Precision gene diagnosis and treatment of epilepsy: a new frontier in medical care.

Epilepsy in the elderly: Unique challenges in an increasingly prevalent population

Research priorities in epilepsy for the next decade—A representative view of the European scientific community: Summary of the ILAE Epilepsy Research Workshop, Brussels, 17–18 January 2008

Introduction–Decision points in epilepsy: Bedside to bench

Aim.To assess the efficacy and tolerability of lamotrigine (Sazar) for various forms of epilepsy, based on long-term experience of Svt. Luka's Association of Medical Institutions for the Diagnosis, Treatment, and Rehabilitation of Nervous System Diseases and Epilepsy. We analyzed the data obtained during 4 years (from June 2018 to August 2022).Materials and methods.We evaluated the efficacy and tolerability of Sazar in 104 patients aged 3 to 37 years (87 children and 17 adults (12 women and 5 men)); their mean age was 9.7 years. The sample included 42 males and 62 females. All of them were treated at Svt. Luka's Association of Medical Institutions for the Diagnosis, Treatment, and Rehabilitation of Nervous System Diseases and Epilepsy.The sample included patients with structural and presumably structural focal epilepsy (n= 44), focal epilepsy of unknown etiology (n= 6), genetic and presumably genetic epilepsy and epileptic encephalopathies (n= 43), idiopathic epilepsy (n= 11).Sazar was used as a monotherapy in 38 patients, whereas 66 patients received it in combination with other antiepileptic drugs (AED) (Sazar + 1 AED in 48 patients; Sazar + 2 AED in 18 patients). Two patients initially receiving polytherapy were successfully transferred to Sazar monotherapy.The dose of Sazar varied between 75 and 400 mg/day. In the majority of patients, including all children, Sazar daily dose was split into 2 portions. Three adult patients received Cazar once a day either in the evening (n= 2) or in the morning (n= 1) at a dose of 200 mg/day. The follow-up time was between 6 months and over 4 years.Results and conclusion.Therapeutic remission was achieved in 47 out of 104 patients (45.2 %) receiving Sazar. As many as 35 patients (33.6 %) demonstrated an at least 50 % reduction in seizure frequency; 22 patients had no effect (21.2 %). None of the participants developed significant aggravation.Only 9 patients (8.6 %) discontinued Caser due to its initial low efficacy, while another 8 patients (7.6 %) stopped to receive Casar because it became ineffective after 6–12 months of treatment. In general, good therapeutic effect (remission or at least 50 % reduction in seizure frequency) was achieved in 82 out of 104 patients (78.8 %). Given the fact that this study included patients with severe epilepsy, we can conclude that treatment was very effective.Casar was most effective in patients with focal epilepsy (including structural, presumably structural, structural-genetic, and that of unidentified etiology) and idiopathic generalized epilepsy.The majority of the patients (n= 94; 90.4 %) demonstrated good tolerability of Casar. Casar-associated side effects were registered in 10 patients (9.6 %). Allergic skin rash was observed in 5 cases (4.8 %) and developed during the first 2 months of therapy. Allergic reactions accounted for 50 % of all side effects and were the only reason for Casar discontinuation due to poor tolerability.Two female patients of reproductive age started Sazar to reduce the valproate dose that caused severe menstrual disorders, weight gain, alopecia, and edema. Halving the dose of valproate (up to 750 mg/day) in combination with Casar significantly improved treatment tolerance. One patient gave birth to a healthy baby when she was receiving monotherapy with Sazar at a dose of 350 mg/day.Eight patients receiving Sazar reported a significant improvement in their mood and behavior (one patient that had earlier been diagnosed with depression discontinued antidepressants after Sazar initiation since she did not need them any longer). None of the patients reported any negative effects of Sazar on their memory, attention, mood, and behavior (as evaluated by patients and parents; in some cases, by a neuropsychologist).Patients’ adherence to treatment confirmed high Sazar efficacy and tolerability: 82 out of 104 patients (78.8 %) continued to receive the drug after 6 months of treatment and 69 patients (66.3 %) still continued it after 12 months of treatment. The follow-up period varied between 6 months and 4 years.Thus, our findings suggest high efficacy and good tolerability of long-term therapy with Sazar in patients with different forms of epilepsy.

Epilepsy is a severe, relapsing, and multifactorial neurological disorder. Studies regarding the accurate diagnosis, prognosis, and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy. The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression, protein expression, ion channel activity, energy metabolites, and gut microbiota composition. Satisfactory results are lacking for conventional treatments for epilepsy. Surgical resection of lesions, drug therapy, and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy. Non-pharmacological treatments, such as a ketogenic diet, gene therapy for nerve regeneration, and neural regulation, are currently areas of research focus. This review provides a comprehensive overview of the pathogenesis, diagnostic methods, and treatments of epilepsy. It also elaborates on the theoretical basis, treatment modes, and effects of invasive nerve stimulation in neurotherapy, including percutaneous vagus nerve stimulation, deep brain electrical stimulation, repetitive nerve electrical stimulation, in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation. Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures. Additionally, many new technologies for the diagnosis and treatment of epilepsy are being explored. However, current research is mainly focused on analyzing patients’ clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level, which has led to a lack of consensus regarding the mechanisms related to the disease.

Introduction. Epilepsy has been considered to be more frequent in Greenland than in Denmark, where the prevalence among children is 0.40 %. Study design. Evaluation of the prevalence, diagnosis and treatment of epilepsy among children in Greenland aged 0–15 years. Methods. During autumn 2000, 13 out of 18 hospitals in Greenland were visited. The population of children in the areas visited was 11,965 of a total of 15,226 in Greenland. All children with the diagnosis of epilepsy were referred for evaluation and the diagnosis was confirmed. When possible, informed consent was obtained to collect data from medical records Results. 43 children (18 boys) had the diagnosis of epilepsy. For 38 (15 boys) further data were obtained. Mean age was 8.5 years (3-14) for boys and 7.9 years (2-14) for girls. The age at diagnosis was 4.9 years (1-11) for boys and 4.2 years (0-10) for girls. The prevalence of epilepsy was 0.34%. In 31 cases an electroencephalograph (EEG) recording was done, comprising sleep recordings in 26 cases. Medication was according to recommendations in Denmark. Conclusion. The prevalence of epilepsy in children and the medical treatment of epilepsy among children in Greenland is the same as in Denmark.

IntroductionEpilepsy is a neurological disorder which causes seizures and may be accompanied by loss of unconsciousness and control of bowel or bladder function. However, other types of epilepsy are only characterised by rapid blinking or a few seconds of staring into space. Many people living with epilepsy in rural communities consult traditional healers as their first line of treatment for epilepsy. Second preference is given to medical practitioners which causes unnecessary delay in the early diagnosis and treatment of epilepsy. This study aimed to explore how traditional healers diagnose epilepsy and its implications on management in the selected rural communities of Limpopo and Mpumalanga Provinces.MethodsA qualitative approach using explorative, descriptive and contextual designs was adopted. Purposive sampling was used to sample six villages in Limpopo and Mpumalanga Provinces. Snowball sampling was used to sample twenty traditional healers. Data were collected through in-depth individual interviews at the participant’s homes. Data were analysed using Tesch’s eight steps of open coding data analysis.ResultsThis study found that traditional healers have varied beliefs and misconceptions regarding the causes and diagnosis of epilepsy, hence this greatly influencing the management. The misconceptions on the causes include a calling by ancestors, urine contents, snake in the stomach, contaminated digestive system and witchcraft. The management included using herbal plants, insects, foam excreted during seizures and urine of the person living with epilepsy.RecommendationIt is recommended that for effective management of epilepsy, there should be coordination between traditional healing and western medicine. Future research should look at the integration of traditional medicine and western medicine.

Previous studies have estimated medical care costs of epilepsy by applying unit costs to estimated utilization or by summing costs for (a) ambulatory care and hospitalizations coded as epilepsy and (b) procedures and drugs specifically associated with the diagnosis or treatment of epilepsy. These methods may underestimate the cost of medical care for epilepsy. Two methods for estimating the medical care costs of epilepsy ("epilepsy-attributable cost method" and "case-control cost method") were compared. The study population was 655 individuals with an epilepsy diagnosis enrolled in a managed care plan in the southwestern United States. The epilepsy-attributable costs were determined by summing costs for inpatient and outpatient encounters coded as epilepsy, procedures for the diagnosis or treatment of epilepsy, and drugs used to treat epilepsy. The case-control method determined costs by calculating the difference in total costs between cases and 1,965 age- and gender-matched controls. The case-control epilepsy costs were $2,923 per case compared with epilepsy-attributable costs of $1,335 per case. The case-control method found statistically significant differences in costs between cases and controls for inpatient care, prescription drugs, and 8 of 11 categories of outpatient care. The largest contributors to the discrepancy between estimates were inpatient care, emergency department care, laboratory tests, and "other specialist" care. Epilepsy-attributable costs accounted for only 46% of the total difference in costs between epilepsy cases and controls. Persons with epilepsy use more medical services than controls, but a substantial portion of this care is not coded to epilepsy.

Recent advances in exome and targeted sequencing have significantly improved the aetiological diagnosis of epilepsy, revealing an increasing number of epilepsy-related pathogenic genes. As a result, the diagnosis and treatment of epilepsy have become more accessible and more traceable. Voltage-gated potassium channels (Kv) regulate electrical excitability in neuron systems. Mutate Kv channels have been implicated in epilepsy as demonstrated in case reports and researches using gene-knockout mouse models. Both gain and loss-of-function of Kv channels lead to epilepsy with similar phenotypes through different mechanisms, bringing new challenges to the diagnosis and treatment of epilepsy. Research on genetic epilepsy is progressing rapidly, with several drug candidates targeting mutated genes or channels emerging. This article provides a brief overview of the symptoms and pathogenesis of epilepsy associated with voltage-gated potassium ion channels dysfunction and highlights recent progress in treatments. Here, we reviewed case reports of gene mutations related to epilepsy in recent years and summarized the proportion of Kv genes. Our focus is on the progress in precise treatments for specific voltage-gated potassium channel genes linked to epilepsy, including KCNA1, KCNA2, KCNB1, KCNC1, KCND2, KCNQ2, KCNQ3, KCNH1, and KCNH5.

The prevalence of epilepsy is higher in people with intellectual disability (ID) and increases with the degree of ID. Although life expectancy for people with ID is increasing, people with ID coexisting with epilepsy have a higher mortality rate, particularly those who had recent seizures. There have been few observational studies of the prevalence and patterns of anti-epileptic prescribing among older people with ID and epilepsy. The aim of this study was to investigate prevalence and patterns of anti-epileptic prescribing in the treatment of epilepsy in a representative population of older people with ID and epilepsy. This was an observational cross-sectional study from wave 1 (2009/2010) of Intellectual Disability Supplement to the Irish Longitudinal Study on Aging, a nationally representative sample of 753 persons with ID aged between 41 and 90years. Participants and/or proxies recorded medicines used on a regular basis and reported doctor's diagnosis of epilepsy; medication data were available for 736 (98%). Prescribing of anti-epileptic drugs (AEDs) for epilepsy in those with a doctor's diagnosis of epilepsy (N=205) was the primary exposure of interest for this study. Participant exposure to these AEDs was then categorised into AED monotherapy and polytherapy. Participants/carers reported seizure frequency, when epilepsy was last reviewed and which practitioner reviewed epilepsy. In addition, medications that may lower the seizure threshold that were listed in the Maudsley prescribing guidelines in psychiatry were examined. Of the 736 participants with reported medicines use, 38.9% (n=287) were exposed to AEDs, and 30.6% (225) had a doctor's diagnosis of epilepsy. Of those with epilepsy (n=225), 90.9% (n=205) reported concurrent use of AEDs and epilepsy. Of these 205 participants, 50.3% (n=103) were exposed to AED polytherapy, and 63 different polytherapy regimes were reported. The most frequently reported AEDs were valproic acid (n=100, 48.7%), carbamazepine (n=89, 46.3%) and lamotrigine (n=57, 27.8%). In total, 13.7% had a concurrent psychotropic, which should be avoided in epilepsy, and 32.6% had a psychotropic where caution is required. Antipsychotics with potential epileptogenic potential accounted for 80% of these medications. Of those with AED polytherapy (n=103), 29.5% (28) reported being seizure free for the previous 2years. Prevalence of epilepsy was high among older people with ID, and half were exposed to two or more AEDs. Despite the use of AED therapy, over half had seizures in the previous 2years. As the primary goals of optimal AED treatment are to achieve seizure freedom without unacceptable adverse effects, this was not achievable for many older patients with ID and epilepsy. Our findings indicated that people with ID and epilepsy were often exposed to psychotropic medications that may lower the seizure threshold. Regular review of epilepsy and medicines (including medicines that may interact with AEDs or lower the seizure threshold) by multidisciplinary teams working to agreed standards may improve quality of prescribing. Improved exchange of information and coordination of care between specialists and primary care practitioners in line with expert consensus recommendations could bring substantial benefit.

Epilepsy treatment gap, associated risk factors and intervention strategies in Kilifi, Kenya

The correct diagnosis of epilepsy leads to an appropriate treatment. The first step is to distinguish epileptic seizures from nonepileptic attacks, and to make a precise seizure diagnosis and classification. The next step is to identify the etiology or basic disorders underlying the epilepsy by physical and neurologic examinations, laboratory tests, including EEGs and neuroradiologic examinations. Although the EEG is the most important laboratory examination for the diagnosis of epilepsy, limitations of EEG interpretations must be recognized. A syndromic classification of the patients, to determine whether they fit known syndromes, should be attempted. If patients do not match a described syndrome, a neurobiologic approach, utilizing genetic, neurophysiological, and neuropharmacologic knowledge, alternatively provides useful information to understand the neurobiologic background of epilepsy. Both approaches have advantages and disadvantages for diagnosing and treating epilepsy. Both approaches can be used interchangeably with patients with seizure disorders, depending upon their condition. The epilepsy diagnosis, etiology, and seizure-type diagnosis should be reevaluated when seizure control is insufficient with first- and second-line antiepileptic drugs.

The symptoms of epileptic seizures in old patients differ from those in younger patients. Therefore, these seizures may be misinterpreted as symptoms of other "typical" diseases in old people. In an old people's home, we assessed whether a standardized questionnaire is able to reveal undiagnosed epilepsy in the elderly. Reported sudden falls, loss of consciousness, and cramps were the criteria for further diagnostic procedures. We found epilepsy in 11 of 389 study participants. In four of them (1% of the total sample), the epilepsy was newly diagnosed; five more cases remained unclear. Therefore, the total number of epileptic patients might have been even higher. Most of the reported sudden falls and unconsciousness (89%) were due to internal medical or other neurological or orthopaedic causes. Once these have been excluded, the diagnosis of epilepsy should be considered. The results of our pilot study suggest that epilepsy in old people's homes is often unrecognised. Early diagnosis and treatment of epilepsy in the elderly is important to improve prognosis and social consequences for affected persons.

ILAE/IBE/WHO Global Campaign "out of the shadows": global and regional developments.

ObjectiveTo estimate the treatment gap between a new epilepsy diagnosis and antiepileptic drug (AED) initiation in the United States.MethodsRetrospective claims-based cohort study using Truven Health MarketScan databases (commercial and supplemental Medicare, calendar years 2010–2015; Medicaid, 2010–2014) and a validation study using PharMetrics Plus Database linked to LRx claims database (2009–2014). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (1 year for persons aged 1 to <2 years; none for persons <1 year), and continuous medical and pharmacy enrollment without epilepsy/seizure diagnosis or AED prescription during baseline. Outcomes included percentage of untreated persons (no AED prescription) up to 3 years' follow-up and comparative outcomes (incidence rate ratio: untreated persons/treated persons), including medical events and health care resource utilization.ResultsIn the primary study, 59,970 persons met selection (or inclusion) criteria; 36.7% of persons with newly diagnosed epilepsy remained untreated up to 3 years after diagnosis. In the validation study (N = 30,890), 31.8% of persons remained untreated up to 3 years after diagnosis. Lack of AED treatment was associated with an adjusted incidence rate ratio (95% confidence interval) of 1.2 (1.2–1.3) for medical events, 2.3 (2.2–2.3) for hospitalizations, and 2.8 (2.7–2.9) for emergency department visits.ConclusionsOne-third of newly diagnosed persons remain untreated up to 3 years after epilepsy diagnosis. The increased risk of medical events and health care utilization highlights the consequences of delayed treatment after epilepsy diagnosis, which might be preventable.