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.

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.

Generalized, Focal, and Combined Epilepsies in Families: New Evidence for Distinct Genetic Factors

Abstract, originally published in Epilepsia

Objective: To determine the roles of shared and distinct genetic influences on generalized and focal epilepsy operating in individuals who manifest features of both types (combined epilepsies), and in families manifesting both generalized and focal epilepsies in separate individuals (mixed families).

Methods: We analyzed the deeply phenotyped Epi4K cohort of multiplex families (≥3 affected individuals per family) using methods that quantify the aggregation of phenotypes within families and the relatedness of individuals with different phenotypes within family pedigrees.

Results: The cohort included 281 families containing 1021 individuals with generalized (n = 484), focal (304), combined (51), or unclassified (182) epilepsies. The odds of combined epilepsy was higher in relatives of participants with combined epilepsy than in relatives of those with other epilepsy types (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.7-16.1, P = .004). Individuals with combined epilepsy co-occurred in families more often than expected by chance (P = .03). Within mixed families, individuals with each type of epilepsy were more closely related to relatives with the same type than to relatives with other types (P < .001).

Significance: These findings suggest that distinct genetic influences underlie the recently recognized entity of combined epilepsies, just as generalized epilepsies and focal epilepsies each have distinct genetic influences. Mixed families may in part reflect chance co-occurrence of these distinct genetic influences. These conclusions have important implications for molecular genetic studies aimed at identifying genetic determinants of the epilepsies.

The COVID-19 Outbreak and Approaches to Performing Eeg in Europe

Abstract, originally published in Epileptic Disord.

The coronavirus SARS-CoV-2 disease (COVID-19) pandemic affects availability and performance of neurophysiological diagnostic methods, including EEG. Our objective was to outline the current situation regarding EEG-based investigations across Europe. A web-based survey was distributed to centers within the European Reference Network on rare and complex epilepsies (ERN EpiCARE). Responses were collected between April 9 and May 15, 2020. Results were analysed with Microsoft Excel, Python Pandas and SciPy. Representants from 47 EpiCARE centers from 22 countries completed the survey. At the time of completing the survey, inpatient video-EEGs had been stopped or restricted in most centers (61.7% vs. 36.2% for adults, and 38.3% vs. 53.2% for children). Invasive investigations and epilepsy surgery were similarly affected. Acute EEGs continued to be performed, while indications for outpatient EEGs were limited and COVID-19 triage put in place. The strictness of measures varied according to extent of the outbreak in a given country. The results indicate a profound impact of COVID-19 on neurophysiological diagnostics, especially inpatient video-EEGs, invasive investigations, and epilepsy surgery. The COVID-19 pandemic may hamper care for patients in need of EEG-based investigations, particularly patients with seizure disorders. ERN EpiCARE will work on recommendations on how to rapidly adapt to such situations in order to alleviate consequences for our patients.

Seizure-Related Injuries in Inadequately Treated Epilepsy Patients: A Case-Control Study

Abstract, originally published in Seizure

Purpose: To compare epilepsy-related injuries in untreated or inadequately treated patients and patients on adequate treatment.

Methods: In a cross-sectional case-control study, seizure-related injuries in patients who were either on no treatment or inadequate treatment were compared with another group of patients receiving appropriate evidence-based epilepsy treatment. The inadequately treated patients or ‘cases’ were drawn from an outreach epilepsy clinic while the adequately treated patients or ‘controls’ were recruited from a tertiary care facility providing comprehensive epilepsy management.

Results: The odds of injury were eight times higher in inadequately treated patients or cases compared to the adequately treated patients or controls. After adjusting for gender, epilepsy duration, seizure frequency, current medication, and number of AEDs, the odds of injury were 15. 8 times higher in the cases. Major injuries such as burns, fractures, and tooth injuries were also higher in the cases.

Conclusion: Untreated or inadequately treated epilepsy patients have a significantly higher risk of injuries. With adequate treatment, some of the risks of injury can be mitigated.

Nasal Pain as an Aura: Amygdala Origin?

Abstract, originally published in Seizure

Purpose: Nasal pain, as an epileptic aura, has been poorly recognized. This study aims to demonstrate clinical features of patients with epilepsy who have nasal pain as an aura.

Methods: We retrospectively investigated consecutive patients who visited the epilepsy clinic of tertiary hospital from April 2000 to September 2019. All included patients underwent epilepsy-dedicated, high-resolution magnetic resonance imaging (MRI) examinations. All MRI studies were analyzed by visual inspection.

Results: Seven patients who presented nasal pain as an aura, were identified. Four patients reported nasal pain as the first aura. Four patients had right amygdala enlargement (isolated amygdala enlargement in three patients; amygdala enlargement in addition to hippocampal sclerosis in one patient), and one patient with compression of an internal carotid-posterior communicating artery aneurysm to right amygdala on brain MRI. Interictal epileptiform or ictal discharges on EEG were found in the right temporal region in five patients. In all four patients with amygdala enlargement, amygdala enlargement was ipsilateral to EEG anomalies. In all patients, nasal pain was accompanied by ictal semiological features, such as autonomic, olfactory, abdominal, or psychic auras, and focal impaired awareness seizures, which are typically associated with mesial temporal lobe epilepsy.

Conclusions: Our findings suggest that nasal pain can occur as an epileptic aura in patients with temporal lobe epilepsy with probable involvement of the amygdala.

Focal Epilepsy Often Overlooked

Article, originally featured on EurekAlert

Having subtler symptoms, a form of epilepsy that affects only one part of the brain often goes undiagnosed long enough to cause unexpected seizures that contribute to car crashes, a new study finds.

The study, published online Oct. 20 in the journal Epilepsia, addressed focal epilepsy, the most common form of this brain disorder. Researchers say the study is among the first to outline failure to recognize symptoms of subtle seizures as a main reason for the delay in diagnosis.

Led by researchers at NYU School of Medicine, the study shows that it can take on average two years for physicians to recognize the early signs of focal epilepsy, particularly in a subset of patients with seizures that do not involve uncontrolled movements of their arms and legs. Symptoms of these “non-motor seizures” instead may include a recurring brief hallucination, a strong sense of déjà vu, or sensations of a dreamlike state while awake.

Subtler cases are often not diagnosed until they have progressed to disruptive “motor” seizures, say the study authors, which can cause the unrestrained, whole-body spasms often portrayed in popular culture.

Review: Current Knowledge of SLC6A1-Related Neurodevelopmental Disorders

Abstract, originally published in Brain Communications

Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 (SLC6A1) gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder, and intellectual disability. The SLC6A1 gene encodes for the GABA transporter protein type 1 (GAT1), which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures. Aggregation of patient variants and observed clinical manifestations expand understanding of the genotypic and phenotypic spectrum of this disorder. Here, we assess genetic and phenotypic features in 116 individuals with SLC6A1 variants, the vast majority of which are likely to lead to GAT1 loss-of-function. The knowledge acquired will guide therapeutic decisions and the development of targeted therapies that selectively enhance transporter function and may improve symptoms. We analyzed the longitudinal and cell type-specific expression of SLC6A1 in humans and localization of patient and control missense variants in a novel GAT1 protein structure model. In this update, we discuss the progress made in understanding and treating SLC6A1-related disorders thus far, through the concerted efforts of clinicians, scientists, and family support groups.