Nerve hyperplasia: a unique feature of ketamine cystitis

Acta Neuropathol Commun. 2013 Oct 8:1:64. doi: 10.1186/2051-5960-1-64.


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.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anesthetics, Dissociative / administration & dosage
  • Anesthetics, Dissociative / adverse effects*
  • Cystitis / metabolism
  • Cystitis / pathology*
  • Humans
  • Hyperplasia
  • Illicit Drugs
  • Immunoenzyme Techniques
  • Ketamine / administration & dosage
  • Ketamine / adverse effects*
  • Middle Aged
  • Nerve Fibers / metabolism
  • Nerve Fibers / pathology*
  • Nerve Tissue Proteins / metabolism
  • Neurofilament Proteins / metabolism
  • Receptors, Nerve Growth Factor / metabolism
  • Substance-Related Disorders / metabolism
  • Substance-Related Disorders / pathology*
  • Urothelium / metabolism
  • Urothelium / pathology
  • Young Adult


  • Anesthetics, Dissociative
  • Illicit Drugs
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Neurofilament Proteins
  • Receptors, Nerve Growth Factor
  • Ketamine