Irregular bladder shapes identified in women with overactive bladder: an ultrasound nomogram.

In this study, an ultrasound-based bladder shape nomogram was developed using data from women without overactive bladder (OAB) and tested in women with OAB to identify irregular bladder shapes. The goal was development of a nomogram that can ultimately be used for non-invasive identification of a bladder shape-associated OAB phenotype. Transabdominal 3-dimensional (3D) bladder ultrasound images were collected at 1-minute intervals during urodynamics studies and at 5-10-minute intervals during oral hydration studies. These prospective studies enrolled women with and without OAB based on International Consultation on Incontinence questionnaire on OAB (ICIq-OAB) question 5a (OAB 5a≥2, without OAB 5a<2). Bladder perimeters were manually traced and refined using GE 4D-View software. Nomograms for the transverse, sagittal and coronal perimeter-volume relationships were developed for women without OAB. A power model was used to approximate upper and lower nomogram bounds with 95% confidence intervals. Nomograms were tested using data from women with OAB, and each participant was classified as having an irregular bladder shape based on the number of perimeter values outside the nomogram bounds. Nomograms were developed using 533 images from 27 women without OAB (14 from urodynamics and 13 from hydration studies) and were tested using 264 images from 24 women with OAB (16 urodynamics and 8 hydration). The sagittal perimeter nomogram provided the best results, with irregular sagittal perimeters identified in 6/24 (25%) women with OAB and 0/27 (0%) without OAB. An irregular sagittal perimeter was significantly associated with OAB (P<0.05). Ultrasound-based nomograms may enable feasible, non-invasive identification of a subgroup of women with bladder shape-associated OAB.

Comparison of Sensation Event Descriptors in Participants with Overactive and Normal Bladders during Non-Invasive Hydration Studies.

PURPOSE: Despite the importance of alterations in bladder sensation, objective metrics to characterize sensation outside of urodynamics remain limited. A real-time sensation meter enables recording of sensation event descriptors throughout filling. The purpose of this study was to evaluate the differences in sensation event descriptor patterns between normal participants and those with OAB. METHODS: Normal and OAB participants were enrolled from responses to the ICIq-OAB survey question on urgency (Q5a: 0 vs. ≥ 3). Real-time bladder sensation on a 0%-100% scale was recorded on a validated tablet sensation meter throughout two fill-void cycles. The first and second fills were considered "slow" and "fast" respectively. After each sensation meter change (sensation event), a pop-up screen asked participants to characterize sensation with one or more of these descriptors: "tense," "pressure," "tingling," "painful," and/or "other." Oral hydration was achieved by rapid consumption of 2L G2® Gatorade. RESULTS: Data from 29 participants (12 normal/17 OAB) were analyzed. The rate of filling from bladder volume and fill duration, was greater for the fast fill in both groups. In the slow fill, "tingling" (64 ± 3% OAB vs. 77 ± 3% normal, p=0.008) and "tense" (78 ± 3% OAB vs. 94 ± 1% normal, p<0.001) occurred at lower sensations in OAB participants. CONCLUSION: During only the slow fill, OAB individuals experience the sensation descriptors of "tingling" and "tense" at earlier sensations than normal individuals. Therefore, this non-invasive method to evaluate real-time sensation descriptors during filling may identify important sensation patterns and improve understanding and phenotyping of OAB.

Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy.

OBJECTIVE: To determine the utility of skin biopsies as a biomarker of disease severity in subjects with amyloid neuropathy. METHODS: Five groups of patients were studied: (1) transthyretin (TTR) familial amyloidotic polyneuropathy (FAP; n = 20), (2) TTR mutation carriers without peripheral neuropathy (TTR-noPN; n = 10), (3) healthy controls (n = 20), (4) diabetic neuropathy disease controls (n = 20), and (5) patients with light-chain (AL) amyloid (n = 2). All subjects underwent neurological examination and 3mm skin biopsies. Sections were stained with anti-PGP9.5, anti-TTR, and Congo red. Intraepidermal (IENFD), sweat gland (SGNFD), and pilomotor nerve fiber densities (PMNFD) were measured. Correlations between the amount of amyloid present (amyloid burden), fiber subtype, and Neuropathy Impairment Score in the Lower Limbs (NIS-LL) were evaluated. RESULTS: IENFD, SGNFD, and PMNFD were all significantly reduced in TTR-FAP patients versus healthy controls, whereas TTR-noPN subjects had intermediate reductions. Lower nerve fiber densities were associated with NIS-LL (p < 0.001). Congo red staining revealed brilliant red amyloid deposits confirmed by apple-green birefringence within dermal collagen, sweat glands, and arrector pili that engulfed axons. The diagnostic sensitivity and specificity to detect amyloid in skin were 70% and 100%. Both AL amyloidosis and 2 of 10 TTR-noPN subjects were Congo red-positive. Amyloid burden correlated with IENFD (r = -0.63), SGNFD (r = -0.67), PMNFD (r = -0.50), and NIS-LL (r = -0.57). Wild-type TTR staining was less prominent in TTR-FAP patients. INTERPRETATION: Cutaneous amyloid was detected in 70% of TTR-FAP and 20% of TTR-noPN subjects. Amyloid burden correlated strongly with reductions in IENFD, SGNFD, PMNFD, and NIS-LL. Skin is an attractive tissue to establish an amyloid diagnosis, and amyloid burden has potential as a biomarker to detect treatment effect in TTR-FAP drug trials. Ann Neurol 2017;82:44-56.

Sensory and autonomic function and structure in footpads of a diabetic mouse model.

Sensory and autonomic neuropathy affects the majority of type II diabetic patients. Clinically, autonomic evaluation often focuses on sudomotor function yet this is rarely assessed in animal models. We undertook morphological and functional studies to assess large myelinated and small unmyelinated axons in the db/db type II diabetes mouse model. We observed that autonomic innervation of sweat glands in the footpads was significantly reduced in db/db mice compared to control db/+ mice and this deficit was greater compared to reductions in intraepidermal sensory innervation of adjacent epidermis. Additionally, db/db mice formed significantly fewer sweat droplets compared to controls as early as 6 weeks of age, a time when no statistical differences were observed electrophysiologically between db/db and db/+ mice studies of large myelinated sensory and motor nerves. The rate of sweat droplet formation was significantly slower and the sweat droplet size larger and more variable in db/db mice compared to controls. Whereas pilocarpine and glycopyrrolate increased and decreased sweating, respectively, in 6 month-old controls, db/db mice did not respond to pharmacologic manipulations. Our findings indicate autonomic neuropathy is an early and prominent deficit in the db/db model and have implications for the development of therapies for peripheral diabetic neuropathy.