Insights into epileptogenesis from post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies. The incidence of PTE after traumatic brain injury (TBI) depends on the severity of injury, approaching one in three in groups with the most severe injuries. The repeated seizures that characterize PTE impair neurological recovery and increase the risk of poor outcomes after TBI. Given this high risk of recurrent seizures and the relatively short latency period for their development after injury, PTE serves as a model disease to understand human epileptogenesis and trial novel anti-epileptogenic therapies. Epileptogenesis is the process whereby previously normal brain tissue becomes prone to recurrent abnormal electrical activity, ultimately resulting in seizures. In this Review, we describe the clinical course of PTE and highlight promising research into epileptogenesis and treatment using animal models of PTE. Clinical, imaging, EEG and fluid biomarkers are being developed to aid the identification of patients at high risk of PTE who might benefit from anti-epileptogenic therapies. Studies in preclinical models of PTE have identified tractable pathways and novel therapeutic strategies that can potentially prevent epilepsy, which remain to be validated in humans. In addition to improving outcomes after TBI, advances in PTE research are likely to provide therapeutic insights that are relevant to all epilepsies.

Stereoelectroencephalography-Guided Radiofrequency Thermocoagulation: Diagnostic and Therapeutic Implications.

Despite recent medical therapeutic advances, approximately one third of patients do not attain seizure freedom with medications. This drug-resistant epilepsy population suffers from heightened morbidity and mortality. In appropriate patients, resective epilepsy surgery is far superior to continued medical therapy. Despite this efficacy, there remain drawbacks to traditional epilepsy surgery, such as the morbidity of open neurosurgical procedures as well as neuropsychological adverse effects. SEEG-guided Radiofrequency Thermocoagulation (SgRFTC) is a minimally invasive, electrophysiology-guided intervention with both diagnostic and therapeutic implications for drug-resistant epilepsy that offers a convenient adjunct or alternative to ablative and resective approaches. We review the international experience with this procedure, including methodologies, diagnostic benefit, therapeutic benefit, and safety considerations. We propose a framework in which SgRFTC may be incorporated into intracranial EEG evaluations alongside passive recording. Lastly, we discuss the potential role of SgRFTC in both delineating and reorganizing epilepsy networks.

A week in the life of the human brain: stable states punctuated by chaotic transitions.

Many important neurocognitive states, such as performing natural activities and fluctuations of arousal, shift over minutes-to-hours in the real-world. We harnessed 3-12 days of continuous multi-electrode intracranial recordings in twenty humans during natural behavior (socializing, using digital devices, sleeping, etc.) to study real-world neurodynamics. Applying deep learning with dynamical systems approaches revealed that brain networks formed consistent stable states that predicted behavior and physiology. Changes in behavior were associated with bursts of rapid neural fluctuations where brain networks chaotically explored many configurations before settling into new states. These trajectories traversed an hourglass-shaped structure anchored around a set of networks that slowly tracked levels of outward awareness related to wake-sleep stages, and a central attractor corresponding to default mode network activation. These findings indicate ways our brains use rapid, chaotic transitions that coalesce into neurocognitive states slowly fluctuating around a stabilizing central equilibrium to balance flexibility and stability during real-world behavior.

Predicting posttraumatic epilepsy using admission electroencephalography after severe traumatic brain injury.

OBJECTIVE: Posttraumatic epilepsy (PTE) develops in as many as one third of severe traumatic brain injury (TBI) patients, often years after injury. Analysis of early electroencephalographic (EEG) features, by both standardized visual interpretation (viEEG) and quantitative EEG (qEEG) analysis, may aid early identification of patients at high risk for PTE. METHODS: We performed a case-control study using a prospective database of severe TBI patients treated at a single center from 2011 to 2018. We identified patients who survived 2 years postinjury and matched patients with PTE to those without using age and admission Glasgow Coma Scale score. A neuropsychologist recorded outcomes at 1 year using the Expanded Glasgow Outcomes Scale (GOSE). All patients underwent continuous EEG for 3-5 days. A board-certified epileptologist, blinded to outcomes, described viEEG features using standardized descriptions. We extracted 14 qEEG features from an early 5-min epoch, described them using qualitative statistics, then developed two multivariable models to predict long-term risk of PTE (random forest and logistic regression). RESULTS: We identified 27 patients with and 35 without PTE. GOSE scores were similar at 1 year (p = .93). The median time to onset of PTE was 7.2 months posttrauma (interquartile range = 2.2-22.2 months). None of the viEEG features was different between the groups. On qEEG, the PTE cohort had higher spectral power in the delta frequencies, more power variance in the delta and theta frequencies, and higher peak envelope (all p < .01). Using random forest, combining qEEG and clinical features produced an area under the curve of .76. Using logistic regression, increases in the delta:theta power ratio (odds ratio [OR] = 1.3, p < .01) and peak envelope (OR = 1.1, p < .01) predicted risk for PTE. SIGNIFICANCE: In a cohort of severe TBI patients, acute phase EEG features may predict PTE. Predictive models, as applied to this study, may help identify patients at high risk for PTE, assist early clinical management, and guide patient selection for clinical trials.

Association of Posttraumatic Epilepsy With Long-term Functional Outcomes in Individuals With Severe Traumatic Brain Injury.

BACKGROUND AND OBJECTIVE: Nearly one-third of patients with severe traumatic brain injury (TBI) develop posttraumatic epilepsy (PTE). The relationship between PTE and long-term outcomes is unknown. We tested whether, after controlling for injury severity and age, PTE is associated with worse functional outcomes after severe TBI. METHODS: We performed a retrospective analysis of a prospective database of patients with severe TBI treated from 2002 through 2018 at a single level 1 trauma center. Glasgow Outcome Scale (GOS) was collected at 3, 6, 12, and 24 months postinjury. We used repeated-measures logistic regression predicting GOS, dichotomized as favorable (GOS 4-5) and unfavorable (GOS 1-3), and a separate logistic model predicting mortality at 2 years. We used predictors as defined by the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) base model (i.e., age, pupil reactivity, and GCS motor score), PTE status, and time. RESULTS: Of 392 patients who survived to discharge, 98 (25%) developed PTE. The proportion of patients with favorable outcomes at 3 months did not differ between those with and without PTE (23% [95% Confidence Interval [CI]: 15%-34%] vs 32% [95% CI: 27%-39%]; p = 0.11) but was significantly lower at 6 (33% [95% CI: 23%-44%] vs 46%; [95% CI: 39%-52%] p = 0.03), 12 (41% [95% CI: 30%-52%] vs 54% [95% CI: 47%-61%]; p = 0.03), and 24 months (40% [95% CI: 47%-61%] vs 55% [95% CI: 47%-63%]; p = 0.04). This was driven by higher rates of GOS 2 (vegetative) and 3 (severe disability) outcomes in the PTE group. By 2 years, the incidence of GOS 2 or 3 was double in the PTE group (46% [95% CI: 34%-59%]) compared with that in the non-PTE group (21% [95% CI: 16%-28%]; p < 0.001), while mortality was similar (14% [95% CI: 7%-25%] vs 23% [95% CI: 17%-30%]; p = 0.28). In multivariate analysis, patients with PTE had lower odds of favorable outcome (odds radio [OR] 0.1; 95% CI: 0.1-0.4; p < 0.001), but not mortality (OR 0.9; 95% CI: 0.1-1.9; p = 0.46). DISCUSSION: Posttraumatic epilepsy is associated with impaired recovery from severe TBI and poor functional outcomes. Early screening and treatment of PTE may improve patient outcomes.

The endoscopic anterior transmaxillary temporal pole approach for mesial temporal lobe epilepsies: a feasibility study.

OBJECTIVE: In mesial temporal lobe epilepsy (MTLE), the ideal surgical approach to achieve seizure freedom and minimize morbidity is an unsolved question. Selective approaches to mesial temporal structures often result in suboptimal seizure outcomes. The authors report the results of a pilot study intended to evaluate the clinical feasibility of using an endoscopic anterior transmaxillary (eATM) approach for minimally invasive management of MTLEs. METHODS: The study is a prospectively collected case series of four consecutive patients who underwent the eATM approach for the treatment of MTLE and were followed for a minimum of 12 months. All participants underwent an epilepsy workup and surgical care at a tertiary referral comprehensive epilepsy center and had medically refractory epilepsy. The noninvasive evaluations and intracranial recordings of these patients confirmed the presence of anatomically restricted epileptogenic zones located in the mesial temporal structures. Data on seizure freedom at 1 year, neuropsychological outcomes, diffusion tractography, and adverse events were collected and analyzed. RESULTS: By applying the eATM technique and approaching the far anterior temporal lobe regions, mesial-basal resections of the temporal polar areas and mesial temporal structures were successfully achieved in all patients (2 with left-sided approaches, 2 with right-sided approaches). No neurological complications or neuropsychological declines were observed. All 4 patients achieved Engel class Ia outcome up to the end of the follow-up period (19, 15, 14, and 12 months). One patient developed hypoesthesia in the left V2 distribution but there were no other adverse events. The low degree of white matter injury from the eATM approach was analyzed using high-definition fiber tractography in 1 patient as a putative mechanism for preserving neuropsychological function. CONCLUSIONS: The described series demonstrates the feasibility and potential safety profile of a novel approach for medically refractory MTLE. The study affirms the feasibility of performing efficacious mesial temporal lobe resections through an eATM approach.

Risk Factors and Incidence of Epilepsy after Severe Traumatic Brain Injury.

We determined the incidence of post-traumatic epilepsy after severe traumatic brain injury. Of 392 patients surviving to discharge, cumulative incidence of post-traumatic epilepsy was 25% at 5 years and 32% at 15 years, an increase compared with historical reports. Among patients with one late seizure (>7 days post-trauma), the risk of seizure recurrence was 62% after 1 year and 82% at 10 years. Competing hazards regression identified age, decompressive hemicraniectomy, and intracranial infection as independent predictors of post-traumatic epilepsy. Patients with severe traumatic brain injury and a single late post-traumatic seizure will likely require long-term antiseizure medicines. ANN NEUROL 2022;92:663-669.

EEG Findings in Coronavirus Disease.

PURPOSE: Neurologic manifestations of coronavirus disease (COVID-19) such as encephalopathy and seizures have been described. To our knowledge, detailed EEG findings in COVID-19 have not yet been reported. This report adds to the scarce body of evidence. METHODS: We identified eight COVID-19 positive patients who underwent EEG monitoring in our hospital system. RESULTS: EEGs were most commonly ordered for an altered level of consciousness, a nonspecific neurologic manifestation. We observed generalized background slowing in all patients and generalized epileptiform discharges with triphasic morphology in three patients. Focal electrographic seizures were observed in one patient with a history of focal epilepsy and in another patient with no such history. Five of eight patients had a previous diagnosis of epilepsy, suggesting that pre-existing epilepsy can be a potential risk factor for COVID-19-associated neurological manifestations. Five of eight patients who underwent EEG experienced a fatal outcome of infection. CONCLUSIONS: Our findings underscore previous observations that neurologic manifestations are common in severe cases. COVID-19 patients with epilepsy may have an increased risk of neurological manifestations and abnormal EEG.

Awakening from post anoxic coma with burst suppression with identical bursts.

BACKGROUND: Electroencephalography (EEG) is commonly used after cardiac arrest. Burst suppression with identical bursts (BSIB) has been reported as a perfectly specific predictor of poor outcome but published case series are small. We describe two patients with BSIB who awakened from coma after cardiac arrest. METHODS: We identified two out-of-hospital cardiac arrest (OHCA) patients with coma and BSIB. We determined the etiology of arrest, presenting neurological examination, potential confounders to neurological assessment, neurodiagnostics and time to awakening. We reviewed and interpreted EEGs using 2021 American Clinical Neurophysiology Society guidelines. We quantified identicality of bursts by calculating pairwise correlation coefficients between the first 500 ms of each aligned burst. RESULTS: In case one we present a 62-year-old man with OHCA secondary to septic shock. EEG showed burst suppression pattern, with bursts consisted of high amplitude generalized spike waves in lock-step with myoclonus (inter-burst correlation = 0.86). He followed commands 3 days after arrest, when repeat EEG showed a continuous, variable and reactive background without epileptiform activity. Case two was a 49-year-old woman with OHCA secondary to polysubstance overdose. Initial EEG revealed burst suppression with high amplitude generalized polyspike-wave bursts with associated myoclonus. She followed commands on post-arrest day 4, when repeat EEG showed a continuous, variable and reactive background with frequent runs of bifrontal predominant sharply contoured rhythmic delta activity. CONCLUSION: These cases highlight the perils of prognosticating with a single modality in comatose cardiac arrest patients.

Last Electrically Well: Intraoperative Neurophysiological Monitoring for Identification and Triage of Large Vessel Occlusions.

INTRODUCTION: Intra-operative stroke (IOS) is associated with poor clinical outcome as detection is often delayed and time of symptom onset or patient's last known well (LKW) is uncertain. Intra-operative neurophysiological monitoring (IONM) is uniquely capable of detecting onset of neurological dysfunction in anesthetized patients, thereby precisely defining time last electrically well (LEW). This novel parameter may aid in the detection of large vessel occlusion (LVO) and prompt treatment with endovascular thrombectomy (EVT). METHODS: We performed a retrospective analysis of a prospectively maintained AIS and LVO database from May 2018-August 2019. Inclusion criteria required any surgical procedure under general anesthesia (GA) utilizing EEG (electroencephalography) and/or SSEP (somatosensory evoked potentials) monitoring with development of intraoperative focal persistent changes using predefined alarm criteria and who were considered for EVT. RESULT: Five cases were identified. LKW to closure time ranged from 66 to 321 minutes, while LEW to closure time ranged from 43 to 174 min. All LVOs were in the anterior circulation. Angiography was not pursued in two cases due to large established infarct (both patients expired in the hospital). EVT was pursued in two cases with successful recanalization and spontaneous recanalization was noted in one patient (mRS 0-3 at 90 days was achieved in all 3 cases). CONCLUSIONS: This study demonstrates that significant IONM changes can accurately identify patients with an acute LVO in the operative setting. Given the challenges of recognizing peri-operative stroke, LEW may be an appropriate surrogate to quickly identify and treat IOS.

The efficacy of somatosensory evoked potentials in evaluating new neurological deficits after spinal thoracic fusion and decompression.

OBJECTIVE: Posterior thoracic fusion (PTF) is used as a surgical treatment for a wide range of pathologies. The monitoring of somatosensory evoked potentials (SSEPs) is used to detect and prevent injury during many neurological surgeries. The authors conducted a study to evaluate the efficacy of SSEPs in predicting perioperative lower-extremity (LE) neurological deficits during spinal thoracic fusion surgery. METHODS: The authors included patients who underwent PTF with SSEP monitoring performed throughout the entire surgery from 2010 to 2015 at the University of Pittsburgh Medical Center (UPMC). The sensitivity, specificity, odds ratio, and receiver operating characteristic curve were calculated to evaluate the diagnostic accuracy of SSEP changes in predicting postoperative deficits. Univariate analysis was completed to determine the impact of age exceeding 65 years, sex, obesity, abnormal baseline testing, surgery type, and neurological deficits on the development of intraoperative changes. RESULTS: From 2010 to 2015, 771 eligible patients underwent SSEP monitoring during PTF at UPMC. Univariate and linear regression analyses showed that LE SSEP changes significantly predicted LE neurological deficits. Significant changes in LE SSEPs had a sensitivity and specificity of 19% and 96%, respectively, in predicting LE neurological deficits. The diagnostic odds ratio for patients with new LE neurological deficits who had significant changes in LE SSEPs was 5.86 (95% CI 2.74-12.5). However, the results showed that a loss of LE waveforms had a poor predictive value for perioperative LE deficits (diagnostic OR 1.58 [95% CI 0.19-12.83]). CONCLUSIONS: Patients with new postoperative LE neurological deficits are 5.9 times more likely to have significant changes in LE SSEPs during PTF. Surgeon awareness of an LE SSEP loss may alter surgical strategy and positively impact rates of postoperative LE neurological deficit status. The relatively poor sensitivity of LE SSEP monitoring may indicate a need for multimodal neurophysiological monitoring, including motor evoked potentials, in thoracic fusion surgery.

Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging.

Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously, we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here, we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 h at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-h retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation.

Influence of long-term social interaction on chirping behavior, steroid levels and neurogenesis in weakly electric fish.

Social interactions dramatically affect the brain and behavior of animals. Studies in birds and mammals indicate that socially induced changes in adult neurogenesis participate in the regulation of social behavior, but little is known about this relationship in fish. Here, we review studies in electric fish (Apteronotus leptorhychus) that link social stimulation, changes in electrocommunication behavior and adult neurogenesis in brain regions associated with electrocommunication. Compared with isolated fish, fish living in pairs have greater production of chirps, an electrocommunication signal, during dyadic interactions and in response to standardized artificial social stimuli. Social interaction also promotes neurogenesis in the periventricular zone, which contributes born cells to the prepacemaker nucleus, the brain region that regulates chirping. Both long-term chirp rate and periventricular cell addition depend on the signal dynamics (amplitude and waveform variation), modulations (chirps) and novelty of the stimuli from the partner fish. Socially elevated cortisol levels and cortisol binding to glucocorticoid receptors mediate, at least in part, the effect of social interaction on chirping behavior and brain cell addition. In a closely related electric fish (Brachyhypopomus gauderio), social interaction enhances cell proliferation specifically in brain regions for electrocommunication and only during the breeding season, when social signaling is most elaborate. Together, these studies demonstrate a consistent correlation between brain cell addition and environmentally regulated chirping behavior across many social and steroidal treatments and suggest a causal relationship.

Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus.

Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape.

Social interaction and cortisol treatment increase cell addition and radial glia fiber density in the diencephalic periventricular zone of adult electric fish, Apteronotus leptorhynchus.

In electric fish, Apteronotus leptorhynchus, both long-term social interaction and cortisol treatment potentiates chirping, an electrocommunication behavior that functions in aggression. Chirping is controlled by the diencephalic prepacemaker nucleus (PPn-C) located just lateral to the ventricle. Cells born in adult proliferative zones such as the periventricular zone (PVZ) can migrate along radial glial fibers to other brain regions, including the PPn-C. We examined whether social interactions or cortisol treatment influenced cell addition and radial glia fiber formation by (1) pairing fish (4 or 7 days) or (2) implanting fish with cortisol (7 or 14 days). Adult fish were injected with bromodeoxyuridine 3 days before sacrifice to mark cells that were recently added. Other fish were sacrificed after 1 or 7 days of treatment to examine vimentin immunoreactivity (IR), a measure of radial glial fiber density. Paired fish had more cell addition than isolated fish at 7 days, coinciding temporally with the onset of socially induced increase in chirping behavior. Paired fish also had higher vimentin IR at 1 and 7 days. For both cell addition and vimentin IR, the effect was regionally specific, increasing in the PVZ adjacent to the PPn-C, but not in surrounding regions. Cortisol increased cell addition at 7 days, correlating with the onset of cortisol-induced changes in chirping, and in a regionally specific manner. Cortisol for 14 days increased cell addition, and cortisol for 7 days increased vimentin IR but in a regionally non-specific manner. The correlation between treatment-induced changes in chirping and regionally specific increases in cell addition, and radial glial fiber formation suggests a causal relationship between such behavioral and brain plasticity in adults, but this hypothesis will require further testing.