Would people living with epilepsy benefit from palliative care?

Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life. Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population. In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.

Quality improvement studies in nursing homes: a scoping review.

BACKGROUND: Quality improvement (QI) is used in nursing homes (NH) to implement and sustain improvements in patient outcomes. Little is known about how QI strategies are used in NHs. This lack of information is a barrier to replicating successful strategies. Guided by the Framework for Implementation Research, the purpose of this study was to map-out the use, evaluation, and reporting of QI strategies in NHs. METHODS: This scoping review was completed to identify reports published between July 2003 through February 2019. Two reviewers screened articles and included those with (1) the term "quality improvement" to describe their methods, or reported use of a QI model (e.g., Six Sigma) or strategy (e.g., process mapping) (2), findings related to impact on service and/or resident outcomes, and (3) two or more NHs included. Reviewers extracted data on study design, setting, population, problem, solution to address problem, QI strategies, and outcomes (implementation, service, and resident). Vote counting and narrative synthesis were used to describe the use of QI strategies, implementation outcomes, and service and/or resident outcomes. RESULTS: Of 2302 articles identified, the full text of 77 articles reporting on 59 studies were included. Studies focused on 23 clinical problems, most commonly pressure ulcers, falls, and pain. Studies used an average of 6 to 7 QI strategies. The rate that strategies were used varied substantially, e.g., the rate of in-person training (55%) was more than twice the rate of plan-do-study-act cycles (20%). On average, studies assessed two implementation outcomes; the rate these outcomes were used varied widely, with 37% reporting on staff perceptions (e.g., feasibility) of solutions or QI strategies vs. 8% reporting on fidelity and sustainment. Most studies (n = 49) reported service outcomes and over half (n = 34) reported resident outcomes. In studies with statistical tests of improvement, service outcomes improved more often than resident outcomes. CONCLUSIONS: This study maps-out the scope of published, peer-reviewed studies of QI in NHs. The findings suggest preliminary guidance for future studies designed to promote the replication and synthesis of promising solutions. The findings also suggest strategies to refine procedures for more effective improvement work in NHs.

Too Many Deaths, Too Many Left Behind: A People's External Review of the U.S. Centers for Disease Control and Prevention's COVID-19 Pandemic Response.

The U.S. population has suffered worse health consequences owing to COVID-19 than comparable wealthy nations. COVID-19 had caused more than 1.1 million deaths in the U.S. as of May 2023 and contributed to a 3-year decline in life expectancy. A coalition of public health workers and community activists launched an external review of the Centers for Disease Control and Prevention's pandemic management from January 2021 to May 2023. The authors used a modified Delphi process to identify core pandemic management areas, which formed the basis for a survey and literature review. Their analysis yields 3 overarching shortcomings of the Centers for Disease Control and Prevention's pandemic management: (1) Centers for Disease Control and Prevention leadership downplays the serious impacts and aerosol transmission risks of COVID-19, (2) Centers for Disease Control and Prevention leadership has aligned public guidance with commercial and political interests over scientific evidence, and (3) Centers for Disease Control and Prevention guidance focuses on individual choice rather than emphasizing prevention and equity. Instead, the agency must partner with communities most impacted by the pandemic and encourage people to protect one another using layered protections to decrease COVID-19 transmission. Because emerging variants can already evade existing vaccines and treatments and Long COVID can be disabling and lacks definitive treatment, multifaceted, sustainable approaches to the COVID-19 pandemic are essential to protect people, the economy, and future generations.

Electrographic seizure monitoring with a novel, wireless, single-channel EEG sensor.

OBJECTIVE: Recording seizures using personal seizure diaries can be challenging during everyday life and many seizures are missed or mis-reported. People living with epilepsy could benefit by having a more accurate and objective wearable EEG system for counting seizures that can be used outside of the hospital. The objective of this study was to (1) determine which seizure types can be electrographically recorded from the scalp below the hairline, (2) determine epileptologists' ability to identify electrographic seizures from single-channels extracted from full-montage wired-EEG, and (3) determine epileptologists' ability to identify electrographic seizures from Epilog, a wireless single-channel EEG sensor. METHODS: Epilog sensors were worn concurrently during epilepsy monitoring unit (EMU) monitoring. During standard-of-care review, epileptologists were asked if the electrographic portion of the seizure was visible on single channels of wired electrodes at locations proximal to Epilog sensors, and if focal-onset, which electrode was closest to the focus. From these locations, single channels of EEG extracted from wired full-montage EEG and the proximal Epilog sensor were presented to 3 blinded epileptologists along with markers for when known seizures occurred (taken from the standard-of-care review). Control segments at inter-ictal times were included as control. The epileptologists were asked whether a seizure event was visible in the single channel EEG record at or near the marker. RESULTS: A total of 75 seizures were recorded from 22 of 40 adults that wore Epilog during their visit to the EMU. Epileptologists were able to visualize known seizure activity on at least one of the wired electrodes proximal to Epilog sensors for all seizure events. Epileptologists accurately identified seizures in 71% of Epilog recordings and 84% of single-channel wired recordings and were 92% accurate identifying seizures with Epilog when those seizures ended in a clinical convulsion compared to those that did not (>55%). CONCLUSIONS: Epileptologists are able to visualize seizure activity on single-channels of EEG at locations where Epilog sensors are easily placed on the scalp below hairline. Manual review of seizure annotations can be done quickly and accurately (>70% TP and >98% PPV) on single-channel EEG data. Reviewing single-channel EEG is more accurate than what has been reported in the literature on self-reporting seizures in seizure diaries, the current standard of care for seizure counting outside of the EMU. SIGNIFICANCE: Wearable EEG will be important for seizure monitoring outside of the hospital. Epileptologists can accurately identify seizures in single-channel EEG, better than patient self-reporting in diaries based on the literature. Automated or semi-automated seizure detection on single channels of EEG could be used in the future to objectively count seizures to complement the standard of care outside of the EMU without the overt burden upon epileptologist review.

Differences in Patient and Parent Informant Reports of Depression and Anxiety Symptoms in a Clinical Sample of Transgender and Gender Diverse Youth.

Purpose: We assessed characteristics of patients at a pediatric gender clinic and investigated if reports of mental health concerns provided by transgender and gender diverse (TGD) youth patients differed from reports provided by a parent informant on their behalf. Methods: This cross-sectional study included 259 TGD patients 8 to 22 years of age attending a pediatric gender clinic in the southeast United States from 2015 to 2020. Pearson correlations and paired sample t-tests compared patient-reported mental health concerns at patient intake with those provided by a parent informant. Clinical symptom severity was assessed with standardized T-scores. Level 2 Patient-Reported Outcomes Measurement Information System (PROMIS) Emotional Distress-Depression Scale and Level 2 PROMIS Emotional Distress-Anxiety Scale assessed depression and anxiety symptoms of patients. Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Parent/Guardian-Rated Level 1 Cross-Cutting Symptom Measure was used with parents. Results: Patients had a mean age of 14.9 at first visit, with most identifying as White (85.5%), non-Hispanic (91.1%), and as a boy or man (63.6%). Half had moderate-to-severe depression (51.2%) or anxiety (47.9%) symptoms. There was a moderate, positive correlation between patient-reported and parent-reported depression symptoms, with no correlation for anxiety symptoms. Informant type differences were statistically significant (patients reporting greater depression and anxiety symptoms). Conclusions: TGD youth patients reported more severe depression and anxiety symptoms compared with parent informants. Despite moderate agreement on depression symptoms, parents did not accurately detect their child's anxiety symptoms. These discrepancies highlight a need for interventions which increase parental recognition of child mental health status.

New antiepileptic drugs: lacosamide, rufinamide, and vigabatrin.

OPINION STATEMENT: The treatment of epilepsy is complicated by the multiple seizure types and epilepsy syndromes needing therapy. In addition, seizures in up to 30% of epilepsy patients are resistant to available medications. The three newest antiepileptic medications (lacosamide, rufinamide, and vigabatrin) all putatively have novel mechanisms of action, which might increase the chance of treatment success in patients failing previous antiepilepsy drug trials and the chance of successful synergy with currently available medications. In our experience, all three drugs generally are well tolerated, although the risk for serious long-term complications with vigabatrin presents special challenges and precautions. Lacosamide is approved for the adjunctive therapy of complex partial seizures in adults and also is available in an intravenous formulation. Rufinamide is a new treatment option for seizures associated with Lennox-Gastaut syndrome, and although it is not FDA approved for partial seizures, it has shown efficacy for that indication as well. Vigabatrin has been approved in adults for drug-resistant complex partial seizures and in infants as a treatment option for infantile spasms.

A novel apparatus for lateral fluid percussion injury in the rat.

Lateral fluid percussion injury (LFPI) is the most commonly used experimental model of human traumatic brain injury (TBI). To date, investigators using this model have produced injury using a pendulum-and-piston-based device (PPBD) to drive fluid against an intact dural surface. Two disadvantages of this method, however, are (1) the necessary reliance on operator skill to position and release the pendulum, and (2) reductions in reproducibility due to variable friction between the piston's o-rings and the cylinder. To counteract these disadvantages, we designed a low-priced, novel, fluid percussion apparatus that delivers a pressure pulse of air to a standing column of fluid, forcing it against the intact dural surface. The pressure waveforms generated by this apparatus are similar to those reported in the LFPI/PPBD literature and had little variation in appearance between trials. In addition, our apparatus produced an acute and chronic TBI syndrome similar to that in the LFPI/PPBD literature, as quantified by histological changes, MRI structural changes and chronic behavioral sequelae.

End-of-dose emergent psychopathology in ambulatory patients with epilepsy on stable-dose lamotrigine monotherapy: a case series of six patients.

OBJECTIVE: Specific psychological withdrawal symptoms following the cessation of treatment with many drugs that affect the central nervous system, including anxiolytics and antidepressants, have been well documented. Studies have investigated withdrawal symptoms associated with some of the older antiepileptic drugs, but the potential for withdrawal symptoms associated with newer antiepileptic drugs, including lamotrigine, has not yet been investigated. METHODS: Using a retrospective chart review, we identified six patients with epilepsy who reported transient emergent psychological symptoms during stable, chronic lamotrigine monotherapy. RESULTS: These symptoms included anxiety, emotional lability, and irritability. In each case, the symptoms resulted in marked subjective distress and reliably occurred in the 1-2h before the patients were due to take their next dose of medication. CONCLUSIONS: Lamotrigine withdrawal symptoms exist and can occur as an end-of-dose phenomenon, even in patients on stable medication doses. End-of-dose withdrawal from lamotrigine is a clinically significant adverse effect that can hamper successful treatment with this medication.

Drug ingestions in children 10-14 years old: an old problem revisited.

To determine changes in rates of drug ingestions in 10-14 year old children in our country, a retrospective chart review of 10-14 year olds hospitalized for drug ingestion between 1993-1995 and 2000-2004 was performed. Odds ratios and Chi-square were used for analyses. From 1993-1995 there were 92.8 ingestions/100,000 children/year; from 2000-2004 there were 63.3 ingestions/100,000 children/year. More males ingested in 2000-2004 than 1993-1995 (26.3% vs.14.2% O.R. 2.15 [1.19, 3.92]). More patients took psychiatric medications in 2000-2004 than 1993-1995 (38.9% vs. 27.0%, O.R. 1.72 [1.06, 2.80]). More patients ingested SSRIs in 2000-2004 than 1993-1995; fewer ingested tricyclics. Hospitalization rates for drug ingestions have decreased. There has been a change in drug ingested, and more males are ingesting drugs.

Use of a safety resource center in a pediatric emergency department.

OBJECTIVE: To describe the use of a safety resource center (SRC) within a pediatric emergency department (ED) about injury prevention (IP) counseling, sales, costs, and parental responses to the services. METHODS: The SRC was established in June 2005 in the waiting area of an urban pediatric ED caring for approximately 96,000 patients annually. Safety resource center staff sells products of proven efficacy (eg, car seats, smoke alarms, and bike helmets) and offers safety education materials to patients and families. Activities including sales, educational content provided, types of inquiries from families, and overall satisfaction with the service were logged into a Microsoft Access database. Follow-up phone calls are made to all families 3 weeks after they purchase a product. RESULTS: Between June 20, 2005 and July 1, 2007, the SRC served approximately 13,000 families. Seven hundred eighty-six families purchased 816 products, generating $14,859. An additional 473 products were given away, totaling 1289 product items provided to families. The most commonly purchased items were car safety seats and bicycle helmets. Roughly 7000 IP-related brochures were distributed to ED families, and 120 car seats were fitted. Of the 786 families who made a purchase, 383 (49%) were reached for follow-up. Ninety-seven percent reported to still be using the purchased product, and 28% made a different change in the home to practice safer behaviors. Ninety-five percent were grateful that the SRC was located in the ED. CONCLUSIONS: The SRC can provide IP product, encourage families to practice safer behaviors, and is well-received within a large, urban pediatric ED.

Skin Irritation during Video-EEG Monitoring.

OBJECTIVES: Video-EEG (VEEG) monitoring, indicated to characterize and diagnose seizures, is recorded over several days with electrodes glued to the patient's scalp. Our investigation was designed to determine the incidence of electrode-related skin irritation during VEEG in the epilepsy monitoring unit (EMU) and implement a series of interventions to reduce the incidence of moderate to severe irritation. METHODS: Between May 2012 and March 2015, EMU patients were assessed for skin lesions before electrode placement and at discharge. Prospectively gathered demographic data included: age, gender, race/ethnicity, length of monitoring (LOM), skin prep medium (SPM) used, self-reported skin sensitivity, history of skin diseases, and skin products used on the day of admission. When present, electrode-related skin irritation was graded as mild, moderate, or severe. Data were collected before any intervention (baseline-group) and thereafter with each intervention: standardization (single SPM, raising awareness, monitoring for electrode-related discomfort); face washing; applying skin barrier; replacing tape with gauze; and using disposable electrodes. RESULTS: Data from 861 patients were analyzed (104-146 per group). At baseline, any skin irritation occurred in 27.3% of patients; it was moderate or severe in 19.1%. LOM ≥4 days and electrode position on facial skin were associated with significantly higher risk. All interventions reduced rates of skin irritation, but only the standardization intervention was statistically significant. CONCLUSIONS: During VEEG admissions, electrode-related skin irritation occurred in about one-third of patients; it was moderate to severe in one-fifth. A standardized care process with regular monitoring for discomfort led to significant improvement in the rate of irritation.

The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis.

BACKGROUND: Late-onset GM2 gangliosidosis (LGG) is a rare disease that is often considered in the differential diagnosis of adolescents and young adults who present with multiple realms of neurologic dysfunction. Cognitive disturbances are common but have not been systematically studied. OBJECTIVE: To determine the natural history of cognitive dysfunction in patients with LGG. DESIGN: Case series and literature review. SETTING: Urban tertiary referral clinic. PATIENTS: Individuals with hexosaminidase A deficiency as the origin of LGG. MAIN OUTCOME MEASURES: Cognitive dysfunction, psychiatric symptoms, and cerebellar, upper motor neuron, lower motor neuron, or extrapyramidal symptoms and signs. RESULTS: Historical and examination data from 62 patients were found. Forty-four percent of LGG patients had some degree of cognitive dysfunction. Cognitive dysfunction was associated with a greater number of other elemental neurologic deficits. In 21 patients with acceptable longitudinal information, 8 (38%) had a static cognitive disorder, whereas progressive dementia was evident in 13 patients (62%), including 2 of our cases with serial neuropsychological testing. Neuroimaging often showed nonspecific cerebellar and/or cerebral atrophy. CONCLUSIONS: Cognitive dysfunction is a frequent manifestation of LGG. Patients who experience cognitive dysfunction are more likely to have a greater number of other neurologic manifestations of the disease. Cognitive dysfunction may take the form of static encephalopathy, but progressive dementia is more often encountered. The pathogenesis of cognitive dysfunction in this disease is unknown, highlighting the need for further study.

JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI.

Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABA(A)R). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABA(A)R subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABA(A)R α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABA(A)R α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABA(A)R α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABA(A)R α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABA(A)R α1 protein levels and improves vestibular motor recovery.

Early false-negative diffusion-weighted imaging in brainstem infarction.

It has been well established that acute ischemic lesions can be identified with diffusion-weighted imaging before they are detected on computed axial tomography or conventional magnetic resonance imaging sequences. Previous studies examining the sensitivity and specificity of diffusion-weighted imaging for acute stroke have dealt primarily with cortical stroke. Only limited information is available on the accuracy and temporal evolution of findings on diffusion-weighted imaging in patients with brainstem infarction. We present a case of lateral medullary infarction with false-negative diffusion-weighted imaging 16 hours after symptom onset and a brief review of the literature on the utility of diffusion-weighted imaging in early detection of brainstem stroke. Cases with false-negative initial imaging are increasingly more commonly reported in the literature, with initial images being obtained from 0.5 to over 24 hours after symptom onset. This delay in radiographic confirmation of brainstem stroke emphasizes the continuing need for accurate clinical diagnoses, especially in the early hours after symptom onset, when thrombolysis remains a treatment option. Delays in diagnosis and initiation of treatment of brainstem stroke may increase the associated morbidity and mortality.

Effects of JAK2-STAT3 signaling after cerebral insults.

The JAK2-STAT3 signaling pathway has been shown to regulate the expression of genes involved in cell survival, cell proliferation, cell-cycle progression, and angiogenesis in development and after cerebral insults. Until recently, little has been known about the effects of this pathway activation after cerebral insults and if blocking this pathway leads to better recovery. This review exams the role of this pathway after 3 cerebral insults (traumatic brain injury, stroke, and status epilepticus).

Pre-admission clinical factors affect length of stay in the epilepsy monitoring unit.

OBJECTIVE: Video-EEG monitoring in the epilepsy monitoring unit (EMU) is a limited clinical resource. Knowledge of the predicting factors for length of stay (LOS) in the EMU may allow providers to more efficiently utilize EMU bed space. METHODS: The records for all consecutive admissions to the EMU at the University of Colorado Hospital between December 1, 2010 and May 31, 2011 (n = 142) were retrospectively reviewed. RESULTS: Univariate analyses focusing on variables known prior to admission showed that EMU LOS (in hours) was not significantly correlated with patient age, number of event types, or number of antiepileptic drugs at admission. Patients who were admitted to the EMU for event characterization had statistically significantly shorter average LOS than patients who had been admitted as a part of a presurgical evaluation. Patients who reported < = 1 seizure per week had a statistically significantly higher average LOS than patients who reported >= 1 seizure per day. These variables were also significantly predictive of total LOS (p < 0.0001 and p = 0.03, respectively) in multivariate analysis. SIGNIFICANCE: Pre-admission clinical variables may predict EMU LOS. These factors could be used at the administrative level for maximum EMU resource utilization.

ADC mapping and T1-weighted signal changes on post-injury MRI predict seizure susceptibility after experimental traumatic brain injury.

OBJECTIVE: Post-traumatic epilepsy (PTE) is a serious complication of traumatic brain injury (TBI). This study is designed to determine the feasibility of using multiparametric MRI endpoints to predict differences in seizure susceptibility after experimental TBI. METHODS: MRI imaging and behavioral measurements were performed at multiple time points after lateral fluid percussion injury (FPI) in rats. Seizure susceptibility was determined by video-electroencephalogram (EEG) monitoring and off-line signal analysis after chemoconvulsant challenge. RESULTS: Multiple MRI endpoints, including measures of injury-related brain swelling (normalized interhemispheric volume difference, NIVD) and T1-weighted signal change with contrast enhancement (a measure of blood-brain barrier disruption, BBBD), reliably distinguished between injured and sham-injured animals at 72 hours after injury. ADC (apparent diffusion coefficient) values (a measure of water diffusivity) in injured cortex at 72 hours and 1 week after injury, BBBD in injured cortex at 72 hours after injury and NIVD at 72 hours after injury were significantly correlated with EEG-based measures of seizure susceptibility to chemoconvulsant challenge at 3 months after injury. CONCLUSIONS: The correlations between our MRI quantitative endpoints and EEG-based measures of seizure susceptibility to chemoconvulsant challenge in injured animals versus sham-injured animals support the feasibility of these MRI endpoints as potential biomarkers for post-traumatic epileptogenesis.

Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits.

Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in the brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arm water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits.

GABA(A) receptor regulation after experimental traumatic brain injury.

The gamma-aminobutyric acid (GABA) type A receptor (GABA(A)R) is responsible for most fast synaptic inhibition in the adult brain. The GABA(A)R protein is composed of multiple subunits that determine the distribution, properties, and dynamics of the receptor. Several studies have shown that the Janus kinase/signal transducer and activator of transcription (JaK/STAT) and early growth response 3 (Egr3) signaling pathways can alter GABA(A)R subunit expression after status epilepticus (SE). In this study we investigated changes in these pathways after experimental TBI in the rat using a lateral fluid percussion injury (FPI) model. Our results demonstrated changes in the expression of several GABA(A)R subunit levels after injury, including GABA(A)R α1 and α4 subunits. This change appears to be transcriptional, and there is an associated increase in the phosphorylation of STAT3, and an increase in the expression of Egr3 and inducible cAMP element repressor (ICER) after FPI. These findings suggest that the activation of the JaK/STAT and Egr3 pathways after TBI may regulate injury-related changes in GABA(A)R subunit expression.

Acute neuroimmune modulation attenuates the development of anxiety-like freezing behavior in an animal model of traumatic brain injury.

Chronic anxiety is a common and debilitating result of traumatic brain injury (TBI) in humans. While little is known about the neural mechanisms of this disorder, inflammation resulting from activation of the brain's immune response to insult has been implicated in both human post-traumatic anxiety and in recently developed animal models. In this study, we used a lateral fluid percussion injury (LFPI) model of TBI in the rat and examined freezing behavior as a measure of post-traumatic anxiety. We found that LFPI produced anxiety-like freezing behavior accompanied by increased reactive gliosis (reflecting neuroimmune inflammatory responses) in key brain structures associated with anxiety: the amygdala, insula, and hippocampus. Acute peri-injury administration of ibudilast (MN166), a glial cell activation inhibitor, suppressed both reactive gliosis and freezing behavior, and continued neuroprotective effects were apparent several months post-injury. These results support the conclusion that inflammation produced by neuroimmune responses to TBI play a role in post-traumatic anxiety, and that acute suppression of injury-induced glial cell activation may have promise for the prevention of post-traumatic anxiety in humans.