that is similar to invasive electrode recordings. This innovative approach has demonstrated utility in both clinical and research settings. For individuals with epilepsy, MEG provides valuable, nonredundant information. MEG accurately localizes the irritative zone associated with interictal spikes, often detecting epileptiform activity other methods cannot, and may give localizing information when other methods fail. These capabilities potentially greatly increase the population eligible for epilepsy surgery and improve planning for those undergoing surgery. MEG methods can be readily adapted to research settings, allowing noninvasive assessment of whole brain neurophysiological activity, with a theoretical spatial range down to submillimeter voxels, and in both humans and nonhuman primates. The combination of clinical and research activities with MEG offers a unique opportunity to advance translational research from bench to bedside and back.

Changes in nonhuman primate brain function following chronic alcohol consumption in previously naïve animals.

INTRODUCTION: Chronic alcohol abuse is associated with neurophysiological changes in brain activity; however, these changes are not well localized in humans. Non-human primate models of alcohol abuse enable control over many potential confounding variables associated with human studies. The present study utilized high-resolution magnetoencephalography (MEG) to quantify the effects of chronic EtOH self-administration on resting state (RS) brain function in vervet monkeys. METHODS: Adolescent male vervet monkeys were trained to self-administer ethanol (n=7) or an isocaloric malto-dextrin solution (n=3). Following training, animals received 12 months of free access to ethanol. Animals then underwent RS magnetoencephalography (MEG) and subsequent power spectral analysis of brain activity at 32 bilateral regions of interest associated with the chronic effects of alcohol use. RESULTS: demonstrate localized changes in brain activity in chronic heavy drinkers, including reduced power in the anterior cingulate cortex, hippocampus, and amygdala as well as increased power in the right medial orbital and parietal areas. DISCUSSION: The current study is the first demonstration of whole-head MEG acquisition in vervet monkeys. Changes in brain activity were consistent with human electroencephalographic studies; however, MEG was able to extend these findings by localizing the observed changes in power to specific brain regions. These regions are consistent with those previously found to exhibit volume loss following chronic heavy alcohol use. The ability to use MEG to evaluate changes in brain activity following chronic ethanol exposure provides a potentially powerful tool to better understand both the acute and chronic effects of alcohol on brain function.

Contrasting Effects of Posttraumatic Stress Disorder and Mild Traumatic Brain Injury on the Whole-Brain Resting-State Network: A Magnetoencephalography Study.

The aim of this study was to evaluate alterations in whole-brain resting-state networks associated with posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI). Networks were constructed from locations of peak statistical power on an individual basis from magnetoencephalography (MEG) source series data by applying the weighted phase lag index and surrogate data thresholding procedures. Networks representing activity in the alpha bandwidth as well as wideband activity (DC-80 Hz) were created. Statistical comparisons were adjusted for age and education level. Alpha network results demonstrate reductions in network structure associated with PTSD, but no differences associated with mTBI. Wideband network results demonstrate a shift in connectivity from the alpha to theta bandwidth in both PTSD and mTBI. Also, contrasting alterations in network structure are noted, with increased randomness associated with PTSD and increased structure associated with mTBI. These results demonstrate the potential of the analysis of MEG resting-state networks to differentiate two highly comorbid conditions. The importance of the alpha bandwidth to resting-state connectivity is also highlighted, while demonstrating the necessity of considering activity in other bandwidths during network construction.

Environmental enrichment: evidence for an unexpected therapeutic influence.

Environmental enrichment produces wide-ranging effects in the brain at molecular, cellular, network, and behavioral levels. The changes in neuronal plasticity are driven by changes in neurotransmitters, neurotrophic factors, neuronal morphology, neurogenesis, network properties of the brain, and behavioral correlates of learning and memory. Exposure to an enriched environment has also demonstrated intriguing possibilities for treatment of a variety of neurodegenerative diseases including Huntington's disease, Alzheimer's disease, and Parkinson's disease. The effect of environmental enrichment in epilepsy, a neurodegenerative disorder with pathological neuronal plasticity, is of considerable interest. Recent reports of the effect of environmental enrichment in the Bassoon mutant mouse, a genetic model of early onset epilepsy, provides a significant addition to the literature in this area.

Localization of interictal epileptiform activity using magnetoencephalography with synthetic aperture magnetometry in patients with a vagus nerve stimulator.

Magnetoencephalography (MEG) provides useful and non-redundant information in the evaluation of patients with epilepsy, and in particular, during the pre-surgical evaluation of pharmaco-resistant epilepsy. Vagus nerve stimulation (VNS) is a common treatment for pharmaco-resistant epilepsy. However, interpretation of MEG recordings from patients with a VNS is challenging due to the severe magnetic artifacts produced by the VNS. We used synthetic aperture magnetometry (g2) [SAM(g2)], an adaptive beamformer that maps the excessive kurtosis, to map interictal spikes to the coregistered MRI image, despite the presence of contaminating VNS artifact. We present a series of eight patients with a VNS who underwent MEG recording. Localization of interictal epileptiform activity by SAM(g2) is compared to invasive electrophysiologic monitoring and other localizing approaches. While the raw MEG recordings were uninterpretable, analysis of the recordings with SAM(g2) identified foci of peak kurtosis and source signal activity that was unaffected by the VNS artifact. SAM(g2) analysis of MEG recordings in patients with a VNS produces interpretable results and expands the use of MEG for the pre-surgical evaluation of epilepsy.

Antiseizure effects of TrkB kinase inhibition.

OBJECTIVE: The principal molecular targets of conventional antiseizure drugs consist of ligand-gated and voltage-gated ion channels and proteins subserving synaptic function. Inhibition of the receptor tyrosine kinase TrkB limits epileptogenesis, but its effect on individual seizures is unknown. We sought to determine whether inhibition of TrkB kinase exerts an antiseizure effect. METHODS: We utilized the kindling model in combination with an inducible conditional knockout of the TrkB gene (Act-CreER TrkB(flox/flox) mice treated with tamoxifen), and also with a chemical-genetic approach in which mice carry a TrkB kinase with a phenylalanine to alanine substitution of residue 616 (TrkB(F) (616A) ), which allows inhibition of the kinase by a blood-brain barrier permeable small molecule, 1'-naphthylmethyl-4-amino-1-tert-butyl-3-(p-methylphenyl)pyrazolo[3,4-d]pyrimidine (1NMPP1). RESULTS: Following induction of kindling, reduction of TrkB protein levels in Act-CreER TrkB(flox/flox) mice treated with tamoxifen was associated with reduced severity of behavioral seizures evoked by stimulation. Treatment with 1NMPP1 for 2 weeks following induction of kindling reversibly elevated both focal electrographic and generalized seizure thresholds in TrkB(F) (616A) , but not wild-type (WT), mice. In contrast to kindled animals, treatment of naive TrkB(F) (616A) mice for 2 weeks had no detectable effect on electrographic seizure threshold (EST). SIGNIFICANCE: This study provides proof of concept of a novel molecular target for antiseizure drugs, namely the receptor tyrosine kinase TrkB.

Altered morphology of hippocampal dentate granule cell presynaptic and postsynaptic terminals following conditional deletion of TrkB.

Dentate granule cells play a critical role in the function of the entorhinal-hippocampal circuitry in health and disease. Dentate granule cells are situated to regulate the flow of information into the hippocampus, a structure required for normal learning and memory. Correspondingly, impaired granule cell function leads to memory deficits, and, interestingly, altered granule cell connectivity may contribute to the hyperexcitability of limbic epilepsy. It is important, therefore, to understand the molecular determinants of synaptic connectivity of these neurons. Brain-derived neurotrophic factor and its receptor TrkB are expressed at high levels in the dentate gyrus (DG) of the hippocampus, and are implicated in regulating neuronal development, neuronal plasticity, learning, and the development of epilepsy. Whether and how TrkB regulates granule cell structure, however, is incompletely understood. To begin to elucidate the role of TrkB in regulating granule cell morphology, here we examine conditional TrkB knockout mice crossed to mice expressing green fluorescent protein in subsets of dentate granule cells. In stratum lucidum, where granule cell mossy fiber axons project, the density of giant mossy fiber boutons was unchanged, suggesting similar output to CA3 pyramidal cell targets. However, filopodial extensions of giant boutons, which contact inhibitory interneurons, were increased in number in TrkB knockout mice relative to wildtype controls, predicting enhanced feedforward inhibition of CA3 pyramidal cells. In knockout animals, dentate granule cells possessed fewer primary dendrites and enlarged dendritic spines, indicative of disrupted excitatory synaptic input to the granule cells. Together, these findings demonstrate that TrkB is required for development and/or maintenance of normal synaptic connectivity of the granule cells, thereby implying an important role for TrkB in the function of the granule cells and hippocampal circuitry.