Primary Care Electronic Medical Records Can Be Used to Predict Risk and Identify Potentially Modifiable Factors for Early and Late Death in Adult Onset Epilepsy

Abstract, originally published in Epilepsia

Objective: To use clinically informed machine learning to derive prediction models for early and late premature death in epilepsy.

Methods: This was a population-based primary care observational cohort study. All patients meeting a case definition for incident epilepsy in the Health Improvement Network database for inclusive years 2000-2012 were included. A modified Delphi process identified 30 potential risk factors. Outcome was early (within 4 years of epilepsy diagnosis) and late (4 years or more from diagnosis) mortality. We used regularized logistic regression, support vector machines, Gaussian naive Bayes, and random forest classifiers to predict outcomes. We assessed model calibration, discrimination, and generalizability using the Brier score, mean area under the receiver operating characteristic curve (AUC) derived from stratified fivefold cross-validation, plotted calibration curves, and extracted measures of association where possible.

Results: We identified 10 499 presumed incident cases from 11 194 182 patients. All models performed comparably well following stratified fivefold cross-validation, with AUCs ranging from 0.73 to 0.81 and from 0.71 to 0.79 for early and late death, respectively. In addition to comorbid disease, social habits (alcoholism odds ratio [OR] for early death = 1.54, 95% confidence interval [CI] = 1.12-2.11 and OR for late death = 2.62, 95% CI = 1.66-4.16) and treatment patterns (OR for early death when no antiseizure medication [ASM] was prescribed at baseline = 1.33, 95% CI = 1.07-1.64 and OR for late death after receipt of enzyme-inducing ASM at baseline = 1.32, 95% CI = 1.04-1.66) were significantly associated with increased risk of premature death. Baseline ASM polytherapy (OR = 0.55, 95% CI = 0.36-0.85) was associated with reduced risk of early death.

Significance: Clinically informed models using routine electronic medical records can be used to predict early and late mortality in epilepsy, with moderate to high accuracy and evidence of generalizability. Medical, social, and treatment-related risk factors, such as delayed ASM prescription and baseline prescription of enzyme-inducing ASMs, were important predictors.

Immune Cells Survey the Brain To Prevent Seizures

Summary, originally published by Gladstone Institutes

An important part of the brain’s immune system, cells called microglia, constantly extend and retract “branches” from their cell body to survey their environment. This continuous and rapid surveillance is a unique feature reserved for microglial cells in the brain. The longstanding theory has been that microglia perform this surveillance to sense invasion by an infectious agent or to sense trauma.

“This never made sense to me,” says Katerina Akassoglou, PhD, a senior investigator at Gladstone Institutes. “Why would a cell expend so much energy for something that might never happen? I always thought there must be another reason for microglia to be moving all the time, likely related to a normal function in the brain.”

As it turns out, Akassoglou was right.

In a recent study published in the journal Nature Neuroscience, she and her team show that, in fact, surveillance by microglia helps prevent seizure activity (or hyperexcitability) in the brain. These findings could open new therapeutic avenues for several diseases, given that hyperexcitability is a feature of many neurological disorders, including Alzheimer’s disease, epilepsy, and autism.

Sudden Unexpected Death in Epilepsy (SUDEP) and Seizure Safety: Modifiable and Non-Modifiable Risk Factors Differences Between Primary and Secondary Care

Abstract, originally published in Epilepsy & Behavior

Introduction: The SUDEP and Seizure Safety Checklist (“Checklist”) is a risk factors checklist based around a person with epilepsy (PWE) demographics, seizure, physical, psychological, and lifestyle issues. The Checklist provides a cumulative picture of current risk when applied to a PWE. This study compares and contrasts risk factors of PWE in primary versus secondary care.

Methods: The Checklist was applied to all PWE registered in four primary care practices in central Cornwall UK (pop: 120,000). Individual, modifiable, non-modifiable, and total risk factors and scores were compared between PWE open to secondary care and those not. Statistical tests were used to calculate significance of individual risk factors in primary or secondary care, to compare the total risk scores between care settings and to find the frequency differences of each risk factor between primary practices.

Results: People with total and non-modifiable risk scores were higher in secondary care (both p < 0.001). However, modifiable risk scores were higher in primary care (p < 0.001). Psychiatric concerns were the most prevalent modifiable risk factor in primary care. There were significant differences in the risk profiles between all four primary care practices.

Conclusion: This study highlights that there is a lack of clarity on who is referred to secondary care and when. There needs to be an evidence-based system to allow for a bidirectional flow of PWE considering their fluctuating risk. The Checklist can be a decision support tool to enable this.

Prevalence of Sleep Disorders in Patients with Epilepsy: A Questionnaire-Based Cross-Sectional Study

Abstract, originally published in Epilepsy and Behavior

Background: Sleep disturbance is a frequent finding in patients with epilepsy. As evaluation of sleep disorders and quality of sleep in patients with epilepsy may provide better management of these patients, we aimed to assess the prevalence of common sleep disorders in patients with epilepsy.

Methods: Patients with epilepsy referred to an outpatient epilepsy clinic in Tehran during one year were included. Validated Persian questionnaires were used by an interviewer to assess Excessive daytime sleepiness (EDS), Restless leg syndrome (RLS), and insomnia. Also, patients’ demographic features and clinical seizure-related characteristics were recorded.

Results: Seventy patients (35 males) aged between 18 and 75 were enrolled. Among patients, 61.4, 35.7, and 28.6% suffered from insomnia, EDS, and RLS, respectively (mild to severe). When considering seizure characteristics, there was no significant correlation between either seizure frequency or its type and the prevalence of sleep disturbance (although sleep disturbance was more common among patients with higher seizure frequency and patients with generalized seizure). Interestingly, age had a positive correlation with EDS.

Conclusion: This study showed that sleep disturbance is a common finding in patients with epilepsy, which may become severe in some cases. Taking this into consideration, we suggest that routine evaluation of sleep disorders may help physicians to boost patients’ sleep quality.

Impact of Diagnostic Delay on Seizure Outcome in Newly Diagnosed Focal Epilepsy

Abstract, originally published in Epilepsia Open

Objective: In the current study, we aimed to assess the diagnostic delay and the impact of diagnostic delay on seizure outcome in a cohort of newly diagnosed patients with focal epilepsy.

Methods: The study material was compiled from eight clinical antiseizure medication monotherapy trials conducted at Kuopio Epilepsy Center during 1995-2016. We analyzed the time from first seizure to diagnosis, the number of seizures before diagnosis, and the response to treatment at five years.

Results: Of the 176 patients (age range 15-75 years) in the cohort, 135 (77%) had had more than two seizures before treatment. The majority of these (79 patients, 45%) had had three to ten seizures. Median number of all seizures before diagnosis was 5 (range 2-2000). Focal aware seizures and focal impaired awareness seizures were more frequent than focal to bilateral tonic-clonic seizures; median number 45 (range 2-2000), 11 (range 2-220), and 3 (range 2-30), respectively (P < .001). Median delay was 12 months (range 0-362). Diagnostic delay alone did not correlate with the treatment response at five years. However, an increasing number of seizures before diagnosis indicated a worse seizure outcome (P < .001).

Significance: This study shows that patients with focal epilepsy experience significant delays in diagnosis even in developed countries, especially with seizure types other than tonic-clonic seizures. In these cases, a long delay in diagnosis alone might not affect the long-term outcome. However, when accompanied with recurrent seizures misinterpreted by the patient or healthcare providers, the effect of such delay on prognosis can be considerable.

A Nationally Representative Study on Discharge Against Medical Advice Among Those Living With Epilepsy

Abstract, originally published in Seizure

Purpose: Discharges against medical advice (DAMA) are associated with adverse patient outcomes among those with epilepsy. Our goal was to examine trends and factors associated with DAMA among those living with epilepsy.

Methods: A retrospective cross-sectional study was performed using the 2003-2014 National Inpatient Sample database. ICD-9-CM diagnosis codes were used to identify admissions of patients with epilepsy. Following outcomes were examined among epilepsy patients: proportion and predictors of DAMA, 12-year DAMA trends and causes of admissions.

Results: In 2014, of the 187,850 admissions in patients with epilepsy, 3783 (2.01 %) were DAMA. Male sex, Black race, younger age, lower household income, Medicaid/self-pay/other as primary payer, lower Elixhauser comorbidities index, weekend admission, non-elective admission, hospital in northeast region, and urban nonteaching hospital were all associated with DAMA. There was a significant increase in the proportion of DAMA in people with epilepsy from 2003 to 2014 (1.13 %-2.01 %, p < 0.0001). The top reasons of admissions for epilepsy patients who were DAMA were: epilepsy/convulsion (21.02 %), alcohol- (8.86 %) and substance-related disorders (3.75 %), and diabetes mellitus with complications (3.33 %).

Conclusions: Our findings provide opportunities to understand discharges against medical advice (DAMA) among those living with epilepsy, which is more prevalent in socially-disadvantaged populations. This study highlights the need to develop electronic medical records-based prediction tools that could be used at the point-of-care to enable the early identification of people at risk for DAMA, since it is often likely preventable. Future mixed methods studies are recommended to identify facilitators of DAMA and strategies for prevention.

The Feasibility of Delivering First Suspected Seizure Care Using Telehealth: A Mixed Methods Controlled Study

Abstract, originally published in Epilepsy Research

Purpose: Prompt access to specialist assessment is critical after a first suspected seizure. We aimed to test the feasibility of providing this service via telehealth, compared with usual care (face-to-face appointment) in patients referred to a first seizure clinic.

Method: This feasibility study was a prospective mixed-methods non-randomized controlled design in a single center. Patients referred to the first seizure clinic chose to receive their consultation by telehealth (intervention group) or face-to-face (usual care). Demand, practicality, acceptability and limited-efficacy testing were assessed using recruitment and routinely collected clinic data, participant surveys and a clinician focus group.

Results: Telehealth in the first seizure clinic was feasible; however, internet connection, computer hardware and software, patient confidence and organizational support impacted on practicality. Of patients who were eligible for telehealth, 25 % chose to use telehealth for their appointment, with more women taking up the opportunity. Geography and age were not factors in likelihood of uptake. There was no significant between-group difference found in acceptability and limited efficacy measures conducted.

Conclusion: Telehealth is a responsive and convenient way to reach some patients who face barriers in access to specialist neurology assessment following a first suspected seizure.

A Role for the Slow Oscillations of the Neocortex in Epileptic Spasm Generation

Featuring the work of CURE Epilepsy grantee Dr. John Swann

Summary, originally published in Eurekalert

Epileptic spasms are a type of brief seizures that are the hallmark of catastrophic seizure disorders, which are characterized by severe cognitive and motor deficits. Researchers from Baylor College of Medicine and Texas Children’s Hospital now provide evidence that epileptic spasms originate from the pyramidal cells in the deep layers of the neocortex. Further, they uncovered a novel neurophysiological phenomenon that explains how cortical neurons generate spasms. This is also the first study to reveal a hitherto unknown relationship between a normal brain state, like sleep, and spasms. The study was recently published in the Annals of Neurology.

An English physician first described epileptic spasms in the mid-1800s. Since then, neuroscientists have tried to understand the cellular and mechanistic origins of epileptic spasms.

“We are excited to finally have some fundamental insights into where and how spasms originate in the brain,” lead author, Dr. John Swann, who is a professor at Baylor College of Medicine, director of the Cain Foundation Laboratories for Pediatric Neurology, and co-director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s, said. “Our findings also reveal a previously unappreciated interplay between wake/sleep brain states and how spasms are generated which opens up new avenues for the development of desperately-needed interventional therapies.”

Epilepsy Research News: December 2020

In this month’s news, we spotlight a publication describing CURE Epilepsy’s Infantile Spasms (IS) Initiativea collaborative research program that brought a team science approach to understanding the causes and potential treatments for IS. Running from 2013-2016, this program led to numerous advances in understanding the pathways in the brain involved in IS. 

Also, this month we feature news from the EPISTOP study showing that preventative treatment with the drug vigabatrin decreased the number of days with seizures as well as the severity of epilepsy in infants with tuberous sclerosis complexWe also highlight recent work from CURE Epilepsy Grantee Dr. Jeffrey Loeb, whose team identified a protein found in healthy brain tissue that may work to prevent the spread of seizures. 

These studies and more are summarized below. 

Research Highlights

Infantile Spasms
This recent publication highlights CURE Epilepsy’s Infantile Spasms (IS) Initiative, established in 2013 to support collaborative, team science-based and milestone-driven effort to advance the understanding of causes of and potential treatments for IS. The combined efforts of the research team led to numerous advances in understanding the causes of IS. It also brought together a diverse group of investigators–who otherwise would not have collaborated–to study therapies for IS.

Learn more

Preventing the Spread of Seizures
New research may explain what prevents seizures in certain areas of the brain from spreading to other areas of the brain. In a study funded by the National Institutes of Health/American Epilepsy Society, CURE Epilepsy Grantee Dr. Jeffrey Loeb and his colleagues found that a protein called DUSP4 was increased in healthy brain tissue directly next to epileptic brain tissue. The research suggests that DUSP4 may work to prevent the spread of epilepsy in the brain and that boosting levels of DUSP4 could be a novel way of preventing or treating epilepsy.

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Tuberous Sclerosis Complex Treatment
Preventive treatment with vigabatrin effectively decreased the risk and severity of epilepsy in infants with tuberous sclerosis complex who were enrolled in the EPISTOP multi-center study. Vigabatrin resulted in a significantly longer time to first clinical seizure compared with conventional treatment as well as a lower proportion of days with seizures until age 2, according to the study findings. The EPISTOP study has shown that it may be possible to change the natural history of severe infantile epilepsy through early intervention with antiepileptic therapy,” the researchers wrote.

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Epilepsy and Dementia
Late-onset epilepsy has been linked to a substantially increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy. “We are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other on-going studies are finding similar results,” she added.

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Epilepsy Treatment Expansion Approval
The FDA expanded its approval of lacosamide, marketed as Vimpat, to include add-on therapy for primary generalized tonic-clonic seizures as well as an IV formulation for patients aged 4 years and older.

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Recalling the COVID-19 Lockdown: Insights From Patients With Epilepsy

Abstract, originally published in Epilepsy & Behavior

Purpose: The purpose of our study was to explore health changes among people with epilepsy (PWE) during a national COVID-19 lockdown in the context of patients’ clinical characteristics and their experience of receiving epilepsy-related medical services.

Methods: A questionnaire was distributed for adult PWE both online and at a tertiary epilepsy center after the end of a national lockdown in Lithuania. PWE were asked to evaluate their health status during the lockdown and estimate changes in their seizure patterns. Additional questions concerned the accessibility and quality of epilepsy-related consultations.

Results: The study sample consisted of 143 PWE (59 [41.3%] male, mean age 35.1 ± 13.4 years), 94 (65.7%) completed the survey in person, 49 (34.3%) – online. A deterioration in reported physical and mental health during lockdown was observed (Z = -4.604, p < 0.0001 and Z = -4.253, p < 0.0001, respectively) and 22 (15.4%) PWE reported seizure exacerbation. In an ordinal logistic regression model (analysis of data from all participants), baseline seizure frequency (b = 0.413, p = 0.031), reported physical health before lockdown (b = -0.462, p = 0.031) and the ease of proper antiepileptic drug (AED) use during the imposed restrictions (b = -0.535, p = 0.006) were statistically significant variables associated with changes in seizure frequency. The latter were not affected by modifications in AED use (Mann-Whitney U = 1127.0, p = 0.307) irrespective of the data collection method. With teleconsultations being predominant during the lockdown, an overall decline in the quality of epilepsy-related consultations was observed (Z = -2.895, p = 0.004). Among all participants, 46 (32.2%) lost an epilepsy-related consultation or medical service because of the lockdown. This loss was found to be associated with seizure exacerbation (Mann-Whitney U = 1622.5, p = 0.046).

Conclusion: Our study indicates that a national COVID-19 lockdown may have led to worse seizure control and health status in some people with epilepsy. Easy access to antiepileptic drugs and their appropriate use may be especially useful to prevent seizure exacerbation during strict COVID-19 restrictions. The quality and accessibility of remote epilepsy-related consultations was suboptimal and may require further improvement during disruption of in-person services.