Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial

Abstract found on PubMed

Abstract

Objective: To test the hypothesis that early vigabatrin treatment in Tuberous Sclerosis Complex (TSC) infants improves neurocognitive outcome at 24 months of age.

Methods: Phase IIb multicenter randomized double-blind placebo-controlled trial of vigabatrin at first epileptiform EEG vs. vigabatrin at seizure onset in infants with TSC.

Primary outcome: Bayley-III cognitive assessment score at 24 months.

Secondary outcomes: prevalence of drug resistant epilepsy, additional developmental outcomes, and safety of vigabatrin.

Results: Of eighty-four infants enrolled, 12 were screen failures, four went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). 56 were randomized to early vigabatrin (n=29) or placebo (n=27). 19 of 27 in the placebo arm transitioned to open label vigabatrin with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups.

Interpretation: Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children; nor delay onset or lower the incidence of focal seizures and drug resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms.

Biological Rhythms and Epilepsy Treatment

Abstract found on PubMed

Approximately one-third of patients with epilepsy are drug-refractory, necessitating novel treatment approaches. Chronopharmacology, which adjusts pharmacological treatment to physiological variations in seizure susceptibility and drug responsiveness, offers a promising strategy to enhance efficacy and tolerance. This narrative review provides an overview of the biological foundations for rhythms in seizure activity, clinical implications of seizure patterns through case reports, and the potential of chronopharmacological strategies to improve treatment. Biological rhythms, including circadian and infradian rhythms, play an important role in epilepsy. Understanding seizure patterns may help individualize treatment decisions and optimize therapeutic outcomes. Altering drug concentrations based on seizure risk periods, adjusting administration times, and exploring hormone therapy are potential strategies. Large-scale randomized controlled trials are needed to evaluate the efficacy and safety of differential and intermittent treatment approaches. By tailoring treatment to individual seizure patterns and pharmacological properties, chronopharmacology offers a personalized approach to improve outcomes in patients with epilepsy.

The Impact of the COVID-19 Pandemic on People with Epilepsy and Epilepsy Specialists

Abstract found on PubMed

Objectives: During the coronavirus disease 2019 (COVID-19) pandemic, the global population experienced changes in diagnosis and treatment patterns. The aim of this study was to evaluate the influence of the COVID-19 pandemic on people with epilepsy (PWE) and epilepsy specialists in China.

Methods: We retrospectively evaluated newly diagnosed PWE from January 2018 to January 2022 at Shanxi Bethune Hospital. The clinical characteristics of PWE and the prescription habits of epilepsy specialists were analyzed. We also explored changes in seizure control among PWE as a result of the COVID-19 pandemic and assessed the possible causes.

Results: After excluding 49 PWE who were lost to follow-up, 421 PWE were included in the study. They were divided into a prepandemic group and a pandemic group, with December 2019 as the boundary. By comparing the two groups, we found that the duration between first symptom detection and diagnosis was longer in the pandemic group than in the prepandemic group. Epilepsy specialists preferred prescribing the fast-acting antiepileptic drug levetiracetam (LEV) in the pandemic group. During the COVID-19 pandemic, 49.57% of PWE reported difficulties in accessing their epilepsy healthcare provider, and 26.96% reported that appointments with their providers occurred as usual. A lack of anti-seizure medication (ASM) availability was reported by 32.17% of subjects. An increase in seizure frequency was noted in 25.22% of the PWE during the pandemic. The factors increasing seizure frequency during the pandemic were fear of COVID-19, exacerbation of mental states, sleep deprivation, cancelation of regular medical visits, difficulties accessing epilepsy healthcare providers, and a lack of ASM availability.

Conclusion: The COVID-19 pandemic exposed PWE to harmful consequences mainly due to medical shortages and worse life states. During the pandemic, there were delays in the diagnosis of PWE, and doctors’ prescription habits changed. We must consider the lessons learned during this period of social restrictions and employ recent technological advances to improve treatment for PWE.

Exploring the Experiences of Self-Determination of Individuals with Mild Intellectual Disabilities and Epilepsy

Abstract found on PubMed

Background: While epilepsy can decrease quality of life and self-determination in individuals without intellectual disabilities, the impact of epilepsy on experienced self-determination in people with intellectual disabilities remains unclear.

Method: We conducted semi-structured interviews with six adults (four men, two women) aged 30-61 with mild intellectual disabilities and drug-resistant epilepsy to investigate their experiences of self-determination. The data were analysed using Interpretative Phenomenological Analysis.

Results: Three main themes were identified: (A) I am a competent person with epilepsy; (B) My social needs: being accepted as I am and stability in relationships; and (C) Being in control.

Conclusions: In this study, the impact of epilepsy on experienced self-determination of people with mild intellectual disabilities outweighs the influence of intellectual disabilities. Identity formation, friendships with peers, and autonomy support in risk management are identified as important topics in supporting this group.

Eating Disorders Occur at High Rates in Adolescents with Epilepsy and are Associated with Psychiatric Comorbidities and Suicidality

Abstract found on PubMed

Objectives: To assess the occurrence rate, characteristics, and impact of eating disorders (EDs) in adolescents with epilepsy.

Methods: In this observational study, adolescents with epilepsy seen in a single center between 2013-2022 who had comorbid EDs were compared to two control groups of adolescents with only epilepsy and only EDs. Patients with intellectual disability or autism spectrum disorder were excluded. Data retrieved included demographic and anthropometric details and clinical variables relating to seizure types, EDs, and psychiatric disorders and behaviors.

Results: A total of 376 subjects were included in the study: 84 adolescents with both epilepsy and eating disorders, 135 with only epilepsy, and 157 with only EDs. The rate of EDs in adolescents with epilepsy was 7.0% (95% CI 5.6-8.5%) overall, 11.3% (95% CI 8.8-14.3%) in females, and 3.1% (95% CI 1.9-4.8%) in males. The median (IQR) time difference between the onset of epilepsy to an ED was 1.6 (0.5-3.6) years. Among adolescents with epilepsy, those with an ED were more likely to be females (p=0.001) and have a lower zBMI percentile (p<0.001). Epilepsy type, seizure frequency, or seizure duration were not specific for having or not having EDs. Amongst adolescents with EDs, those with epilepsy had a younger onset of their EDs (p<0.001), included relatively more males (p=0.007), and consisted of more cases of anorexia-nervosa-restrictive type (p<0.001), and fewer cases of bulimia nervosa (p=0.04) and binge eating disorder (p=0.003). Adolescents with epilepsy and a comorbid ED were more likely to have psychiatric comorbidities such as depression, anxiety, and suicidality than adolescents with only epilepsy or EDs.

Significance: EDs should be suspected and screened for in intellectually intact female and male adolescents with epilepsy, irrespective of their epilepsy type. If disturbed eating behaviors or EDs are identified, further evaluation should be directed at detecting other psychopathologies, including suicidality.

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Abstract found on PubMed

The inhibitory neurotransmitter ?-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarizes available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABAA receptors and includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the ?2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomized double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABAA receptor ? and ? subunits is being investigated, with Lennox-Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.

The Modified Atkins Diet for Epilepsy: Two Decades of an “Alternative” Ketogenic Diet Therapy

Abstract found on PubMed

In 2003, the first case series of six patients treated with an Atkins diet for epilepsy was published in the journal Neurology. The concept was a simple, outpatient-initiated diet in which ketosis could be maintained by eating high-fat foods while tracking and limiting daily carbohydrate counts based on food ingredient labels. Twenty years later, after dozens of studies encompassing hundreds of patients, including several randomized controlled trials, the Modified Atkins Diet is a proven method of providing ketogenic dietary therapy for epilepsy. It is a diet therapy of choice for adolescents and adults, is being investigated for new-onset epilepsy, and is researched for neurological conditions other than epilepsy. Adverse effects do exist but may be less common than the classic ketogenic diet. This review will cover the history, clinical trials, implementation, current utilization, and future directions of this “alternative” ketogenic diet therapy on its 20-year anniversary.

A Review on Epilepsy, Current Treatments, and Potential of Medicinal Plants as an Alternative Treatment

Abstract found on PubMed

Epilepsy is considered common neurological diseases that threaten the lives of millions of people all around the world. Since ancient times, different forms of medications have been used to treat this condition. Adverse events associated with treatments and the residence time of available drugs caused to search for safer and more efficient therapies and drugs remain one of the major areas of research interest for scientists. As one of the therapeutics with fewer side effects, plants and their essential oils can be considered replacements for existing treatments. Medicinal plants have proven to be an effective natural source of antiepileptic drugs; most of them have their mechanism of action by affecting GABA receptors in different paths. Cannabis indica and Cymbopogon winterianus are well-known plant species with antiepileptic activities. The current review presenting a list of plants with antiepileptic effects aims to pave the way for finding alternative drugs with fewer side effects for scientists.

Intraoperative Seizures During Awake Craniotomy for Brain Tumor Resection

Abstract found on Curesus

Background: Intra-operative seizures (IOS) can occur during awake craniotomies (AC) for brain tumors. They can potentially result in an increased risk of morbidity; however, literature is scarce on IOS, its risk factors, and predictors. This study aims to ascertain the frequency of IOS in patients undergoing AC and determine possible IOS predictors.

Methods: In this retrospective study, we reviewed the records of all patients who underwent AC for tumor resection at a single university hospital between January 2016 and December 2020. IOS was defined as any seizure, including partial or generalized, experienced by any patient at any time from the beginning of the procedure till the end of surgery.

Results: Two hundred patients underwent AC during the study period. Seven (3.5%) patients experienced IOS. Compared to the non-seizure group, no significant correlation existed with any demographic variable. No significant difference was seen between the initial complaints presented by the two groups. In addition, the post-operative course of the seizure group did not significantly differ from the non-seizure group. Due to the low frequency of IOS in our cohort, an extensive analysis to determine predictors could not be performed.

Conclusion: In this study, we observed a low frequency of IOS (3.5%) during AC. The possible predictors and risk factors must be further investigated in large cohorts; to help limit the consequences of this possible intraoperative complication.

HCN1 epilepsy: From Genetics and Mechanisms to Precision Therapies

Abstract found on PubMed

Pathogenic variation in HCN1 is now an established cause of epilepsy and intellectual disability. Variation in HCN1 causes a spectrum of disease with a genotype-phenotype relationship emerging. De novo pathogenic variants that occur in the transmembrane domains of the channel typically cause a cation ‘leak’ that associates with severe developmental and epileptic encephalopathy (DEE). Genotype-phenotype associations for variants that fall outside of the transmembrane domains are less well established but do include milder forms of epilepsy that can be either de novo or inherited. HCN1 DEE mouse models have been generated which recapitulate the seizures and learning difficulties seen in human patients. These mice have also acted as powerful preclinical models which share pharmacoresponsiveness with human HCN1 DEE patients. Data from these mouse models support the conclusion that anti-seizure medications with sodium channel block as their primary mechanism of action should be used with caution in HCN1 DEE. Other comorbidities of HCN1 DEE including retinal dysfunction have also been modelled in HCN1 DEE mice, suggesting HCN1 variants can cause a dramatically reduced sensitivity to light with limited ability to process temporal information. Our understanding of the genetics and pathophysiological mechanisms underlying HCN1 epilepsy has progressed significantly and is already influencing therapy. However, more research effort is needed to fully understand the natural histories of HCN1 epilepsies and to develop precision therapeutic approaches.