Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. FINDINGS: Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. INTERPRETATION: Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. FUNDING: Marinus Pharmaceuticals.

Electrographic Features of Epilepsy With Eyelid Myoclonia With Photoparoxysmal Responses.

PURPOSE: Epilepsy with eyelid myoclonia (EMA) is characterized by eyelid myoclonia, eyelid closure sensitivity, and photosensitivity. EEG may manifest with frontal-predominant (FPEDs) or occipital-predominant epileptiform discharges (OPEDs). Data on clinical and electrographic features of these two subtypes are lacking. The purpose of our research was to look at baseline electroclinical features of EMA subtypes and to study electrographic findings of patients with EMA during intermittent photic stimulation (IPS). METHODS: We retrospectively identified all patients who had photoparoxysmal responses on EEGs performed at Cleveland clinic between January 01, 2012, and December 31, 2019. Patients who met diagnostic criteria for EMA were studied further. RESULTS: Of the 249 patients with photoparoxysmal responses, 70 (28.1%) had EMA (62 [88.6%] female; the mean age of epilepsy onset: 7.0 ± 7.9 years). Patients with EMA had either FPEDs or OPEDs. Eleven patients with EMA (15.7%) had seizures (4 absence, 5 myoclonic and 2 bilateral tonic-clonic) during IPS. Patients with OPEDs were more likely to have drug-resistant epilepsy; occipital focal IEDs and other focal IEDs (other than frontal/occipital) on baseline EEG; and generalized IEDs with occipital predominance, generalized IEDs with no predominance, or focal IEDs during IPS. Predictors of seizure occurrence during photic stimulation included the presence of focal occipital IEDs on baseline EEG, generalized IEDs with frontal predominance during IPS, and photoparoxysmal response outlasting the stimulus. CONCLUSIONS: Our study provides evidence that EMA has two distinct subtypes, which differ in clinical characteristics, baseline EEG, and EEG during photic stimulation. We highlight diagnostic and prognostic implications of these findings. Our study also details EEG characteristics of patients with EMA during IPS.

A Scoping Review of Medications Studied in Pediatric Polypharmacy Research.

PURPOSE: The purpose of this study is to describe medications most commonly studied in pediatric polypharmacy research by pharmacologic classes and disease using a scoping review methodology. METHODS: A search of electronic databases was conducted in July 2019 that included Ovid Medline, PubMed, Elsevier Embase, and EBSCO CINAHL. Primary observational studies were selected if they evaluated polypharmacy as an aim, outcome, predictor, or covariate in children 0-21 years of age. Studies not differentiating between adults and children or those not written in English were excluded. Study characteristics, pharmacologic categories, medication classes, and medications were extracted from the included studies. RESULTS: The search identified 8790 titles and after de-duplicating and full-text screening, 414 studies were extracted for the primary data. Regarding global pharmacologic categories, central nervous system (CNS) agents were most studied (n = 185, 44.9%). The most reported pharmacologic category was the anticonvulsants (n = 250, 60.4%), with valproic acid (n = 129), carbamazepine (n = 123), phenobarbital (n = 87), and phenytoin (n = 83) being the medications most commonly studied. In studies that reported medication classes (n = 105), serotonin reuptake inhibitors (n = 32, 30.5%), CNS stimulants (n = 30, 28.6%), and mood stabilizers (n = 27, 25.7%) were the most studied medication classes. CONCLUSION: While characterizing the literature on pediatric polypharmacy in terms of the types of medication studied, we further identified substantive gaps within this literature outside of epilepsy and psychiatric disorders. Medications frequently identified in use of polypharmacy for treatment of epilepsy and psychiatric disorders reveal opportunities for enhanced medication management in pediatric patients.

Outcome measures in pediatric polypharmacy research: a scoping review.

INTRODUCTION: Various methods have been used to interpret the reports of pediatric polypharmacy across the literature. This is the first scoping review that explores outcome measures in pediatric polypharmacy research. OBJECTIVES: The aim of our study was to describe outcome measures assessed in pediatric polypharmacy research. METHODS: A search of electronic databases was conducted in July 2017, including Ovid Medline, PubMed, Elsevier Embase, Wiley Cochrane Central Register of Controlled Trials (CENTRAL), EBSCO CINAHL, Ovid PsyclNFO, Web of Science Core Collection, ProQuest Dissertations and Thesis A&I. Data were extracted about study characteristics and outcome measures, and also synthesized by harms or benefits mentioned. RESULTS: The search strategy initially identified 8169 titles and screened 4398 using the inclusion criteria after de-duplicating. After the primary screening, a total of 363 studies were extracted for the data analysis. Polypharmacy (prevalence) was identified as an outcome in 31.4% of the studies, prognosis-related outcomes in 25.6%, and adverse drug reactions in 16.5%. A total of 265 articles (73.0%) mentioned harms, including adverse drug reactions (26.4%), side effects (24.2%), and drug-drug interactions (20.9%). A total of 83 studies (22.9%) mentioned any benefit, 48.2% of which identified combination for efficacy, 24.1% combination for treatment of complex diseases, and 19.3% combination for treatment augmentation. Thirty-eight studies reported adverse drug reaction as an outcome, where polypharmacy was a predictor, with various designs. CONCLUSIONS: Most studies of pediatric polypharmacy evaluate prevalence, prognosis, or adverse drug reaction-related out-comes, and underscore harms related to polypharmacy. Clinicians should carefully weigh benefits and harms when introducing medications to treatment regimens.

Aicardi syndrome: epilepsy surgery as a palliative treatment option for selected patients and pathological findings.

The optimal treatment for medically refractory epilepsy in Aicardi syndrome (AS) is still unclear. Palliative surgical treatment, including vagus nerve stimulation and corpus callosotomy, has therefore been used. There is limited data on the role of resective epilepsy surgery as a treatment choice in patients with AS. Here, we describe the seizures, anatomo-pathological findings, and neurodevelopmental outcome of palliative epilepsy surgery in two children with AS who had resective epilepsy surgery at the Cleveland Clinic. The related literature is also reviewed. Case 1 had a left functional hemispherectomy and was free of seizures and hypsarrhythmia for six months after surgery. Her gross motor skills improved after surgery. Outcome at 43 months was 1-3 isolated spasms per day. Case 2 had a right fronto-parietal lobectomy. Her seizures improved in frequency and severity, but remained daily after epilepsy surgery. Neurodevelopment changes included improved alertness and recognition of caregivers. This patient died 21 months after epilepsy surgery of unclear causes. Surgical pathology in both cases showed focal cortical dysplasia associated with other findings, such as nodular heterotopia and polymicrogyria. Epilepsy surgery could be an alternative palliative treatment choice in selective cases of AS, but studies on a larger patient cohort are needed to identify the possible role of surgery in children with AS. The complexity of the pathological findings may offer an explanation for the severity of seizures in AS.

Paroxysmal non-epileptic events in infants and toddlers: A phenomenologic analysis.

AIM: The aim of this study was to analyze in detail the clinical phenomenology of paroxysmal non-epileptic events (PNEE) in infants and toddlers. METHODS: We studied all children aged ≤2 years who were diagnosed with PNEE based on video-electroencephalographic (VEEG) recordings. We analyzed the following four clinical domains of each clinical event: (i) motor manifestations (body/limb jerking, complex motor, and asymmetric limb posturing); (ii) oral/vocal (crying, vocalization, sighing); (iii) behavioral change (arrest of activity, staring); (iv) and autonomic (facial flushing, breath holding). RESULTS: Thirty-one of 81 (38.3%) infants and toddlers had 38 PNEE recorded during the study period (12 girls and 19 boys, mean age 10.5 months). The predominant clinical features were as follows: motor in 26/38 events, oral/verbal in 14/38 events, behavioral in 11/38 events, and autonomic in 8/38 events. Epileptic seizures and PNEE coexisted in four children (12.9%). Seventeen children (54.8%) had one or more risk factors suggestive of epilepsy. Twelve children (38.7%) had a normal neurologic examination, 10 (32.3%) had developmental delay, and eight (25.8%) had a family history of epilepsy or seizures. CONCLUSION: VEEG recorded PNEE in nearly 40% of 81 infants and toddlers referred for unclear paroxysmal events in our cohort. Non-epileptic staring spells and benign sleep myoclonus were the most common events recorded, followed by shuddering attacks and infantile masturbation. In addition, greater than one-half of the infants and toddlers had risk factors, raising a concern for epilepsy in the family and prompting the VEEG evaluation, suggesting that paroxysmal non-epileptic seizures may frequently coexist in young children with epilepsy.

Gaucher disease: successful treatment of myoclonic status epilepticus with levetiracetam.

We present the first reported case of a rapid clinical and electroencephalographic response to intravenous levetiracetam infusion of myoclonic status epilepticus in a patient with progressive myoclonus epilepsy due to Gaucher disease. Under continuous video-EEG monitoring, the clinical myoclonic status and the electrographic ictal discharges resolved within 10 minutes after the infusion was initiated. The patient tolerated the treatment well without any reported side effects. This case suggests that levetiracetam may be a safe, effective, and well tolerated intravenous drug in patients with metabolic myoclonic status epilepticus such as Gaucher disease.