Parent‐reported benefits of flupirtine in juvenile neuronal ceroid lipofuscinosis (Batten disease; CLN3) are not supported by quantitative data

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood that typically presents at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. No therapy has been shown to slow the progression of disease in JNCL patients, and all current treatments are symptomatic. Flupirtine has been shown in vitro to reduce apoptosis in CLN3 lymphocytes. Based on that preclinical study, several children with JNCL were given flupirtine by their parents. The purpose of this study was to determine if there was evidence of attenuated disease progression in any JNCL symptom domain. We administered a survey to parents of JNCL children to qualitatively assess flupirtine efficacy. We used the Unified Batten Disease Rating Scale (UBDRS) to determine specific aspects of disease progression and investigated three age-related factors: loss of independent ambulation, loss of intelligible speech, and loss of ability to perform independent activities of daily living. The median scores for the UBDRS physical, behavior, and capability subscales were determined in flupirtine-exposed subjects and compared to age-, sex-, and genotype-matched subjects who had never taken flupirtine. Twenty-one percent of survey responders reported administering flupirtine to their JNCL child, and 56% of these families perceived beneficial changes that they attributed to flupirtine. However, our quantitative, prospectively obtained data did not show any change in JNCL disease progression that could be attributed to flupirtine. This study highlights the need for prospective experimental therapeutic research.

Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses

“…Also, retigabine is in trials for treatment of amyotrophic lateral sclerosis (Clinicaltrial.gov ID: NCT02450552). A case report on one case treated with flupirtine in NCL disease is published …”

Reliability and validity of the Wolfram Unified Rating Scale (WURS)

“…In addition, the UBDRS Behavioral Assessment subscale has been cross validated with the Achenbach Child Behavior Checklist, with r s ranging from 0.39 to 0.72 with related items [8]. The UBDRS has been used in studies to quantify decline in physical functioning [9], measure change in disease severity over time in longitudinal studies, to compare sex and genotype differences [8,10], and to determine treatment efficacy [11]. …”

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

“…70 Some parents giving the drug flupirtine to their children with juve nile CLN3 disease have anecdotally reported benefit; how ever, quantitative, See Online for appendix prospectively obtained data did not show any change in disease progression that could be attributed to this drug. 71 A clinical trial treat ing 19 children with juvenile CLN3 disease with a nonsteroidal immunosuppressive drug, mycophenolate mofetil, over two 8week treatment periods with a 4week intervening washout 68,69 showed that this drug was well tolerated, but there was no clinical benefit. 58 A trial in nine children with CLN1 disease that tested the com bination of phospho cysteamine and Nacetylcysteine, reported no clinical benefit (table 2).…”