Claire C. Yang

Interstitial Cystitis/Painful Bladder Syndrome and Associated Medical Conditions With an Emphasis on Irritable Bowel Syndrome, Fibromyalgia and Chronic Fatigue Syndrome

PURPOSE We characterized and compared the impact of clinical phenotypic associations between interstitial cystitis/painful bladder syndrome and controls in relation to potentially related conditions, particularly irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. MATERIALS AND METHODS Female patients with interstitial cystitis/painful bladder syndrome and controls with no interstitial cystitis/painful bladder syndrome completed a biopsychosocial phenotyping questionnaire battery which included demographics/history form, self-reported history of associated conditions, and 10 validated questionnaires focused on symptoms, suffering/coping and behavioral/social factors. RESULTS Questionnaires were completed by 205 patients with interstitial cystitis/painful bladder syndrome and 117 controls matched for age. Prevalence of self-reported associated condition diagnosis in interstitial cystitis/painful bladder syndrome vs controls was irritable bowel syndrome 38.6% vs 5.2%, fibromyalgia 17.7% vs 2.6% and chronic fatigue syndrome 9.5% vs 1.7% (all p <0.001). In the interstitial cystitis/painful bladder syndrome cohort 50.3% reported no other associated condition, 24.4% had interstitial cystitis/painful bladder syndrome + irritable bowel syndrome only, 2.5% had interstitial cystitis/painful bladder syndrome + fibromyalgia only, 1.5% had interstitial cystitis/painful bladder syndrome + chronic fatigue syndrome only, while 20.2% had multiple associated conditions. As the number of associated conditions increased (ie localized, regional, systemic), pain, stress, depression and sleep disturbance increased while social support, sexual functioning and quality of life deteriorated. Anxiety and catastrophizing remained increased in all groups. Symptom duration was associated with this apparent phenotypic progression. CONCLUSIONS Irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome are more prevalent in patients with interstitial cystitis/painful bladder syndrome than in asymptomatic control subjects, and result in significant impact. There are at least 3 distinct clinical phenotypes based on identification of overlapping syndrome patterns. A suggestion that remains to be proven with longitudinal studies is that there may be progression over time from an organ centric to a regional and finally to a systemic pain syndrome with progression of symptom severity, and deterioration of cognitive and psychosocial parameters.

Effect of amitriptyline on symptoms in treatment naive patients with interstitial cystitis/painful bladder syndrome.

PURPOSE Amitriptyline is frequently used to treat patients with interstitial cystitis/painful bladder syndrome. The evidence to support this practice is derived mainly from a small, single site clinical trial and case reports. MATERIALS AND METHODS We conducted a multicenter, randomized, double-blind, placebo controlled clinical trial of amitriptyline in subjects with interstitial cystitis/painful bladder syndrome who were naïve to therapy. Study participants in both treatment arms received a standardized education and behavioral modification program. The drug dose was increased during a 6-week period from 10 up to 75 mg once daily. The primary outcome was a patient reported global response assessment of symptom improvement evaluated after 12 weeks of treatment. RESULTS A total of 271 subjects were randomized and 231 (85%) provided a global response assessment at 12 weeks of followup. Study participants were primarily women (83%) and white (74%), with a median age of 38 years. In an intent to treat analysis (271) the rate of response of subjects reporting moderate or marked improvement from baseline in the amitriptyline and placebo groups was 55% and 45%, respectively (p = 0.12). Of the subgroup of subjects (207) who achieved a drug dose of at least 50 mg, a significantly higher response rate was observed in the amitriptyline group (66%) compared to placebo (47%) (p = 0.01). CONCLUSIONS When all randomized subjects were considered, amitriptyline plus an education and behavioral modification program did not significantly improve symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. However, amitriptyline may be beneficial in persons who can achieve a daily dose of 50 mg or greater, although this subgroup comparison was not specified in advance.

Psychosocial phenotyping in women with interstitial cystitis/painful bladder syndrome: a case control study.

PURPOSE We characterized and compared psychosocial phenotypes in a female interstitial cystitis/painful bladder syndrome cohort and an age matched cohort without that diagnosis. MATERIALS AND METHODS Female patients with interstitial cystitis/painful bladder syndrome and controls without the condition completed a psychosocial phenotyping questionnaire battery, including a demographics/history form and validated questionnaires focused on a range of presenting symptoms, psychosocial parameters and quality of life. Specific measures included interstitial cystitis symptom and problem index, McGill Pain Questionnaire, Medical Outcomes Study Sleep Scale, Center for Epidemiological Studies Depression Scale, State-Trait Anxiety Inventory, Pain Catastrophizing Scale, Female Sexual Functioning Index and Multidimensional Scale of Perceived Social Support and Medical Outcomes Study Short Form-12 quality of life. Direct comparisons and correlations were made to establish group differences and the strength of associations for psychosocial parameters in patients with interstitial cystitis/painful bladder syndrome. RESULTS Questionnaires completed by 207 patients with interstitial cystitis/painful bladder syndrome were compared to those of 117 controls matched for age, partner status and education. Compared to controls patients reported significantly more pain (total, sensory and affective), worse physical quality of life, increased sleep dysfunction, depression, catastrophizing, anxiety, stress and moderately more sexual/social function problems. These suffering, coping and social parameters correlated with the degree of general pain but stress, anxiety, depression and catastrophizing further correlated with IC specific symptoms and strongly with decreased quality of life. Pain was strongly associated with physical quality of life, while depression, catastrophizing and stress, and to a lesser extent social support were associated with poor mental quality of life. CONCLUSIONS Patients with interstitial cystitis/painful bladder syndrome have significant cognitive and psychosocial alterations compared to controls.

The MAPP research network: design, patient characterization and operations

BackgroundThe “Multidisciplinary Approach to the Study of Chronic Pelvic Pain” (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network’s central study and common data elements are described.MethodsThe primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as “positive” controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.DiscussionThe MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.Trial registrationClinicalTrials.gov identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”. http://clinicaltrials.gov/show/NCT01098279

PERIPHERAL DISTRIBUTION OF THE HUMAN DORSAL NERVE OF THE PENIS

PURPOSE The integrity of the dorsal nerve of the penis is crucial for normal erectile and ejaculatory function. To our knowledge a description of this nerve along the phallus has not been formally described. We illustrate the distribution of the dorsal nerve of the penis to the penile shaft, anterior urethra and glans. MATERIALS AND METHODS Neuroanatomical dissections were performed on 28 cadaver penis specimens. Electrodiagnostic testing was conducted on 10 healthy male subjects to confirm the anatomical findings. RESULTS The dorsal nerve of the penis consists of 2 populations of axons, one to innervate the penile shaft and urethra, and the other to innervate the glans. Stimulation of the urethra resulted in responses recorded in the main trunk of the dorsal nerve of the penis and stimulation of the nerve evoked responses within the urethra. Bulbocavernosus muscle contraction was elicited following urethral stimulation. CONCLUSIONS Urethral innervation by the dorsal nerve of the penis supports the view that urethral afferent impulses are a component of reflex ejaculatory activity. The pattern of glanular innervation by the dorsal nerve of the penis identifies the glans as a sensory end organ for sexual reflexes. The undulating character of the dorsal nerve of the penis is a mechanism by which the nerve can accommodate to significant changes in penile length with erection. Electrodiagnostic studies of the dorsal nerve of the penis should be modified to consider the anatomical findings.

Sexually responsive vascular tissue of the vulva

To better understand the genital changes that occur during the female sexual response, using a gross anatomical and histological study of the vascular tissue of the vulva, supplemented with magnetic resonance imaging (MRI).

Cortical evoked potentials of the dorsal nerve of the clitoris and female sexual dysfunction in multiple sclerosis

PURPOSE We evaluated whether disrupting genital central nervous system pathways is associated with subjective reports of sexual dysfunction in women with multiple sclerosis. MATERIALS AND METHODS We performed pudendal somatosensory evoked potential testing in and had sexual questionnaires completed by 14 women with a mean age of 47 years who had multiple sclerosis. RESULTS The mean expanded disability status score was 5. All but 1 woman reported the desire for sexual intercourse. There was a high rate of dissatisfaction with their sex life and all study participants had concomitant bladder and bowel function problems. The most common sexual complaint was difficult or no orgasm, which was statistically associated with abnormalities or absence of 1 or both pudendal cortical evoked potentials. Fatigue and arousal disorders were also common. CONCLUSIONS Women with multiple sclerosis have a high self-reported rate of sexual dysfunction, which decreases quality of life. Electrodiagnostic data imply that pudendal somatosensory innervation is necessary for normal female orgasmic function. More study is needed to confirm these findings.

Innervation of the human glans penis.

PURPOSE We demonstrate the innervation of the glans penis through nerve blockade and electrophysiological tests. MATERIALS AND METHODS The study was conducted in 14 healthy, sexually potent volunteers. The dorsal nerves of the penis were anesthetized bilaterally with lidocaine. Electrophysiological testing was performed by stimulating the dorsal nerve of the penis at the penile base distal to the block and recording action potentials at the glans. RESULTS Dorsal nerve of the penis block resulted in anesthesia of the dorsal, lateral and glanular aspects of the penis. The ventral surface, including the frenulum, was intact to pinprick sensation. Dorsal nerve of the penis stimulation resulted in responses from the corona, dorsal and ventral mid glans, and penile shaft. Frenular responses were less consistently obtained. The most common recorded pattern was a monophasic waveform representing the arrival of a standing potential at a nerve terminal. Latencies were progressively longer with increasing distance from the point of stimulation with the longest latencies measured at the frenulum. Amplitudes of the responses decreased with increasing distance from the point of stimulation. CONCLUSIONS The dorsal nerve of the penis innervates the glans, including the frenulum which is also innervated by a branch of the perineal nerve. Branches of the dorsal nerve of the penis extend through the glans ventrolaterally. Electrical representation of glanular innervation reveals the glans to be filled with nerve endings supporting its function as a sensory structure.

Magnetic Resonance Imaging and the Female Sexual Response: Overview of Techniques, Results, and Future Directions

INTRODUCTION Magnetic resonance imaging (MRI) is becoming a frequently used tool in the study of sexual physiology and neurophysiology. AIM This report reviews various MRI methods used to study the female sexual arousal response. METHODS Retrospective review of pertinent literature. RESULTS Dynamic genital MRI studies enable the visualization of the physiologic arousal response that provides the direct observation of the time course and magnitude of this response, along with the variability that appears to occur in women with sexual arousal disorder. Functional brain MR studies are described and summarized along with an overview of what we have learned. Finally, the speculation on how we may be able to use MRI technology to better understand the female sexual response and to help in validating new drug treatments or in devising new treatment strategies for sexual dysfunction is also presented. CONCLUSIONS Neuroimaging has already been proven as an invaluable research tool to study the sexual response in women both in the pelvis as well as within the brain. Using these techniques, major inroads are being made to improve the understanding of the sexual arousal process in women.

MRI of female genital and pelvic organs during sexual arousal

We utilized contrast enhanced magnetic resonance imaging (MRI) to delineate the anatomy of the female genital and pelvic organs during sexual arousal. Eleven healthy pre-menopausal women and eight healthy post-menopausal women underwent MRI of the pelvis while watching an erotic video. A 1.5 Tesla MR system was used to produce T1-weighted images following administration of MS-325, a gadolinium-based blood pool contrast agent. Selected structural dimensions and enhancement were measured prior to and during sexual arousal. In both pre- and post-menopausal subjects, vestibular bulb and labia minora width increased with arousal. Enhancement measurements increased in the bulb, labia minora and clitoris in both pre- and post-menopausal subjects, and in the vagina in pre-menopausal subjects. There were no marked changes in size or enhancement of the labia majora, urethra, cervix, or rectum during sexual arousal in pre- or post-menopausal subjects. Using MRI, we observed specific changes in the female genitalia and pelvic organs with sexual arousal, in both pre- and post-menopausal women. MRI can potentially provide detailed anatomical information in the assessment of female sexual function, particularly with regard to changes in blood flow.