Prioritizing Hormone Therapy Over Vigabatrin as the First Treatment for Infantile Spasms: A Quality Improvement Initiative.

BACKGROUND AND OBJECTIVES: Infantile spasms (IS) are early childhood seizures with potentially devastating consequences. Standard therapies (adrenocorticotropic hormone [ACTH], high-dose prednisolone, and vigabatrin) are strongly recommended as the first treatment for IS. Although this recommendation comes without preference for one standard therapy over another, early remission rates are higher with hormone therapy (ACTH and high-dose prednisolone) when compared with vigabatrin. Using quality improvement (QI) methodology that included hormone therapy as the first treatment, we sought to increase the percentage of children with new-onset nontuberous sclerosis complex (TSC)-associated IS achieving 3-month electroclinical remission from a mean of 53.8% to ≥70%. METHODS: This was an observational consecutive sample cohort study at a single academic tertiary care hospital that compared a prospective intervention cohort (May 2019-January 2022, N = 57) with a retrospective baseline cohort (November 2015-April 2019, N = 67). Our initiative addressed key drivers such as the routine use of vigabatrin over hormone therapy as first treatment and the common initiation of a second treatment after 14 days for initial nonresponders. We included consecutive children without TSC presenting with new-onset IS diagnosed and treated between ages 2 and 24 months. We displayed our primary outcome and process measures as control charts in which the centerline is the quarterly (previous 3 months) mean based on statistical process control methodology. RESULTS: QI interventions that included the standardization of hormone therapy as the first treatment resulted in higher rates of 3-month remission, rising from 53.8% (baseline cohort) to 75.9% (intervention cohort). Process measure results included an increased rate of children receiving hormone therapy as first treatment (mean, 44.6%-100%) and a decreased number of days to both clinical follow-up after first treatment (mean, of 16.3-12.6 days) and starting a second treatment within 14 days for initial nonresponders (mean, 36.3-17.2 days). DISCUSSION: For children with IS, improved rates of 3-month electroclinical remission can be achieved with QI methodology. Implementation of similar QI initiatives at other centers may likewise improve local remission rates.

Using quality improvement to implement the CNS/AAN quality measure on rescue medication for seizures.

OBJECTIVE: A multidisciplinary quality improvement (QI) team was established to conduct analysis of data for prescribed seizure rescue medication doses from January 2013 to December 2015 to identify and improve inappropriately low dose prescriptions. The QI team identified areas of focus for improvement opportunities and developed the project objective based on the 2017 American Academy of Neurology (AAN) and Child Neurology Society (CNS) quality measure. METHODS: Within a freestanding children's hospital, the QI team developed key drivers and implemented interventions, such as the midazolam prefilled syringe program with use of standardized dosing, electronic chart tools, monthly pharmacy review of all underdosed prescriptions, and provider and nursing education. The team created an automated monthly report to monitor prescribed seizure rescue medication dosing compliance. The year 2015 was used as the preliminary data baseline period with an average noncompliance rate of 3.5%. RESULTS: From January 2016 to December 2019, the team has decreased and sustained the noncompliance rate to an average of 0.38%. The data for the project included 12,975 seizure rescue medication prescribed by a neurology provider from January 2015 to December 2019. Compliance with properly dosed diazepam orders continues to be the largest area of opportunity. The data demonstrated a centerline shift in January 2019, moving the baseline average of 7.2% noncompliance to the current average rate of 0.22%. In comparison, underdosed midazolam orders occurred at an average rate of 0.037% in the same timeframe. SIGNIFICANCE: Using quality improvement methodologies, the team successfully and substantially decreased provider prescribed and signed underdosed rescue medication orders by an average of 89%. This QI project demonstrates successful implementation and improvement addressing the AAN/CNS quality measure of proper rescue seizure treatment dosing.

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX.

Mutations in the Aristaless-related homeobox gene (ARX) lead to a range of X-linked intellectual disability phenotypes, with truncating variants generally resulting in severe X-linked lissencephaly with ambiguous genitalia (XLAG), and polyalanine expansions and missense variants resulting in infantile spasms. We report two male patients with early-onset infantile spasms in whom a novel c.34G>T (p.(E12*)) variant was identified in the ARX gene. A similar variant c.81C>G (p.(Y27*)), has previously been described in two affected cousins with early-onset infantile spasms, leading to reinitiation of ARX mRNA translation resulting in an N-terminal truncated protein. We show that the novel c.34G>T (p.(E12*)) variant also reinitiated mRNA translation at the next AUG codon (c.121-123 (p.M41)), producing the same N-terminally truncated protein. The production of both of these truncated proteins was demonstrated to be at markedly reduced levels using in vitro cell assays. Using luciferase reporter assays, we demonstrate that transcriptional repression capacity of ARX was diminished by both the loss of the N-terminal corepressor octapeptide domain, as a consequence of truncation, and the marked reduction in mutant protein expression. Our study indicates that premature termination mutations very early in ARX lead to reinitiation of translation to produce N-terminally truncated protein at markedly reduced levels of expression. We conclude that even low levels of N-terminally truncated ARX is sufficient to improve the patient's phenotype compared with the severe phenotype of XLAG that includes malformations of the brain and genitalia normally seen in complete loss-of-function mutations in ARX.

Acceptance of the use of diazepam rectal gel in school and day care settings.

This study was conducted to identify how often parents of children with epilepsy encounter barriers to the use of diazepam rectal gel in day care or school settings and how these barriers affect the child and family. Sixty-four parents completed an 18-item questionnaire documenting their experience with asking their child's school to administer diazepam rectal gel. No data regarding its actual use in the school was obtained. Forty-three parents (68%) had asked their school to administer diazepam rectal gel; 35 (81%) reported school agreement, and 8 (19%) reported refusal. In 5 of these refusals, the cited reason was legal concerns, and in 5 cases the refusal had some adverse effect on their family's life. Most children prescribed diazepam rectal gel do not encounter resistance to its use in school and day care settings. Barriers to its use are usually due to legal concerns and significantly affect the family's quality of life.