Small fiber polyneuropathy is prevalent in patients with interstitial cystitis/bladder pain syndrome

Abstract

Purpose:

The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is imperfectly understood. Recent studies reported that small fiber polyneuropathy (SFPN) is common in fibromyalgia, a condition commonly comorbid with IC/BPS. The objective of this study was to determine the prevalence of SFPN in a large cohort of IC/BPS patients.

Materials and Methods:

Adults diagnosed with IC/BPS scheduled to undergo either therapeutic hydrodistention (n=97), or cystectomy with urinary diversion (n=3), were prospectively recruited to this study. A skin biopsy obtained from the lower leg was used for intraepidermal nerve fiber density (IENFD) measurement. SFPN (+/−) status was determined by comparing linear IENFD (fibers/mm²) with normative reference values. Demographic information, medical history, and diagnoses for 14 conditions (both urologic and non-urologic) known to co-occur with IC/BPS were documented from self-report and electronic medical record.

Results:

In this large cohort of patients with IC/BPS, 31% (31/100) were positive for SFPN. IENF density was below the median for age and gender in 81% (81/100) of patients. Approximately one-third (31%) of SFPN+ patients reported co-occurring chronic fatigue syndrome (CFS), compared to 10.6% of the SFPN− group (p = 0.034). SFPN+ patients reported significantly fewer allergies than SFPN− patients (37.9% vs 60.6%; p = 0.047). There were no significant differences in bladder capacity or Hunner’s lesion status between the SFPN+ and SFPN− subgroups.

Conclusions:

Small fiber polyneuropathy is a common finding in patients with IC/BPS and SFPN status is significantly correlated with co-occurring CFS, and negatively correlated with the presence of allergies in this population.

Common Language Summary:

Interstitial cystitis/bladder pain syndrome is a poorly understood chronic pain condition. While patients experience chronic pain in their bladders and changes to their urinary habits, they also commonly experience widespread pain and issues beyond their bladder. The cause(s) of these symptoms is not well understood. Our research found evidence that patients with interstitial cystitis commonly have damage/thinning to the nerves in their skin which is associated with being chronically fatigued. This finding may explain some of the widespread symptoms these patients experience.

Introduction:

Interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic pain condition characterized by pain perceived to emanate from the bladder, poses a clinical challenge due to its poorly defined pathophysiology. While the diagnostic criteria for those with IC/BPS is bladder-centric pain (e.g., pain with bladder filling/distention) often with associated urinary symptoms such as urinary frequency and nocturia, each patient’s presentation is widely variable.¹ Many patients experience systemic symptoms,² and are frequently diagnosed with concomitant non-urological associated syndromes (NUAS) that can be further categorized into pelvic pain (e.g., vulvodynia, chronic pelvic pain (CPP)) and systemic syndromes (e.g., irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), allergies).³ It is evident that the heterogeneity of this condition represents a major obstacle for effective diagnosis and treatment.

Recently it was reported that many patients with fibromyalgia met diagnostic standards for small fiber polyneuropathy (SFPN), a condition wherein damage to the small somatic and autonomic unmyelinated c fibers and A-delta fibers results in widespread pain and autonomic symptoms such as fatigue and bowel/bladder dysfunction.⁴ Clinically, SFPN presents with symptoms including numbness and tingling, shooting pains in extremities, general fatigue, difficulty with motor coordination, and extreme sensitivity to touch. It has also been found to coincide with many pain-related conditions and syndromes.⁵ Like IC/BPS, FM lacks a clearly defined etiology and shares many of the same co-occurring conditions (e.g., migraine headaches, IBS, CFS, major depression, and panic disorder). The relationship and clinical overlap between IC/BPS and FM has been well-documented,⁶ and because SFPN is a common finding in FM, we hypothesized that SFPN may serve as a biomarker and potential therapeutic target for IC/BPS patients.⁵ To test this hypothesis, a small pilot study involving 11 participants was conducted in which SFPN was found to be significantly associated with a subgroup of non-bladder centric (i.e., non-low bladder capacity (BC > 400cc), Hunner’s lesion negative) IC/BPS patients, and correlated with a higher prevalence of co-occurring NUAS (FM, migraines, psychiatric disorders, allergies, and asthma).⁷ The objective of the present study was to examine the prevalence of small fiber polyneuropathy in a large, prospectively recruited, IC/BPS patient cohort and evaluate for associated systemic diseases.

Materials and Methods:

Study Design & Patient Recruitment

Adult patients (18-80 years old), diagnosed with IC/BPS according to American Urological Association (AUA) guidelines,¹ who were scheduled to undergo either therapeutic hydrodistention (HOD) (n=97) or simple cystectomy with urinary diversion (n=3) were prospectively recruited to this study following written informed consent (IRB00018552). Exclusion criteria included patients who were pregnant, had an active urogenital infection (i.e., urinary tract infection, genital herpes outbreak, tuberculosis), or had current urethral catheter use (either currently indwelling or chronic intermittent catheterization). Further exclusion criteria included any history of urethral diverticulum, cyclophosphamide use, radiation cystitis, any urogenital cancer, or neurologic disease (e.g., stroke, neurogenic bladder, etc.).

Data Collection

Medical history was obtained during patient recruitment and included demographic data (e.g., age, gender, race), validated IC/BPS symptom scores (e.g., O’Leary Sant Interstitial Cystitis Symptom and Problem Indices (ICSI/ICPI) and Pelvic Pain and Urinary Urgency Frequency (PUF) scores), together with patient reported history of diagnosis with any of the following medical conditions (14): fibromyalgia, complex chronic pelvic pain (CPP), vulvodynia, pelvic floor dysfunction (PFD), Sjogren’s syndrome, postural orthostatic hypotension (POTS) syndrome, endometriosis, irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), migraines, major depression, panic disorder, allergies, and asthma.

Patient co-morbidities that are known to be potentially causative for SFPN were also documented based on patient’s medical history and included the following: current or past smoking history, diabetes mellitus (DM), thyroid disease (e.g., hyperthyroidism, hypothyroidism), vitamin B12 deficiency, celiac disease, sarcoidosis, any autoimmune/systemic inflammatory disease, and infection with human immunodeficiency virus (HIV).^8,9 Anesthetic bladder capacity (BC) was recorded during hydrodistention of the bladder, in which the height of water infusion was placed at a maximum of 100cm above the pelvis and held for five minutes, as well as the presence or absence of glomerulations and Hunner’s lesions (HL). Two of the three patients undergoing cystectomy had previously participated in one of our prospective database collections, and thus their anesthetic bladder capacity and the presence of glomerulations and Hunner’s lesions were available and recorded for these patients, resulting in a total of 99 patients with BC, HL, and glomerulation data.

Tissue Procurement & Processing

Skin samples were collected from patients while under general anesthesia for their scheduled hydrodistention/cystectomy procedure. The following tissue processing protocol follows the European Federation of Neurological Societies guidelines for diagnosis of peripheral neuropathies, currently the most reliable and recommended protocol for quantifying IENFD to assess polyneuropathy.⁹ A 3-mm punch biopsy was obtained from the right distal leg of each patient, 10 cm proximal to the medial malleolus and immediately placed in 1 mL of Zamboni’s (2% paraformaldehyde, picric acid) fixative for at least 24 hours at room temperature. Skin specimens were then washed with PBS and placed in cryoprotectant solution (30% sucrose) for an additional 24 hours before OCT embedding and flash-freezing of the blocks with liquid nitrogen. Frozen samples were stored at −20° C prior to cryostat sectioning. Thin section (5μm) slices were collected onto microscope slides (Fisher Scientific; Waltham, MA) and allowed to air-dry for 7 days prior to immunohistochemical staining with pre-diluted (1ug/ml) protein gene product (PGP) 9.5 rabbit monoclonal antibody (Sigma-Aldrich) to visualize neuronal axons within the epidermis (Figure 1).

Figure 1: Representative skin biopsy slides used for evaluation of small fiber polyneuropathy.

(A) 47-year-old female with an IENFD of 7.27 fibers/mm2 (SFPN−). (B) 34-year-old female with an IENFD of 0.61 fibers/mm2 (SFPN+). Vertical black arrows indicate intraepidermal nerve fibers. Diagonal green arrows indicate the dermal-epidermal junction. Horizontal red arrows indicate the dermis. Images were captured at 40x magnification.

Immunohistochemical staining

A single dermatopathologist experienced in the diagnosis of SFPN (CA) and blinded to patient characteristics then performed brightfield microscopic quantitative analysis of the intraepidermal nerve fiber (IENF) density (fibers/millimeter²) for each sample by calculating the average nerve counts within the epidermis over three fields at 40x magnification. SFPN status (+/−) was then determined by comparing patient IENF densities with worldwide normative IENFD reference values stratified by both age and sex, with a positive diagnosis confirmed when the IENF density was below the 5th percentile for the patient’s demographics.¹⁰

Statistical Analysis

All statistics were performed using SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM corp. Characteristics of those with SFPN and without were compared utilizing independent t-tests for continuous variables and Fisher’s exact tests for categorical variables (two sided; alpha set to P < 0.05).

Results:

IC/BPS Demographic/Clinical Data

The mean age of this cohort of 100 IC/BPS patients (88 females, 12 males) was 50.00 (± 15.82) years old, and the average BMI was 28.83 (± 7.02). The population was 87% White, 10% African American, 1% Hispanic, and 2% Other. Average anesthetic bladder capacity, as determined during therapeutic hydrodistention, was 776.26 mL (± 367.93), and Hunner’s lesions were present in 14.1% (14/99) of the patient cohort. The average number of non-urologic associated syndromes (NUAS) was 4.24.

SFPN Status (SFPN+ vs. SFPN−)

Of 100 patients, 31 (31%) had skin samples with IENF densities below the 5th percentile for their age and sex, corresponding to the diagnosis of SFPN (i.e., they were SFPN+). There were no significant differences in age, BMI, bladder capacity, HL status, presence/absence of glomerulations, or symptom scores between those with and without objective evidence of SFPN (Tables 1 and 2). Furthermore, 81 (81%) of patients had IENF densities below the median for their age and sex.

Table 1:

Demographic characteristics for patients with and without a diagnosis of small fiber polyneuropathy

Variable	Negative (n=69) Mean (SD)	Positive (n=31) Mean (SD)	P-Value
Age	52.00 (14.70)	46.55 (17.50)	0.059
Sex (F)	59 (85.5%)	29 (93.5%)	0.33
BMI	28.5 (6.60)	29.57 (7.94)	0.485
Smoker	24 (34.8%)	6 (19.4%)	0.16
Race (White)	63 (91.3%)	24 (77.4%)	0.103
Diabetes Mellitus	9 (13.0%)	7 (22.6%)	0.25
Thyroid Disease	8 (11.6%)	4 (12.9%)	>0.99
Vitamin B12 Deficiency	2 (2.9%)	1 (3.2%)	>0.99
Celiac Disease	1 (1.4%)	1 (3.2%)	0.53
Sarcoidosis	0 (0%)	0 (0%)	>0.99
HIV	0 (0%)	0 (0%)	>0.99
Any autoimmune disease	14 (20.2%)	7 (22.5%)	0.796

Table 2:

Clinical characteristics for patients with and without a diagnosis of small fiber polyneuropathy

Variable		SFPN− (n=69) Count (%)	SFPN+ (n=31) Count (%)	P-Value
IENF Density (fibers/mm2)		9.1 (4.43)	3.71 (2.10)	< 0.001
Bladder Capacity (mL)		765.81 (374.66)	799.19 (357.68)	0.68
Duration of diagnosis (months)		96.95 (90.42)	81.93 (83.83)	0.45
ICPI		12.94 (3.11)	12.46 (2.80)	0.50
ICSI		12.92 (4.65)	13.08 (4.17)	0.88
PUF		23.48 (6.40)	23.70 (5.64)	0.89
Hunner’s Lesions (n=99)		12 (17.6%)	2 (6.5%)	0.21
Glomerulations (n=99)		54 (78.2%)	26 (83.9%)	>0.99

Of the 100 participants, 5 did not complete the questionnaire in full, leaving data from 95 patients available for NUAS analysis. Examination of NUAS prevalence found a significantly higher prevalence of reported chronic fatigue syndrome (31% vs 10.6%; p = 0.034) and a significantly lower prevalence in reported allergies (37.9% vs 60.6%; p=0.047) in SFPN+ patients without significant differences in total number of NUAS or the frequency of other diagnoses (Table 3).

Table 3:

Associated syndromes of patients with and without a diagnosis of small fiber polyneuropathy

Associated syndrome	SFPN− (n=66) Count (%)	SFPN+ (n=29) Count (%)	P-Value
Number NUAS	4.06 (2.95)	4.66 (3.30)	0.39
CPP	24 (36.4%)	16 (55.2%)	0.12
Vulvodynia	11 (16.7%)	7 (24.1%)	0.41
Endometriosis	14 (21.2%)	10 (34.5%)	0.20
PFD	22 (33.3%)	11 (37.9%)	0.82
Dyspareunia	0 (0%)	2 (6.9%)	0.09
POTS	0 (0%)	1 (3.4%)	0.31
Sjogren’s	2 (3%)	0 (0%)	>0.99
Fibromyalgia	21 (31.8%)	11 (37.9%)	0.64
IBS	23 (34.8%)	14 (48.3%)	0.26
Migraines	30 (45.5%)	8 (27.6%)	0.12
Depression	28 (42.4%)	13 (44.8%)	0.83
Panic Disorder	26 (39.4%)	15 (51.7%)	0.27
CFS	7 (10.6%)	9 (31.0%)	0.034
Allergies	40 (60.6%)	11 (37.9%)	0.047
Asthma	19 (28.8%)	6 (20.7%)	0.46

Finally, there were no significant differences in the prevalence of other comorbidities that have been suggested as potential causes of small fiber polyneuropathy including a history of smoking, diabetes mellitus, thyroid disease, vitamin B12 deficiency, celiac disease, sarcoidosis, any autoimmune/systemic inflammatory disease, or HIV (Table 1).

Discussion:

While pilot studies have reported the prevalence of SFPN status in patients with and without a bladder-centric phenotype⁷ and in HL+ versus HL− patient subgroups,¹¹ this current study represents the largest cohort to date of IC/BPS patients examined for objective evidence of SFPN. Approximately one third (31%) of patients with IC/BPS were found to meet the standard for diagnosis of SFPN which is significantly higher than what was reported in a comprehensive national survey performed in the Netherlands which found a prevalence of SFPN of 0.5% in the general population.¹² Furthermore, a total of 81 patients (81%) in our IC/BPS cohort had IENF densities below the median for their age and sex, reflecting a widespread neurologic abnormality. We found no significant associations in IC/BPS patients with other disease processes that have been linked to SFPN, e.g., diabetes mellitus, autoimmune disease, etc., however up to 50% of cases of isolated SFPN are idiopathic in nature.⁸ The underlying cause of these findings in IC/BPS patients remains undetermined but SFPN presents a novel therapeutic target in this challenging population.

An additional important finding in this study was the observed correlation of SFPN+ status with self-reported chronic fatigue syndrome, which frequently co-occurs with IC/BPS,⁶ especially in those patients with widespread systemic pain.¹³ In this study 31% (9/29) of SFPN+ patients had co-occurring CFS, whereas only 10.6% (7/66) SFPN− patients were CFS+. Our analysis relies on patient self-reporting of previous diagnoses, and it is possible these patients have been incorrectly (or self) diagnosed with CFS as, like IC/BPS, it is a diagnosis of exclusion. Fatigue is a common complaint among patients with IC/BPS,^2,13 and it is possible that SFPN is correlated with increased severity of fatigue without an underlying connection to CFS as a disorder. However, there is also evidence that SFPN may be related to CFS independently of IC/BPS. The symptoms which characterize CFS, i.e., longstanding fatigue, exertional intolerance, and dysautonomia have been proposed to be explained by SFPN wherein altered autonomic control of vasculature leads to either impaired venous return resulting in preload failure or impaired systemic oxygen extraction.¹⁴ This relationship has also been proposed to account for the widespread fatigue and ischemic muscle pain in fibromyalgia^8,15.

The significance of our finding that patients with the broad category of allergies were found to be less likely to have SFPN than those without allergies is not clear. IC/BPS is known to have a strong association with allergies, present at nearly twice the rate as found in the general population.¹⁶ This non-specific term includes allergies to foods, “hay fever”, and skin sensitivity/allergies.¹⁷ Patients have reported that allergens can trigger flares in symptoms,¹⁸ and there is some evidence that increases in pollen counts in the air is associated with symptom flares in patients with IC/BPS.¹⁹ Therefore, the presence of allergies may be a proxy for some aspect of the underlying pathophysiology of IC/BPS, and the absence of allergies may be a phenotypic indicator of a different pathophysiologic origin.

The fact that no NUAS other than allergies and CFS were found to be significantly different between those IC/BPS patients with and without SFPN is noteworthy for multiple reasons. First, these results conflict with our earlier hypothesis (stemming from our prior small cohort study)⁷ that SFPN could be an underlying pathophysiologic link for a non-bladder centric phenotype and the increased systemic symptoms in these patients.³ Secondly, our results conflict with the known association of fibromyalgia with SFPN, which has been found to have evidence of SFPN in ~45% (range of 32-50%) of patients diagnosed by skin biopsy.¹⁵ It is notable that our sample of patients with FM is at the low end of this range (31.8% and 37.9% among SFPN− and SFPN+ groups, respectively). In fact, a limitation of the present study is reporting of NUAS based on patient report. As with all such patient reported data, recall and survey biases could contribute to either overestimation or underestimation of co-occurring NUAS as we did not perform full evaluations of these patients’ symptoms and associated diagnostic criteria. It is likely that some of these diseases are underreported by our patients as we are not regional referral centers that specialize in these disorders. The diagnosis of fibromyalgia in many IC/BPS patients may reflect their widespread systemic pain¹³ and thus rely on a physician focusing on their widespread pain over their IC/BPS symptoms in accordance with their clinical bias.

Our findings contribute to the growing literature regarding neurologic abnormalities in patients with IC/BPS. These patients have increased visceral sensitivity to bladder filling with decreased habituation to repeated stimuli in the pelvic region.²⁰ Furthermore, approximately 75% of IC/BPS patients have widespread systemic pain beyond their pelvis¹³ with an associated characteristic signature and changes to brain structure visualized with functional imaging.²¹ This is reflected in the increased pain sensitivity in the skin overlying the pelvis,²² which in some cases extends to extra-pelvic regions.²³ This ‘central sensitization’ (more recently coined nociplastic pain) has been linked to increased excitatory neurotransmission in brain regions such as the insula.^24,25 Critically, inducing chronic elevations in insular glutamate has been found to lead to a fibromyalgia-like state in mice with concomitant decreases in IENF density,²⁶ thereby offering a potential mechanistic link between these seemingly disparate findings. There is controversy whether the skin biopsy findings in patients with FM reflect true SFPN causing their symptoms or if they are a peripheral marker of the underlying pathophysiology of their disease state (dubbed small fiber pathology [SFP]).¹⁵ The fact that 81% of IC/BPS patients have IENF densities below the median for their age and sex reflects a widespread abnormality in the peripheral small fibers in these patients. Whether they reflect cause or consequence of the underlying IC/BPS pathophysiology, these findings merit further research.

Further evidence of neurologic abnormalities is the fact that IC/BPS patients are known to experience several dysautonomic symptoms with objective evidence of damage to their autonomic sudomotor system, without widespread damage to their cardiovascular autonomic function.²⁷ Isolated SFPN is commonly associated with dysfunction of the autonomic nervous system,⁸ and patients with fibromyalgia and findings of SFPN have more microvascular autonomic symptoms than those without.²⁸ We have previously suggested that SFPN may be contributing to the subtle autonomic system abnormalities found in IC/BPS patients,²⁹ and this association and potential etiologic link requires further research.

IENF density is known to decrease with age as reflected in normative reference values.¹⁰ Additionally, symptomatic SFPN is more commonly diagnosed in the elderly than younger cohorts.¹² It is therefore interesting that in our cohort, SFPN+ patients were nearly 7 years younger than SFPN− patients (average age of 46.55 years vs 52.00; p=0.059), suggesting that there may be age-independent causes of sensory dysfunction involved. However, a larger cohort is necessary to validate this finding.

We had originally reported that the significantly higher prevalence of SFPN in non-bladder-centric patients, who also report higher rates of co-occurring medical conditions, supports the hypothesis that SFPN may be associated with and contributing to the constellation of pain symptoms and syndromes experienced by this patient subgroup.⁷ The original findings and conclusions were derived through data from 11 patients. In the current study, based on an analysis of 100 patients with IC/BPS, we found that 31 were positive for SFPN. Within the SFPN+ IC/BPS patient subgroup, 25/31 (80.6%) were non-bladder-centric (e.g., BC > 400 mL and low prevalence of HL+ (2/31; 6.5%)). We believe the results of this study support the hypothesis that SFPN is common in patients with IC/BPS and is more prevalent in non-bladder-centric IC/BPS patients. It is clear, however, that screening a much larger cohort will be necessary to validate these findings.

Limitations of this observational study included the lack of a control group (i.e., collecting skin biopsies from patients without a clinical diagnosis of IC/BPS) and lack of uniform collection by the same provider when collecting skin biopsies in the operating room.

Finally, screening for this disease is potentially clinically important as some cases of autoimmune SFPN have been successfully treated with intravenous immunoglobulin (IVIG).^8,30 Although there is yet to be a targeted treatment for SFPN, current management strategies include general neuropathic pain treatments such as tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors (SNRIs). Additional treatment options that have been utilized for patients with both FM and SFPN include intravenous lidocaine, IVIG, and other immunomodulatory therapies, but none have been specifically used among patients with IC/BPS and SFPN.⁵ If SFPN is causational for these patients’ pain and/or widespread symptoms, the possibility of a disease modifying treatment should be pursued fully

Conclusions:

Within this large cohort study of patients with IC/BPS, nearly a third of patients were found to have evidence of small fiber polyneuropathy. A higher prevalence of chronic fatigue, and a reduced prevalence of allergies were associated with SFPN in these patients. These data contribute to the growing understanding of neurologic abnormalities in this patient population and may help to explain some of the systemic symptoms these patients experience. Additional research is needed to define the underlying causation and implications of these findings.