Nerve hyperplasia: a unique feature of ketamine cystitis

Abstract

Background: There 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.

Results: In 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.

Conclusions: The 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.

Figure 1

Representative images from haematoxylin and eosin stained sections of ketamine cystitis tissue. (A) Typical ketamine-induced changes with increased sub-epithelial capilliarisation and oedema of the lamina propria. In this sample there is early lymphoid aggregate formation which is not uncommon. The overlying urothelium is reduced to a patchy single layer of epithelial cells showing atypical cytological changes. (B) Lamina propria with prominent nerve fascicles and conspicuous perineurium; some eosinophils in the background. Scale bar represents 100 μm.

Figure 2

Representative images of NFP immunohistochemistry in bladder biopsies from ketamine cystitis patients, showing positive fibres in close proximity, but not infiltrating, the urothelium (left) and large clusters of fibres in the lamina propria (right). Scale bar represents 100 μm.

Figure 3

Representative images of NGFR and SMA immunohistochemistry showing the stromal NGFR⁺ cells in ketamine cystitis tissue and a serial section demonstrating that NGFR⁺ cells are SMA^-. SMA⁺ labelling of vascular walls also highlights the appearance of prominent blood vessels in the bladder wall of ketamine cystitis biopsies. NGFR⁺ peripheral nerve fascicles are arrowed in ketamine cystitis and “control” non-diseased bladder taken during radical prostatectomy. Scale bar represents 100 μm.

Figure 4

Proximal sections showing an example of the NFP⁺, NGFR⁺ and S100⁺ labelling patterns in peripheral nerve fascicle identified in ketamine cystitis tissue and observed in nearly all ketamine cystitis samples. EMA showed a perineural labelling pattern. The prominent perineural spindle cell cuff was also NGFR⁺ and exhibited scanty SMA⁺ restricted to occasional cells. Note, the adjacent blood vessel, which showed SMA labelling of the mural smooth muscle cells, but unlike the nerve fascicle was NFP^-, NGFR^- and S100^-. Scale bar represents 100 μm.

Figure 5

Representative images of NGFR immunohistochemistry showing urothelial localisation in a range of bladder conditions including “A” non-diseased bladder taken during radical prostatectomy, “B” idiopathic detrusor overactivity and “C” stress urinary incontinence and “D” interstitial cystitis. Supra-basal expansion of NGFR labelling was only occasionally observed in idiopathic detrusor overactivity and stress urinary incontinence (see Table 2). In ketamine cystitis biopsies (“E”, “F” & “G”), supra-basal expansion of the intense NGFR labelling was observed in 10 of the 16 patients who retained intermediate urothelial cells. Scale bar in panel “G” represents 100 μm.