Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

OBJECTIVE: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

Epilepsy with generalized tonic-clonic seizures alone: Electroclinical features and prognostic patterns.

OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. METHODS: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. RESULTS: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. SIGNIFICANCE: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.

Idiopathic generalized epilepsy with phantom absences, absence status, and generalized tonic-clonic seizures: A case report.

RATIONALE: Phantom absences refer to mild and short-lasting absence seizures, which are usually accompanied by infrequent generalized tonic-clonic seizures and absence status. Generally, phantom absences do not impair the individual neurological functions. Herein, we report the case of a young woman with idiopathic generalized epilepsy, phantom absences, absence status, and generalized tonic-clonic seizures. PATIENT CONCERNS: A 31-year-old woman presented with a 16-year history of paroxysmal convulsions. DIAGNOSES: Electroencephalogram (EEG) showed recurrent universal and synchronized 3~4 Hz spike waves and spike-slow waves in the interictal phase with normal background activity. During the ictal phases, EEG revealed bursts of 3~4 Hz spike waves and spike-slow waves that were universal, synchronized, and symmetrical. Additionally, there was 1 seizure episode induced by a 3-Hz flash in the current case. Based on these findings, a diagnosis of idiopathic generalized epilepsy was made. INTERVENTIONS: The patient was treated with oral sodium valproate, and the epileptic seizures were controlled. OUTCOMES: The frequency of absence seizures was significantly reduced and there were no generalized tonic-clonic seizures. LESSONS: Idiopathic generalized epilepsy with phantom absences, absence status, and generalized tonic-clonic seizures is an extremely rare condition. EEG is the exclusive method for diagnosis. Antiepileptic drugs are effective for controlling epileptic seizures in this disease.

Two-year efficacy of lacosamide as adjunctive therapy for generalized tonic-clonic seizures in patients with juvenile myoclonic epilepsy.

OBJECTIVE: To report the long-term efficacy of adjunctive lacosamide therapy in patients with juvenile myoclonic epilepsy whose generalized tonic-clonic seizures were significantly reduced by treatment. METHODS: A retrospective study was conducted in patients who visited the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital and the Department of Pediatrics, National Hospital Organization Nagasaki Medical Center. Among patients who had been diagnosed with juvenile myoclonic epilepsy, those who received lacosamide as adjunctive therapy for refractory generalized tonic-clonic seizures for at least 2 years from January 2017 to December 2022, and who achieved seizure freedom or >50% seizure reduction in tonic-clonic seizures were included. The medical records and neurophysiological data of the patients were reviewed retrospectively. RESULTS: Four patients met the inclusion criteria. The mean age at the onset of epilepsy was 11.3 years (range 10-12), and the mean age of starting lacosamide was 17.5 years (range 16-21). All patients received two or more antiseizure medications prior to lacosamide. Three of four patients had seizure freedom for more than 2 years, and the one remaining patient had >50% seizure reduction for more than one year. Only one patient had recurrent myoclonic seizures after starting lacosamide. The mean lacosamide dose at the last visit was 425 mg/day (range 300-600). CONCLUSION: Adjunctive lacosamide therapy might be a treatment option for juvenile myoclonic epilepsy with generalized tonic-clonic seizures, which are not responsive to standard antiseizure medications.

Frequency of non-generalized tonic clonic seizures in a referral population of dogs.

Absence seizures are a type of generalized onset seizure associated in humans with brief activity interruptions, unresponsiveness and staring. Absence seizures are infrequently reported in veterinary patients, visually indistinguishable from focal seizures, and so may be grouped as non-generalized tonic clonic seizures (non-GTCS). The objective of this retrospective study was to provide a preliminary understanding of the frequency of non-GTCS in dogs and estimate its prevalence by evaluating the distribution of seizure types presented to a referral hospital over 4 years (May 2017-April 2021), as determined from the medical record history and electroencephalography (EEG) diagnostic testing where available. A total of 528 cases were included via a medical record search for dogs with epilepsy and/or seizures presented to the neurology or emergency services. Cases were categorized into seizure types based on reported clinical signs. Each year, 53-63 % of seizure cases were described as generalized tonic clonic seizures (GTCS), 9-15 % GTCS with additional events and 29-35 % suspected non-GTCS. EEG confirmed absence seizures in 12 of 44 EEGs, 5 cases having a history of GTCS and seven without prior GTCS. This preliminary study suggests that non-GTCS may be relatively common as one third of seizure cases in the referral population presented with non-GTCS clinical signs. Prospective studies using EEG are merited to definitively determine the prevalence of these different seizure types in dogs. Acknowledging the impact of these seizures will improve awareness, aiding veterinarians in their recognition, diagnosis and potential treatment options.

Registro de epilepsias na gravidez, complicações obstétricas e fetais e o uso de drogas antiepilépticas em Alagoas-BR / Registry of epilepsy during pregnancy, obstetric and fetal complications and the use of antiepileptic drugs in Alagoas-BR

Objetivos: artigo 1: Descrever a prevalência das nas mulheres gestantes com epilepsia (MGCE), perfil sociodemográfico e desfechos obstétricos e analisar associação dessas variáveis com a doença. Artigo 2: Descrever o perfil de MAC (medicação anticrise) e tipos de crises e analisar a associação desses perfis com a incidência de complicações maternas e fetais nas MGCE. Artigo 3: Descrever a prevalência, perfil sociodemográfico e clínico, perfil de MAC, tipos de crises e analisar a associação da incidência de complicações maternas e fetais com essas variáveis nas MGCE. Métodos: Artigos 1 e 2: coortes retrospectivas com 234 MGCE e 492 MGSE. Artigo 3 coorte prospectiva coletou dados de 95 MGCE e 380 sem epilepsia (MGSE). Ambas as coortes com idade 40 anos em prontuários e entrevistas em 4 maternidades de alto risco em Alagoas no período de 2008 a 2021 na coorte retrospectiva e 2021 e 2022 na prospectiva. Resultados: A prevalência de MGCE nas coortes retrospectiva e prospectiva foi de 0,49% (n = 224/44917) e 0,53% (n = 105/19.624) com médias de idade (24,94 ± 6,25 e 23,98 ± 6,89); (24,42 ± 5,64 e 24,42 ± 5,62) anos. MGCE procederam da zona rural (58,2%; 64,2%), eram de cor parda (88,6%;98%), (7%; 3,2%) analfabetas e com ensino fundamental (40%; 52,1%), solteiras (47,3%; 49,5%) e (76,9%; 78,9%) donas de casa, respectivamente. Em relação a partos, a maioria (60,3%; 54,8%) eram multíparas, (74,6%; 70,8%) tiveram parto cesáreo, respectivamente. Na coorte prospectiva 15,8% sem renda, 54,7% com menos de 1 salário mínimo, 44,2% eram de religião católica e 87.4% não planejou a gravidez. A análise dos desfechos obstétricos e neonatais mostrou um risco maior nas MGCE para hipertensão relacionada à gravidez (HRG) (OR =6.29; 95% CI =3.50-11.30), pré-eclâmpsia (OR=8.04; 95% CI=2.22-29.10) na coorte retrospectiva, e em ambas coortes um risco de sangramento vaginal (OR=2.54; 95% CI=1.15-5.59);(OR=4.13; 95% CI=1.45-9.11), aborto espontâneo (OR=1.75; 95% CI=1.16-2.63); (OR=1.50; 95% CI=1.00-2.22) e natimorto (OR=11,16; 95% CI=2.22-29.10); (OR=5.27; 95% CI=2.29-10.30). Nas coortes retrospectiva e prospectiva (14%; 14,7%) não usaram MAC, (50,2%; 85,3%) monoterapia (35,8%; 12,6%) politerapia, respectivamente. O fenobarbital foi o MAC mais prescrito seguido pela carbamazepina em ambas coortes. Na prospectiva MGCE que usaram MAC e em politerapia tiveram maior risco de hemorragia vaginal, admissão em UTI materna e natimorto. Analisando os tipos de epilepsia a maioria 40% tinha o tipo generalizada. A respeito do tipo de crise, a maioria 53,3% apresentou crise focal na coorte retrospectiva, enquanto na prospectiva a maioria delas 48,4% teve CTCG e 19% estado de mal epiléptico associados a desfechos obstétricos e neonatais adversos. Conclusão: Ambos os estudos relatam um perfil sociodemográfico da MGCE de alta vulnerabilidade social e alto risco de desfechos obstétricos e neonatais adversos, provavelmente devido à procedência de uma região pobre do Brasil. Foi constatado algumas limitações na distribuição de MACs apropriados para essa população.

Objectives: article 1: To describe the prevalence of epilepsy in pregnant women, sociodemographic profile and obstetric outcomes and analyze the association of these variables with a disease. Article 2: Describe the profile of ASM (anti-crisis medication) and types of seizures and analyze the association of these profiles with the incidence of maternal and fetal complications in pregnat women with epilepsy (PWWE). Article 3: Describe the prevalence, sociodemographic and clinical profile, types of ASM used and seizures and analyze the association of the incidence of maternal and fetal complications with these variables in PWWE. Methods: Articles 1 and 2: retrospective cohorts with 234 PWWE and 492 pregnant women without epilepsy (PWNE). Article 3 prospective cohort collected data from 95 PWWE and 380 PWNE. Both cohorts aged 40 years in medical records and interviews from four high-risk maternity hospitals in Alagoas. The period from 2008 to 2021 in the cohort retrospective and 2021 and 2022 in the prospective. Results of the articles: The prevalence of PWWE in the retrospective and prospective cohorts were 0.49% (n = 224/44917) and 0.53% (n = 105/19,624) with mean ages (24.94 ± 6.25 and 23 .98 ± 6.89); (24.42 ± 5.64 and 24.42 ± 5.62) years, respectively. PWWE came from the countryside (58.2%; 64.2%), had brown skin (88.6%; 98%), illiterate (7%; 3.2%) and had primary education (40%; 52 .1%), single (47.3%; 49.5%) and (76.9%; 78.9%) homemakers, respectively. Regarding deliveries, the most of them (60.3%; 54.8%) were multiparous, (74.6%; 70.8%) had cesarean delivery, respectively. In the prospective cohort, 15.8% had no income, 54.7% earned less than 1 minimum wage, 44.2% were Catholic religious and 87.4% had not planned the pregnancy. Analysis of obstetric and neonatal outcomes showed a higher risk in PWWE for pregnancy-related hypertension (PrH) (OR=6.29; 95% CI=3.50-11.30), preeclampsia OR=8.04; 95% CI=2.22-29.10) in the retrospective cohort, and in the retrospective and prospective cohorts a risk of vaginal bleeding (OR=2.54; 95% CI=1.15-5.59);(OR=4.13; 95% CI=1.45-9.11), miscarriage (OR=1.75; 95% CI=1.16-2.63); (OR=1.50; 95% CI=1.00-2.22) and stillbirth (OR=11.16; 95% CI=2.22-29.10); (OR=5.27; 95% CI=2.29-10.30), respectively. In both cohorts (14%; 14.7%) they did not use MAC, (50.2%; 85.3%) monotherapy (35.8%; 12.6%) polytherapy, respectively. Phenobarbital was the most prescribed ASM followed by carbamazepine in both cohorts. In prospective PWWE who used ASM and polytherapy had a higher risk of vaginal bleeding, maternal ICU admission and stillbirth. Analyzing the types of epilepsy, most of them 40% had the generalized type. Regarding the type of seizure, most 53.3% had focal seizures in the retrospective cohort, while in the prospective cohort, most of them 48.4% had GTCS (tonic-clonic generalized) and 19% had status epilepticus, associated with adverse obstetric and neonatal outcomes. Conclusion: Both studies report a sociodemographic profile of PWWE with high social vulnerability and higher risk of adverse obstetric and neonatal outcomes, probably due to the origin of a poor region of Brazil. Some limitations were found in the distribution of appropriate ASM for this population

Seizures and COVID-19: Results from the Spanish Society of Neurology's COVID-19 registry.

We describea series of patients with COVID-19 who presented with seizures, reported in the Spanish Society of Neurology's COVID-19 Registry. This observational, descriptive,multicentre, registry-based study includes patients with confirmed COVID-19 who experienced seizures during active infection.Wedescribe theclinicalpresentation of COVID-19,seizures,and resultsof complementary tests.Wealsodescribe the suspectedaetiologyof the seizures. Of 232 reported cases, 26 (11.2%) presented with seizures;7 of these patients (26.9%) had prior history of epilepsy, whereas the remaining 19 (73.1%) had no history of seizures.In most cases, seizures presented on days 0 and 7 after onset of COVID-19. By seizure type, 8 patients (30.7%) presentedgeneralised tonic-clonic seizures, 7 (26.9%) status epilepticus, 8 (30.7%) focal impaired-awareness seizures, and 4 (11.7%) secondary generalised seizures.Six patients (23.1%) also presented other neurological symptoms, includingaltered mental status and decreased level of consciousness. Predisposing factors for seizures (eg, dementia, tumour, cerebrovascular disease) were observed in 10 of the 19 patients with no prior history of epilepsy (52.6%). Patients with COVID-19 may present with seizures over the course of the disease,either alone or in the context of encephalopathy.Seizures may present in patients with no prior history of epilepsy; however, most of these patients present predisposing factors.

Network connectivity in primary generalized tonic-clonic seizures.

OBJECTIVE: To determine EEG spatiospectral activation and connectivity in the generalized tonic-clonic seizure (GTCS) semiological subtypes. METHODS: 39 patients with genetic generalized epilepsy (GGE) who had GTCS (n = 58) during video-EEG monitoring were identified in the Vanderbilt Epilepsy database. GTCSs were classified as absence tonic-clonic, myoclonic tonic-clonic, or tonic-clonic. Patient characteristics and semiological features were compared. Spectral power and node degree, a network measure of connectivity, were calculated at two seizure epochs, electrographic and tonic-start. RESULTS: Different GTCS subtypes occurred within individual patients. At electrographic-onset, all subtypes activated midline frontal cortex at delta/theta and beta frequencies but differed in network connectivity. In all subtypes, GTCS evolution from electrographic to tonic-start associated with preserved beta frequency spectral power, but reduced connectivity and delta/theta power. CONCLUSIONS: Our findings suggest that at GTCS onset, the subtypes activate similar cortical regions and their different initial semiologies relate to their distinct onset long-range connectivity. Upon transition to the tonic-start epoch, the ictal activity is predominantly conveyed by ß frequency activity and connectivity. SIGNIFICANCE: Future neurostimulation therapies for medically intractable GTCSs may target the same brain regions for all GTCS subtypes and may be most effective prior to the tonic-start epoch.

Evaluation of serum levels of asprosin and other metabolic profiles in patients with idiopathic tonic-clonic generalized epilepsy on treatment with valproic acid.

BACKGROUND: This cross-sectional research was undertaken to determine the serum levels of asprosin, a novel white adipose tissue-derived glucogenic adipokine, in epileptic patients on valproic acid treatment. METHODS: Sixty-six patients diagnosed with idiopathic tonic-clonic generalized epilepsy were divided into three groups: those treated with valproic acid (n = 22), those treated with lamotrigine (n = 22), and twenty-two newly diagnosed or untreated patients. A control group was twenty-two, healthy volunteers with a similar distribution of gender and age. Body mass index (BMI) and fasting serum levels of asprosin, glucose, glycohemoglobin (HbA1c), insulin, and lipid profile were measured for both patients and control groups. Additionally, homeostasis model assessment for insulin resistance (HOMA-IR) was also calculated for the investigated groups. RESULTS: The mean BMI values and fasting serum levels of glucose, HbA1c, insulin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride were much higher in subjects treated with valproic acid than those in the other study groups. Furthermore, a higher number of participants in the valproic acid group fulfilled the insulin resistance criterion (defined as HOMA-IR > 2.5) compared with those in other study groups. The mean fasting serum asprosin concentration was also significantly higher in the valproic acid group than in other study groups. This was while the values of the study parameters were comparable in the healthy, un-treated, and lamotrigine groups. CONCLUSIONS: Our finding suggested that elevated asprosin level might be one of the pathological mechanisms involved in the development of obesity, insulin resistance, and metabolic disturbances related to valproic acid treatment.

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an X-linked pharmacoresistant neurogenetic disorder characterized by global developmental delays and uncontrolled seizures. Fenfluramine (FFA), an antiseizure medication (ASM) indicated for treating convulsive seizures in Dravet syndrome, was assessed in six patients (five female; 83%) with CDD whose seizures had failed 5-12 ASMs or therapies. Median age at enrollment was 6.5 years (range: 2-26 years). Mean FFA treatment duration was 5.3 months (range: 2-9 months) at 0.4 mg/kg/day (n = 2) or 0.7 mg/kg/day (n = 4; maximum: 26 mg/day). One patient had valproate added for myoclonic seizures. The ASM regimens of all other patients were stable. Among five patients with tonic-clonic seizures, FFA treatment resulted in a median 90% reduction in frequency (range: 86%-100%). Tonic seizure frequency was reduced by 50%-60% in two patients with this seizure type. One patient experienced fewer myoclonic seizures; one patient first developed myoclonic seizures on FFA, which were controlled with valproate. Adverse events were reported in two patients. The patient with added valproate experienced lethargy; one patient had decreased appetite and flatus. No patient developed valvular heart disease or pulmonary arterial hypertension. Our preliminary results suggest that FFA may be a promising ASM for CDD. Randomized clinical trials are warranted.

[Efficacy and tolerability of perampanel as adjunctive treatment of focal and generalized tonic-clonic epileptic seizures in children over 4 years of age]. / Effektivnost' i perenosimost' perampanela kak dopolnitel'nogo preparata v lechenii fokal'nykh i generalizovannykh toniko-klonicheskikh epilepticheskikh pristupov u detei v vozraste ot 4 do 12 let.

The article is a short review of an observational study that proves the good efficacy and tolerability of perampanel suspension in the adjunctive treatment of epilepsy in children over 4 years of age. The study demonstrated a high level of 50% responders: 47% with focal seizures, 65% with transition of focal seizures to bilateral tonic-clonic seizures, 65% with primary generalized tonic-clonic seizures. Cessation of seizures was achieved in 12%, 19% and 55% of patients, respectively. The most common side-effects were fatigue (26%), nasopharyngitis (19%), lightheadedness, irritability, fever (13% each), and vomiting (11%). There were no significant clinical negative changes in cognitive functions according to the assessment on the Aldenkamp-Baker scale, both on the total score and subscales. Also, there were no significant changes in laboratory data, vital functions and ECG parameters.

Anti-seizure medications and efficacy against focal to bilateral tonic-clonic seizures: A systematic review with relevance for SUDEP prevention.

We conducted a systematic review of anti-seizure medications (ASMs) and their efficacy for the control of focal to bilateral tonic-clonic seizures (FBTCS). FBTCS, especially when nocturnal, are recognized as one of the major risk factors for Sudden Unexpected Death in Epilepsy (SUDEP). We searched different online databases for all the randomized, double-blinded, and placebo-controlled clinical trials of ASMs that were FDA-approved after 1990 and that reported specifically on the reduction in FBTCS; when possible, this was compared to reduction in focal impaired awareness (FIA) seizures. The ASMs that yielded the most data (3 or more studies) were topiramate (TPM), followed by tiagabine (TGB), brivaracetam (BRV), and lamotrigine (LTG). TPM trials showed a reduction in FBTCS of 44.8% to 100% (4.5-99% over placebo); TGB 21.8% to 46.7% (21.8-61% over placebo); BRV 33.9% to 82.1% (11.6-57.4% over placebo); and LTG 55.2% (20.3-52% over placebo). Promising results, but with data from only one or two studies, were seen with cenobamate (18-59% efficacy above placebo), lacosamide (45.1-78.7%), levetiracetam (40.1-60.3%), oxcarbazepine (58.5-81.5%), and gabapentin (50-53.8%). Higher responses were often seen at higher doses, including at doses above those currently approved by the FDA. Results specific to nocturnal FBTCS were never reported for any ASM. Moreover, complete freedom from FBTCS specifically was very rarely reported, despite its relevance for SUDEP prevention. In conclusion, there are few data specifically comparing the efficacy of ASMs for prevention of FBTCS despite the known strong association of BTCS with SUDEP. This review was our attempt at filling a gap in the literature and calling for universal reporting of data specific to BTC seizure reduction in all future studies, preferably including specific reporting on nocturnal BTCS. This will help enable rational ASM selection to minimize BTC seizures and thereby decrease the risk of SUDEP.

Antihistamines as a common cause of new-onset seizures: a single-center observational study.

OBJECTIVE: Scarce data are available regarding the proportion of drugs that have provoked new-onset seizures. The aim of this study was to investigate the types of causative drugs of drug-induced new-onset seizures in a relatively large population of patients who were admitted to our epilepsy monitoring unit. METHODS: Using a hospital-based database, patients with new-onset seizures were selected and the underlying etiology of new-onset seizures was reviewed. Based on the etiologic conditions, acute symptomatic seizure was classified into 7 groups of provocation factors: drug, alcohol, encephalitis, stroke, hypoxic injury, metabolic, and unclassified. Causative drugs for new-onset seizures were further investigated. RESULTS: Altogether, 363 patients with new-onset seizures were reviewed in this study. The most common cause of new-onset seizures was epilepsy, followed by syncope, acute symptomatic seizure, and others. Drugs were found to be the most common provocation factor for acute symptomatic seizures. The most common causative drug was antihistamine, followed by stimulants, antibiotics, and other drugs. Most patients with antihistamine-induced seizures had normal renal function and were under treatment at the therapeutic dose. CONCLUSION: In our population, antihistamine accounted for the highest proportion of drug-induced seizures. Considering that antihistamines are widely used as over-the-counter drugs around the world, they should be considered a possible cause of new-onset seizures.

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic-clonic seizure model in mice.

BACKGROUND: Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug-drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. AIM: To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. MATERIALS AND METHOD: The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. RESULTS: The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. CONCLUSIONS: The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

Lamotrigine add-on therapy for drug-resistant generalised tonic-clonic seizures.

BACKGROUND: This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic-clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs. OBJECTIVES: To assess the effectiveness and tolerability of add-on lamotrigine for drug-resistant primary generalised tonic-clonic seizures. SEARCH METHODS: For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine. SELECTION CRITERIA: Randomised controlled parallel or cross-over trials of add-on lamotrigine for people of any age with drug-resistant primary generalised tonic-clonic seizures. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE-assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic-clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention-to-treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing. MAIN RESULTS: We included three studies (total 300 participants): two parallel-group studies and one cross-over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta-analysed data extracted from the two parallel-group studies, and conducted a narrative synthesis for data from the cross-over study. Both parallel-group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic-clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low-certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low-certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low-certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low-certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low-certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low-certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low-certainty evidence). The cross-over trial (26 participants) reported that 7/14 participants with generalised tonic-clonic seizures experienced a 50% or greater reduction in seizure frequency with add-on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects. None of the included studies measured cognition. One parallel-group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74). AUTHORS' CONCLUSIONS: This review provides insufficient information to inform clinical practice. Low-certainty evidence suggests that lamotrigine reduces the rate of generalised tonic-clonic seizures by 50% or more. Very low-certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different. More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.

Meta-analysis of drug efficacy in adult vs pediatric trials of patients with PGTC seizures.

OBJECTIVE: A meta-analysis of published studies was performed to determine whether the efficacy of antiseizure drugs in adults with primary generalized tonic-clonic seizures (PGTCS) is comparable with that in the pediatric population (2-12 years of age). METHODS: Electronic searches were conducted in EMBASE, Medline, and the Cochrane Central Register of Controlled Trials for clinical trials of PGTCS in adults and children 2-12 years of age. Neurologists used standardized search and study evaluations to select eligible trials. Median percent reduction in seizure frequency from baseline and ≥50% responder rates were used to compare drug efficacy in adults and children. RESULTS: Among 7 adjunctive-therapy PGTCS trials in adults and children (2-12 years of age) that met evaluation criteria, effect sizes were consistent between adults and children for lamotrigine and topiramate. The baseline-subtracted median percent seizure reduction in seizure frequency ranged from 50.0% to 79.7% in children and 57.0% to 64.0% in adults. The ≥50% responder rate was similar between children and adults in a topiramate study (50% in children compared with 58% in adults). CONCLUSIONS: This meta-analysis supports the use of drug response from antiseizure drug clinical trials for PGTCS in adults to predict comparable treatment response in children 2-12 years of age with PGTCS.

Efficacy and safety of adjunctive perampanel 4 mg/d for the treatment of focal seizures: A pooled post hoc analysis of four randomized, double-blind, phase III studies.

OBJECTIVE: This post hoc analysis evaluated the efficacy and safety of adjunctive perampanel 4 mg/d received as modal dose, which may have differed from randomized dose, for treatment of focal seizures. METHODS: Data were pooled from four randomized, double-blind, placebo-controlled, phase III studies of adjunctive perampanel in patients (aged ≥12 years) with focal seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures: studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), and 335 (NCT01618695). Efficacy assessments included median percentage reductions in seizure frequency per 28 days and seizure-freedom rates for patients receiving placebo and perampanel 4 mg/d (modal dose). Treatment-emergent adverse events (TEAEs) were assessed in patients receiving perampanel 4 mg/d at their TEAE onset. Outcomes were also assessed with/without enzyme-inducing antiseizure medications (EIASMs). RESULTS: The full analysis set included 979 patients with focal seizures (placebo: n = 616 [235 with FBTC seizures]; perampanel 4 mg/d: n = 363 [134 with FBTC seizures]). Compared with placebo, perampanel 4 mg/d conferred significantly greater median percentage reductions in seizure frequency per 28 days for focal (12.6% vs 21.1%; P = .0004) and FBTC seizures (17.4% vs 49.8%; P < .0001), and seizure-freedom rates for focal (0.8% vs 3.6%; P = .0018) and FBTC seizures (11.1% vs 18.7%; P = .0424). Seizure improvements with perampanel 4 mg/d were greater without EIASMs than with EIASMs. For assessment of TEAEs, overall 1376 patients with focal seizures received perampanel 4 mg/d at any time (FBTC seizures, n = 499). TEAEs with perampanel 4 mg/d occurred in 419 of 1376 (30.5%) and 148 of 499 (29.7%) patients with focal and FBTC seizures, respectively; most common was dizziness. The proportion of TEAEs was similar with or without EIASMs. SIGNIFICANCE: This post hoc analysis showed adjunctive perampanel 4 mg/d was efficacious and well tolerated in patients with focal seizures, with or without FBTC seizures. This dose may be a valuable treatment option in patients unable to tolerate higher perampanel doses up to 12 mg/d.

The effects of antihistamine on the duration of the febrile seizure: A single center study with a systematic review and meta-analysis.

BACKGROUND: Several studies have investigated the potential effects of antihistamines on febrile seizure. However, these findings are inconsistent across the studies. METHOD: A retrospective observational study was conducted on a total of 434 consecutive patients aged between 6 months and 5 years with the diagnosis of febrile seizure. Patients with chronic medical conditions were excluded. Multivariable generalized linear models were conducted to ascertain the effects of antihistamine use on duration of febrile seizure. Also, we conducted a systematic review and meta-analyses of the medical literatures to calculate the pooled estimates using random effects models. RESULTS: The adjusted mean duration of febrile seizure in the antihistamine group was 4.9 min shorter than that in the non-user group (95% confidence interval (CI), 0.4-9.5). The risk of duration in febrile seizure >5 min among antihistamine users was also 0.83 times that among the non-users (95%CI, 0.58-1.19), whereas the risk of duration in febrile seizure >10 min among first-generation antihistamine users was 1.21 times that among non-users (95%CI, 0.69-2.13). According to the systematic review of the literature, 8 observational studies were included in the meta-analyses. Comparing to non-users, the antihistamine users had prolonged duration of febrile seizure by 1.07 min (95%CI, -1.13 to 3.27), elevated risk of duration in febrile seizure >5 min (Risk ratio, 1.16; 95%CI, 0.90-1.49), and similar duration from fever to febrile seizure onset (pooled mean difference, -0.01 h; -1.43 to 1.41), but these estimates were imprecise. Similar results were obtained when we stratified the data by types of antihistamine (first vs. second generation). CONCLUSIONS: Our study may indicate the effects of antihistamine on prolonging febrile seizure duration, but they are still controversial given the limited evidence, highly heterogeneous results, and concerns of the internal and external validities.

Pharmacokinetics of Phytocannabinoid Acids and Anticonvulsant Effect of Cannabidiolic Acid in a Mouse Model of Dravet Syndrome.

Cannabis sativa produces a complex mixture of many bioactive molecules including terpenophenolic compounds known as phytocannabinoids. Phytocannabinoids come in neutral forms (e.g., Δ9-tetrahydrocannabinol, THC; cannabidiol, CBD; etc.) or as acid precursors, which are dominant in the plant (e.g., Δ9-tetrahydrocannabinolic acid, THCA; cannabidiolic acid, CBDA; etc.). There is increasing interest in unlocking the therapeutic applications of the phytocannabinoid acids; however, the present understanding of the basic pharmacology of phytocannabinoid acids is limited. Herein the brain and plasma pharmacokinetic profiles of CBDA, THCA, cannabichromenic acid (CBCA), cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), and cannabigerovarinic acid (CBGVA) were examined following intraperitoneal administration in mice. Next it was examined whether CBDA was anticonvulsant in a mouse model of Dravet syndrome (Scn1aRX/+ mice). All the phytocannabinoid acids investigated were rapidly absorbed with plasma tmax values of between 15 and 45 min and had relatively short half-lives (<4 h). The brain-plasma ratios for the acids were very low at ≤0.04. However, when CBDA was administered in an alternate Tween 80-based vehicle, it exhibited a brain-plasma ratio of 1.9. The anticonvulsant potential of CBDA was examined using this vehicle, and it was found that CBDA significantly increased the temperature threshold at which the Scn1aRX/+ mice had a generalized tonic-clonic seizure.