Structural Basis of Neurogenic Bladder Dysfunction. II. Myogenic Basis of Detrusor Hyperreflexia

0022-5347/03/1692-0547/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 169, 547–554, February 2003 Printed in U.S.A.

DOI: 10.1097/01.ju.0000042667.26782.c7

STRUCTURAL BASIS OF NEUROGENIC BLADDER DYSFUNCTION. II. MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA ¨ RSAM, NEIL M. RESNICK,‡ SUBBARAO V. YALLA AXEL HAFERKAMP,* , † JOACHIM DO AND AHMAD ELBADAWI From the Department of Pathology, Upstate Medical University, State University of New York, Syracuse, New York, the Department of Urology, University of Heidelberg, Heidelberg, Germany, the Division of Gerontology, Brigham and Women’s Hospital, Hebrew Rehabilitation Center for the Aged, and Division of Urology and Geriatric Research, Education and Clinical Center, Veterans Administration Boston Health Care System, Boston, Massachusetts

ABSTRACT

Purpose: We describe the ultrastructure of detrusor smooth muscle in long-standing neurogenic bladder dysfunction in the human. Materials and Methods: Detrusor biopsies were obtained from (15 female and 31 male) patients 7 to 96 years old with neurogenic bladder dysfunction for less than 1 to 43 years. Of the patients 9 had meningomyelocele, 25 spinal cord injury and 12 brain disorder. Urodynamically, all patients had detrusor hyperreflexia (neurogenic detrusor overactivity) in addition to bladder outlet obstruction in 4, impaired detrusor contractility in 19, decreased bladder compliance in 4, and detrusor-sphincter dyssynergia in 24. Ultrastructural changes in detrusor, including those associated with detrusor overactivity, impaired detrusor contractility and bladder outlet obstruction, were evaluated qualitatively and quantitatively. Results: Intermediate junctions of muscle cells were absent or reduced in 45 biopsies, which instead had dominant intimate cell appositions with much narrower junctional gaps. A greater than 2 intimate cell apposition-to-intermediate junction ratio was present in 45 biopsies (98%), and intimate cell apposition linked chains of 5 muscle cells or greater in all biopsies (100%). Muscle cell degeneration was observed in 34 biopsies from 20 of 27 patients (74%) with normal contractility and 14 of 19 (74%) with impaired detrusor contractility. No particular changes were associated with functional bladder outlet obstruction due to detrusor-sphincter dyssynergia. Conclusions: The ultrastructural complete dysjunction pattern is a feature of hyperreflexia as well as nonneuropathic detrusor overactivity of various etiology. A greater than 2 intimate cell apposition-to-intermediate junction ratio had 98% sensitivity but its specificity remains to be determined. The lack of relationship between muscle cell degeneration and detrusor contractility probably reflects limitations of urodynamic measurement of contractility in patients with spinal cord injury and meningomyelocele. KEY WORDS: bladder, neurogenic; reflex, abnormal; intercellular junctions; muscle, smooth

Structural changes in the neurogenic bladder have been studied ultrastructurally in feline models that mimic some clinical settings.1– 4 Changes in neuromuscular detrusor ultrastructure were described in 10 weeks in the bladder decentralized by sacral ventral rhizotomy and following infraspinal (postganglionic) neurectomy by extirpation of the pelvic plexus. Hyperreflexia (neuropathic detrusor overactivity) is a constant feature of suprasacral spinal cord injury5 and occurs in about 45% of patients with meningomyelocele.6 Nonneurogenic geriatric and obstructive detrusor overactivity is associated with altered muscle cell junctions that are also observed in detrusor overactivity in young adults.7 Intermediate junctions predominating in normal detrusor mediate contraction coupling of muscle cells mechanically.8 The intermediate junction has strictly parallel sarcolemmas with paired symmetrical subsar-

colemmal dense plaques separated by a 25 to 60 nm. junctional gap containing a central linear density. The overactive detrusor has a distinctive ultrastructural pattern (complete dysjunction) of the 3 essential components of reduction or loss of intermediate junctions, abundance (or exclusive presence) of new cell junctions with close separation gaps (protrusion junctions, ultraclose abutments) and chain-like linkage of 5 or more muscle cells by the close junctions.8 –10 Having close gaps (6 to 12 nm.), these junctions were suggested to mediate electrical coupling of muscle cells as the myogenic basis of involuntary contractions during bladder filling (that is detrusor overactivity).11 Following a standardized protocol12 we investigate changes in detrusor smooth muscle and its cell junctions in long-standing hyperreflexic neurogenic bladder dysfunction in humans. The study involved neurogenic bladder dysfunction resulting from upper motoneuron lesions (spinal cord injury, brain disorder) or from combined lower and upper motoneuron deficit (meningomyelocele). Muscular changes will be presented in this report, and concomitant neural changes, studied concurrently, in a subsequent report.

Accepted for publication August 9, 2002. Supported by Grants AG 04390 and AG 08812 from the National Institutes of Health, and by industrial funds from La Roche Diagnostics and Farco Pharma. * Current address: Department of Urology, University of Bonn, Sigmund-Freud Str. 25, 53105 Bonn, Germany. MATERIALS AND METHODS † Financial interest and/or other relationship with Farco Pharma Corp. and La Roche Diagnostics. This prospective study was conducted on 15 female and 31 ‡ Current address: Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, 300 Keystone, 3520 Fifth Ave., male patients with hyperreflexic neurogenic bladder dysfunction for 3 months to 43 years. Patient data, details of Pittsburgh, Pennsylvania 15213. 547

548

MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA

clinical and urodynamic evaluation and procedure of detrusor biopsy (table 1) are presented in the preceding report.12 Detrusor biopsies were obtained endoscopically from all patients with brain disorder and, depending on scheduled urological procedure, either endoscopically (for example sphincterotomy) or at open surgery (for example ileocystoplasty) from the meningomyelocele and spinal cord injury groups. One patient with spinal cord injury 3 months in duration had no spinal shock and was hyperreflexic for 2 months. He underwent biopsy at endoscopic evaluation of false passage created by catheterization. Urodynamic evaluation was performed in Heidelberg (meningomyelocele, spinal cord injury groups) and Boston (brain disorder group) following previously standardized protocols.8, 10, 12 Anticholinergic medication was discontinued 1 week before the evaluation. Randomly number coded biopsies were selected blindly at random and evaluated (A. H., A. E.) qualitatively and quantitatively by electron microscopy without knowledge of the source or clinical data. Standardized criteria9, 10, 12 were verified in 10 biopsies and followed in the remaining 36 at ⫻ 3,300 to 31,500 microscopic magnification. Observations on muscle cell arrangement, ultrastructural morphology and patterns associated with impaired detrusor contractility, bladder outlet obstruction and detrusor overactivity8 –10 were documented (45 or more photomicrographs per biopsy) at ⫻ 8,500 to 80,500 magnification. The number of biopsies displaying various muscular changes was analyzed in terms of biopsy groups, duration of neurogenic bladder dysfunction, and different aspects of detrusor dysfunction. Muscle cell profiles and junctions were counted. Cell-cell contacts were verified as intermediate junctions or intimate cell appositions by measurements of the shortest widths of their separation gaps. Intimate cell appositions include protrusion junctions and ultraclose abutments described previously in geriatric detrusor overactivity,8, 9 as well as newly recognized morphologic variants of the abutments with comparably narrow (6 to 12 nm.) junctional gaps. Assessment of cell junctions included ratios of intermediate junctions and intimate cell appositions-to-

TABLE 1. Patients and clinical data Meningomyelocele Group Total No. pts.:* Males Females Age range: No. younger than 65 No. 65 or older Disease duration (yrs) range:

9 5 4 14–28 9 0 14–28

Spinal Cord Brain Injury Disorder Group Group 25 19 6 7–70 23 2 Less than 1–33 4 11 5 5

12 7 5 65–96 0 12 Less than 1–43† 1 6 1 3

Less than 1 0 1–5 0 Greater than 5–10 0 Greater than 10 9 No. voiding dysfunction: Hyperreflexia 9 25 12 Impaired detrusor contractility‡ 6§ 10 3㛳 Bladder outlet obstruction 0 0 4㛳 Detrusor-sphincter dyssynergia¶ 5 19 0 No. detrusor biopsy: Endoscopic 1 18 12 Open 8 7 0 * Of the originally recruited 51 cases 5 biopsies with deficient smooth muscle were excluded from study. † Duration unknown in 1 case with diagnosis of brain tumor 18 months after biopsy. ‡ Contractility could not be evaluated in 1 patient (meningomyelocele group) with cutaneous vesicostomy. § Two more cases questionable. 㛳 Includes 1 case with bladder outlet obstruction and impaired detrusor contractility. ¶ Considered functional bladder outlet obstruction when accompanied by greater than 40 cm. H2O leak point pressure.

muscle cells and intimate cell apposition linked muscle cell chains. Quantitative data were analyzed by various tests (chi-square, Fisher, Student t, ANOVA, Student-NewmanKeuls) using computer software (GraphPad Prism version 3.02 and Glantz’s Primer of Biostatistics, version 4.0213) as explained in the preceding report.12 RESULTS

A total of 6,923 muscle cells were counted (table 2). Recognizably grouped muscle cells in 44 biopsies were classified as compact (near-normal) fascicles (152 to 230 mean intercellular space) in 13 (fig. 1, A), intermediate fasciles with slightly wider spaces (mean 174 to 291 nm.) in 10 (fig. 1, B), and compact and intermediate fascicles in 21. In 2 brain disorder group biopsies with generalized severe degeneration muscle fascicles were loose and shrunken muscle cells were widely separated (up to several ␮m.) by abundant collagen fibers and clear spaces, obscuring their arrangement (fig. 1, C). Compact fascicles were more common in spinal cord injury than meningomyelocele or brain disorder group biopsies (p ⫽ 0.011 and 0.026, respectively). No consistent change of interstitium was observed. Biopsies from the 4 patients with brain disorder and bladder outlet obstruction displayed the myohypertrophy pattern.8 –10 The dense band pattern of aged detrusor (fig. 1, A) was identified in 14 biopsies obtained from 65 to 96-year-old patients (spinal cord injury 2, brain disorder 12).8, 9 No meningomyelocele group biopsy had this pattern but a similar pattern was observed patchily in 4 more spinal cord injury group biopsies from 50 to 65-year-old patients. The muscular changes were observed as early as 3 months after neurogenic bladder dysfunction (30-year-old patient with spinal cord injury), and were present in the 3 biopsy groups across the wide range of patient age and duration of neurogenic bladder dysfunction. Muscle cell junctions: ultrastructural dysjunction pattern. The complete dysjunction pattern of detrusor overactivity (fig. 2, A)9 was observed in all biopsies, including 2 with generalized severe degeneration (fig. 2, B). Intermediate junctions (fig. 3, A) were absent in 7 (15%) and variably reduced in 38 (82%) biopsies but were preserved and more frequent than intimate cell appositions in 1 brain disorder group biopsy. Intimate cell appositions of various forms (figs. 2 and 3) were obvious in all biopsies. Some cell pairs were attached by intimate cell apposition and intermediate junction (fig. 3, A). Digitate intimate cell appositions were the most common, including broad-based thumb-like cell projections (fig. 3, A) and slender finger-like protrusion junctions (fig. 3, B and D). Planar intimate cell appositions (ultraclose abutments) at flat apposed cell surfaces (fig. 3, C) and narrow-pedicled bulbous cell projections (fig. 3, E) were less common. Some quasi-syncytial appositions simulated sarcoplasmic continuity of adjacent cells but had telltale features of sarcolemmas, caveolae or distinctly different sarcoplasms of 2 attached cells (fig. 4, A and B). Rarely, 3 or 4 muscle cells were attached at the same site by complex intimate cell apposition (fig. 4, C). One brain disorder group biopsy with dominant intermediate junctions had a 0.8 intimate cell apposition-to-intermediate junction ratio. This ratio was increased (2 to 45⫹) in the other 45 biopsies (table 2). The intimate cell appositionto-intermediate junction ratio was less than 3 in 4 biopsies and 3 or more in 42 (91% sensitivity). The ratio was generally higher in meningomyelocele and spinal cord injury than brain disorder group biopsies (greater than 10 in 89%, 60% and 25%, respectively, p ⫽ 0.035). However, there was no association of high intimate cell apposition-to-intermediate junction ratios (30 or greater) and neurogenic bladder dysfunction of protracted (greater than 5 years) duration. Muscle cell degeneration. Muscle cell degeneration was

549

MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA TABLE 2. Biopsies and muscle cell junctions Meningomyelocele Group

Spinal Cord Injury Group

Brain Disorder Group

Totals

920 (101)

3,735 (123)

2,268 (175.5)

6,923 (114.5)

2 0–0.02 0.1–0.4

3 0–0.09 0.1–0.5

2 0–0.2 0.2–0.9

7 (15) – –

Total No. muscle cells: (median %/biopsy) Muscle cell junctions: No. biopsies intermediate junction not observed (%) Intermediate junction-to-muscle cell ratio* Intimate cell apposition-to-muscle cell ratio* No. biopsies intimate cell apposition-to-intermediate junction ratio (%): Low less than 3 Increased 3 or greater Subtotals

0 9

1 24

3† 9

4 (9) 42 (91)

9

25

12

46

High (greater than 10)‡ 8 15 3 26 (56) Very high (30 or greater)§ 4 8 2 14 (30) * Range of true values, junctions to muscle cells. † Includes 1 biopsy with 0.8 intimate cell apposition-to-intermediate junction ratio (intermediate junction-to-muscle cell ⫽ 0.4, intimate cell apposition-tomuscle cell ⫽ 0.3) and 2 biopsies with 2 and 2.3 ratios. ‡ Indicates statistically significant difference between groups. § Includes 7 biopsies with no observed intermediate junctions.

FIG. 1. Detrusor smooth muscle. A, compact muscle cell arrangement. Muscle cell profiles display dense band pattern (sarcolemmas with long dense bands and sparse caveolae) but otherwise normal morphology (spinal cord injury ⫻ 3,410). B, intermediate fascicles with mildly separated muscle cells (brain disorder ⫻ 3,350). C, widely separated muscle cells in loose vague fascicles. Note marked muscle cell degeneration (brain disorder ⫻ 4,400).

observed in all biopsies (fig. 5, A).8 –10 It was widespread in 6, focal in 28 and rare in 12 biopsies (table 3). The extent of degeneration in spinal cord injury group biopsies was not associated with anatomical levels of injury or its degree (complete versus incomplete). There was widespread or focal degeneration in biopsies from 14 of 19 (74%) patients with impaired detrusor contractility as well as biopsies from 20 of 24 (74%) with normal detrusor contractility (table 3). Thus, the degeneration was not associated with impaired detrusor contractility (p ⫽ 0.883) in collective analysis of all biopsies. However, there was strong association in 9 of 11 brain disorder group biopsies in which contractility could be ascertained when analyzed separately. Biopsies from 8 patients with normal contractility or mild impaired detrusor contractility had minimal to focal (limited) degeneration.9 Biopsy of the ninth patient with severe impaired detrusor contractility had the full degeneration pattern.9 Ancillary features. Sarcoplasmic mitochondria were indiscernible in the 2 brain disorder group biopsies with generalized severe degeneration. Mitochondria in the other 44 biopsies were normal (fig. 5, B) or slightly distorted with

preserved cristae in 38 (meningomyelocele 5, spinal cord injury 24, brain disorder 9) had mitochondria, and had moderately to severely distorted cristae with a bloated rather empty overall appearance (fig. 5, C) in 6 (meningomyelocele 4, spinal cord injury 1, brain disorder 1). Mitochondrial change was unrelated to detrusor contractility (p ⫽ 0.275) or muscle cell degeneration (p ⫽ 0.814) but was more marked in meningomyelocele than spinal cord injury and brain disorder group biopsies (p ⫽ 0.009). Although normal as well as variably distorted mitochondria were observed in endoscopic and open biopsies, moderate to marked distortion appeared to be 121⁄2 times more common in open biopsies (p ⫽ 0.018). Bosselated muscle cell profiles displaying protuberant globules of clarified sarcoplasm around cell perimeters were identified in 12 biopsies (meningomyelocele 4, spinal cord injury 8) (fig. 6, A). These resembled oak-leaf profiles described in interstitial cystitis and attributed to tissue and cellular edema.14 There was little association (p ⫽ 0.083) with the presence or absence of oak-leaf profiles and the distribution of muscle cell degeneration (that is widespread, focal, rare). Oak-leaf profiles were absent or incomplete (lim-

550

MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA

FIG. 2. Intimate muscle cell apposition. A, 5 muscle cells linked by intimate cell appositions (arrowheads). Complex intimate cell apposition of 4 cells (box) magnified in fig. 4, C. B, markedly separated severely degenerated muscle cells linked by protrusion junctions (arrows) with barely discernible gaps (brain disorder ⫻ 11,850).

ited bosselation and sarcoplasmic clearing) in 8 of the 15 (50%) open and 26 of the 31 (84%) endoscopic biopsies, including all of the brain disorder group, but were established in the remainder, that is 8 (50%) open versus 4 (13%) endoscopic biopsies (p ⫽ 0.014 and p ⫽ 0.03, respectively). DISCUSSION

The ultrastructural complete dysjunction pattern has been documented as the distinctive feature of geriatric detrusor overactivity with high sensitivity and specificity.8, 9 This finding led to the introduction of the ratio of ‘abnormal’ (protrusion)-to-normal (intermediate) junctions as a diagnostic morphologic marker of detrusor overactivity. Detrusor overactivity was considered with a ratio greater than 3 (sensitivity 77%, specificity 96%), sensory urgency with a 2 to 3 ratio and a stable detrusor with a ratio less than 2 (sensitivity 100%, specificity 96%).7 Our observations confirm abnormal junctions (protrusion and various forms of similarly close intimate cell appositions) as a constant feature of neuropathic hyperreflexia, as it has been recognized in nonneuropathic obstructive or idiopathic detrusor overactivity in the elderly,8, 10 and idiopathic detrusor overactivity in young adults.7 Different conclusions in a recent study of a small female population may represent fundamentally different (incomplete, inadequate or faulty) urodynamic procedure and interpretation, different method of tissue preparation for electron microscopy, different application of standardized criteria for ultrastructural evaluation and/or different unconvincing interpretation or analysis of reported findings.9, 10, 15, 16 The issue of sensory urgency was moot in the 4 biopsies with less than 3 intimate cell apposition-to-intermediate junction ratio in our study, since all were obtained from patients with urodynamically documented detrusor overactivity (hyperreflexia). Whereas the originally proposed greater than 3 ratio of abnormal-to-normal junctions had 77% sensitivity as a criterion for non-neuropathic detrusor overactivity,7 a greater than 2 ratio was 98% sensitive for hyperreflexia in our study. However, the criterion of intimate cell apposition linked chains of 5 muscle cells or greater had 100% sensitivity. They were identified in all biopsies,

including the 4 with less than 3 intimate cell appositionto-intermediate junction ratio, as well as both biopsies with generalized severe muscle cell degeneration. Specificity of the complete dysjunction pattern and intimate cell appositionto-intermediate junction ratios could not be evaluated since we had no patients with neurological deficit but stable bladder. Because of the narrow separation gaps, protrusion junctions and ultraclose abutments were described as resembling gap junctions.11 Gap junctions provide a low resistance pathway that mediates electrical muscle cell coupling11 as do simple cell appositions (approximately 15 nm. separation gaps) in organs that lack gap junctions (arterioles, mesosalpinx, ureter17). However, the intimate cell appositions described are not identical ultrastructurally to bona fide gap junctions, which have still narrower intercellular gaps of 2 to 3 nm. Therefore, intimate cell appositions remain to be so or differently characterized when their associated proteins are identified, particularly those of the connexin family and/or other cytoskeletal and extracellular proteins.18 It has been proposed that muscle cell separation with subsequent reduction of intermediate junctions leads to development of protrusion junctions in the overactive geriatric detrusor.8, 11 These and similarly close cell appositions have been observed in enzymatically isolated differentiated cells during the first few days of their growth in primary culture.19 Cell separation is a constant feature of the aged detrusor and is particularly evident in its various associated voiding dysfunctions (bladder outlet obstruction, impaired detrusor contractility, detrusor overactivity).8 –10 In our study 35 of the 44 biopsies (80%) with recognizable smooth muscle fascicles had only compact fascicles with near normal intercellular spaces or compact plus intermediate fascicles with slightly widened spaces. Nonetheless, widened intercellular spaces still may have been a factor in reduction of intermediate junctions in our study. The observed higher frequency of intermediate fascicles in meningomyelocele and brain disorder group biopsies may have been related (at the time of occurrence of neurogenic bladder dysfunction) to muscle cell immaturity in the former19 and aged nature8, 10, 16 in the latter group biopsies. Muscle cell degeneration in all biopsies may be another factor, although widespread or generalized degeneration

MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA

551

FIG. 3. Variants of intimate cell apposition. Thin sarcolemmas and caveolae mark barely discernible intercellular gaps of most. A, broad digitate intimate cell apposition (solid arrow) contrasts with normal intermediate junction (open arrow) of same cells (spinal cord injury ⫻ 11,400). B, slender digitate (protrusion) cell junction (arrow) (meningomyelocele ⫻ 15,250). C, planar intimate cell apposition with ultraclose abutment (arrow) (spinal cord injury ⫻ 27,700). D, protrusion junction (thick arrow) and surface-to-surface planar intimate cell apposition (thin arrow). Barely discernible junctional gaps contrast with 60 nm. gap of short intermediate junction (open arrow) (spinal cord injury ⫻ 18,270). E, bulbous intimate cell apposition (arrow) (meningomyelocele ⫻ 16,400).

(fig. 1, C) that could appreciably separate the muscle cells was identified in only 6 biopsies and rare degeneration that would not in 12. The observed lack of association of ultrastructural degeneration pattern (characteristic of nonneuropathic impaired detrusor contractility) and detrusor contractility probably reflects inherent difficulties of assessing contractility in patients with spinal cord injury, especially those with complete lesions (68% of our patients12) and menin-

gomyelocele. Clinical urodynamic studies, regardless of evaluation procedure (pressure-flow study or continuous occlusion test for isovolumetric pressure determination) are inadequate and may fail to determine the full contractile potential of detrusor. Reflexogenic detrusor contractions are most often unsustained because of lack of appropriate spinal cord continuity with the pontine micturition center. However, isovolumetric detrusor contraction may not attain its potential magnitude because of simultaneous

552

MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA

FIG. 4. Less common forms of intimate cell apposition. A, sarcoplasm of 2 muscle cells seemingly continuous, that is quasi-syncytial (arrowhead) but different sarcoplasmic densities, focally thick sarcolemma and sarcolemmal caveolae (arrow) mark independence of apposed cells (meningomyelocele ⫻ 17,000). B, quasi-syncytial intimate cell apposition (arrow) marked by abruptly different sarcoplasmic densities and orientation of myofilaments (meningomyelocele ⫻ 27,000). C, complex intimate cell apposition of 4 cells at same point (arrowheads, enlarged box from fig. 2, A) (spinal cord injury ⫻ 25,200).

FIG. 5. Muscle cell degeneration. A, degenerated muscle cells with shredded vacuolated sarcoplasm (arrow) (meningomyelocele ⫻ 8,050). B, near normal cell structure with normal mitochondria and intact sarcoplasm (spinal cord injury ⫻ 12,200). C, markedly bloated mitochondria of empty appearance in sarcoplasm (spinal cord injury ⫻ 3,150).

detrusor inhibition (negative feedback) resulting from dyssynergic striated urethral sphincter and/or pelvic floor contraction. Our observations confirm the previously described ultrastructural dense band and myohypertrophy patterns in the aged bladder and associated with bladder outlet obstruction, respectively.8 –10 In contrast, detrusor-sphincter dyssynergia, which is tantamount to functional obstruction of the outlet, did not result in myohypertrophy or other specific pattern in our study. The reason for this is unknown but may be related

to duration of the neurological deficit and severity of detrusor-sphincter dyssynergia or its intermittence. Observed ancillary features of muscle cells (oak-leaf appearance, distorted mitochondria) appear to have been related to biopsy procurement by open operation with unavoidable manipulation of the bladder wall leading to tissue edema and possibly ischemia. Nondegenerative nature of the oak-leaf appearance is supported by the absence of muscle cell degeneration in interstitial cystitis,14 its lack of association with smooth muscle degeneration in our study, as well as

553

MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA TABLE 3. Muscle cell degeneration versus detrusor contractility No. Widespread Meningomyelocele group biopsies Spinal cord injury group biopsies Brain disorder group biopsies Total No. (%)

No. Focal

2 2 2

5 17 6

6 (13)

28 (61)

Impaired detrusor contractility* 2 Normal contractility 4 * Rated moderate or severe in 15 patients (33%). † Widespread or focal degeneration in 14 patients (74%). ‡ Widespread or focal degeneration in 20 patients (74%).

12 16

No. Rare 2 6 4 12 (26) 5 7

Total No. (%) 9 25 12 46 19 (41)† 27 (59)‡

FIG. 6. Oak-leaf appearance of muscle cells. A, muscle cell perimeters have prominent bosselations with rarefied sarcoplasm (meningomyelocele ⫻ 5,330). B, slight change with smaller less rarefied less prominent bosselations (meningomyelocele ⫻ 4,270).

its absence in endoscopically obtained biopsies of geriatric detrusors with impaired detrusor contractility and associated muscle cell degeneration.8, 10 CONCLUSIONS

Our observations confirm that the ultrastructural complete dysjunction pattern is a structural feature of neuropathic detrusor overactivity (hyperreflexia), just as it has previously been recognized in nonneuropathic detrusor overactivity of various etiology. It seems that 3 months are sufficient for development of muscular changes of neurogenic bladder dysfunction. As markers of the upper motoneuron induced detrusor hyperreflexia, reduction to depletion of intermediate junctions, dominance of intimate cell appositions, and greater than 2:1 intimate cell apposition-to-intermediate junction ratio had 98% sensitivity, whereas 5 muscle cell or greater linkage by intimate cell appositions was 100% sensitive. Specificity of these features is currently under investigation in the rare entity of upper motoneuron neuropathic bladder with stable (nonhyperreflexic) detrusor. The observed lack of relationship between muscle cell degeneration and detrusor contractility probably reflects limitations of urodynamic measurement of contractility in patients with spinal cord injury and meningomyelocele. Dr. H.J. Gerner, Department of Orthopedic Surgery and Rehabilitation Medicine, University of Heidelberg, helped with patient recruitment; Dr. M. Fußer, Department of

Urology, University of Heidelberg, helped obtain detrusor biopsies; Dr. W. Richter, Orthopedic Research Laboratories, University of Heidelberg, and Ms Fo¨ hr initially processed and prepared the biopsies obtained in Heidelberg for electron microscopy; Margaret Bergmann, Kathy Juliano and Maryrose P. Sullivan helped with patient recruitment, clinical evaluation and detrusor biopsy procedure in Boston, Massachusetts; and Ms J. Sherman-Tamber prepared the biopsies from Boston and provided help throughout the study. REFERENCES

1. Elbadawi, A., Atta, M. A. and Franck, J. I.: Intrinsic neuromuscular defects in the neurogenic bladder. I. Short-term ultrastructural changes in muscular innervation of the decentralized feline bladder base following unilateral sacral ventral rhizotomy. Neurourol Urodyn, 3: 93, 1984 2. Atta, M. A., Franck, J. I. and Elbadawi, A.: Intrinsic neuromuscular defects in the neurogenic bladder. II. Long-term innervation of the unilaterally decentralized feline bladder base by regenerated cholinergic, increased adrenergic and emergent probable “peptidergic” nerves. Neurourol Urodyn, 3: 185, 1984 3. Elbadawi, A. and Atta, M. A.: Intrinsic neuromuscular defects in the neurogenic bladder. III. Transjunctional, short- and longterm ultrastructural changes in muscle cells of the decentralized feline bladder base following unilateral sacral ventral rhizotomy. Neurourol Urodyn, 3: 245, 1984 4. Elbadawi, A., Atta, M. A. and Hanno, A. G.-E.: Intrinsic neuromuscular defects in the neurogenic bladder: VIII. Effects of unilateral pelvic and pelvic plexus neurectomy on ultrastruc-

554

MYOGENIC BASIS OF DETRUSOR HYPERREFLEXIA

ture of the feline bladder base. Neurourol Urodyn, 7: 77, 1988 5. Watanabe, T., Rivas, D. A. and Chancellor, M. B.: Urodynamics of spinal cord injury. Urol Clin N Am, 23: 459, 1996 6. Light, J. K., Faganel, J., Roth, D. R. and Dimitrijevic, M. R.: Meningomyelocele: a clinical, urodynamic and neurophysiological evaluation. J Urol, 131: 717, 1984 7. Tse, V., Wills, E., Szonyi, G. and Khadra, M. H.: The application of ultrastructural studies in the diagnosis of bladder dysfunction in a clinical setting. J Urol, 163: 535, 2000 8. Elbadawi, A.: Functional pathology of urinary bladder muscularis: the new frontier in diagnostic uropathology. Semin Diagn Pathol, 10: 314, 1993 9. Hailemariam, S., Elbadawi, A., Yalla, S. V. and Resnick, N. M.: Structural basis of geriatric voiding dysfunction. V. Standardized protocols for routine ultrastructural study and diagnosis of endoscopic detrusor biopsies. J Urol, 157: 1783, 1997 10. Elbadawi, A., Hailemariam, S., Yalla, S. V. and Resnick, N. M.: Structural basis of geriatric voiding dysfunction. VI. Validation and update of diagnostic criteria in 71 detrusor biopsies. J Urol, 157: 1802, 1997 11. Elbadawi, A. Discussion: the neostructural myogenic mechanism of detrusor overactivity. Urology, suppl., 50: 71, 1997 12. Elbadawi, A., Resnick, N. M., Do¨ rsam, J., Yalla, S. V. and Haferkamp, A.: Structural basis of neurogenic bladder dys-

13. 14. 15. 16.

17. 18. 19.

function. I. Methods of prospective ultrastructural study and overview of the findings. J Urol, 169: 540, 2003 Glantz, S. A.: Primer of Biostatistics, 4th ed. New York: McGraw-Hill Inc., 1996 Elbadawi, A.: Interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis. Urology, suppl., 49: 14, 1997 Mastropietro, M. A., Geary, W., Fuller, E. and Benson, J. T.: Detrusor biopsy as a potential clinical tool. Int Urogynecol J Pelvic Floor Dysfunct, 12: 355, 2001 Elbadawi, A., Hailemariam, S., Yalla, S. V. and Resnick, N. M.: Structural basis of geriatric voiding dysfunction. VII. Prospective ultrastructural/urodynamic evaluation of its natural evolution. J Urol, 157: 1814, 1997 Henderson, R. M.: Cell-to-cell contacts. In: Methods in Pharmacology. Edited by E. E. Daniel and D. M. Paton. New York: Plenum Press, vol. 3, pp. 47–77, 1975 Geiger, B., Yehuda-Levenberg, S. and Bershadsky, A. D.: Molecular interactions in the submembrane plaque of cell-cell and cellmatrix adhesions. Acta Anat, 154: 46, 1995 Burnstock, G.: Development of smooth muscle and its innervation. In: Smooth Muscle: An Assessment of Current Knowledge. Edited by E. Bu¨ lbring, A. F. Brading, A. W. Jones and A. Tomita. Austin: University of Texas Press, chapt. 20, pp. 432– 458, 1981