Hypothesis / aims of study
Complex (refractory or multisystem) chronic pelvic pain (CPP) patients have been found to suffer from 2.4 pain comorbidities (e.g. fibromyalgia, migraine) on average. Previous findings suggest that small fiber polyneuropathy (SFPN) is present in 64% of complex (refractory or multisystem) cases of CPP. (1) SFPN is a condition that affects sensory myelinated A𝛅 and unmyelinated C fibers, which are responsible for pain transmission, temperature signals, and autonomic function. Afferent innervation of the bladder consists primarily of small myelinated and unmyelinated nerve fibers. Small fiber dysfunction, the main process implicated in SFPN, can negatively impact the autonomic control of micturition. This can result in parasympathetic dysfunction of the detrusor or sympathetic dysfunction of the bladder neck (primary bladder neck obstruction [PBNO]). Given our clinical observation that CPP patients with SFPN commonly have underactivity and PBNO on urodynamics, we sought to document the association.
Study design, materials and methods
The study design was a retrospective observational study. IRB approval was obtained prior to record queries. Inclusion criteria included: diagnosis of complex CPP (refractory or multisystem pelvic pain present for > 3 months), complete subspecialty autonomic neurology evaluation including skin biopsy, and availability of high quality video urodynamic images and tracings performed according to ICS standards, by a single urodynamicist, present in the room for the study. Exclusion criteria included the presence of urodynamic confounders (e.g. neobladder, recent botulinum toxin injection, and male gender, including one post-PVP,). PBNO was diagnosed according to the Video urodynamic criteria of Nitti et al 1999: “Bladder outlet obstruction was defined as radiographic evidence of obstruction between the bladder neck and distal urethra in the presence of a sustained detrusor contraction of any magnitude, which was usually associated with reduced or delayed urinary flow rate. Radiographic obstruction at the bladder neck was diagnosed when the bladder neck was closed or narrow during voiding.“ (2) Subspecialty neurology evaluation (clinical history, exam, skin biopsy, and autonomic testing) was used to determine the presence of SFPN. Statistical analysis was performed with IBM SPSS V27 using chi-square analysis for categorical variables, and student t-tests for numerical variables.
Results
55 patients with complex CPP underwent skin biopsy and video urodynamics. Of these, 43 completed subspecialty autonomic neurology evaluation for SFPN. 28 of the 43 complex CPP patients (65%) were ultimately diagnosed with SFPN.
Of the 55, 4 were excluded due to urodynamic confounders (1 PVP, 2 Botox, and 1 Neobladder). Of these 51, 43 were female and 8 male. The 8 men were removed for consistency of data, given that obstructive parameters in men cannot be compared to obstruction in women).
Of the remaining 43 female patients, 32 had undergone complete subspecialty autonomic neurology evaluation. 23 were SFPN positive patients and 9 negative.
Refer to Table 1 for urodynamic findings in women with SFPN.
SFPN positive patients were more likely to demonstrate autonomic bladder dysfunction (either BNO or Atonic, p = 0.007). PVR was higher in the SFPN group (p = 0.011) and UUI was more likely to be present (p = 0.000). Clinical complaint of difficulty emptying (p = 0.100), dizziness on standing (0.095), sexual pain (0.097), and loss of sensation (0.134) did not reach significance for difference between the SFPN + and SFPN – groups. Abnormal pinprick on physical exam was more likely to be reported in SFPN (p = 0.001). No particular other symptoms including bladder capacity (p=0.574) and number of allergies (p=0.861) were significantly correlated with SFPN.
We removed all confounders that may impact the interpretability of bladder neck obstruction. 8 were therefore excluded due to either atonic bladder or extreme straining to void, rendering interpretation of the study unreliable for contraction and flow.
Refer to Table 2 for comparison of bladder neck obstruction in patients with and without SFPN.
Patients with bladder neck obstruction on VUDS had an increased likelihood of SFPN (OR= 5.778 [95% CI (1.118,29.847)], p = 0.029 ) on neuro evaluation.
Interpretation of results
Overall, complex CPP patients with a diagnosis of SFPN were more likely to have urologic abnormalities associated with autonomic dysfunction on videourodynamics in our study (underactive bladder and/or PNBO). Pinprick testing and elevated postvoid residual volume were also associated with SFPN.
Identification of SFPN – related somatic and autonomic dysfunction impacting the bladder in complex pelvic pain has two converse benefits: 1) small nerve fiber dysfunction expands the therapeutic targets, such as bladder neck obstruction, treatable with alpha blockers, botulinum toxin, and neuromodulation and 2) identification of characteristic bladder dysfunction in people presenting with complex pelvic pain may raise suspicion for SFPN.
The diagnosis of SFPN can offer significant validation to an individual with seemingly unrelated and vague symptoms impacting multiple areas of life. Symptoms of SFPN include migraines, GERD, hair loss, dizziness, bladder and bowel dysfunction, tinnitis and other small nerve fiber associated symptoms. Work up for neurological symptoms aimed at the large nerve fibers (e.g. reflexes, MRI, EMG) will have been normal in these cases. Beyond validation, identification of SFPN leads to discovery of a specific causative etiology in 40% of cases, some of which are reversible (e.g. gluten allergy), and regardless of etiology can shift focus toward neuromodulator – based pain interventions.