Perampanel's forgiveness factor in a variable medication adherence paradigm in a rat model of chronic epilepsy.

BACKGROUND: Poor medication adherence contributes to increased morbidity and mortality in patients with epilepsy and may be under-addressed in clinical practice. Ethical concerns make it impossible to study the impact of medication nonadherence in clinical trials, but our previous work emphasizes the importance of using preclinical approaches to address these questions. With over 30 clinically available antiseizure medicines (ASM's), it remains an important question to understand the relationship between poor adherence and seizure incidence across mechanistically distinct ASM's, including the broad-spectrum ASM, perampanel (PER). METHODS: We formulated PER into chow pellets to deliver to rats in a 100% fully adherent or 50% variable nonadherent paradigm via our novel automated medication-in-food delivery system. Chronic oral dosing was initiated in male rats with chronic epilepsy while monitoring 24/7 for videoEEG evidence of seizures during a 4-week placebo baseline and 4-week treatment phase. PER concentrations were monitored in plasma at 1-week intervals and correlated with degree of seizure control. The relationship between missed doses and extended patterns of nonadherence were correlated with breakthrough seizures. RESULTS: Fully adherent rats demonstrated a median reduction in seizure frequency of 50%, whereas nonadherent rats had a median increase of 54%. Plasma concentrations of PER were stable over the 4-week treatment period in both fully adherent and nonadherent groups, with levels being twice as high in fully adherent animals. There was no correlation between a single missed dose or series of missed doses and the incidence of breakthrough seizures. However, those animals in the nonadherent group that received PER for every meal during a 24-h period had a reduced likelihood of seizure incidence. CONCLUSIONS: If our preclinical data is supported in the clinic, PER's favorable pharmacokinetic profile in humans, combined with a lowered risk of breakthrough seizures suggests that it may provide a certain forgiveness factor if a dose is missed within a 24-h window.

Extended follow-up after anterior temporal lobectomy demonstrates seizure recurrence 20+ years postsurgery.

OBJECTIVE: Anterior temporal lobectomy (ATL) for medication-resistant localized epilepsy results in ablation or reduction of seizures for most patients. However, some individuals who attain an initial extended period of postsurgical seizure freedom will experience a later seizure recurrence. In this study, we examined the prevalence and some risk factors for late recurrence in an ATL cohort with extensive regular follow-up. METHODS: Included were 449 patients who underwent ATL at Austin Health, Australia, from 1978 to 2008. Postsurgical follow-up was undertaken 2-3 yearly. Seizure recurrence was tested using Kaplan-Meier analysis, log-rank test, and Cox regression. Late recurrence was qualified as a first disabling seizure >2 years postsurgery. We examined risks within the ATL cohort according to broad pathology groups and tested whether late recurrence differed for the ATL cohort compared to patients who had resections outside the temporal lobe (n = 98). RESULTS: Median post-ATL follow-up was 22 years (range = .1-38.6), 6% were lost to follow-up, and 12% had died. Probabilities for remaining completely seizure-free after surgery were 51% (95% confidence interval [CI] = 53-63) at 2 postoperative years, 36% (95% CI = 32-41) at 10 years, 32% (95% CI = 27-36) at 20 years, and 30% (95% CI = 25-34) at 25 years. Recurrences were reported up to 23 years postoperatively. Late seizures occurred in all major ATL pathology groups, with increased risk in the "normal" and "distant lesion" groups (p ≤ .03). Comparison between the ATL cohort and patients who underwent extratemporal resection demonstrated similar patterns of late recurrence (p = .74). SIGNIFICANCE: Some first recurrences were very late, reported decades after ATL. Late recurrences were not unique to any broad ATL pathology group and did not differ according to whether resections were ATL or extratemporal. Reports of these events by patients with residual pathology suggest that potentially epileptogenic abnormalities outside the area of resection may be implicated as one of several possible underlying mechanisms.

Estudio observacional, prospectivo y multicéntrico sobre el uso de citrato de fentanilo transmucosa en la práctica clínica habitual para el control de las crisis de dolor irruptivo en pacientes oncológicos / Observational, prospective and multicenter study on the use of transmucosal fentanyl citrate in regular clinical practice for the control of breakthrough pain crises in cancer patients

Objetivo: Evaluar el grado de satisfacción de los pacientes y/o cuidadores con el tratamiento de citrato de fentanilo transmucosa en la gestión de las crisis de dolor irruptivo oncológico en términos de facilidad de uso. Métodos: Se realizó un estudio observacional, prospectivo y multicéntrico con 48 pacientes sometidos a tratamiento de mantenimiento con opioides para el dolor crónico basal provocado por el cáncer y que, además, sufrían crisis de dolor irruptivo para las que estaban recibiendo tratamiento con citrato de fentanilo. La variable principal del estudio fue el grado de satisfacción de los pacientes y/o sus cuidadores con el citrato de fentanilo en el manejo de las crisis de dolor irruptivo oncológico, evaluadas mediante cuestionarios Escala Visual Analógica (EVA). Resultados: El 90,6 % de los pacientes/cuidadores muestran un elevado grado de satisfacción con el empleo de citrato de fentanilo en términos de facilidad de uso (valor medio EVA de 8,2). Por su parte, tanto la valoración general por parte de los pacientes/cuidadores como por parte de los sanitarios ha sido muy positiva (valor medio EVA 7,7). Conclusiones: El citrato de fentanilo es una terapia fácil de usar y eficaz para el tratamiento de las crisis de dolor irruptivo oncológico, con amplia aceptación tanto por parte de pacientes y cuidadores como de los profesionales sanitarios.(AU)

Objective: To assess the degree of satisfaction of patients and/or caregivers with transmucosal fentanyl citrate treatment in the management of breakthrough cancer pain crises in terms of ease of use. Methods: An observational, prospective and multicenter study was carried out with 48 patients undergoing maintenance treatment with opioids for baseline chronic cancer pain and who, in addition, suffered breakthrough pain crises for those who were receiving treatment with fentanyl citrate. The main variable of the study was the degree of satisfaction of the patients and/or their caregivers with fentanyl citrate in the management of breakthrough cancer pain crises, evaluatedby means of Visual Analogue Scale (VAS) questionnaires. Results: 90.6 % of patients/caregivers show a high degree of satisfaction with the use of fentanyl citrate in terms of ease of use (mean VAS value of 8.2). For its part, both the general assessment by the patients/caregivers and by the healthcare professionals has been very positive (mean VAS value 7.7). Conclusions: Fentanyl citrate is an easy-to-use and effective therapy for the treatment of breakthrough cancer pain crises, widely accepted by both patients and caregivers as well as health professionals.(AU)

Low Serum Pyridoxine Levels Worsen Seizure Control in Adult Epilepsy Patients.

BACKGROUND: Vitamin B6 (pyridoxine) is an important cofactor in the process by which glutamic acid decarboxylase (GAD) converts the excitatory, pro-epileptogenic neurotransmitter, glutamate, into the inhibitory, anti-epileptogenic neurotransmitter, gamma-aminobutyric acid (GABA). This concept has been established in infants with pyridoxine-dependent epilepsy as well as adult patients with other epilepsy subtypes who presented with medication-resistant status epilepticus, with both patient groups experiencing cessation of seizure activity following pyridoxine administration. Given our knowledge of the role of vitamin B6 in the conversion of glutamate to GABA, its effect on seizure control in infants with specific epilepsy subtypes, reports of adult-onset seizures associated with vitamin B6 deficiency, and vitamin B6's role in terminating status epilepticus in adult patients with other types of epilepsy, we suspect that low vitamin B6 levels in adult epilepsy patients may correlate with poor seizure control across all epilepsy subtypes. This study seeks to determine whether there is a relationship between pyridoxine levels and the level of seizure control in adults with epilepsy, regardless of their seizure type. METHODS: After obtaining institutional review board approval, we prospectively enrolled 32 patients (age range: 25-57 years) with epilepsy who presented to our clinic. Patients who did not meet the study criteria or who were diagnosed with psychogenic non-epileptic seizures (PNES) were excluded from the study (n = 2). Patients were classified as well-controlled (WC) or poorly controlled (PC) based on the absence or presence of a seizure within the last three months, respectively. After classification as WC or PC, pyridoxine serum levels and anti-seizure medication (ASM) levels were drawn in that clinic visit, following patient consent. All patients were contacted regarding pyridoxine and serum ASM levels, and patients that were found to be deficient in pyridoxine were treated with appropriate supplementation. At the end of the recruitment period, we performed analyses to determine if there was a statistically significant relationship between PC status and serum pyridoxine levels. RESULTS: Of 32 patients, two patients were diagnosed with psychogenic non-epileptic events and were subsequently excluded. Of 30 patients, 10 had PC epilepsy. Median (interquartile range) serum B6 levels were 35.8 (26.8-54.2) in patients with WC epilepsy and 17.5 (10.1-41.3) in patients with PC epilepsy (P = 0.11). In the PC group, 6/10 (60%) of the patients demonstrated low serum pyridoxine compared to 3/20 (15%) in the WC group (P = 0.03). CONCLUSION: There was a statistically significant relationship between serum pyridoxine levels and seizure control. If appropriate, pyridoxine supplementation should be considered, especially in critically ill adult patients with refractory or PC seizures despite good adherence to ASMs.

An analysis of breakthrough seizures and related factors in paediatric epilepsy patients.

OBJECTIVE: To determine the frequency of breakthrough seizures among paediatric patients suffering from epilepsy, and factors related to the precipitation of these seizures. METHODS: The cross-sectional study was conducted from July 1, 2018, to July 1, 2020, at the Combined Military Hospital Lahore and the Military Hospital, Rawalpindi, Pakistan, and comprised children of either gender aged 2-12 years diagnosed with any type of epilepsy presenting at the children outpatient department. Diagnosis of epilepsy was established by either a consultant adult neurophysician or a consultant paediatrician. The presence of breakthrough seizures was assessed by obtaining detailed history from the patient and the primary caregiver. Socio-demographic profile, duration of epilepsy and poly-pharmacy were noted. Data was analysed using SPSS 23. RESULTS: Of the 450 subjects, 259(57.6%) were boys and 191(42.4%) were girls. The overall mean age was 6.353±4.732 years. The presence of breakthrough seizures was noted in 227(50.4%) subjects. Children with young age, with low family income, and those in need of poly-pharmacy showed significantly higher odds for breakthrough seizures (p<0.05). CONCLUSIONS: The incidence of breakthrough seizures in epileptic children was high despite the anticonvulsant agents that were previously effective in controlling seizures.

Predictors of successful Ramadan fasting in Muslim patients with epilepsy: A prospective study.

PURPOSE: Ramadan fasting represents a challenge for both Muslim patients with epilepsy (MPWE) as well as their treating neurologists who aim to minimize the risk of fasting-related seizures. Several factors may contribute to the risk of fasting-related seizures such as the half-life of antiepileptic drugs (AEDs), seizure control before Ramadan, and sleep fragmentation. The aim of this work was to investigate these factors. METHODS: An observational prospective study included all MPWE who completed Ramadan fasting in 2019, about 16 h per day for 30 days. They were assessed regarding seizure control, AEDs, and sleep alterations using The Pittsburgh Sleep Quality Index. RESULTS: The study included 430 MPWE. The majority of patients (75.58%) completed Ramadan fasting without breakthrough seizures. Patients achieved successful Ramadan fasting were significantly younger, had shorter disease duration, longer periods of seizure freedom before Ramadan, more efficient and longer sleep hours. There was no significant difference between patients receiving monotherapy regimens with short versus intermediate long t½. Maximum seizure freedom before Ramadan and sleep hours were identified as independent predictors of successful Ramadan fasting, using multivariate analysis. Every extra week of being seizure free before Ramadan and every extra hour of sleep was associated with an increase in the probability of successful Ramadan fasting by 10% and 30%, respectively. CONCLUSION: Neurologists should guide their MPWE who wish to fast Ramadan about the risks and precautions. Proper seizure control and ensuring adequate sleep duration can increase the probability of a successful Ramadan fasting.

Facilitating ethical, legal, and professional deliberations to resolve dilemmas in daily healthcare practice: A case of driver with breakthrough seizures.

OBJECTIVE: The present study was conducted among pharmacy students to use an 8-step systematic approach to facilitate discussions, deliberations, and decision-making on what to do when facing a dilemma of a patient with epilepsy who drives while having breakthrough seizures. METHODS: A hypothetical case was developed using the 12-tips for developing dilemma case-based assessments in health education. A mixed method was used in this study. A serial group discussions based on the nominal group technique (NGT) method were applied. A thorough review of the literature and interviews with key experts in the domain (n = 12) were conducted to obtain pertinent data to inform discussions, deliberations, and decision-making. The analytic hierarchy process (AHP) was used to pairwise compare countervailing arguments and alternative courses of action. RESULTS: In this study, 3 nominal groups were held, and for each 3, discussion rounds were conducted. A total of 27 panelists took part in the nominal groups. Compared with other alternative courses of action, significantly higher weight scores (p-value < 0.001) were given to the course action, "the pharmacist could counsel/educate the patient on the dangers/risks of driving while experiencing breakthrough seizures, inform the patient to refrain from driving in this period, and make a shared decision with the patient to refrain from driving in this period and inform the state authorities". CONCLUSION: This study demonstrates that the 8-step approach when combined with the AHP can be a handy method in facilitating decision-making while addressing and resolving ethical/legal/professional dilemmas in daily healthcare practice.

Risk of a seizure recurrence after a breakthrough seizure and the implications for driving: further analysis of the standard versus new antiepileptic drugs (SANAD) randomised controlled trial.

OBJECTIVES: A breakthrough seizure is one occurring after at least 12 months seizure freedom while on treatment. The Driver and Vehicle Licensing Agency (DVLA) allows an individual to return to driving once they have been seizure free for 12 months following a breakthrough seizure. This is based on the assumption that the risk of a further seizure in the next 12 months has dropped <20%. This analysis considers whether the prescribed 1 year off driving following a breakthrough seizure is sufficient for this and stratifies risk according to clinical characteristics. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS AND MAIN OUTCOME MEASURES: The multicentre UK-based Standard versus New Antiepileptic Drugs (SANAD) study was a randomised controlled trial assessing standard and new antiepileptic drugs for patients with newly diagnosed epilepsy. For participants aged at least 16 with a breakthrough seizure, data have been analysed to estimate the annual seizure recurrence risk following a period of 6, 9 and 12 months seizure freedom. Regression modelling was used to investigate how antiepileptic drug treatment and a number of clinical factors influence the risk of seizure recurrence. RESULTS: At 12 months following a breakthrough seizure, the overall unadjusted risk of a recurrence over the next 12 months is lower than 20%, risk 17% (95% CI 15% to 19%). However, some patient subgroups have been identified which have an annual recurrence risk significantly greater than 20% after an initial 12-month seizure-free period following a breakthrough seizure. CONCLUSIONS: This reanalysis of SANAD provides estimates of seizure recurrence risks following a breakthrough seizure that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be used. TRIAL REGISTRATION NUMBER: SANAD is registered with the International Standard Randomised Controlled Trial Number Register ISRCTN38354748.

Antiepileptic drug adherence and persistence in children with epilepsy attending a large tertiary care children's hospital.

We aimed to evaluate antiepileptic drug treatment persistence and adherence in paediatric epilepsy patients and investigate the association between medication-taking behaviours and clinical outcome. Medical and prescription records of newly treated paediatric epilepsy patients, aged 1-18 years who initiated antiepileptic drug monotherapy in a tertiary teaching hospital, were retrospectively reviewed. The rates of overall treatment, non-persistence, a treatment gap >60 days, and adherence, as measured by a medication possession ratio ≥0.8, were assessed. The relationship between non-adherence and clinical outcome, defined as an emergency department visit or hospitalisation due to seizure-related reasons, was analysed. A total of 1,172 patients met the inclusion criteria. The proportion of patients who were both persistent and adherent at one year was 70.14% and decreased to 56.83% at two years. Patients who started an antiepileptic drug at one year of age, took older generation antiepileptic drugs as the initial treatment, and those diagnosed with localized seizures were less likely to be adherent to and persistent with overall antiepileptic drug treatment. Patients who were non-adherent to antiepileptic drug treatment were at an increased risk of hospitalisation or emergency department visits for seizure-related reasons (adjusted HR 2.10, 95% CI 1.25-3.55). This large population study shows that 70% of paediatric epilepsy patients were persistent with and adherent to antiepileptic drugs after one year of treatment and confirms that non-adherence to antiepileptic drug treatment is an important factor in seizure-related clinical outcome.

Clinical and economic burden of breakthrough seizures.

PURPOSE: The purpose of this study was to measure health-care resource utilization and costs in treatment-adherent, previously seizure-free patients with epilepsy who were treated in the inpatient/emergency room (ER) setting for new-onset seizures, compared with matched controls. METHODS: The study used a retrospective case/control study design using administrative claims from the IMS PharMetrics™ database. We identified adult patients with epilepsy with 1+ ER visit/hospitalization with primary diagnosis of epilepsy between 1/1/2006 and 3/31/2011, preceded by 6months of seizure-free activity and antiepileptic drug (AED) treatment adherence (≥80% of days covered by any AED); the first observed seizure defined the "breakthrough" seizure/index event. Treatment-adherent patients with epilepsy without any ER/hospital admission for seizures served as controls: an outpatient epilepsy-related medical claim within the selection window was chosen at random as the index date. The following were continuous enrollment requirements for all patients: ≥12-month pre- and ≥6-month postindex. Each case matched 1:1 to a control using propensity score matching. All-cause and epilepsy-related (epilepsy/convulsion diagnosis, AED pharmacy) resource utilization and unadjusted and adjusted direct health-care costs (per person, 2012 US dollars (USD)) were assessed in a 6-month follow-up period. PRINCIPAL RESULTS: There were 5729 cases and 14,437 controls eligible. The final sample comprised 5279 matched case/control pairs. In unadjusted analyses, matched cases had significantly higher rates of all-cause hospitalization and ER visits compared to controls and significantly higher total all-cause direct health-care costs (median $12,714 vs. $5095, p<0.001) and total epilepsy-related costs among cases vs. controls (median $7293 vs. $1712, p<0.001), driven by higher inpatient costs. Among cases, costs increased with each subsequent seizure (driven by inpatient costs). Cases had 2.3 times higher adjusted all-cause costs and 8.1 times higher adjusted epilepsy-related costs than controls (both p<0.001). CONCLUSION: Inpatient/ER-treated breakthrough seizures occurred among 28.4% of our treatment-adherent study sample and were associated with significant incremental health-care utilization and costs, primarily driven by hospitalizations. Our findings suggest the need for better seizure control via optimal patient management and the use of effective AED therapy, which can potentially lower health-care costs.

Posterior Reversible Encephalopathy Syndrome and Acute Post-Streptococcal Glomerulonephritis Mimicking Breakthrough Seizures.

We report the case of a 14-year-old boy with a past history of primary generalized seizures, who had been seizure-free for 2 years on sodium valproate and presented with generalized tonic clonic seizures suggestive of breakthrough seizures. Examination revealed hypertension, impetiginous lesions of the lower limbs, microscopic hematuria, elevated anti-streptolysin O titre and low complement levels consistent with acute post-streptococcal glomerulonephritis. Cranial magnetic resonance imaging (MRI) demonstrated changes consistent with posterior reversible encephalopathy syndrome. Hypertension was controlled with intravenous nitroglycerin followed by oral captopril and amlodipine. Brain MRI changes returned normal within 2 weeks. The nephritis went in to remission within 2 months and after 8 months the patient has been seizure free again. Posterior reversible encephalopathy syndrome appeared to have neither short nor intermediate effect on seizure control in this patient. The relationship between posterior reversible encephalopathy syndrome and seizures is reviewed.

Phenytoin, folic acid and gingival enlargement: Breaking myths.

BACKGROUND: Epilepsy is described as a chronic neurological disorder characterized by recurrent seizures of cerebral origin, presenting with episodes of sensory, motor or autonomic phenomenon with or, without loss of consciousness. A recent meta-analysis of published and unpublished studies puts an overall prevalence rate of epilepsy in India at 5.59 per 1,000 populations. There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the anti-epileptic therapy in the prevention of anti-epileptic drug induced gingival enlargement. However, studies conducted in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy so as to justify the use of folic acid as a routine adjuvant to the usual anti-epileptic therapy to prevent this inevitable adverse effect without destabilizing the ongoing regimen leading to the precipitation of seizures in an otherwise stable patient (breakthrough seizures). MATERIALS AND METHODS: A total of 100 patients between the ages 18 and 50 years were clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was performed prior to the start of and after 1 year of phenytoin therapy. STATISTICAL ANALYSIS USED: The statistical analysis was carried out using t-test and the baseline serum folate levels and the serum folate levels obtained after 1 year of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula. RESULTS: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin induced gingival enlargement. CONCLUSIONS: The results of the study suggest a higher incidence of gingival enlargement with an early onset and increased severity in phenytoin treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.