Objective:In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase risk of sudden death in patients with structural or ischaemic cardiac disease, however its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear.
Methods: This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at time of admission, and survival analyses from time of admission up to 16?years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors.
Results: Proportions of cases and controls prescribed lamotrigine (p=0.166), one NaM-ASM (p=0.80) or ?2NaM-ASMs (p=0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR]=0.56; p=0.054), one NaM-ASM (aHR=0.8; p=0.588) or ?2 NaM-ASMs (aHR=0.49; p=0.139) at EMU admission were not at increased SUDEP risk up to 16?years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR=2.24; p=0.031) or NaM-ASM use (aHR=2.25; p=0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results.
Significance: This study provides additional evidence that lamotrigine and other sodium channel-modulating anti-seizure medications are unlikely to be associated with an increased long-term risk of SUDEP, up to 16?years post epilepsy monitoring unit admission.
There are only a few drugs that can seriously lay claim to the title of “wonder drug” and ivermectin, the world’s first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B1a and B1b in a ratio of 80:20), exerts its highly potent antiparasitic effect by activating the glutamate-gated chloride channel that is absent in vertebrate species. However, in mammals, ivermectin activates several other Cys-loop receptors, including the inhibitory GABAA and glycine receptors and the excitatory nicotinic acetylcholine receptor of brain neurons. Based on these effects on vertebrate receptors, ivermectin has recently been proposed to constitute a multifaceted wonder drug for various novel neurological indications, including alcohol use disorders, motor neuron diseases, and epilepsy. This review critically discusses the preclinical and clinical evidence of anti-seizure effects of ivermectin and provides several arguments why ivermectin is not a suitable candidate drug for the treatment of epilepsy. First, ivermectin penetrates the mammalian brain poorly, so it does not exert any pharmacological effects via mammalian ligand-gated ion channels in the brain unless it is used in high, potentially toxic doses or the blood-brain barrier is functionally impaired. Second, ivermectin is not selective but activates numerous inhibitory and excitatory receptors. Third, the preclinical evidence for anti-seizure effects of ivermectin is equivocal and, at least in part, ED50 s in seizure models are in the range of the LD50 . Fourth, the only robust clinical evidence of anti-seizure effects stems from the treatment of patients with onchocerciasis in which the reduction of seizures is due to a reduction in microfilariae densities but not a direct anti-seizure effect of ivermectin. We hope that this critical analysis of available data will avert that the unjustified hype associated with the recent use of ivermectin to control COVID-19 recurs also in neurological diseases such as epilepsy.
The association between attention deficit hyperactivity disorder (ADHD) and tuberous sclerosis complex (TSC) is widely reported, with support for the role of epilepsy, yet the mechanisms underlying the association across development are unclear. The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of TSC. In Phase 1 of the study, baseline measures of epilepsy, cortical tuber load and mutation were obtained with 125 children aged 0 – 16 years. In Phase 2, at an average of 8 years later, ADHD symptoms were measured for 81 of the participants. Structural equation modelling revealed an indirect pathway from genetic mutation, to cortical tuber load, to epileptic spasm severity in infancy, to ADHD symptoms in middle childhood and adolescence, in addition to a pathway linking current seizure severity to ADHD symptoms. Findings were retained when IQ was entered as a correlated factor. The findings support a cascading developmental pathway to ADHD symptoms mediated by early-onset and severe epilepsy in the first two years of life. This warrants detailed investigation of seizure characteristics and cognitive and behavioural sequelae associated with ADHD from early in life, to further understanding of the association between ADHD and early-onset epilepsy across syndromic and non-syndromic populations.
In an aging world, it is important to know the burden of epilepsy affecting populations of older persons. We performed a selective review of epidemiological studies that we considered to be most informative, trying to include data from all parts of the world. We emphasized primary reports rather than review articles. We reviewed studies reporting the incidence and prevalence of epilepsy that focused on an older population as well as studies that included a wider age range if older persons were tabulated as a subgroup. There is strong evidence that persons older than approximately 60 years incur an increasing risk of both acute symptomatic seizures and epilepsy. In wealthier countries, the incidence of epilepsy increases sharply after age 60 or 65 years. This phenomenon was not always observed among reports from populations with lower socioeconomic status. This discrepancy may reflect differences in etiologies, methods of ascertainment, or distribution of ages; this is an area for more research. We identified other areas for which there are inadequate data. Incidence data are scarcer than prevalence data and are missing for large areas of the world. Prevalence is lower than would be expected from cumulative incidence, possibly because of remissions, excess mortality, or misdiagnosis of acute symptomatic seizures as epilepsy. Segmentation by age, frailty, and comorbidities is desirable, because “epilepsy in the elderly” is otherwise too broad a concept. Data are needed on rates of status epilepticus and drug-resistant epilepsy using the newer definitions. Many more data are needed from low-income populations and from developing countries. Greater awareness of the high rates of seizures among older adults should lead to more focused diagnostic efforts for individuals. Accurate data on epilepsy among older adults should drive proper allocation of treatments for individuals and resources for societies.
Objective: Medication adherence is considered an important risk factor for Sudden Unexpected Death in Epilepsy (SUDEP) although measurement accuracy is difficult. Using prescription dispensations, this study aims to estimate antiseizure medication (ASM) adherence and identify adherence patterns that influence epilepsy mortality.
Methods: Retrospective cohort study of tertiary epilepsy outpatients seen at St Vincent’s Hospital (Melbourne), Victoria, Australia, from 1/01/2012 until 31/12/2017. Privacy preserving data-linkage with the Australian national prescription, death and coroner’s databases was performed. We fitted a 4-cluster longitudinal group-based trajectory model for ASM adherence from recurring 90-day windows of prescription dispensations during a 3-year ‘landmark period’ 1/1/2012 to 31/12/2014, using the AdhereR package. We estimated the risk of SUDEP and all cause death for each adherence pattern during an ‘observation period,’ 1/1/2015 to 31/12/2017. The Cox-proportional hazards and logistic regression models were adjusted for age, sex, socioeconomic status, epilepsy duration, comorbidity, drug resistance and inadequate seizure control.
Results: 1,187 participants were observed for a median of 3.2 years (IQR 2.4-4.0 years). We observed 66 deaths with 10 SUDEP cases during the observation period. We identified 4 patterns of ASM adherence: good 51%, declining 24%, poor 16%, and very poor 9%. Declining adherence was associated with an increased risk for SUDEP, hazard ratio 8.43 (95%CI 1.10, 64.45) at 1 year, and HR 9.17 (95%CI 1.16,72.21) at 3 years. Compared to no ASM therapeutic change, the addition of a 2nd to 4th ASM offered increased protection against SUDEP in patients with continuing drug resistant epilepsy.
Significance: ASM non-adherence was observed in half of outpatients with epilepsy. A declining pattern of adherence, observed in a quarter of patients, is associated with more than eight times increased risk of SUDEP. Any ongoing medication interventions must include strategies to maintain and improve ASM adherence if we are to reduce the risk of SUDEP.
Background and Study Aims: Antiepileptic drugs are the first choice of treatment for patients with epilepsy. However, the withdrawal of antiepileptic drugs after seizure-free remains a significant focus for the majority of patients with epilepsy and their families. In this study, we evaluated the risk factors associated with relapse after drug withdrawal in patients with seizure free for 2 years. We aimed to guide patients in seizure-free to assess the risk of drug withdrawal.
Patients and Methods: Through screening, 452 patients with epilepsy were included in the study. Patients were followed up for at least 2 years or more. Analyzed their clinical data by applying the ? 2-test, Kaplan-Meier survival analysis and multivariate Cox regression analysis.
Results: 423 patients completed follow-up, of which 304 cases recurred (71.9%). Related recurrence factors include age of onset, type of seizure, number of AEDs, seizure-free time before withdrawal, and electroencephalogram (EEG) results before drug withdrawal (P< 0.05). The results of correlation analysis showed that age of onset, seizure frequency, seizure type, number of AEDs, the period from AEDs treatment to a seizure-free status, EEG results before drug withdrawal, and pre-medication course, were all significantly related to the recurrence of seizures after drug reduction and withdrawal (P< 0.05). We identified a range of independent risk factors, including onset age, seizure frequency, Multiple AEDs and the period from AEDs treatment to a seizure-free status.
Conclusion: The overall recurrence rate of epilepsy in our patient cohort was high, and the peak recurrence period was within one year of drug withdrawal. Patients with partial seizures, a short seizure-free time before withdrawal, severe EEG abnormalities before drug reduction, and a long course of the disease, are prone to relapse. Patients with an older age at onset and a high frequency of attack, those taking multi-drug combination therapy, and those that take a long time to gain control, should be managed carefully to AEDs withdrawal.
Objective: Identifying factors associated with surgical decision making is important to understand reasons for underutilization of epilepsy surgery. Neurologists’ recommendations for surgery and patients’ acceptance of these recommendations depend on clinical epilepsy variables, e.g., lateralization and localization of seizure onset zones. Moreover, previous research shows associations with demographic factors, e.g., age and sex. Here, we investigate the relevance of patients’ psycho-social profile for surgical decision making.
Methods: We prospectively studied 296 patients from two large German epilepsy-centers. Multiple logistic regression analyses were used to investigate variables linked to neurologists’ recommendations for and patients’ acceptance of surgery or intracranial video-EEG monitoring. Patients’ psycho-social profiles were assessed via self-reports and controlled for various clinical-demographic variables. Model selection was performed using the Akaike Information Criterion.
Results: As expected, models for neurologists’ surgery recommendations primarily revealed clinical factors such as lateralization and localization of the seizure onset zone, load with antiseizure medication (ASM) and site of the epilepsy-center. For this outcome, employment was the only relevant psycho-social aspect (OR = 0.38; 95%-CI = [0.13; 1.11]). In contrast, three of the five relevant predictors for patients’ acceptance were psycho-social: Higher odds were found for those with more subjective ASM adverse events (OR = 1.04; 95%-CI = [0.99;1.00]), more subjective seizure severity (OR = 1.12; 95%-CI= [1.01;1.24]), and lower subjective cognitive impairment (OR = 0.98; 95%-CI = [0.96;1,00]).
Significance: We demonstrated the relevance of patients’ psycho-social profile for decision making in epilepsy surgery – particularly for the patients’ decisions. Thus, in excess to clinical-demographic variables, patients’ individual psycho-social characteristics add to the understanding of surgical decision making. From a clinical perspective, this calls for individually tailored counseling to assist patients in finding the optimal treatment option.
On behalf of the entire team at CURE Epilepsy, I would like to thank you for your support and generosity throughout 2022. Your ongoing support makes our mission of funding breakthrough research to find a cure possible.
2023 marks an incredibly significant milestone for CURE Epilepsy. This year we are celebrating 25 years of inspiring hope and delivering impact for the epilepsy community. Twenty-five years ago Susan Axelrod and a small group of parents of children with epilepsy who were frustrated with their inability to protect their children from seizures and the side effects of medications joined forces to accelerate the search for a cure. From that frustration, CURE Epilepsy was born, and through their persistence and dedication, as well as the commitment of thousands of parents, caregivers, researchers, clinicians, people living with epilepsy and so many more along the way, we continue paving the path to advance science to find the cures for epilepsy.
During the past 25 years, we have raised over $90 million to achieve our missionand awarded more than 280 grants. We will not stop until we are all able to live in the world we envision. A world without epilepsy.
With commitment to inspire hope and deliver impact.
In this CURE Epilepsy Update, please find information on:
In 2022, the Monast family from Eastern Pennsylvania, along with fellow CURE Epilepsy Champions, the Rosini family, organized the first annual Reagan’s Run. Reagan Monast, the inspiration for the race, was diagnosed with epilepsy nearly eight years ago before her second birthday. Reagan’s Run was a 5K or 1-mile run/walk to raise awareness and critical funds for epilepsy research in honor of Regan, family friend Dominic Rosini, and the 3.4 million other Americans living with epilepsy.
With the help of their friends and families, the Monasts and Rosinis raised nearly $30,000 to fund research to find a cure. You can become a Champion like the Monast and Rosini families by starting an awareness and fundraising event of your own to support CURE Epilepsy. If you need some ideas to get started or want additional information, you can contact CURE Epilepsy at events@CUREepilepsy.org. And stay tuned for more details about our 25th Anniversary CURE Epilepsy Champions Challenge.
Please join us in welcoming the newest addition to our Board of Directors, Justin Gover. Justin has over twenty-five years of experience in leadership positions in the biotechnology industry in the UK and the US, most recently as the CEO of GW Pharmaceuticals prior to its acquisition by Jazz Pharmaceuticals.
Start Your 2023 Off Right by Choosing to #SayEpilepsy
2022 may have come to an end, however, our Say the Word #SayEpilepsy campaign continues into 2023 as a way to help continue to raise epilepsy awareness. By saying and sharing Say the Word #SayEpilepsy, you can help make a difference in the lives of those within the epilepsy community who are in need of a cure.
Mark your calendars now for Purple Day on Sunday, March 26! Purple Day is an annual, international grassroots effort to help build awareness for epilepsy around the globe. Join with the epilepsy community on this is a day of celebration, recognition, and awareness. You can also participate in the Purple Day Expo at Disney World on March 25th.
Dr. Eva Alden, a Neuropsychologist at the Mayo Clinic joins us to explain the connection between stress and seizures, and offers advice, insights, and recommendations for those with epilepsy and their caregivers to help cope with stress and seizure triggers during the holidays.
Objective: Psychiatric conditions are frequently co-morbid in epilepsy and studies examining Veterans with epilepsy suggest this population may present with unique psychiatric and clinical features Drug-resistant epilepsy (DRE) may confer a greater risk of psychiatric dysfunction; however, there is a paucity of literature documenting this. To expand our clinical understanding of Veterans with DRE, we assessed a comprehensive Veterans Health Administration (VHA)-wide sample, describing psychiatric conditions, medications, and healthcare utilization.
Methods: Psychiatric and hospitalization data were collected on 52,579 Veterans enrolled in VHA healthcare between FY2014-2ndQtr. FY2020 from the VHA Corporate Data Warehouse administrative data. Data examined include psychiatric diagnosis, psychotropic medication use, and utilization of hospital services.
Results: At least one psychiatric diagnosis was present in 70.2% of patients, while 49.8% had two or more diagnoses. Depression (51.7%), posttraumatic stress disorder (PTSD) (38.8%), and anxiety (38.0%) represented the most common psychiatric co-morbidities. Psychiatric medication use was present in 73.3%. Emergency room (ER) visits were highest in those with suicidality (mean 14.9 visits), followed by bipolar disorder (10.3), and schizophrenia (12.1). Psychiatric-related hospitalizations were highest for schizophrenia (mean 2.5 admissions) and bipolar disorder (2.3). Females had more psychiatric diagnoses (2.4 vs. 1.6, p < 0.001), psychiatric medications (3.4 vs. 2.3, p < 0.001), and ER utilization than males (6.9 vs. 5.5, p < 0.001).
Significance: A substantial psychiatric burden exists among Veterans with drug-resistant epilepsy (DRE). Compared to prior epilepsy literature, results suggest that Veterans with DRE evidence more prevalent psychiatric comorbidity, emergency care usage, and inpatient psychiatric admissions. Females were especially impacted, with greater rates of psychiatric conditions and treatment. Considering the relationship of psychiatric comorbidities in epilepsy with psychosocial functioning and quality of life, our findings highlight the need for screening and provision of services for those with DRE.
Epilepsy is a chronic neurological disorder that presents as recurrent, unprovoked seizures. Pharmacotherapy is the main treatment for epilepsy, but at least 30% of patients with epilepsy have pharmacoresistant epilepsy. Therefore, non-pharmacological treatments are still required. In addition to electrophysiological aberrations contributing to epileptogenesis and pathophysiology in epilepsy, neuroinflammation, oxidative stress, and metabolic derangement have been investigated as drug targets in the treatment of epilepsy. Vitamins have antioxidant, anti-inflammatory, and immunomodulatory effects, which can be beneficial for the treatment of epilepsy. Herein, we comprehensively review the role of vitamins in epilepsy. Certain epilepsies are vitamin-dependent or vitamin-responsive. Most studies on vitamins in epilepsy are of low evidence level or limited to animal studies. Nevertheless, vitamin supplementation should be considered in epilepsy therapy. Additionally, certain anti-seizure medications may alter the serum levels of certain vitamins. Monitoring the serum levels of vitamins and supplementing vitamins when needed are suggested during the follow-up of patients with epilepsy.