Article, originally published in Annals of Neurology

Preventive treatment with vigabatrin effectively altered the natural history of seizures among infants with tuberous sclerosis complex, decreasing the risk for and severity of epilepsy, according to results published in Annals of Neurology.

Katarzyna Kotulska, MD, PhD, of the department of neurology and epileptology at the Children’s Memorial Health Institute in Poland, and colleagues conducted the present study as part of the EPISTOP project, a long-term prospective study examining clinical and molecular biomarkers for epileptogenesis in a genetic model of epilepsy/TSC. The trial was conducted from March 2014 through October 2018 at nine sites in Europe and one site in Australia.

In both the RCT and OLT, no patients who received preventive treatment developed infantile spasms compared with four of 13 (31%) patients receiving conventional treatment in the RCT and six of 12 (50%) patients in the OLT, for a statistically significant difference in both the OLT and the pooled analysis (P = .015 and P < .001, respectively). No EPISTOP subject who completed the study developed a severe intellectual disability at the age of 2 years.

“… This 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.

Press release, originally published on the UCB website

UCB, a global pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved VIMPAT^® (lacosamide) CV as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures (PGTCS) in patients four years of age and older and VIMPAT injection for intravenous use in children four years of age and older. PGTCS is a type of seizure that occurs all over the brain, affecting both sides of the brain from the start, causing muscles to stiffen and convulsions to occur for up to a few minutes.

“These approvals underscore UCB’s commitment to people living with epilepsy and our focus on finding solutions for specific unmet needs within the epilepsy community,” said Mike Davis, Head of U.S. Neurology at UCB. “We are pleased that VIMPAT is now available as a treatment option for people living with primary generalized tonic-clonic seizures on their journey to seizure control.”

The PGTCS approval is based, in part, on results of a Phase 3 study recently published in the Journal of Neurology, Neurosurgery & Psychiatry.  Adjunctive treatment with VIMPAT resulted in a significantly lower risk of developing a second PGTCS during the 24-week treatment period, with the corresponding risk reduction being 45% (p=0.001), and a significantly higher rate of freedom from PGTCS during the treatment period compared with placebo (31.3% vs 17.2%, p=0.011).

People living with generalized tonic-clonic seizures have an increased risk of injury and those who experienced three or more in one year had a fifteen-fold increased risk of sudden unexpected death in epilepsy.

“The treatment of primary generalized tonic-clonic (convulsive) seizures is challenging, with about one-third of patients still being refractory while on therapy,” said David Vossler, MD, FAAN FACNS FAES, Department of Neurology, University of Washington, Seattle, USA. “Bolstered by a wealth of data demonstrating the efficacy and safety of VIMPAT, this new indication gives people suffering from PGTCS a chance at freedom from these seizures, which many have never experienced.”

Results from the Phase 3 study showed that VIMPAT was generally tolerated in patients with Idiopathic Generalized Epilepsy (IGE) and PGTCS. The most common adverse reactions (?10%) reported in patients treated with VIMPAT were dizziness (23%), somnolence (17%), headache (14%), and nausea (10%) compared to 7%, 14%, 10%, and 6%, respectively, of patients who received placebo.

Regarding the expanded pediatric population, VIMPAT tablets and oral solution were already approved to treat partial-onset seizures in adults and children four years and older as monotherapy and adjunctive therapy. VIMPAT injection was previously approved for the treatment of partial-onset seizures only in adult patients (17 years of age and older).

In October 2020, The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for VIMPAT as adjunctive therapy in the treatment of PGTCS in adults, adolescents and children from four years of age with idiopathic generalized epilepsy. Regulatory reviews for use of VIMPAT in the treatment of PGTCS are also underway in Japan and Australia.

Abstract, originally published in Epilepsia

Precision medicine can be distilled into a concept of accounting for an individual’s unique collection of clinical, physiologic, genetic, and sociodemographic characteristics to provide patient?level predictions of disease course and response to therapy. Abundant evidence now allows us to determine how an average person with epilepsy will respond to specific medical and surgical treatments. This is useful, but not readily applicable to an individual patient. This has brought into sharp focus the desire for a more individualized approach through which we counsel people based on individual characteristics, as opposed to population?level data. We are now accruing data at unprecedented rates, allowing us to convert this ideal into reality. In addition, we have access to growing volumes of administrative and electronic health records data, biometric, imaging, genetics data, microbiome, and other “omics” data, thus paving the way toward phenome?wide association studies and “the epidemiology of one.” Despite this, there are many challenges ahead. The collating, integrating, and storing sensitive multimodal data for advanced analytics remains difficult as patient consent and data security issues increase in complexity. Agreement on many aspects of epilepsy remains imperfect, rendering models sensitive to misclassification due to a lack of “ground truth.” Even with existing data, advanced analytics models are prone to overfitting and often failure to generalize externally. Finally, uptake by clinicians is often hindered by opaque, “black box” algorithms. Systematic approaches to data collection and model generation, and an emphasis on education to promote uptake and knowledge translation, are required to propel epilepsy?based precision medicine from the realm of the theoretical into routine clinical practice.

Abstract, originally published in Epilepsia

Objective: Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and pharmacoresistance is common. To better assess the clinical phenotype, most effective treatment, and determinants of cognitive and seizure outcomes, three major pediatric epilepsy centers combined data, creating the largest cohort of patients with EMAS ever studied to date.

Methods: Authors performed a retrospective chart review of patients with EMAS who received care at the authors’ institutions.

Results: A total of 166 children were identified. Global developmental delay (>1 domain) was present in 2% of children at onset and 49% during the course of the disease. Afebrile seizures occurred after the age of 2 years in 88%, generalized tonic-clonic seizures in 60%, and drop attack or myoclonic seizures in 30%. At onset, electroencephalography (EEG) found 28% normal, background slowing in 20%, and epileptiform discharges or seizures in 69%. Subsequent EEG found slowing in 62% and discharges or seizures in 90%. Response (>50% seizure reduction) to the first three antiseizure drugs (ASDs) was 26% (levetiracetam, 17%; valproic acid, 31%; other ASDs combined, 26%). Diet therapy was used as a second or third therapy in 19% and ultimately used in 57%; response was 79%, significantly greater than the first three ASDs (P = .005, ?2). Seizure freedom occurred in 57% and was less likely in the case of persistent global developmental delays (P < .001), seizure recorded on subsequent EEGs (P = .027), and failure to respond to diet therapy (P = .005). Development was normal in 47%, and 12% had delays in one domain, which was less likely in the case of global developmental delay after epilepsy onset (P < .001) and failure to achieve seizure freedom (P < .001).

Significance: This large cohort of children with EMAS clarifies areas of variability in practice. Diet therapy is by far the most effective treatment; failure to respond was associated with failure to attain seizure freedom. This therapy should be used early in the treatment in EMAS. This study also identified a bidirectional link between cognitive and seizure outcomes.

Abstract, originally published in Epilepsy Research

Objective: We conducted a long-term follow-up of a cohort of children with newly diagnosed unprovoked seizures to assess treatment with antiepileptic drugs (AEDs), neuroleptics, antidepressants and medication for attention deficit hyperactivity disorder (ADHD) with special attention to the impact of comorbidities on the use of such medication.

Methods: Our study cohort comprised 769 children (28 days-18 years), living in Stockholm Sweden, with a first unprovoked seizure identified between 2001 and 2006. Information on neurodevelopmental comorbidities and Cerebral Palsy (CP) at seizure onset was collected from medical records. Information on treatment with AEDs, neuroleptics, antidepressants and ADHD medication was retrieved by linkage to the Swedish National Prescription Registry between 2005 and 2014. The association between comorbidities and drug treatments was assessed by odds ratios (OR) with 95 % confidence intervals (CI), adjusted for age and sex.

Results: Eight years after the index seizure, 31 % of the children were on AEDs, and this was more common among children with any of the comorbidities studied (OR; 4.0 95 % CI 2.9-5.6) compared to those without such comorbidities, and within this group of comorbidities particularly for those with CP (OR; 5.2 95 % CI: 2.9-9.3). Children with neurodevelopmental comorbidity or CP at baseline were more likely to receive neuroleptics (ORs 8 years after the index seizure; 6.9, 95 % CI: 2.4-19.8), antidepressants (OR; 2.3, 95 % CI: 1.0-5.5) and ADHD medication (OR; 3.6, 95 % CI: 1.8-7.2) than children without the studied comorbidities.

Conclusion: Children with seizures in combination with neurodevelopmental comorbidities or cerebral palsy (CP), especially CP, have a more frequent use of antiepileptic drugs, neuroleptics, antidepressants, and ADHD medication up to 13 years following the initial seizure than children without comorbidity. Our data highlight the treatment burden in children with epilepsy and comorbidities.

A new FDA alert has been issued for Lamotrigine/Lamictal. If you are taking this drug and have a cardiac condition, especially arrhythmia, there are new warnings, including the potential for sudden death. If you have concerns or questions about using this product, please call your doctor.

Please see the links below for more details:

• FDA Drug Alerts
• Lamotrigine Drug Warning Label

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.

Abstract, originally published in Epilepsia

Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition.

In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM’s preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.