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.”

Sunflower Syndrome: A Poorly Understood Photosensitive Epilepsy

Abstract, originally published in Developmental Medicine and Child Neurology

Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy’s stereotyped handwaving motion in front of light characterized the behavior as self-inducing seizures via mimic of stroboscopic effect. However, the relationship between handwaving episodes and attendant generalized electroencephalogram abnormalities, and an appreciation of the compulsive attraction the sun and other light sources hold for these patients, suggest the handwaving motion may be a part of the seizure rather than a mechanism of self-induction. The lack of awareness of Sunflower syndrome often leads to misdiagnosis. The seizures are often refractory to traditional anticonvulsant medication, and patients resort to behavioral intervention, such as hats and sunglasses, to reduce handwaving episodes. Further study is required to determine the syndrome’s natural history and to identify more effective treatment options.

Incidence of Potential Adverse Events During Hospital-Based Ketogenic Diet Initiation Among Children with Drug-Resistant Epilepsy

Abstract, originally published in Epilepsia

Objective: Due to the possibility of serious adverse events (AE), patients are commonly admitted to hospital for 3–5 days for ketogenic diet (KD) initiation. This study examined the incidence of potential AE during admission for KD initiation to investigate the possibility of safely initiating a KD at home.

Methods: Children with drug-resistant epilepsy (DRE) who were admitted to hospital for five days for KD initiation were retrospectively studied.

Results: A total of 66 children (59% female) were analyzed. The mean age at the initiation of the KD was 48.0±38.4 months and the mean weight was 14.6±6.3 kilograms. The median number of anticonvulsant medications used at the time of KD initiation was 3. The etiology of the DRE was structural in 4.5%, hypoxic ischemic encephalopathy in 10.6%, genetic/metabolic in 31.8%, acquired in 10.6% and unknown in 42.2%. The potential AE occurred in 28.7% of patients, including hypoglycemia (20%), hypoactivity (6.1%), somnolence (3%), and vomiting (7.6%). A univariate analysis of the clinical characteristics of the AE and no AE groups showed a statistically significant difference in weight (P = 0.003) and age (P = 0.033). The concurrent use of topiramate was found to have a near significant association (P = 0.097) between the groups. The groups’ urine ketone levels on all five days were compared and a statistically significant difference was found on day three (P = 0.026). A statistically significant difference in the serum bicarbonate levels (P = 0.038) was found between the patients taking topiramate and those not taking it.

Significance: The incidence of adverse events during admission for ketogenic diet initiation was found to be low. The adverse events either required no intervention or were easily managed with simple interventions. Thus, it may be possible to initiate a ketogenic diet at home if the parents are adequately prepared and monitored.

Review: Cognitive Disorders in Epilepsy I: Clinical Experience, Real-World Evidence and Recommendations

Abstract, originally published in Seizure

This is the first of two narrative reviews on cognitive disorders in epilepsy (companion publication: Cognitive disorders in epilepsy II: Clinical Targets, Indications and Selection of Test Instruments). Its focus is on clinical experience, real-world evidence, and clinical recommendations. Cognitive disorders are a common comorbidity in children and adults with epilepsy. These cognitive disturbances may preceed the onset of seizures and are multifactorial including contributions by pre-existing brain damage, seizures, interictal epileptic discharges, and treatments including medications and surgery. Comorbid cognitive impairments can have a negative impact on the quality of life in people with epilepsy. They are under-identified and frequently not treated. This narrative review discusses these issues from a Comorbid psychiatric disorders, such as ADHD can also contribute to a worse cognitive performance and can benefit from pharmacotherapy with CNS stimulants. Likewise, mood disorders cause a subjective perception of poor memory and attention, which can be reversed with antidepressants of the SSRI family, real-world clinical perspective in children and adults with newly diagnosed and chronic epilepsy. The need for further research to understand and treat these disorders is noted.

Review: Cross Talk Between Drug-Resistant Epilepsy and the Gut Microbiome

Abstract, originally published in Epilepsia

One-third of epilepsy patients have drug-resistant epilepsy (DRE), which is often complicated by polydrug toxicity and psychiatric and cognitive comorbidities. Advances in understanding the microbiome and gut-brain-axis are likely to shed light on epilepsy pathogenesis, anti-seizure medication (ASM) resistance, and potential therapeutic targets. Gut dysbiosis is associated with inflammation, blood-brain barrier disruption, and altered neuromodulators. High-throughput and metagenomic sequencing has advanced the characterization of microbial species and functional pathways. DRE patients show altered gut microbiome composition compared to drug-sensitive patients and healthy controls. The ketogenic and modified Atkins diets can reduce seizures in some patients with DRE. These low-carbohydrate dietary therapies alter the taxonomic and functional composition of the gut microbiome, and composition varies between diet responders and nonresponders. Murine models suggest that specific phyla are necessary to confer efficacy from the diet, and antibiotic treatment may eliminate efficacy. The impact of diet might involve alterations in microbiota, promotion of select microbial interactions, and variance in brain neurotransmitter levels that then influence seizures. Understanding the mechanics of how diet manipulates seizures may suggest novel therapies. Most ASMs act on neuronal transmission via effects on ion channels and neurotransmitters. However, ASMs may also assert their effects via the gut microbiota. In animal models, the microbiota composition (eg, abundance of certain phyla) can vary with ASM active drug metabolites. Given the developing understanding of the gut microbiome in DRE, probiotics are another potential therapy. Probiotics alter the microbiota composition, and small studies suggest that these supplements can reduce seizures in some patients. DRE has enormous consequences to patients and society, and the gut microbiome holds promise as a potential therapeutic target. However, the exact mechanism and recognition of which patients are likely to be responders remain elusive. Further studies are warranted.

The Mediating Role of Epileptic Seizures, Irritability, and Depression on Quality of Life in People With Epilepsy

Abstract, originally published in Epilepsy Behav.

Purpose: Psychiatric comorbidity is common in epilepsy and has a considerable impact on patient quality of life (QoL). This study aimed to analyze the relationship between seizure frequency, irritability, and depression and describe how they mediate each other’s effect on QoL in epilepsy.

Methods: This is a cross-sectional study of consecutive adults seen at an outpatient epilepsy clinic of a tertiary hospital in Barcelona, Spain. All the patients were evaluated for psychiatric comorbidity and administered the State-Trait Anger Expression Inventory-2 (STAXI-2), the Hospital Anxiety and Depression Scale (HADS), and the Quality Of Life in Epilepsy Inventory-10 (QOLIE-10). Mediation analysis with multiple linear regression followed by the Sobel test was performed.

Results: We studied 157 patients. Seizure frequency (R = -0.193, P = .053), irritability (R = 0.216, P = .039), and depression (R = -0.598, P < .001) had all a negative effect on QoL. In the adjusted linear regression model, depression was the only independent predictor of impaired QoL (B = -2.453 [95% confidence interval (CI): -3.161, -1.744], P < .001). The Sobel test showed that depression exerted a significant mediating effect on seizure frequency (Z = -1.984; P = .047) and irritability (Z = -3.669; P < .001) in their influence on QoL.

Conclusion: Depression is an independent predictor of worse quality of life and significantly mediated the effects of irritability and poor seizure control on quality of life impairment in patients with epilepsy.

Systematic Review of EEG Findings in 617 Patients Diagnosed With COVID-19

Abstract, originally published in Seizure

Objective: We performed a systematic review of the literature to synthesize the data on EEG findings in COVID-19. Frontal EEG patterns are reported to be a characteristic finding in COVID-19 encephalopathy. Although several reports of EEG abnormalities are available, there is lack of clarity about typical findings.

Methods: Research databases were queried with the terms “COVID” OR “coronavirus” OR “SARS” AND “EEG”. Available data was analyzed from 617 patients with EEG findings reported in 84 studies.

Results: The median age was 61.3 years (IQR 45-69, 33.3 % female). Common EEG indications were altered mental status (61.7 %), seizure-like events (31.2 %), and cardiac arrest (3.5 %). Abnormal EEG findings (n = 543, 88.0 %) were sub-classified into three groups: (1) Background abnormalities: diffuse slowing (n = 423, 68.6 %), focal slowing (n = 105, 17.0 %), and absent posterior dominant rhythm (n = 63, 10.2 %). (2) Periodic and rhythmic EEG patterns: generalized periodic discharges (n = 35, 5.7 %), lateralized/multifocal periodic discharges (n = 24, 3.9 %), generalized rhythmic activity (n = 32, 5.2 %). (3) Epileptiform changes: focal (n = 35, 5.7 %), generalized (n = 27, 4.4 %), seizures/status epilepticus (n = 34, 5.5 %). Frontal EEG patterns comprised of approximately a third of all findings. In studies that utilized continuous EEG, 96.8 % (n = 243) of the 251 patients were reported to have abnormalities compared to 85.0 % (n = 311) patients who did not undergo continuous EEG monitoring (?2 = 22.8, p =< 0.001).

Significance: EEG abnormalities are common in COVID-19 related encephalopathy and correlates with disease severity, preexisting neurological conditions including epilepsy and prolonged EEG monitoring. Frontal findings are frequent and have been proposed as a biomarker for COVID-19 encephalopathy.

Learnings From 30 Years of Reported Efficacy and Safety of Vagus Nerve Stimulation (Vns) for Epilepsy Treatment: A Critical Review

Abstract, originally published in Seizure

Three decades after its introduction as an adjuvant therapeutic option in the management of selective drug-resistant epilepsy cases (DRE), vagus nerve stimulation (VNS) retains growing interest. An implantable device was first approved for epilepsy in Europe in 1994 and in the United States (US) in 1997. Subsequent modifications improved the safety and the efficacy of the system. The most recent application of vagal neurostimulation is represented by transcutaneous devices that are claimed to have strong therapeutic potential. In this review, we sought to analyze the most meaningful available data describing the indications, safety and efficacy of the different approaches of VNS in clinical practice. Therefore, we identified studies reporting VNS efficacy and/or safety in epilepsy and its comorbidities from January 1990 to February 2020 from various databases including PubMed, Scopus, Cochrane, US government databases and VNS manufacturer published resources. In general, VNS efficacy becomes optimal around the sixth month of treatment and a 50-100 % seizure frequency reduction is achieved in approximately 45-65 % of the patients. However, some clinically relevant differences have been reported with specific factors such as epilepsy etiology or type, patient age as well as the delay of VNS therapy onset. VNS efficacy on seizure frequency has been demonstrated in both children and adults, in lesional and non-lesional cases, in focal and generalized epilepsies, on both seizures and epilepsy comorbidities. Regarding the latter, VNS can lead to an improvement of about 25-35 % in depression scores, 35 % in anxiety scores and 25 % in mood assessment scores. If non-invasive devices are undeniably safer, their efficacy is limited due to the scarcity of large cohort studies and the disparity of methodological approaches (study design and stimulation parameters). Overall, we believe that there is a progress margin for improving the safety of implantable devices and, above all, the effectiveness of the various VNS approaches.

Long-Term Seizure, Comorbidity and Socioeconomic Outcomes of Patients With Convulsive Epilepsy in Rural West China

Abstract, originally published in Epilepsy Res.

Purpose: This study aimed to investigate the long-term outcomes of patients with convulsive epilepsy in rural West China and to explore potential related factors.

Methods: Patients who were provided Phenobarbital as a treatment and followed-up monthly were enrolled from the Convulsive Epilepsy Control and Management Program in West China. Their clinical and demographic information were obtained from the program database and a questionnaire. Seizure outcomes, comorbidities, annual income, marital status, employment and quality of life (QOL) were evaluated as long-term outcomes. Logistic regression was used to analyze the related factors.

Results: Of 473 eligible patients with a median follow-up time of nearly 7 years, 312 (66 %) had one-year terminal remission. A total of 320 (67.7 %) patients had a low annual income (<5000 Yuan), and 198 (41.9 %) patients reported a comorbidity. Among 460 patients of marriageable age, 137 (29.8 %) were unmarried. 60.4 % (333) patients reported improved QOL. Time of follow-up, seizure frequency during early treatment, compliance, annual cost for epilepsy treatment and annual income were related to the seizure outcome. Baseline seizure frequency was associated with comorbidities. Sex, annual cost for epilepsy treatment and seizure outcomes were associated with annual income. Age, sex and age at onset were correlated with current marital status. Compliance and taking traditional Chinese medicine were associated with QOL.

Conclusion: The prognosis of epilepsy goes beyond being seizure-free. Comorbidities, income and marriage outcomes in resource-poor areas are less promising. Systematic management considering prognosis-related factors for epilepsy by a collaboration of health providers and society is needed.

Anti-Seizure Medication Use During Pregnancy and Risk of ASD and ADHD in Children

Abstract, originally published in Neurology

Objective: To determine whether children born to women who use anti-seizure medications (ASMs) during pregnancy have higher risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) independent of confounding factors.

Methods: We used Swedish-register data (n = 14,614 children born 1996-2011 and followed through 2013) to examine associations in children of women with epilepsy, using the largest sample to date and adjusting for a range of measured confounders. We examined maternal-reported first-trimester use of any ASM (22.7%); and the 3 most commonly reported individual drugs (valproic acid, 4.8%; lamotrigine, 6.8%; and carbamazepine, 9.7%). We identified ASD with ICD-10 diagnoses and ADHD with ICD-10 diagnoses or filled prescriptions of ADHD medication.

Results: Examination of individual drugs revealed that after adjustment for confounding, use of valproic acid was associated with ASD (Hazard Ratio = 2.30, 95% CI = 1.53-3.47) and ADHD (HR = 1.74, 95% CI = 1.28-2.38). Whereas a small, non-statistically significant association with ASD (HR = 1.25, 95% CI = 0.88-1.79) and ADHD (HR = 1.18, 95% CI = 0.91-1.52) remained for reported use of carbamazepine, confounding explained all of the associations with lamotrigine (HRASD = 0.86, 95% CI = 0.67-1.53; HRADHD = 1.01, 95% CI = 0.67-1.53).

Conclusions: We found no evidence of risk related to exposure to lamotrigine, whereas we observed elevated risk of autism spectrum disorder and ADHD related to maternal use of valproic acid. Associations with carbamazepine were weak and not statistically significant. Our findings add to a growing body of evidence that suggest that certain anti-seizure medications may be safer than others in pregnancy.