Real-life data comparing the efficacy of vigabatrin and oral steroids given sequentially or combined for infantile epileptic spasms syndrome.

AIMS: The prognosis of Infantile epileptic spasm syndrome (IESS), relates to the underlying etiology and delay in controlling epileptic spasms. Based on the spasm-free rate, a randomized controlled trial has demonstrated the superiority of combining oral steroids and vigabatrin over oral steroids alone but confirmation in real-life conditions is mandatory. METHODS: We compared two real-life IESS cohorts: a multicenter, retrospective cohort of 40 infants treated with vigabatrin followed by a sequential (ST) addition of steroids, and a prospective, single-center cohort of 58 infants treated with an immediate combination of vigabatrin and steroids (CT). RESULTS: The two cohorts were similar. When the rate of spasm-free infants in the two cohorts was compared on day 14, a significant difference was observed between the ST (27,5 %) and CT cohorts (64 %) (p < 0.0004). This difference remained significant on day 30, with 55 % spasm-free patients in the ST cohort compared to 76 % in the CT cohort (p = 0.03). After the infants had received both vigabatrin and steroids, without taking into account the time point after treatment initiation, no significant difference was observed in the spasm-free rate between the two cohorts (p = 0.38). INTERPRETATION: Real-life data confirm the interest of combination therapy as a first-line treatment for IESS.

SYNGAP1-DEE: A visual sensitive epilepsy.

OBJECTIVE: To further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants. METHODS: Participants with pathogenic SYNGAP1 variants and available video-electroencephalogram (EEG) recordings were recruited within five European epilepsy reference centers. We obtained molecular and clinical data, analyzed EEG recordings and archived video-EEGs of seizures and detailed characteristics of interictal and ictal EEG patterns for every patient. RESULTS: We recruited 15 previously unreported patients and analyzed 72 EEGs. Two distinct EEG patterns emerged, both triggered by eye closure. Pattern 1 (14/15 individuals) consisted of rhythmic posterior/diffuse delta waves appearing with eye-closure and persisting until eye opening (strongly suggestive of fixation-off sensitivity). Pattern 2 (9/15 individuals) consisted of diffuse polyspike-and-wave discharges triggered by eye closure (eye-closure sensitivity). Both patterns presented in 8/15. Including archived video-EEG clips of seizures from 9/15 patients, we analyzed 254 seizures. Of 224 seizures experienced while awake, 161 (72%) occurred at or following eye closure. In 119/161, pattern 1 preceded an atypical absence, myoclonic seizure or myoclonic absence; in 42/161, pattern 2 was associated with eyelid myoclonia, absences and myoclonic or atonic seizures. CONCLUSIONS: Fixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort. SIGNIFICANCE: Combining these clinical and electroencephalographic features could help guide genetic diagnosis.

Real-life use of videos in pediatric epilepsy consultations.

Paroxysmal events are usually not directly observed by physicians. The diagnosis remains challenging and relies mostly on the description of witnesses. The effectiveness of videos for seizure diagnosis has been validated by several studies, but their place in clinical practice is not yet clear. The aim of our study was to evaluate the real-life use of videos by child neurologists. We conducted a three-month prospective study in which child neurologists were asked to use a short questionnaire to evaluate all videos that were watched in their clinical practice for an initial diagnosis or during follow-up. A click-off meeting during the French pediatric neurology meeting allowed to recruit participants. A total of 165 questionnaires were completed by 15 physicians over the study period. The physicians were child neurologists working in secondary and tertiary/university hospitals, consulting children with epilepsy. Based on the evaluation of child neurologists, 51% of the videos consisted of epileptic seizures; 40%, nonepileptic paroxysmal events; and 9%, psychogenic nonepileptic seizures. Most of the videos were made on parental initiative. The use of video has modified the first diagnosis hypothesis in 35% of cases. The physicians' feelings regarding the interest of the video used during the diagnostic phase were similar to those of the video used during follow-up. It appears that videos have become a part of the epilepsy clinic and are helpful for diagnosis as well as during follow-up. Unfortunately, one of the limitations of this study is the absence of private practitioner.

Slow Titration of Cannabidiol Add-On in Drug-Resistant Epilepsies Can Improve Safety With Maintained Efficacy in an Open-Label Study.

Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice. Methods: We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB-). Results: One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10-12), 14 (10-20), and 15.5 mg/kg/day (10-20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 0.03). At M6, total seizure frequency change from baseline was -41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB- patients. Significance: A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.

Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline.

SYNJ1 encodes a polyphosphoinositide phosphatase, synaptojanin 1, which contains two consecutive phosphatase domains and plays a prominent role in synaptic vesicle dynamics. Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology. We performed whole exome or genome sequencing in three independent sib pairs with early onset refractory seizures and progressive neurological decline, and identified novel segregating recessive SYNJ1 defects. A homozygous missense variant resulting in an amino acid substitution (p.Tyr888Cys) was found to impair, but not abolish, the dual phosphatase activity of SYNJ1, whereas three premature stop variants (homozygote p.Trp843* and compound heterozygote p.Gln647Argfs*6/p.Ser1122Thrfs*3) almost completely abolished mRNA transcript production. A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing that SYNJ1 deficiency is rare and probably linked to a specific phenotype. While variants leading to early onset parkinsonism selectively abolish Sac1 function, our results provide evidence that a critical reduction of the dual phosphatase activity of SYNJ1 underlies a severe disorder with neonatal refractory epilepsy and a neurodegenerative disease course. These findings further expand the clinical spectrum of synaptic dysregulation in patients with severe epilepsy, and emphasize the importance of this biological pathway in seizure pathophysiology.

Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases.

Several case reports suggest that rituximab (RTX) could be effective in steroid-dependent nephrotic syndrome, but RTX efficacy has not yet been studied in a series of patients. Safety and efficacy of RTX were assessed in a multicenter series of 22 patients aged 6.3-22 years with severe steroid-dependent nephrotic syndrome or steroid-resistant but cyclosporin-sensitive idiopathic nephrotic syndrome. Patients were treated with two to four infusions of RTX. Seven patients were nephrotic at the time of RTX treatment. Peripheral B cells were depleted in all subjects. Remission was induced in three of the seven proteinuric patients. One or more immunosuppressive (IS) treatments could be withdrawn in 19 patients (85%), with no relapse of proteinuria and without increasing other IS drugs. RTX was effective in all patients when administered during a proteinuria-free period in association with other IS agents. When relapses occurred, they were always associated with an increase in CD19 cell count. Adverse effects were observed in 45% of cases, but most of them were mild and transient. This study suggests that RTX could be an effective treatment for severe steroid-dependent nephrotic syndrome.