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.

Lennox–Gastaut Syndrome: Perspective of a Parent and a Physician

Abstract, originally published in Neurology and Therapy

This article is co-authored by a parent of a 32-year-old male patient with Lennox–Gastaut syndrome (LGS) and his epileptologist. It discusses the parent’s experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician’s perspective when treating this devastating epilepsy syndrome. The patient’s mother, who is his legal representative, provided written consent for publication of this article.

Recognizing and Refuting the Myth of Tongue Swallowing During a Seizure

Abstract, originally published in Seizure

Objective: There is a harmful myth that persists in modern culture that one should place objects into a seizing person’s mouth to prevent “swallowing the tongue.” Despite expert guidelines against this, the idea remains alive in popular media and public belief. We aimed to investigate the myth’s origins and discredit it.

Methods: A medical and popular literature review was conducted for the allusions to “swallowing one’s tongue” and practice recommendations for and against placing objects into a seizing person’s mouth. Current prevalence of these beliefs and relevant anatomy and physiology were summarised.

Results: The first English language allusions to placing objects in a patient’s mouth occurred in the mid-19th century, and the first allusions to swallowing one’s tongue during a seizure occurred in the late 19th century. By the mid-20th century, it was clear that some were recommending against the practice of placing objects in a patient’s mouth to prevent harm. Relatively recent popular literature and film continue to portray incorrect seizure first aid through at least 2013. There is ample modern literature confirming the anatomical impossibility of swallowing one’s tongue and confirming the potential harm of putting objects in a patient’s mouth.

Conclusion: One cannot swallow their tongue during a seizure. Foreign objects should not be placed into a seizing person’s mouth. We must continue to disseminate these ideas to our patients and colleagues. As neurologists, we have an obligation to champion safe practices for our patients, especially when popular media and culture continue to propagate dangerous ones.

Characteristics and Treatment Outcomes of Newly Diagnosed Epilepsy in Older People: A 30-Year Longitudinal Cohort Study

Abstract, originally published in Epilepsia

Objectives: To describe the clinical characteristics and evaluate the long-term treatment outcomes in older people with newly diagnosed epilepsy over the past 30 years.

Methods: We included patients newly diagnosed with epilepsy and commenced on antiseizure medications (ASMs) at age 65 years or older between July 1982 and October 2012 at the Western infirmary in Glasgow, Scotland. They were followed up until April 2016 or death. Seizure freedom was defined as no seizure for at least 1 year on unchanged medication at the last follow-up.

Results: A total of 201 patients (median age 73 years, 59% male) were included. The median duration from initial seizure to starting treatment was 8 months (interquartile range: 3.0-24.0 months); 42.2% (85/201) patients had more than five seizures before commencing treatment. Brain imaging showed potentially epileptogenic lesions in 19.7% (38/193) of patients and other abnormalities in 56.5% (109/193); 78.6% patients (158/201) were seizure-free at the last follow-up, of whom 94.9% were taking monotherapy. Concomitant aspirin use (n = 80) was associated with a lower probability of being seizure-free (relative risk 0.82, 95% confidence interval 0.70-0.97; P = .02). The use of second-generation ASMs as the initial monotherapy increased from 31.5% (23/73) before 2000 to 70.3% (90/128, P < .001) from 2000 onward. However, the seizure freedom rates (67.1% vs 55.5%; P = .35) and intolerable adverse-effect rates (16.4% vs 19.5%; P = .45) did not show any significant difference.

Significance: There was often a long interval between seizure onset and the initiation of treatment in older people with new-onset epilepsy, although the majority responded well to antiseizure medication treatment. Brain imaging showed a high rate of abnormalities. Despite the increased use of second-generation antiseizure medications, treatment outcomes in later-onset epilepsy have not improved over time. The possible effect of aspirin on treatment response warrants further investigation.