Ahmad Elbadawi

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.

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.

Acute Biochemical and Functional Alterations in The Partially Obstructed Rabbit Urinary Bladder

Rapid structural and functional alterations have been noted in several models of partial outlet obstruction. To better characterize the rapid progression of alterations, the partially obstructed urinary bladders of mature NZW male rabbits were studied at 1, 3, 5, 7 and 14 days of outlet obstruction with respect to muscarinic receptor density, DNA, RNA, lipid and hydroxyproline content. Functional characteristics were assessed by measuring the in vitro response of the whole bladder to cholinergic and field stimulation. Wet weight increased eight-fold by day 7, decreasing to four-fold at day 14. Receptor density decreased by 50% by day 1 and remained low throughout. Although DNA concentration varied only slightly from controls, RNA increased four-fold by day 7. Hydroxyproline concentration per mg. tissue decreased in the obstructed bladder, yet total hydroxyproline content of the obstructed bladder significantly increased. Total lipids increased significantly during day 3 through 7 and decreased by day 14. Cystometry revealed a large capacity low pressure system at day 1 which rapidly changed to a low compliance system of lesser volume by day 14. Bladder emptying was significantly impaired in all obstructed specimens. Additionally, electrical field stimulation was significantly less effective than cholinergic stimulation in effecting bladder emptying. The above findings suggest that rapid changes in biochemical parameters occur during the early stage of acute obstruction which may in part be secondary to metabolic or inflammatory alterations in the detrusor. It additionally suggests that the myogenic alterations in partial outlet obstruction are rapid and partially adaptive, while neurogenic alterations appear degenerative and display a lesser degree of short term adaptation.

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.

ROLE OF OVARIAN HORMONES IN THE PATHOGENESIS OF IMPAIRED DETRUSOR CONTRACTILITY: EVIDENCE IN OVARIECTOMIZED RODENTS

PURPOSEnAlthough detrusor hyperactivity with impaired contractility is a common urodynamic finding in elderly subjects, to our knowledge its pathogenesis remains unknown. Biopsy studies indicate that subjects with detrusor hyperactivity and impaired contractility have ultrastructural evidence of dysjunction and degeneration patterns in isolated detrusor hyperactivity and impaired contractility, respectively. Based on the known cellular effects of estrogen we postulated that declines in ovarian hormone production may contribute to the pathogenesis of detrusor hyperactivity with impaired contractility.nnnMATERIALS AND METHODSnMature 13 to 14-month-old female Fisher 344 rats were studied 4 months after bilateral ovariectomy or sham surgery. Detrusor structure was evaluated by electron microscopy and contractility was evaluated by muscle strip studies.nnnRESULTSnAfter bilateral ovariectomy detrusor smooth muscle decreased by 25% with a 12% decrease in the number of nucleated muscle profiles and degenerative changes in many axons. Muscle strips from bilaterally ovariectomized animals generated 40% to 50% less tension per strip in response to carbachol than strips of equal size from sham operated animals with no apparent change in muscarinic receptor affinity.nnnCONCLUSIONSnBilateral ovariectomy resulted in many changes of the degeneration ultrastructural pattern but in none of the characteristic features of the dysjunction pattern. Our results indicate that the mature rodent detrusor and its innervation are sensitive to prolonged ovarian hormonal deficiency, contributing to impaired contractility in rodents. Future studies are required to establish whether estrogen has a role in the degeneration ultrastructural pattern or impaired contractility in humans.

Structural Basis of Geriatric Voiding Dysfunction. VII. Prospective Ultrastructural/Urodynamic Evaluation of Its Natural Evolution

PURPOSEnIn cross-sectional studies ultrastructure of geriatric detrusors consistently correlates with their urodynamic behavior. This study was conducted to determine whether the ultrastructural observations were stable with time, changed in concert with urodynamic change and predicted or preceded such change.nnnMATERIALS AND METHODSnTwenty-three elderly subjects underwent clinical and urodynamic evaluation plus endoscopic detrusor biopsy with ultrastructural study. The subjects were grouped according to urodynamic status. All were followed for up to 67 months and the same studies were repeated once in 19 (mean followup 27 months) and twice in 4 (mean followup 42 months) subjects. Biopsies (50) were classified according to their distinctive ultrastructural patterns without knowledge of clinical and urodynamic information. After all cases were studied, ultrastructural and urodynamic observations were correlated.nnnRESULTSnUltrastructural and urodynamic diagnoses matched in all 23 cases at baseline. After 1 followup period both diagnoses were unchanged in 16 (70%) and both changed concordantly in 7 (30%), as expressed by progression of ultrastructural features with new development or increased severity of the associated dysfunction. Auxiliary ultrastructural features underwent some change as well. One of 4 subjects with 2 followup studies had the same ultrastructural and urodynamic diagnoses, while in the other 3 complete dysjunction pattern developed with detrusor overactivity after the first followup and both remained unchanged after the second study.nnnCONCLUSIONSnUltrastructure of the detrusor corresponds perfectly to its urodynamic behavior with time whether the latter remains stable or changes. Although we cannot as yet determine the temporal sequence of changes in detrusor ultrastructure and function, the change in the former is clearly not a mere result of long-standing change in the latter. Auxiliary ultrastructural features may represent transitional changes that precede development of the ultrastructural patterns and the corresponding urodynamic abnormalities.

STRUCTURAL BASIS OF GERIATRIC VOIDING DYSFUNCTION. VI. VALIDATION AND UPDATE OF DIAGNOSTIC CRITERIA IN 71 DETRUSOR BIOPSIES

PURPOSEnRefined criteria of distinctive patterns of detrusor ultrastructure in geriatric voiding dysfunctions have been developed as standard protocols for pathological evaluation of detrusor biopsies. This study was performed to test completeness and routine applicability of these protocols, corroborate our original ultrastructural/urodynamic correlations in larger material and identify subtle correlations that may have been elusive in our original study of 35 cases.nnnMATERIALS AND METHODSnA total of 71 endoscopic detrusor biopsies was obtained from 44 elderly subjects grouped following comprehensive clinical and urodynamic evaluation into those with normal aging bladder, detrusor overactivity, impaired detrusor contractility, bladder outlet obstruction or a combination. Biopsies were evaluated ultrastructurally and randomly, and blinded to clinical information. Using standard protocols the primary ultrastructural pattern(s) was identified, additional auxiliary features were recorded and pathological diagnoses were made. Biopsies were grouped accordingly, still blindly, and correlated with urodynamic groups determined independently prior to biopsy.nnnRESULTSnOur observations confirmed that the standard protocols are complete and readily applicable to routine ultrastructural evaluation of detrusor biopsies. They corroborated our previously reported ultrastructural/urodynamic matching of the biopsies in every case and revealed new constant features of the normally aging detrusor. We identified ultrastructural correlates distinguishing moderate and severe from mild or borderline (but not moderate from severe) impairment of detrusor contractility.nnnCONCLUSIONSnThe proposed protocols are consistently applicable to the routine pathological diagnosis of geriatric voiding dysfunction in detrusor biopsies. A diagnostic algorithm was developed to serve as a practical guide for making such diagnoses, and gaining insights into the pathophysiology of geriatric and possibly other voiding dysfunctions.

Structural basis of neurogenic bladder dysfunction. III. Intrinsic detrusor innervation.

PURPOSEnWe studied the ultrastructure of intrinsic detrusor innervation in long-standing neurogenic bladder dysfunction in the human.nnnMATERIALS AND METHODSnEndoscopic or open detrusor biopsies were obtained from 15 female and 31 male patients 7 to 96 years old who had hyperreflexic neurogenic bladder dysfunction for less than 1 to 43 years. Of the patients 9 had meningomyelocele, 25 had spinal cord injury and 12 had a brain disorder. Changes in intrinsic detrusor nerves were evaluated by electron microscopy qualitatively and quantitatively according to predefined criteria.nnnRESULTSnAxonal degeneration was observed in 44 of the 45 biopsies with discernible intrinsic nerves. Structurally normal axons were 5(1/2) or 4 times more common in brain disorder than meningomyelocele or spinal cord injury group biopsies (median 33%, 6%, 8%, respectively). Axonal regeneration, not encountered in nonneuropathic dysfunctional detrusors, was observed in restricted distribution in most biopsies (76%) and was independent of the duration of neurogenic bladder dysfunction. Axon sprouts were observed in 17 biopsies (38%), and copeptidergic axons formed 20% (median per biopsy) of discernible axon profiles in contrast to less than 1% in normal detrusor. Activated Schwann cells were observed in all but 1 biopsy. The axonal changes were not associated with the level or degree of spinal cord lesion in patients with meningomyelocele or spinal cord injury.nnnCONCLUSIONSnCombined degeneration and regeneration is the characteristic change in intrinsic nerves of detrusor in upper motoneuron neurogenic bladder dysfunction. The observed changes offer the possibility of clinically recognizing neuropathic contribution to a dysfunctional detrusor, as well as the potential to distinguish its spinal versus supraspinal etiology.

Structural Basis of Geriatric Voiding Dysfunction. V. Standardized Protocols for Routine Ultrastructural Study and Diagnosis of Endoscopic Detrusor Biopsies

PURPOSEnPrevious ultrastructural and clinical studies have established criteria for distinctive ultrastructural patterns in the normal, overactive, hypocontractile and obstructed detrusor of the elderly. This study was conducted to standardize procedures of detrusor biopsy processing, identify and address pitfalls and difficulties in applying the criteria to routine evaluation of biopsies in the surgical pathology laboratory, verify reproducibility of ultrastructural observations and diagnosis in biopsies from different sites in the bladder wall, and develop a standard approach to routine ultrastructural evaluation of the biopsy.nnnMATERIALS AND METHODSnBlinded to clinical information, 25 randomly selected detrusor biopsies were evaluated by a pathologist with prior knowledge of electron microscopy but none of detrusor ultrastructure. The observations and diagnoses made were subsequently correlated with urodynamic bladder behavior evaluated comprehensively before biopsy. Biopsies from different sites of 4 detrusors and specimen samples of multiple sites from a bladder obtained at autopsy were also blindly assessed to determine the reproducibility of single site biopsies.nnnRESULTSnEssential parameters of all criteria were verified. Potential pitfalls and sources of difficulty in some were identified and corrected to refine the criteria. Diagnoses were reproducible in all 5 detrusors with multiple site biopsies. Detailed protocols for electron microscopic study and diagnosis of dysfunctional detrusor biopsies were generated.nnnCONCLUSIONSnThe protocols eliminate problems that may be encountered in ultrastructural evaluation of biopsies from dysfunctional detrusors, and have been applied readily and successfully in our subsequent studies. Uniformity of structural organization of detrusor allows valid application of the protocols and study criteria to small biopsies obtained from different sites in the bladder wall.