Human KCC1 structure

Structure of Human Cotransporter Protein Family Member Solved

In work that could someday improve treatments for epilepsy, UT Southwestern scientists have published the first three-dimensional structure of a member of a large family of human proteins that carry charged particles — ions — across the cell membrane.

The potassium chloride cotransporter 1 (KCC1) structure solved in this study carries positively charged potassium ions (K+) and negatively charged chloride (Cl-) ions across cell membranes to help regulate the volume of the cell. The protein is one of a large family of cotransporters found in many of the body’s tissues, particularly in the kidneys and the brain.

Despite extensive study of cotransporters, the lack of high-resolution structures has hindered a deeper understanding of their actions. The scientists solved the structure using cryo-electron microscopy (cryo-EM) — an advanced technology in which samples are frozen at extremely low temperatures at speeds that prevent the formation of ice crystals.

Mutations in this family of cotransporters can lead to diseases such as hereditary epilepsy, including one form that starts in infancy, said Dr. Xiao-chen Bai, corresponding author of the Science study. Drugs that target cotransporters are currently used as diuretics to treat high blood pressure.

Are Seizures Predictors of Mortality in Critically Ill Patients in the Intensive Care Unit (ICU)?

PURPOSE: This study aimed to determine if seizures in critically ill patients are predictive of in-hospital mortality.

METHODS: Patients above the age of 55 who underwent continuous electroencephalogram (cEEG) monitoring between 2015 and 2018 at the Hackensack Meridian Health and JFK Neuroscience Institute were included in the present study. Patients were subdivided into those with and without seizures. Age, sex, seizure types, CNS disorders, and other associated comorbidities were collected by chart review. After descriptive analysis, we used multiple logistic regression analyses to evaluate if seizures and mortality were associated. P-values less than 0.05 were considered statistically significant.

RESULTS: One hundred and one critically ill patients (62.4% female) were included in this study. Sixty-six (65.3%) were between 55 and 75 years of age, while 35 (34.7%) were above 75 years of age. Most patients (n = 31, 83.8%) had focal-onset seizures, and 10 had nonconvulsive status epilepticus (NCSE). Twelve (11.9%) patients with seizures did not survive. However, seizures were not independently associated with mortality in either unadjusted (OR 1.13, CI 0.47-2.72, p = 0.773) or adjusted (OR 1.20, CI 0.35-4.05, p = 0.760) regression models. Secondary predictors of mortality included mechanical ventilation (OR 5.36, CI 1.69-16.96,  p = 0.001) and acute ischemic stroke (OR 2.77, CI 1.08-7.09, p = 0.034).

CONCLUSION: Seizures did not predict in-hospital mortality in critically ill patients. Larger prospective studies are needed to confirm our current findings.

High Levels of Socioeconomic Deprivation Seen in Those With Dissociative Seizures

Dissociative seizures are associated with high levels of socioeconomic deprivation, according to study results published in Epilepsia. The multicenter cohort study included 698 patients, making it the largest study of adults with dissociative seizures to date.

Laura H. Goldstein, PhD, MPhil, from the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, United Kingdom, and colleagues evaluated demographic and clinical data from 698 adults (mean age, 37.1 years; 73.8% women) with dissociative seizures within the previous 8 weeks. Patients were recruited from 27 neurology and specialist epilepsy clinics in the United Kingdom between October 2014 and February 2017.

In accordance with the literature, dissociative seizures were more common in women than men. By age 40 years, 77% of women had developed dissociative seizures compared with only 59% of men. Overall, the median age at dissociative seizure onset was 28 years and the median duration of dissociative seizures was 3 years. In addition, 27% of patients self-reported a previous epilepsy diagnosis, although the reliability of these diagnoses was unclear, and 30% of the sample reported taking anti-epileptic drugs.

Patients with hypokinetic seizures (32% of the sample) had a longer duration of the disorder (<.001) than patients with hyperkinetic seizures (68%), whose symptom onset most commonly occurred in their late teens. Gender differences were not associated with dissociative seizure type.

Personality Profiles Differ Between Patients with Epileptic Seizures and Patients with Psychogenic Non-Epileptic Seizures

Highlights

  • Epilepsy is associated with lower openness compared to psychogenic seizures.
  • Openness in patients with epilepsy is also lower than the general population.
  • These effects are statistically meaningful and robust.
  • The application to screening for psychogenic seizures, however, is limited.

Abstract

Purpose: Psychogenic non-epileptic seizures (PNES) and epileptic seizures (ES) are often difficult to differentiate, leading to incorrect or delayed diagnosis. The aim of the study was to determine whether patients of these two diagnostic groups possess different personality profiles, and whether they could be used to efficiently screen for PNES in clinical settings.

Methods: Collection of data was conducted on 305 patients who completed the NEO-Five Factor Inventory questionnaire during a Video EEG Monitoring admission to the Royal Melbourne Hospital between 2002–2017. Personality differences were investigated using Bayesian linear mixed effects models, with receiver operating characteristic curve analysis computed to evaluate diagnostic accuracy.

Results: The ‘openness to experience’ domain (BF10 = 21.55, d = -0.43 [95% CI -0.71, -0.17]) and the ‘aesthetic interest’ facet (B10 = 7.98, d = -0.39 [95% CI -0.66, -0.12]) were the only personality factors demonstrating strong evidence for a group difference, with patients with PNES having higher scores compared to the ES group. ES patients had lower scores on these measures compared to the normal population, while PNES patients did not. Both openness to experience and aesthetic interest showed poor sensitivities (53%, 46% respectively) and specificities (69%, 46% respectively) for classifying PNES and ES patients.

Conclusion: While openness and aesthetic interests differ greatly between PNES and ES groups, low sensitivity and specificity suggests their use is limited in a clinical setting. Nevertheless, these findings open up new avenues of research using modern personality models to further understand patients with epilepsy and related presentations.

Factors Associated with 30-Day Re-Admission for Patients Hospitalized for Seizures

In this retrospective cohort study, researchers ascertained the cumulative incidence of re-admissions after a seizure-related hospitalization and identified risk factors and readmission diagnoses.

Logistic regressions were performed to explore the impacts of patient, hospital, and community factors on re-admissions within 30 days of discharge. The sample consisted of adult patients hospitalized with a primary discharge diagnosis of seizure using the State Inpatient Databases across 11 states from 2009 to 2012. From the American Hospital Association and Robert Wood Johnson Foundation, hospital and community characteristics were obtained.

Within 30 days, 13,929 of 98,712 patients were readmitted. Epilepsy/convulsions, mood disorders, schizophrenia, and septicemia were the included reasons for readmission. Diagnoses of CNS tumor or psychosis, urgent index admission, transfer to nonacute facilities, long length of stay, and for-profit hospitals were the strongest predictors of readmission.

Overall, the authors concluded that readmission after hospitalization for seizures is common. Recurrent seizures, the most common readmission diagnosis, should be the subject of preventive strategies. While re-admissions remain difficult to predict, several factors have been associated with readmission.

Study Uses High-Fidelity Driving Simulation to Investigate Driving Behavior During Generalized Epileptiform Discharges

Objective: Generalized epileptiform discharges (GEDs) can occur during seizures or without obvious clinical accompaniment. Motor vehicle driving risk during apparently subclinical GEDs is uncertain. The goals of this study were to develop a feasible, realistic test to evaluate driving safety during GEDs, and to begin evaluating electroencephalographic (EEG) features in relation to driving safety.

Methods: Subjects were aged 15 years of age or older with generalized epilepsy, GEDs on EEG, and no clinical seizures. Using a high-fidelity driving simulator (miniSim) with simultaneous EEG, a red oval visual stimulus was presented every 5 minutes for baseline testing, and with each GED. Participants were instructed to pull over as quickly and safely as possible with each stimulus. Researchers analyzed driving and EEG signals during GEDs.

Results: Nine subjects were tested, and five experienced 88 GEDs total with mean duration 2.31 ± 1.89 (SD) seconds. Of these five subjects, three responded appropriately to all stimuli, one failed to respond to 75% of stimuli, and one stopped driving immediately during GEDs. GEDs with no response to stimuli were significantly longer than those with appropriate responses (8.47 ± 3.10 vs 1.85 ± 0.69 seconds, P < .001). Reaction times to stimuli during GEDs were significantly correlated with GED duration (r = 0.30, P = .04). In addition, EEG amplitude was greater for GEDs with no response to stimuli than GEDs with responses, both for overall root mean square voltage amplitude (66.14 microV vs 52.99 microV, P = .02) and for fractional power changes in the frequency range of waves (P < .05) and spikes (P < .001).

Significance: High-fidelity driving simulation is feasible for investigating driving behavior during GEDs. GEDs with longer duration and greater EEG amplitude showed more driving impairment. Future work with a large sample size may ultimately enable classification of GED EEG features to predict individual driving risk.

Refractory Epilepsy and Non-Adherence to Drug Treatment

In patients with epilepsy, non-adherence to agreed antiepileptic drug (AED) treatment may result in seizure relapse, and at worst Sudden Unexpected Death in Epilepsy (SUDEP). The aim of this study was to examine the extent of both unintentional and intentional non-adherence among Norwegian patients with refractory epilepsy and try to identify possible risk factors.

At the National Centre for Epilepsy in Norway, 333 consecutive adult in- and outpatients with refractory epilepsy participated in an anonymous survey about adherence to drug treatment.

Twenty-two percent of participants admitted they sometimes or often forgot to take their drugs as scheduled, and 19% reported they, rarely, sometimes, or often intentionally did not follow the AED-treatment plan agreed upon with their physician. Young age and depression was significantly correlated with unintentional non-adherence. Intentional non-adherence was associated with young age (36 years or younger). This study found non-adherence not to be associated with any specific AED.

In conclusion, about one fifth of patients with refractory epilepsy admitted that they did not adhere to the agreed drug treatment plan, either intentionally or unintentionally. Measures to reduce non-adherence in this patient group may improve seizure control and should be tailored to address both unintentional and intentional lack of adherence.

Study Finds Fewer Google Searches for Epilepsy Surgery Over 15-Year Period

BACKGROUND: Epilepsy surgery is an effective treatment for drug-resistant epilepsy. Some centers have noticed changes in referral patterns.

AIM: The aim of this study was to determine if online infodemiological data related to epilepsy surgery reflect reported changes in referrals to surgical centers.

METHODS: Google Trends and Pageview analysis of temporal trends of searches conducted in Google and Wikipedia for epilepsy surgery, using key search terms such as “epilepsy surgery” and terms related to pathology, operation type, and investigative practice.

RESULTS: Over the 15-year time period studied by Google trend analysis, when the initial three-year epoch and final three-year epoch are compared, a 56.1% decline in search volume for “epilepsy surgery” was observed. Vagus nerve stimulation and laser ablation are increasingly searched items. Pageview analysis shows that temporal lobe epilepsy remains the most commonly searched subtype of epilepsy and hippocampal sclerosis was searched for more than focal cortical dysplasia.

CONCLUSION: This study suggests a lower search interest over time in epilepsy surgery, and various associated terms, with increased interest in vagus nerve stimulation and laser ablation procedures over time. There is no clear indication from these data regarding the apparent shift from mesial temporal cases to an increase in extratemporal case workload.

Review: Promise of Extracellular Vesicles for Diagnosis and Treatment of Epilepsy

Extracellular vesicles (EVs) released from cells play vital roles in intercellular communication. Moreover, EVs released from stem cells have therapeutic properties. This review confers the potential of brain-derived EVs in the cerebrospinal fluid (CSF) and the serum as sources of epilepsy-related biomarkers, and the promise of mesenchymal stem cell (MSC)-derived EVs for easing status epilepticus (SE)-induced adverse changes in the brain.

Extracellular vesicles shed from neurons and glia in the brain can also be found in the circulating blood as EVs cross the blood-brain barrier (BBB). Evaluation of neuron and/or glia-derived EVs in the blood of patients who have epilepsy could help in identifying specific biomarkers for distinct types of epilepsies. Such a liquid biopsy approach is also amenable for repeated analysis in clinical trials for comprehending treatment efficacy, disease progression, and mechanisms of therapeutic interventions. Extracellular vesicle biomarker studies in animal prototypes of epilepsy, in addition, could help in identifying specific micro ribonucleic acid (miRNAs) contributing to epileptogenesis, seizures, or cognitive dysfunction in different types of epilepsy. Furthermore, intranasal (IN) administration of MSC-derived EVs after SE has shown efficacy for restraining SE-induced neuroinflammation, aberrant neurogenesis, and cognitive dysfunction in an animal prototype. Clinical translation of EV therapy as an adjunct to antiepileptic drugs appears attractive to counteract the progression of SE-induced epileptogenic changes, as the risk for thrombosis or tumor is minimal with nanosized EVs. Also, EVs can be engineered to deliver specific miRNAs, proteins, or antiepileptic drugs to the brain since they incorporate into neurons and glia throughout the brain after IN administration.

Prospective Study Fines Multidisciplinary Management Improves Anxiety, Depression, Medication Adherence, and Quality of Life Among Patients with Epilepsy in Eastern China

OBJECTIVE: The objective of this study was to investigate the effect of a multidisciplinary program on anxiety, depression, medication adherence, and quality of life in patients with epilepsy in eastern China.

METHODS: A cohort of 184 patients with epilepsy from the epilepsy clinic of a tertiary hospital in eastern China completed this program, out of which 92 were randomized into the intervention group and 92 the control group. Patients in both groups received standard antiepileptic drugs (AEDs), while those of the intervention group received an additional 12-month multidisciplinary program developed by a group of the epileptologist, pharmacist, psychiatrist, and epilepsy specialist nurse. Patients were assessed both before and after the 12-month period. The Beck Depression Inventory (BDI), the Beck Anxiety Inventory (BAI), and the eight-item Morisky Medication Adherence Scale (MMAS-8) were used to assess the severity of depression, anxiety, and medication adherence, respectively, along with Quality of life in Epilepsy-31 (QOLIE-31) and self-reported seizure frequency for life quality and seizure severity.

RESULTS: The 12-month multidisciplinary program significantly reduced the number of patients with severe depression (p?=?0.013) and anxiety (p?=?0.002), increased the number of patients with moderate-to-high AED adherence (p = 0.006) and the overall QOLIE-31 score (p < 0.001) in the intervention group. Both groups demonstrated a significant increase in the number of patients with a low seizure frequency after the 12-month period (p < 0.001).

CONCLUSION: The 12-month multidisciplinary program offers an effective management strategy in improving psychiatric comorbidities, medication adherence, and quality of life in patients with epilepsy in eastern China.