Clinical characteristics and treatment experience of individuals with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE): Findings from an online caregiver survey.

PURPOSE: SCN8A developmental epileptic encephalopathy (SCN8A-DEE) is a rare and severe genetic epilepsy syndrome characterized by early-onset developmental delay, cognitive impairment, and intractable seizures. SCN8A gene variants are associated with a broad phenotypic spectrum and variable disease severity. A caregiver survey, solicited by the advocacy group The Cute Syndrome Foundation (TCSF), was conducted to gather information on the demographics/disease presentation, seizure history, and treatment of patients with SCN8A-related epilepsies. METHODS: A 36-question online survey was developed to obtain de-identified data from caregivers of children with SCN8A-related epilepsy. The survey included questions on genetic diagnosis, disease manifestations/comorbidities, seizure severity/type, current/prior use of antiseizure medicines (ASMs), and best/worst treatments per caregiver perception. RESULTS: In total, 116 survey responses (87 USA, 12 Canada, 12 UK, 5 Australia) were quantitatively analyzed. Generalized tonic/clonic was the most common seizure type at onset and time of survey; absence and partial/focal seizures were also common. Most patients (77%) were currently taking ≥2 ASMs; 50% had previously tried and stopped ≥4 ASMs. Sodium channel blockers (oxcarbazepine, phenytoin, lamotrigine) provided the best subjective seizure control and quality of life. CONCLUSION: The SCN8A-DEE patient population is heterogeneous in seizure characteristics and ASMs taken and is difficult to treat, with high seizure burden and multiple comorbidities. The high proportion of patients who previously tried and stopped ASMs indicates large unmet treatment need. Further collaboration between families, caregivers, patient advocates, clinicians, researchers, and industry can increase awareness and understanding of SCN8A-related epilepsies, improve clinical trial design, and potentially improve patient outcomes.

Capturing seizures in clinical trials of antiseizure medications for KCNQ2-DEE.

Literature review of patients with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) reveals, based on 16 reports including 139 patients, a clinical phenotype that includes age- and disease-specific stereotyped seizures. The typical seizure type of KCNQ2-DEE, focal tonic, starts within 0-5 days of life and is readily captured by video-electroencephalography VEEG for clinical and genetic diagnosis. After initial identification, KCNQ2-DEE seizures are clinically apparent and can be clearly identified without the use of EEG or VEEG. Therefore, we propose that the 2019 recommendations from the International League against Epilepsy (ILAE), the Pediatric Epilepsy Research Consortium (PERC), for capturing and recording seizures for clinical trials (Epilepsia Open, 4, 2019, 537) are suitable for use in KCNQ2-DEE‒associated antiseizure medicine (ASM) treatment trials. The ILAE/PERC consensus guidance states that a caregiver-maintained seizure diary, completed by caregivers who are trained to recognize seizures using within-patient historical recordings, accurately captures seizures prospectively in a clinical trial. An alternative approach historically endorsed by the Food and Drug Administration (FDA) compares seizure counts captured on VEEG before and after treatment. A major advantage of the ILAE/PERC strategy is that it expands the numbers of eligible patients who meet inclusion criteria of clinical trials while maintaining accurate seizure counts (Epilepsia Open, 4, 2019, 537). Three recent phase 3 pivotal pediatric trials investigating ASMs to treat syndromic seizures in patients as young as 2 years of age (N Engl J Med, 17, 2017, 699; Lancet, 21, 2020, 2243; Lancet, 17, 2018, 1085); and ongoing phase 2 open-label pediatric clinical trial that includes pediatric epileptic syndromes as young as 1 month of age (Am J Med Genet A, 176, 2018, 773), have already used caregiver-maintained seizure diaries successfully. For determining the outcome of a KCNQ2-DEE ASM treatment trial, the use of a seizure diary to count seizures by trained observers is feasible because the seizures of KCNQ2-DEE are clinically apparent. This strategy is supported by successful precedent in clinical trials in similar age groups and has the endorsement of the international pediatric epilepsy community.

Vernakalant: conversion of atrial fibrillation in patients with ischemic heart disease.

BACKGROUND: Vernakalant is a novel, relatively atrial-selective antiarrhythmic drug. This analysis assessed the efficacy and safety of intravenous vernakalant for the rapid conversion of atrial fibrillation (AF) to sinus rhythm in patients with a history of ischemic heart disease (IHD). METHODS: The presence of IHD was extracted from the medical history of patients from four randomized placebo-controlled studies and one open label study. The efficacy analysis included patients with recent onset AF (consistent with the European labeled indication), while the safety analysis included all patients with AF or atrial flutter (AFL) (3h to 45 days duration) who were exposed to study drug. RESULTS: A total of 1052 adult patients were enrolled and treated; 274 patients (91 placebo, 183 vernakalant) with a history of IHD and 778 patients (224 placebo, 554 vernakalant) without IHD. Conversion of AF to sinus rhythm was not influenced by IHD. In patients with recent onset AF, the placebo-subtracted conversion rate with vernakalant was 45.7% in the IHD group and 47.3% in the non-IHD group. In the 24h following treatment, the rate of treatment-emergent serious adverse events and discontinuations due to adverse events was similar in both the IHD and non-IHD groups, and there was no case of torsades de pointes, ventricular fibrillation, or death in patients with IHD. CONCLUSIONS: Vernakalant was safe and well tolerated in AF/AFL patients with a history of IHD, and was significantly more effective than placebo for the acute conversion of AF regardless of IHD status.

A randomized, placebo-controlled study of vernakalant (oral) for the prevention of atrial fibrillation recurrence after cardioversion.

BACKGROUND: Vernakalant, a relatively atrial-selective antiarrhythmic drug, has previously demonstrated efficacy for the acute conversion of atrial fibrillation (AF) to sinus rhythm. This study was designed to determine the most appropriate oral dose of vernakalant for the prevention of AF recurrence postcardioversion. METHODS AND RESULTS: Patients with nonpermanent AF were randomized to 150, 300, or 500 mg vernakalant or placebo twice daily for up to 90 days. The efficacy analysis was conducted on 605 of 735 patients who entered the maintenance phase on day 3 after cardioversion. The time to the first recurrence of symptomatic sustained AF was significantly longer in the 500 mg vernakalant group, with a median of >90 days versus 29 days in the placebo group (hazard ratio, 0.735; P=0.0275). No significant effect was seen at the lower doses. The percent of patients in sinus rhythm at day 90 was 41%, 39%, and 49% in the 150-mg (n=147), 300-mg (n=148), and 500-mg (n=150) vernakalant groups, respectively, compared with 36% in the placebo group (n=160). There were no vernakalant-related proarrhythmic events. Related serious adverse events occurred in 2 patients in the 150-mg vernakalant group and in 1 patient in each of the other groups. CONCLUSIONS: Vernakalant, 500 mg twice daily, appears to be effective and safe for the prevention of AF recurrence after cardioversion. The absence of proarrhythmia and favorable safety profile is an important finding for the drug. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526136.

Vernakalant hydrochloride: A novel atrial-selective agent for the cardioversion of recent-onset atrial fibrillation in the emergency department.

OBJECTIVES: Vernakalant is a relatively atrial-selective antiarrhythmic agent that has been shown to successfully convert atrial fibrillation (AF) to normal sinus rhythm for some patients whose onset of dysrhythmia occurred less than 7 days previously. This study sought to evaluate the efficacy and safety of vernakalant for patients with recent-onset AF. METHODS: This was a post hoc analysis of patients with recent-onset AF (> 3 to ≤ 48 hours) enrolled in the double-blind, placebo-controlled Atrial arrhythmia Conversion Trial (ACT) I and the open-label ACT IV trials. The studies enrolled adults presenting with AF to 78 emergency departments (ED) and cardiac clinics in six countries. Patients received a 10-minute intravenous infusion of vernakalant or placebo, followed by an additional infusion if necessary. Efficacy assessments included conversion to sinus rhythm within 90 minutes and median time to conversion. Safety evaluations included telemetry, Holter monitoring, and adverse events (AEs). RESULTS: Of the 290 patients, 229 received vernakalant, 61 received placebo, and the overall mean age was 59 years. The vernakalant and placebo groups were similar. Of all patients given vernakalant, 136 (59.4%) converted to sinus rhythm within 90 minutes, compared with three (4.9%) placebo patients. The median time to conversion with vernakalant was 12 minutes (interquartile range = 7-24.5 minutes). Clinically significant bradycardia and hypotension were uncommon, and no cases of torsade de pointes or ventricular fibrillation occurred. CONCLUSIONS: Vernakalant rapidly converted recent-onset AF to sinus rhythm in over half of patients, was well tolerated, and has the potential to offer an important therapeutic option for rhythm control of recent-onset AF in the ED.

A prospective, double-blind, randomized cross-over study evaluating changes in urinary pH for relieving the symptoms of interstitial cystitis.

OBJECTIVE: To provide evidence for the clinical efficacy of changes in urinary pH on the pain associated with interstitial cystitis (IC). PATIENTS AND METHODS: A prospective, randomized, double-blind cross-over study was conducted with 26 women with IC between 2000 and 2002, consisting of cross-over instillations of urine at physiological pH (5.0), and neutral buffered pH (NaH(2)PO(4) buffered to pH 7.5). The outcome measured was the subjective symptom of pain assessed using a visual analogue scale at baseline, after the initial instillation of solution, at washout, and after the crossover instillation. Data were analysed using repeated-measures analysis of variance. RESULTS: There was no statistically significant difference between the mean (sd) change from baseline pain scores after instilling neutral buffered solution, at 0.50 (2.78), and acidic solution, at 0.33 (3.43) (P = 0.85). Secondary outcomes were analysed, including baseline variability and treatment-order effects; neither were significantly different between the groups. CONCLUSIONS: There was no statistically significant difference in subjective pain scores on instilling urine at physiological pH or sodium-phosphate buffered saline in these patients with IC. Further work is required to define the role, if any, of urinary pH in the pathophysiology and treatment of IC.

Under "real world" conditions, desflurane increases drug cost without speeding discharge after short ambulatory anesthesia compared to isoflurane.

PURPOSE: To compare the measured "real world" perioperative drug cost and recovery associated with desflurane- and isoflurane-based anesthesia in short (less than one hour) ambulatory surgery. METHODS: We conducted a prospective, randomized, blinded trial with patients undergoing arthroscopic meniscectomy under general anesthesia. Following iv induction, patients received either isoflurane (group I; n = 25) or desflurane (group D; n = 20) for maintenance. The primary outcome variable was total perioperative drug cost per patient in Canadian dollars. Secondary outcome variables included volatile agent consumption and cost, adjuvant anesthetic and postanesthesia care unit (PACU) drug cost, readiness for PACU discharge, and incidence of adverse events. RESULTS: Total perioperative drug cost per patient was 14.58 +/- 6.83 Canadian dollars (mean +/- standard deviation) for group I, and 21.47 +/- 5.18 Canadian dollars for group D (P < 0.001). Isoflurane consumption per patient was 6.0 +/- 3.0 mL compared to 18.6 +/- 7.7 mL for desflurane (P < 0.0001); corresponding costs were 0.83 +/- 0.42 Canadian dollars vs 7.61 +/- 3.15 Canadian dollars (P < 0.0001). There were no differences in adjuvant anesthetic or PACU drug cost. All but one patient from each group were deemed ready for PACU discharge at 15 min postoperatively (Aldrete score >or= 9). One patient in group D experienced postoperative nausea. No other adverse events were noted. CONCLUSIONS: Measured total perioperative drug cost for a short ambulatory procedure (less than one hour) under general anesthesia was higher when desflurane rather than isoflurane was used for maintenance, essentially due to volatile agent cost. Desflurane use did not translate into faster PACU discharge under "real world" conditions.

Propofol reduces cognitive impairment after electroconvulsive therapy.

BACKGROUND: Cognitive impairments are the main complication after electroconvulsive therapy (ECT). Modification of treatment parameters has been shown to affect the magnitude of these impairments, but the role of anesthetic type remains unclear. This study tested whether there is a difference in cognitive impairments immediately after ECT with propofol compared to thiopental anesthesia. METHODS: This randomized, double-blind, crossover study included 15 patients receiving right unilateral ECT for depression. Patients received propofol or thiopental on alternating ECTs up to 6 treatments. Immediate and delayed verbal memory, motor speed, reaction speed, visuospatial, and executive functions were assessed 45 minutes after each ECT. Differences were assessed with repeated measures analysis of variance. RESULTS: Cognitive impairments were reduced after ECT with propofol compared to thiopental. Time to emergence was quicker and EEG seizure duration was shorter after propofol treatments. There was no significant correlation between seizure duration and neuropsychological test performance. CONCLUSIONS: Our results indicate that cognitive impairments in the early recovery period after ECT are reduced with propofol compared to thiopental anesthesia. We suggest that, in addition to ECT parameters, the type of anesthetic agent should be considered to reduce cognitive impairments after ECT.

The effect of repeated isoflurane anesthesia on spatial and psychomotor performance in young and aged mice.

UNLABELLED: Exposure to general anesthesia may contribute to postoperative cognitive impairment in elderly patients, but the relationship remains poorly understood. We investigated whether aged mice, 18-19 mo, are more susceptible to postanesthetic cognitive impairment than young mice, 3-4 mo, using spatial memory (Barnes maze) and psychomotor (rotarod) tasks. Initially we studied the effect of a single anesthetic episode on asymptotic maze performance. We then tested whether repeated anesthesia would impair spatial memory and psychomotor performance to a greater extent in aged mice. Mice were anesthetized with isoflurane (1.4% atm) for 30 min; controls received 90% oxygen. Anesthesia, administered during the asymptotic period of maze learning, did not impair performance tested the following day (P > 0.05). Repeated anesthesia, 2-3 h after each session, did not impair overall maze or rotarod performance in young or aged mice (P > 0.05). Spatial learning appeared to be facilitated by anesthesia, F(1,204) = 7.97, P < 0.01 for pooled results. Asymptotic performance-when learning had stabilized-remained unimpaired in both the maze and rotarod tasks. These results suggest that an age-related risk of anesthetic-induced impairment appears to be limited to acquisition of a novel motor skill and that anesthesia alone does not lead to prolonged cognitive impairments in aged mice. IMPLICATIONS: This study demonstrates that repeated isoflurane general anesthesia impaired psychomotor performance in aged mice during the initial learning period; however, spatial learning improved and, overall, spatial memory and psychomotor performance were unimpaired. Thus, general anesthesia alone does not appear to result in prolonged cognitive deficits in aged mice.