Nerve hyperplasia: a unique feature of ketamine cystitis

Abstract

BackgroundThere is an emerging association between ketamine abuse and the development of urological symptoms including dysuria, frequency and urgency, which have a neurological component. In addition, extreme cases are associated with severe unresolving bladder pain in conjunction with a thickened, contracted bladder and an ulcerated/absent urothelium. Here we report on unusual neuropathological features seen by immunohistology in ketamine cystitis.ResultsIn all cases, the lamina propria was replete with fine neurofilament protein (NFP+) nerve fibres and in most patients (20/21), there was prominent peripheral nerve fascicle hyperplasia that showed particular resemblance to Morton’s neuroma. The nerve fascicles, which were positive for NFP, S100 and the p75 low-affinity nerve growth factor receptor (NGFR), were generally associated with a well-developed and in places, prominent, epithelial membrane antigen+/NGFR+ perineurium. This peripheral nerve fascicle hyperplasia is likely to account for the extreme pain experienced by ketamine cystitis patients. Urothelial damage was a notable feature of all ketamine cystitis specimens and where urothelium remained, increased NGFR expression was observed, with expansion from a basal-restricted normal pattern of expression into the suprabasal urothelium.ConclusionsThe histological findings were distinguishing features of ketamine cystitis and were not present in other painful bladder conditions. Ketamine cystitis afflicts predominantly young patients, with unknown long-term consequences, and requires a strategy to control severe bladder pain in order to remove a dependency on the causative agent. Our study indicates that the development of pain in ketamine cystitis is mediated through a specific neurogenic mechanism that may also implicate the urothelium.

Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

“…As an anesthetic, ketamine might have a direct effect on nerve fibers, thereby causing voiding dysfunction. For example, nerve hyperplasia has been reported in ketamine cystitis patients (1). The prevalence of inflammation and apoptosis in the ketamine-treated bladder wall also favors the autoimmune response theory.…”

Risk Factors of Lower Urinary Tract Syndrome among Ketamine Users

“…The mechanism of lower urinary tract destruction in ketamine users is associated with neuroinflammation and changes in visceral pain transmission . Patients with ketamine cystitis develop peripheral nerve fascicle hyperplasia in their bladder tissue . Recent study reports that excreted ketamine and potentially its metabolites are the main driver of LUTS in ketamine users, by the evidence in a patient undergoing cystectomy for unremitting pain following ketamine abuse where near total loss of bladder urothelium was observed from regions in contact with urine, whereas the urachal epithelium (not exposed to urine) remained healthy .…”

Upregulation of neurotrophins and transforming growth factor‐β expression in the bladder may lead to nerve hyperplasia and fibrosis in patients with severe ketamine‐associated cystitis

“…Therefore, the pathogenesis of KC could involve nerve system hypersensitivity in the bladder. Previous studies have provided histological evidence of abnormal nerve hyperplasia in the bladders of patients with KC, and nerve hyperplasia could reasonably contribute to the cause of bladder hypersensitivity in these patients. We found upregulation of neuzhe entire KC bladder, including epithelium, vessels, inflammatory cells, and bladder muscle.…”

“…Since ketamine mainly acts on NMDAR in neurons, and the main symptoms of KC are bladder hypersensitivity and pain, it is reasonable to suspect that neural dysregulation might participate in the pathogenesis of KC. A previous study showed the lamina propria of KC bladders was replete with fine neurofilament protein, and p75 low‐affinity NGF receptor was prominently increased . Previous histopathology studies revealed whole‐layer nerve hyperplasia and increased collagen deposition in the bladder wall of KC patients .…”