Subbarao V. Yalla

Structural basis of geriatric voiding dysfunction. III: Detrusor overactivity

Detrusor overactivity in the absence of outlet obstruction is common in the elderly. The few available studies on structure of the overactive detrusor generally have dealt only with its innervation. We conducted a prospective study to examine the ultrastructure of muscle cells, interstitium and nerves of the detrusor in biopsies from 35 elderly subjects to identify structural correlates of various urodynamically defined forms of voiding dysfunction. A distinctive dysjunction structural pattern was identified blindly in 15 detrusor biopsies. These patterns matched 12 women and 3 men 66 to 96 years old (mean age 79 years) who were segregated independently as a detrusor overactivity group by prospective urodynamic evaluation. All but 1 patient had incontinence and/or other symptoms, and none had diabetes or a significant neurological deficit. The dysjunction pattern was characterized by moderately widened intercellular spaces, scarce intermediate muscle cell junctions, abundant distinctive protrusion junctions and ultra-close cell abutments, and absence of profiles characteristic of enlarged hypertrophic cells. There was superimposed widespread degeneration of muscle cells and axons in 8 specimens, which matched the subgroup of patients with impaired detrusor contractility. The remaining 7 specimens with no degeneration matched the patients with normal contractility. Protrusion junctions and abutments are proposed as a possible manifestation of a process of muscle cell de-differentiation associated with natural aging, as well as the mediator in overactive detrusor of electrical coupling of muscle cells, in lieu of their normal mechanical coupling curtailed by marked reduction of intermediate cell junctions. On this basis, a bipartite myogenic mechanism is proposed to account for the involuntary contractions yet allow neurally triggered unitary voiding contractions in the overactive detrusor. Superimposed degeneration is proposed as the structural basis of impaired detrusor contractility, when also present.

Structural basis of geriatric voiding dysfunction. II. Aging detrusor: normal versus impaired contractility.

Little information on the structural norm of the aging detrusor is currently available. To gain insight into the pathophysiology of geriatric voiding dysfunction, detrusor biopsies were examined by electron microscopy to identify structural correlates of specific, urodynamically defined abnormalities of vesical function in 35 elderly subjects. Prospective urodynamic grouping of the subjects and segregation of the detrusor specimens by ultrastructural features were done independently and blindly. One structural pattern so identified, the dense band pattern, matched the urodynamic group with neither detrusor overactivity nor bladder outlet obstruction. This neither group included 11 women and 2 men 65 to 91 years old (mean age 76 years). Except for 2 patients with minimal stress incontinence, all were symptom-free. None of the patients had diabetes or a neurological deficit. Urodynamically, 10 patients had impaired and 3 had normal detrusor contractility. The dense band structural pattern was characterized by overall normal configuration of muscle cells and cell junctions, sarcolemma (muscle cell membrane) dominated by dense bands with depleted caveolae in interposed zones and slight widening of spaces between muscle cells with little-collagen content. Specimens from the 10 subjects with impaired contractility displayed, in addition, widespread degeneration of muscle cells and axons. The remaining 3 specimens, without degeneration, matched the subjects with normal contractility, who were continent and symptom-free. It is proposed that the dense band pattern represents the structural norm of aging detrusor, heralds a process of muscle cell de-differentiation in the detrusor accompanying natural aging, and may affect exchange and storage of ions involved in the excitation-contraction coupling mechanism of muscle cells through depletion of caveolae. Widespread degeneration of muscle cells and axons, superimposed on the dense band pattern, is proposed as the structural correlate of impaired detrusor contractility in the aging detrusor.

Bladder Cancer and Squamous Metaplasia in Spinal Cord Injury Patients

The influence of long-term indwelling urethral catheterization was studied by random bladder and urethral biopsies in 62 spinal cord injury patients. Six patients (10 per cent) had diffuse squamous cell bladder carcinoma, 4 of whom had no tumor visible endoscopically. Five of the patients with cancer were among 25 patients (20 per cent) managed with an indwelling urethral catheter for more than 10 years (average 21 years, range 15 to 30 years). The other cancer patient had been free of the catheter for 27 years after suprapubic cystotomy for 4 years. Gross and microscopic hematuria was associated with cancer. Squamous metaplasia of the bladder was significantly greater in patients who had been catheterized for more than 10 years (80 per cent), compared to those catheterized for less than 10 years (42 per cent) and patients without catheters (20 per cent). Urethral squamous metaplasia increased slightly in long-term catheterization patients. Urinary infection was universal and did not distinguish patients with inflammation, metaplasia or cancer. Therefore, the duration of indwelling catheterization seems to be the major factor in squamous changes in these patients.

Structural basis of geriatric voiding dysfunction. IV. Bladder outlet obstruction.

Several aspects of the pathogenesis of voiding dysfunction in bladder outlet obstruction remain unresolved. The structural basis of obstructive versus nonobstructive dysfunction was investigated in a prospective ultrastructural/urodynamic study of 35 elderly subjects of comparable age. Detrusor structure was examined by electron microscopy, with blinded clinical and urodynamic information. Seven detrusor specimens were segregated by a distinctive myohypertrophy, structural pattern, which matched with 6 male and 1 female subjects 72 to 96 years old (mean age 83) who had urodynamically proved outlet obstruction. This pattern was characterized by widely separated muscle cells with reduction of intermediate cell junctions, collagenosis, that is abundant collagen plus some elastic fibers, in the markedly widened spaces between individual muscle cells and abundant profiles characteristic of enlarged, hypertrophic muscle cells. Superimposed degeneration of muscle cells and axons in 6 specimens matched those of 5 men and 1 woman who had impaired detrusor contractility. In 3 specimens there were also abundant protrusion junctions and ultra-close abutments; these matched those of 2 men and 1 woman with obstruction plus detrusor overactivity. Observations on the degree of bladder trabeculation in the entire population of 35 subjects are presented. It is concluded that bladder outlet obstruction is associated with changes in detrusor structure that can account for the resultant voiding dysfunction. Features of the myohypertrophy pattern, with or without superimposed degeneration, can explain overall weakness of the obstructed detrusor despite hypertrophy of its cells. Protrusion junctions and abutments probably mediate electrical coupling of muscle cells leading to involuntary contractions in the overactive (unstable) obstructed detrusor. Excessive deposits of elastic fibers (hyperelastosis) between widely separated muscle cells and in interstitium are suggested as the probable structural basis for increased bladder distensibility and chronic retention.

Correlation of American Urological Association Symptom Index With Obstructive and Nonobstructive Prostatism

The precise role of the American Urological Association (AUA) symptom index in the management of benign prostatic hyperplasia (BPH) is not well established. The AUA symptom index has been recommended only for quantifying the symptoms of BPH but not for its diagnosis. However, to our knowledge the ability to discriminate obstructive from nonobstructive BPH using the AUA symptom index has never been investigated. To establish the relationship between the AUA symptom index and prostatic obstruction 125 men (mean age 67.7 +/- 8.4 years) with voiding dysfunction presumably related to BPH were analyzed. Patients were given the AUA symptom questionnaire, following which video urodynamic studies were done, including micturitional urethral pressure profilometry for specifically diagnosing outlet obstruction. The patients were divided into 2 groups: group 1-78 with primary BPH dysfunction and group 2-47 with prostatism of ambiguous etiology. The mean AUA symptom index in group 1 (15.5 +/- 7.1) was not statistically different from that in group 2 (14.8 +/- 7.9). In both groups the mean AUA symptom index in the patients with obstruction (15.3 +/- 7.2 for group 1 and 13.9 +/- 7.9 for group 2) was not statistically different from that in the nonobstructed group (17.0 +/- 5.4 and 16.1 +/- 7.9, respectively). Of the severely symptomatic patients 22% did not have obstruction whereas all mildly symptomatic patients did. No significant correlations were found between the severity of obstruction and the AUA symptom index in either group. These observations indicate that the AUA symptom index cannot discriminate obstructed from nonobstructed BPH cases, not all severely symptomatic BPH patients will have outlet obstruction, a significant proportion of mildly symptomatic BPH patients can have outlet obstruction and voiding dysfunctions in elderly men, regardless of the etiology, produce similar symptoms.

Structural Basis of Geriatric Voiding Dysfunction. I. Methods of a Prospective Ultrastructural/Urodynamic Study and an Overview of the Findings

Voiding dysfunctions are common in the elderly. Yet the pathogenesis and pathophysiology have remained largely unknown. To date there has been little information on structure of the aging detrusor. To gain insight into the structural basis of voiding dysfunction in the elderly, we examined detrusor biopsy specimens by electron microscopy. The specimens were obtained from 24 women and 11 men 65 to 96 years old (mean age 79 years) who were carefully selected by detailed clinical and neurological examination. Symptom-free subjects were particularly sought to identify those who might provide the structural/functional norm of aging detrusor. Comprehensive urodynamic study was performed in all subjects. A transurethral detrusor biopsy was obtained and processed to study ultrastructure of the smooth muscle, intrinsic nerves and interstitium. Subjects were segregated purely by urodynamic findings, regardless of symptoms, into detrusor overactivity, outlet obstruction, obstruction plus overactivity and neither (that is no obstruction and no overactivity) groups, each with a subgroup of normal and another of impaired contractility. Specimens were segregated blindly and independently by ultrastructural features into dysjunction, myohypertrophy, myohypertrophy plus dysjunction and dense band patterns, each with a subset with widespread degeneration of muscle cells and nerves, and another with minimal or no degeneration. When codes were broken, each structural pattern (and subset) matched with a specific urodynamic group (and subgroup)--with no overlap. The dysjunction pattern matched with overactivity, the myohypertrophy pattern with obstruction, the myohypertrophy plus dysjunction pattern with obstruction plus overactivity, and the dense band pattern with the neither group. Structural subsets of widespread degeneration matched with impaired contractility subgroups, and subsets with minimal or no degeneration matched with normal contractility subgroups. These observations identify specific structural bases of the major forms of geriatric voiding dysfunction, provide important insights into their pathogenesis, and introduce detrusor biopsy as a potentially valuable tool in their diagnosis and clinical management.

Detrusor-Urethral Sphincter Dyssynergia

Inappropriate contraction or failure of relaxation of either the internal (smooth muscle) or external (striated muscle) urethral sphincter or both coincident with detrusor contraction results in a micturitional disorder known as detrusor-urethral sphincter dyssynergia. Based on our clinical experience with more than 200 spinal cord subjects and serial urodynamic observations on some of these individuals from the time of injury, various grades of dyssynergia (1 to 3) were recognized. The duration and completeness of suprasacral cord injury essentially determined the degree of dyssynergia. Internal sphincter dyssynergia was encountered less often in this group. A review in relation to pathophysiology and management of this micturitional dysfunction is presented.

Evaluation of cranberry tablets for the prevention of urinary tract infections in spinal cord injured patients with neurogenic bladder.

Study Design:Randomized, double blind, placebo-controlled trial with a crossover design.Objective:To evaluate cranberry tablets for the prevention of urinary tract infection (UTI) in spinal cord injured (SCI) patients.Setting:Spinal Cord Injury Unit of a Veterans Administration Hospital, MA, USA.Methods:Subjects with spinal cord injury and documentation of neurogenic bladder were randomized to receive 6 months of cranberry extract tablet or placebo, followed by the alternate preparation for an additional 6 months. The primary outcome was the incidence of UTI.Results:Forty-seven subjects completed the trial. We found a reduction in the likelihood of UTI and symptoms for any month while receiving the cranberry tablet (P<0.05 for all). During the cranberry period, 6 subjects had 7 UTI, compared with 16 subjects and 21 UTI in the placebo period (P<0.05 for both number of subjects and incidence). The frequency of UTI was reduced to 0.3 UTI per year vs 1.0 UTI per year while receiving placebo. Subjects with a glomerular filtration rate (GFR) greater than 75 ml min−1 received the most benefit.Conclusion:Cranberry extract tablets should be considered for the prevention of UTI in SCI patients with neurogenic bladder. Patients with a high GFR may receive the most benefit.Sponsorship:Spinal Cord Research Foundation, sponsored by the Paralyzed Veterans of America

Micturitional Static Urethral Pressure Profile: A Method of Recording Urethral Pressure Profile During Voiding and the Implications

Using a tri-lumen graduated 10F catheter we attempted to record static (lateral) pressures at successive points in the urethra, synchronous with intravesical pressure recorded during voiding. Based on our understanding of the essential physical principles described by many earlier investigators we attempted numerous studies in a predominantly male population, which included normal male and female subjects, and male subjects with bladder outlet obstruction of varied etiology. We also attempted to evaluate the effects of the Valsalva maneuver, augmenting the detrusor contraction and artificial distal obstruction (penile compression) on the micturitional static urethral pressure profiles. Studies also were performed to compare the static urethral pressure profiles obtained with the anterograde (catheter withdrawal) and with the retrograde (catheter insertion during voiding) techniques. All of these studies have helped in understanding the various factors, such as double obstructions, artifactual catheter obstructions and incompetent distal sphincter mechanisms, in the interpretation of the micturitional static urethral pressure profile.

URODYNAMIC CHARACTERIZATION OF NONOBSTRUCTIVE VOIDING DYSFUNCTION IN SYMPTOMATIC ELDERLY MEN

PURPOSE The pathogenesis of lower urinary tract symptoms in men without bladder outlet obstruction has not been well characterized. Therefore, we defined the urodynamic abnormalities associated with symptomatic nonobstructive voiding dysfunction, and determined the relationship between age and type of dysfunction. MATERIALS AND METHODS Video urodynamic studies of symptomatic men without outlet obstruction were examined. The criterion for a normal bladder outlet was a pressure gradient across the prostatic urethra of 5 cm. water or less in the absence of distal stricture. A maximum isometric contraction pressure less than 60 cm. water was regarded as impaired detrusor contractility. Detrusor instability was defined as involuntary detrusor contractions during filling or the inability to suppress a detrusor contraction after initiation of flow. Patients were categorized into 4 groups based on the urodynamic findings. RESULTS Of 193 men (mean age 69.6+/-10.5 years) 40.9% had detrusor instability (group 1), 31.1% had impaired contractility (group 2), 10.8% had detrusor instability and impaired contractility (group 3), and 17.1% were urodynamically normal (group 4). Average patient age was significantly lower in group 4 than all other groups. Bladder capacity was lowest in group 1, and group 3 had the lowest voiding efficiency. Maximum flow rate, bladder compliance and symptom scores were not different among the 4 groups. The prevalence of detrusor instability with and without impaired contractility increased, while the proportion of patients without urodynamic abnormalities decreased with age. Bladder contractility did not correlate with age. CONCLUSIONS The nonobstructed patient population comprises several groups that are functionally distinct while symptomatically similar. Thus, treatment of nonobstructed cases based on symptoms may lead to inappropriate pharmacological therapy and unsuccessful clinical outcomes.