Abstract
Management of neurogenic detrusor overactivity (NDO) remains a clinical priority to improve patients’ quality of life and prevent dramatic urological complications. Intradetrusor injection of onabotulinumtoxinA (BoNT/A1, botulinum neurotoxin A1) is approved as second therapeutic line in these patients, demonstrating a good efficacy. However, a loss of its efficacy over time has been described, with no clear understanding of the underlying mechanisms. This paper aims at shedding new light on BoNT/A1 secondary failure in NDO through functional and structural analysis. Three groups of patients (either non-NDO, NDO with no toxin history or toxin secondary failure) were investigated using an ex vivo bladder strip assay. Detrusor strips were tensed in organ baths and submitted to electrical field stimulation to generate contractions. Recombinant BoNT/A1 was then added at various concentrations and contractions recorded for 4 h. Histology exploring BoNT/A1 targets, fibrosis and neuronal markers was also used. Detrusor strips from patients with BoNT/A1 secondary failure displayed a smaller sensitivity to toxin ex vivo at 3 nM compared to the other groups. Histological evaluation demonstrated the presence of cleaved Synaptosomal-Associated Protein, 25 kDa (c-SNAP25) in the detrusor from the toxin-secondary failure population, indicating some remaining in vivo sensitivity to BoNT/A1 despite the therapeutic escape. Moreover, residual c-SNAP25 did not affect parasympathetic-driven contractions observed ex vivo. This study confirms the slightly lower efficacy of BoNT/A1 in the BoNT/A1 secondary failure NDO group, suggesting that the escape from BoNT/A1 efficacy in NDO occurs at least at the parasympathetic level and could imply compensatory mechanisms for detrusor contraction.
Highlights
Up to 80% of patients with multiple sclerosis (MS) or traumatic spinal cord injury (SCI) and more than 60% of patients with spina bifida (SB) suffer from neurogenic bladder mostly related to neurogenic detrusor overactivity (NDO) [1,2,3]
A non-significant trend for a more severe fibrosis was found for both NDO groups compared to control/non-NDO patients
We demonstrated that bladder strips of patients inefficiently treated by BoNT/A1 were less sensitive to the paralyzing effect of rBoNT/A1 ex vivo, with a significantly slower paresis of detrusor contractions observed at 3 nM when compared to naïve patients
Summary
Up to 80% of patients with multiple sclerosis (MS) or traumatic spinal cord injury (SCI) and more than 60% of patients with spina bifida (SB) suffer from neurogenic bladder mostly related to neurogenic detrusor overactivity (NDO) [1,2,3]. NDO induces urine leakage, significantly decreasing patients’ quality of life (QoL) leading to urological complications including urinary tract infections, urinary lithiasis and renal failure. NDO management aims to improve patients’ QoL and to prevent urological complications by achieving regular bladder emptying without post-void residue, avoiding high intra-detrusor pressure and maintaining continence. The current management strategy is well characterized and includes intradetrusor injection of onabotulinumtoxinA (Botox® )
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