Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy.

AIM: To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP). METHODS: This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together. CONCLUSIONS: Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.

Early-Onset Dementia Associated with a Heterozygous, Nonsense, and de novo Variant in the MBD5 Gene.

The haploinsufficiency of the methyl-binding domain protein 5 (MBD5) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5-neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients with atypical early-onset dementia.

Effectiveness and safety of perampanel monotherapy for focal and generalized tonic-clonic seizures: Experience from a national multicenter registry.

OBJECTIVE: To assess the effectiveness and tolerability of perampanel (PER) monotherapy in routine clinical practice for the treatment of focal onset and generalized tonic-clonic seizures (GTCS). METHODS: This multicenter, retrospective, observational study was conducted in patients aged ≥12 years treated with PER as primary monotherapy or converted to PER monotherapy by progressive reduction of background antiepileptic drugs. Outcomes included retention, responder, and seizure-free rate after 3, 6, and 12 months and tolerability throughout the follow-up. RESULTS: A total of 98 patients (mean age = 49.6 ± 21.7 years, 51% female) with focal seizures and/or GTCS were treated with PER monotherapy for a median exposure of 14 months (range = 1-57) with a median dose of 4 mg (range = 2-10). The retention rates at 3, 6, and 12 months and last follow-up were 93.8%, 89.3%, 80.9%, and 71.4%, respectively. The retention rates according to the type of monotherapy (primary vs conversion) did not differ (log-rank P value = .57). Among the 98 patients, 61.2% patients had seizures throughout the baseline period, with a median seizure frequency of 0.6 seizures per month (range = 0.3-26). Responder rates at 3, 6, and 12 months were 79.6%, 70.1%, and 52.8%, respectively, and seizure freedom rates at the same points were 62.7%, 56.1%, and 41.5%. Regarding the 33 patients who had GTCS in the baseline period, 87.8% were seizure-free at 3 months, 78.1% at 6 months, and 55.1% at 12 months. Over the entire follow-up, PER monotherapy was generally well tolerated, and only 16% of patients discontinued PER due to adverse events (AEs). Female patients were found to be at a higher risk of psychiatric AEs (female vs male odds ratio = 2.85, 95% confidence interval = 1-8.33, P = .046). SIGNIFICANCE: PER demonstrated good effectiveness and a good safety profile when used as primary therapy or conversion to monotherapy at relatively low doses, in a clinical setting with patients with focal seizures and GTCS.

Peripapillary retinal nerve fibre layer thinning in genetic generalized epilepsy.

PURPOSE: The purpose of this study was to compare the peripapillary retinal nerve fibre layer (RNFL) between patients with genetic generalized epilepsy (GGE) and healthy controls. METHODS: This prospective observational study was conducted on adults aged 18-60 years. The study group comprised 26 consecutive patients who met the inclusion criteria and 26 healthy age- and sex-matched healthy adults. Peripapillary RNFL thickness was measured by spectral domain optical coherence tomography. RESULTS: The average peripapillary RNFL thickness was significantly thinner for GGE patients (98.61 µm) than for healthy controls (104.77 µm) (p = 0.016). Similar results were obtained for the left eye. The peripapillary RFNL thickness of all quadrants was lower for GGE patients than for healthy controls, but it was significant only in the superior (p = 0.009) and inferior (p = 0.024) quadrants for both eyes. CONCLUSIONS: Our results suggest that the peripapillary RNFL is significantly thinner in GGE patients than in healthy participants. We concluded that this microstructural feature might be an intrinsic feature of GGE.

Early add-on lacosamide in a real-life setting: results of the REALLY study.

BACKGROUND AND OBJECTIVES: Many patients with epilepsy are treated with antiepileptic drug (AED) polytherapy. Several factors influence the choice of early add-on therapy, and deciding on the most appropriate drug can be difficult. This study aimed to assess the efficacy and tolerability of lacosamide as early add-on therapy in patients with partial-onset seizures. METHODS: REALLY (REtrospective study of lAcosamide as earLy add-on aLong one Year) was a multicenter, retrospective, 1-year, real-life study. Patients included were aged older than 16 years, had partial-onset seizures, and were treated with lacosamide as add-on therapy after one or two prior AEDs. Data were collected retrospectively from clinical records. The primary study objective was to assess the efficacy of lacosamide over 12 months (seizure-free and responder rates), and the secondary objective was to assess the tolerability of lacosamide at 3, 6, and 12 months [adverse events (AEs) and discontinuation]. RESULTS: One hundred and ninety-nine patients were enrolled in the study; 89 patients (44.7 %) had tried one AED and 110 patients (55.3 %) had tried two AEDs before lacosamide. At 12 months, the proportion of patients who were seizure free was 44.9 %, and 76 % of patients were responders. The seizure-free rate at 12 months for patients who had previously received one or two AEDs was 58 and 34.3 %, and the responder rate at 12 months was 83.0 and 70.4 %, respectively. The AE rate was 21.5 % at 3 months, 27.1 % at 6 months, and 31.2 % at 12 months, with 7.0 % of patients discontinuing treatment because of an AE. The most common AE reported was dizziness (11.6 %). Cryptogenic epilepsy, a higher number of prior AEDs, and the use of a sodium channel blocker at onset were associated with a worse outcome. The number of concomitant AEDs decreased over 1 year (Z = 5.89; p < 0.001). Twenty-two patients were converted to lacosamide monotherapy with at least one evaluation ≥6 months from the beginning of monotherapy conversion. CONCLUSIONS: Lacosamide was effective and well tolerated as early add-on treatment in patients who had received one or two previous AEDs.

Control of seizures in different stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of lacosamide.

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) tried is associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500 adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associated with better efficacy/tolerability were analyzed. After 12months, the responder rate (≥50% reduction in seizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide was the first or second add-on AED, although there was a small chance to be seizure-free even for patients who had received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, but differences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage-titration schedule was associated with a lower adverse event rate. Further investigation of the timing of initiation of lacosamide add-on therapy and ideal combinations of AEDs is required.

Relief of intractable posthypoxic myoclonus after administration of agomelatine.

Chronic posthypoxic myoclonus is characterized by myoclonic jerks that are specifically triggered by action. It is a rare but devastating sequela of hypoxic encephalopathy. We report a 42-year-old female patient with treatment-resistant chronic posthypoxic myoclonus, which improved with administration of the drug agomelatine. We suggest that agomelatine could represent a useful therapeutic option in the treatment of chronic posthypoxic myoclonus.

Diagnosis of epilepsy over the course of the disease.

BACKGROUND: At the onset of the disease, differential diagnosis should be established between an epileptic seizure and a series of paroxysmal phenomena, such as syncope, pseudoseizure, or migraine aura, which may manifest with similar symptoms. But even when the initial differential diagnosis is established rigorously, we will see that it is often necessary to reconsider the diagnosis of epilepsy during the course of the disease. REVIEW SUMMARY: Prospective studies analyzing initial recognition of epilepsy found that on half of occasions the diagnosis was reached late, when the patient had already suffered repeated seizures. On other occasions, it is noted that, although the diagnosis of epilepsy was correct, the epileptic syndrome of the patient was classified erroneously, which can lead to inappropriate management. There are a number of reasons that can explain these delays or errors in diagnosis, and we will devote this entire article to their discussion. CONCLUSIONS: Based on a detailed medical history and with the aid of the electroencephalogram and magnetic resonance imaging, the diagnosis of epilepsy can be made and the specific epileptic syndrome identified in many patients from the time of the first seizure. However, various studies show that it is often necessary to modify the initial diagnosis during the follow-up of a patient because of progression of the disease itself (infantile stage), a previous diagnostic error, or because of diagnostic difficulties or inadequate interpretation of tests such as the electroencephalogram or magnetic resonance imaging.