Is Severe Head Injury Associated with Functional (Psychogenic) Seizures?

Abstract, published in Seizure

Objectives: The aim of the current study was to compare the frequency of significant head injuries in three groups of people with seizures [idiopathic generalized epilepsies (IGE) vs. temporal lobe epilepsy (TLE) vs. functional seizures (FS)].

Methods: This was a retrospective study. All patients with a diagnosis of IGE, TLE, or FS were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2020.

Results: One thousand and four hundred ninety-two patients were studied (559 patients with IGE, 646 people with TLE, and 287 persons with FS). Overall, 77 (5.2%) individuals of the studied people reported experiencing severe head injuries before the onset of their seizures [9 patients (1.6%) with IGE, 56 people (8.7%) with TLE, and 12 persons (4.2%) with FS; p = 0.0001]. Compared to people with IGE, the odds ratio of having a premorbid history of severe head injury in the FS group was 2.67 [95% Confidence Interval (CI): 1.11-6.40; p = 0.0280]. Compared to people with TLE, the odds ratio of having a premorbid history of severe head injury in the FS group was 0.46 (95% CI: 0.24-0.87; p = 0.0170).

Conclusion: Severe head injury is significantly associated with functional (psychogenic) seizures. However, since head injury is also a significant risk factor for focal epilepsies, it may be necessary to ascertain the diagnosis of post-traumatic seizures by obtaining a detailed clinical history and also by performing video-EEG monitoring in order to adopt an appropriate treatment strategy in these patients.

In-depth Characterization of a Mouse Model of Post-traumatic Epilepsy for Biomarker and Drug Discovery

Abstract, published in Acta Neuropathologica Communications

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies and 10–20% of the acquired forms. The latency between traumatic brain injury (TBI) and epilepsy onset in high-risk patients offers a therapeutic window for intervention to prevent or improve the disease course. However, progress towards effective treatments has been hampered by the lack of sensitive prognostic biomarkers of PTE, and of therapeutic targets. There is therefore a pressing clinical need for preclinical PTE models suitable for biomarker discovery and drug testing.

We characterized in-depth a model of severe TBI induced by controlled cortical impact evolving into PTE in CD1 adult male mice. To identify sensitive measures predictive of PTE development and severity, TBI mice were longitudinally monitored by video-electrocorticography (ECoG), examined by MRI, and tested for sensorimotor and cognitive deficits and locomotor activity. At the end of the video-ECoG recording mice were killed for brain histological analysis. PTE occurred in 58% of mice with frequent motor seizures (one seizure every other day), as determined up to 5 months post-TBI. The weight loss of PTE mice in 1 week after TBI correlated with the number of spontaneous seizures at 5 months. Moreover, the recovery rate of the sensorimotor deficit detected by the SNAP test before the predicted time of epilepsy onset was significantly lower in PTE mice than in those without epilepsy. Neuroscore, beam walk and cognitive deficit were similar in all TBI mice. The increase in the contusion volume, the volume of forebrain regions contralateral to the lesioned hemisphere and white matter changes over time assessed by MRI were similar in PTE and no-PTE mice. However, brain histology showed a more pronounced neuronal cell loss in the cortex and hippocampus contralateral to the injured hemisphere in PTE than in no-PTE mice.

The extensive functional and neuropathological characterization of this TBI model, provides a tool to identify sensitive measures of epilepsy development and severity clinically useful for increasing PTE prediction in high-risk TBI patients. The high PTE incidence and spontaneous seizures frequency in mice provide an ideal model for biomarker discovery and for testing new drugs.

Determinants of Caregiver Burden in Male Patients with Epilepsy Following Penetrating Traumatic Brain Injury

Abstract, originally published in Epilepsy & Behavior

Purpose: We determined burden of caring for patients with post-traumatic epilepsy (PTE) following penetrating traumatic brain injury (TBI) and identified factors predicting higher burden.

Method: We assessed 331 caregiver-veteran dyads in Phase 2 (136 PTE, 136 non-PTE, and 59 HC dyads), 133 in Phase 4 (47 PTE, 56 non-PTE, and 30 HC dyads) – 30 years later, and 46 dyads in the follow-up study (18 PTE, 19 non-PTE, and 9 HC). Caregiver’s burden was measured by Zarit Burden Index and a questionnaire. Veterans completed demographic, mental and physical well-being, quality-of-life, and medical-related information. Caregivers provided information about burden and their assessments of cognitive decline and neuropsychiatric status of the veterans.

Results: PTE caregivers perceived significantly more burden than comparison groups at all phases. Bivariate analyses revealed that caregiver distress due to the veteran’s neuropsychiatric state including cognitive decline, apathy, and disinhibition and the veteran’s characteristics including older age at epilepsy onset and role limitation due to physical problems were associated with higher burden. Finally, we revealed disinhibition distress, and role imitation due to physical problems as the predictors in a model of caregiver burden.

Conclusion: Elevated PTE caregiver burden is persistent across the life span suggesting that caregivers could benefit from counseling and targeted psychosocial interventions to reduce their burden.

Preventing Seizures After Brain Injury Could Stave Off Dementia

Summary, originally published by the University of Alberta

Blocking seizures after a head injury could slow or prevent the onset of dementia, according to new research by University of Alberta biologists.

“Traumatic brain injury is a major risk factor for dementia, but the reason this is the case has remained mysterious,” said Ted Allison, co-author and professor in the Department of Biological Sciences in the Faculty of Science. “Through this research, we have discovered one important way they are linked—namely, post-injury seizures.”

“Our data suggest that, at least in animal models, blocking these seizures also could have a benefit later in life by slowing or preventing the onset of dementia,” he explained. “A prophylactic treatment to prevent dementia is an exciting possibility, though there is much work to be done to develop our concept.”

Study Characterizes Mouse Model of Neocortical Injury–Induced Status Epilepticus

Abstract, originally published in Epilepsia

Objective: To characterize neocortical onset status epilepticus (SE) in the C57BL/6J mouse.

Methods: We induced SE by administering homocysteine 16-18 hours after cobalt (Co) implantation. SE was monitored by video and electroencephalography (EEG). We evaluated brain structure with magnetic resonance imaging (MRI). Neurodegeneration was evaluated 72 hours after SE using Fluoro-Jade C staining.

Results: Cobalt triggered seizures in a dose-dependent manner (median effective dose, ED50 = 0.78 mg) and the latency to peak seizure frequency shortened with increased dose. Animals developed SE after homocysteine administration. SE began with early intermittent focal seizures, consisting of frontal onset rhythmic spike-wave discharges manifested as focal dystonia with clonus. These focal seizures then evolved into generalized continuous convulsive activity. Behavioral manifestations of SE included tonic stiffening, bilateral limb clonus, and bilateral tonic-clonic movements, which were accompanied by generalized rhythmic spike-wave discharges on EEG. After prolonged seizures, animals became comatose with intermittent bilateral myoclonic seizures or jerks. During this period, EEG showed seizures interspersed with generalized periodic discharges on a suppressed background. MRI obtained when animals were in a coma revealed edema, midline shift in frontal lobe around the Co implantation site, and ventricular effacement. Fluoro-Jade C staining revealed neurodegeneration in the cortex, amygdala, and thalamus.

Significance: We have developed a mouse model of severe, refractory cortical-onset SE, consisting of convulsions merging into a coma, EEG patterns of cortical seizures, and injury, with evidence of widespread neocortical edema and damage. This model replicates many features of acute seizures and SE resulting from traumatic brain injury, subarachnoid, and lobar hemorrhage.

Sleep-Wake Characteristics in a Mouse Model of Severe Traumatic Brain Injury: Relation to Post-Traumatic Epilepsy

Abstract, originally published in Epilepsia Open

Study objectives: Traumatic brain injury (TBI) results in sequelae that include post-traumatic epilepsy (PTE) and sleep-wake disturbances. Here we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI.

Methods: Following controlled cortical impact (CCI) or sham injury (craniotomy only) CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2 or 3) 1-week long video EEG recordings were performed after the injury to examine epileptiform activity. High amplitude interictal events were extracted from EEG using an automated method. After scoring sleep-wake patterns, sleep spindles and EEG delta power were derived from non-rapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed in sham and CCI cohorts to quantify the brain lesions. We then employed a no craniotomy (NC) control to perform 1-week long EEG recordings at week 1 and month 1 after surgery.

Results: Posttraumatic seizures were seen in CCI group only, whereas interictal epileptiform activity was seen in CCI or sham. Sleep-wake disruptions consisted of shorter wake or NREM bout lengths and shorter duration or lower power for spindles in CCI and sham. NREM EEG delta power increased in CCI and sham groups compared to NC though CCI group with post-traumatic seizures had lower power at a chronic time point compared to those without. Follow up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes.

Significance: In our TBI model, tracking changes in NREM delta power distinguishes CCI acutely and animals that will eventually develop PTE, but further work is necessary to identify sleep biomarkers of PTE. Employing NC controls together with sham controls should be considered in future TBI studies.

Inhibiting Epileptic Activity in the Brain

Abstract, originally published in Neurobiology of Disease featuring the work of CURE Grantee Dr. Jeffrey Loeb

Epileptic seizures often originate in small, localized areas of the brain where neurons abnormally fire in unison. These electrical impulses disrupt proper brain functioning and cause seizures. But what makes regions where seizures start different from parts of the brain where electrical impulses remain normal? More importantly, what prevents these epileptic centers from growing?

The answer to these questions may lie in a new discovery by researchers at the University of Illinois Chicago. In non-CURE funded work, CURE Grantee Dr. Jeffrey Loeb and his colleagues found that a protein — called DUSP4 — was increased in healthy brain tissue directly adjacent to epileptic tissue. Their research suggests that boosting levels of DUSP4 could be a novel way of preventing or treating epilepsy.

Their findings are reported in the journal Neurobiology of Disease.

“If epileptic brain regions spread throughout the brain with nothing to stop them, the seizures would overwhelm the brain, it would not be survivable,” said Loeb, UIC professor and head of neurology and rehabilitation at the College of Medicine and corresponding author on the study. “We wondered if there were natural ways that epileptic brain areas are quarantined. We searched for genes at the border between epileptic and normal brain tissue that may help prevent the spread of epilepsy.”

Study Finds That Psychotherapy via Telehealth Is a Viable Treatment Option for Psychogenic Nonepileptic Seizures (PNES)

Abstract, originally published in Epilepsia

Objective: Previous studies have shown the effectiveness of manual-based treatment for psychogenic nonepileptic seizures (PNES), but access to mental health care still remains a problem, especially for patients living in areas without medical professionals who treat conversion disorder. Thus, we evaluated patients treated with cognitive behavioral therapy–informed psychotherapy for seizures with clinical video telehealth (CVT). We evaluated neuropsychiatric and seizure treatment outcomes in veterans diagnosed with PNES seen remotely via telehealth. We hypothesized that seizures and comorbidities will improve with treatment.

Methods: This was a single–arm, prospective, observational, cohort, consecutive outpatient study. Patients with video–electroencephalography–confirmed PNES (n = 32) documented their seizure counts daily and comorbid symptoms prospectively over the course of treatment. Treatment was provided using a 12–session manual–based psychotherapy treatment given once per week, via CVT with a clinician at the Providence Veterans Affairs Medical Center.

Results: The primary outcome, seizure reduction, was 46% (P = .0001) per month over the course of treatment. Patients also showed significant improvements in global functioning (Global Assessment of Functioning, P = < .0001), quality of life (Quality of Life in Epilepsy Inventory–31, P = .0088), and health status scales (Short Form 36 Health Survey, P < .05), and reductions in both depression (Beck Depression Inventory–II, P = .0028) and anxiety (Beck Anxiety Inventory, P = .0013) scores.

Significance: Patients with PNES treated remotely with manual-based seizure therapy decreased seizure frequency and comorbid symptoms and improved functioning using telehealth. These results suggest that psychotherapy via telehealth for PNES is a viable option for patients across the nation, eliminating one of the many barriers of access to mental health care.

Study Shows Novel Mobile Technology Improves Quality of Life for Adults with Epilepsy

In an externally-funded grant, CURE PTE Initiative investigators Dr. Jeffrey Loeb, Dr. Dilip Pandey, and Research Associate Jessica Levy investigate the ways technology can improve outcomes in individuals living with epilepsy


Purpose: People with epilepsy (PWE) come from a wide variety of social backgrounds and educational skillsets, making self-management (SM) education for improving their condition challenging. Here, we evaluated whether a mobile technology-based personalized epilepsy SM education intervention, PAUSE to Learn Your Epilepsy (PAUSE), improves SM measures such as self-efficacy, epilepsy SM behaviors, epilepsy outcome expectations, quality of life (QoL), and personal impact of epilepsy in adults with epilepsy.

Methods: Recruitment for the PAUSE study occurred from October 2015 to March 2019. Ninety-one PWE were educated using an Internet-enabled computer tablet application that downloads custom, patient-specific educational programs from Validated self-reported questionnaires were used for outcome measures. Participants were assessed at baseline (T0), the first follow-up at completion of the PWE-paced 8–12-week SM education intervention (T1), and the second follow-up at least 3 months after the first follow-up (T2).

Results: The study population was diverse and included individuals with a wide variety of SM educational needs and abilities. The median time for the first follow-up assessment (T1) was approximately 4 months following the baseline (T0) and 8 months following baseline for the second follow-up assessment (T2). Participants showed significant improvement in all SM behaviors, self-efficacy, outcome expectancy, QOL, and personal impact of epilepsy measures from T0 to T1. Participants who scored lower at baseline tended to show greater improvement at T1. Similarly, results showed that participant improvement was sustained in most SM measures from T1 to T2.

Conclusion: This study demonstrated that a mobile technology-based personalized SM intervention is feasible to implement. The results provide evidence that epilepsy SM behavior and practices, QoL, outcome expectation for epilepsy treatment and management, self-efficacy, and outcome expectation and impact of epilepsy significantly improve following a personalized SM education intervention. This underscores a greater need for a pragmatic trial to test the effectiveness of personalized SM education, such as PAUSE to Learn Your Epilepsy, in broader settings specifically for the unique needs of the hard-to-reach and hard-to-treat population of PWE.

Assessing the Personal Impact of Epilepsy in a Population-Based Cohort of Veterans


Epilepsy impacts patient lives in multidimensional ways. Although previous work has investigated epilepsy impact on health status, little is known about the overall quantified impact of epilepsy in Veterans. The goal of this study was to describe the impact of epilepsy on Veterans’ lives using the Personal Impact of Epilepsy Scale (PIES) and determine the patient and clinical characteristics most strongly correlated with epilepsy impact. The researchers described cohort characteristics and developed regression models to determine which characteristics were most strongly associated with PIES subscale (seizure, medication, comorbidity) scores and quality of life (QOL).


Approximately 36% of those who were invited responded to the survey. Of the 438 respondents included in the analyses, roughly 50% were aged 45-64 years (35% >65; 14% 18-44); 19% were women. Almost 90% had previously received care by an epilepsy specialist, 37% of which was in Veterans Health Administration (VHA) and 38% in both VHA and community. The PIES overall and subscale scores were significantly lower for older Veterans with epilepsy (VWE) (>65) compared with younger (18-44 years) and middle-aged (45-64 years) VWE, indicating that older Veterans had a lower epilepsy impact overall, and for seizures, medication, and comorbidity.

The younger and middle-aged VWE had a significantly higher proportion with psychiatric diagnosis compared with older VWE. There was a trend for significance for the overall PIES scores by gender, with women having total higher (worse) scores (mean = 93.10, SD = 69.68) than men (mean = 74.39, SD = 59.97), which was driven by a statistically higher score on the seizure subscale for women (mean = 27.66, SD = 27.97) compared with men (mean = 9.29, SD 25.35). Regression models revealed that frequent seizures (>1/month, >2/month) and diagnoses of dementia significantly predicted higher (more negative) Seizure Severity PIES score. Frequent seizures (>1/month), number of antiepileptic drugs (AEDs), and diagnosis of dementia predicted negative impact, and older age predicted positive impact for medication subscale. Frequent seizures (>1/month) and diagnoses of depression and dementia predicted negative mood and social impact. Seizure frequency (>2/month) was the only variable that significantly predicted lack of excellent quality of life. Effects for gender were not significant after controlling for other variables.


Findings were similar to a prior study of generic health outcomes in younger and older VWE using the 36-Item Short Form Survey (SF-36). Seizure frequency was consistently associated with negative impact of epilepsy in all age groups. While dementia and other diagnosed health conditions also contributed to epilepsy impact, older VWE (veterans with epilepsy) had significantly lower PIES (Personal Impact of Epilepsy Scale) scores even after controlling for physical conditions and dementia. Lower (better) scores for comorbidity and medication scales in older VWE may be due to fewer diagnosed psychiatric comorbidities and psychiatric medication that have similar cognitive impact as AEDs (antiepileptic drugs), and which may also interact with AEDs. Implementation of patient self-management programs to improve seizure control may reduce epilepsy impact for Veterans and reduce Veterans Affairs (VA) healthcare utilization. The PIES may also be useful to measure outcomes of self-management interventions.