Lower urinary tract dysfunction and disability status in patients with multiple sclerosis

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Lower Urinary Tract Dysfunction and Disability Status in Patients With Multiple Sclerosis Antonella Gianaantoni, MD, Giorgio Scivoletto, MD, Savino M. Di Stasi, MD, PhD, Maria Grazia Grasso, MD, Enrico Finazzi Agr6, MD, Giuseppe Cobra, MD, Giuseppe Vespasiani, MD ABSTRACT. Giannantoni A, Scivoletto G, Di Stasi SM, Grass0 MG, Agrb EF, Collura G, Vespasiani G. Lower urinary tract dysfunction and disability status in patients with multiple sclerosis.Arch Phys Med Rehabil1999;80:437-41. Objective: To investigate the correlation between neurologic and urologic status in patients with multiple sclerosis (MS). Materials and Methods: Between January 1993 and December 1995, 116 patients with MS symptoms were fully assessed neurologically and urologically with urodynamic studies. Results: Urodynamic abnormalities were detected in 104 patients (89.6%). Several significant relationships between urinary tract findings and neurologic dysfunction were: (1) the relation between voiding disorder as the presenting symptom of the disease and a higher severity of bladder dysfunction; (2) the relation between reduced bladder sensation and longer duration of voiding disorders, lower detrnsor uninhibited contractions threshold, and lower bladder capacity; and (3) the relation between voiding disorders and cerebellar system score. Finally, a significant inverse relationship was found between detrusor hypocontractility and neurologic status (from the Expanded Disability Status Scale, pyramidal system score, and Barthel Index). Conclusions: In this series a high incidence of patients reported voiding disorder as the presenting symptom of MS. These patients also showed a higher severity of urodynamic disorders. They should be rigorously followed up. Furthermore, our data suggest that although the most common cause of altered bladder control in MS is spinal cord pathology, involvement of cortical centers and/or peripheral neuronal lesions may occur. 0 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

M

ULTIPLE SCLEROSIS (MS) is a central nervous system demyelinating disease affecting the subcortical, brain stem, and spinal cord nerve fibers.’ Disruption of the myelin sheath and, later, neuron loss produce a block or slowing of nerve conduction in the central nervous system and lead to a broad spectrum of neurologic abnormalities that are subject to exacerbations and remissions over time.’ Voiding dysfunctions occur in more than 80% of patients with MS and may be part of the presenting symptom complex as well as the most socially

From the S. Lucia IRCCS Rehabilitation Hospital (Drs. Giannantoni, Scivoletto), and the Department of Surgery “Tor Vergata” University of Rome School of Medicine (Drs. Di Stasi, Gram, Agrb, Collura, Vespasiani), Rome, Italy. Submitted for publication August 17, 1998. Accepted in revised form November 3, 1998. No commercial party having a direct financial interest in the subject matter of this article has or will confer a benefit upon the authors or upon my organization with which the authors are associated. Reprint requests to Dr. A. Giannantoni, c/o I.R.C.C.S. Rehabilitation Hospital S. Lucia, via Ardeatina 306,00179 Rome, Italy. 0 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003.9993/99/8004-516X$3.00/0

disabling feature of the disease.2 Most symptomatic patients have irritative and obstructive symptoms and urge incontinence.3Detrusor hyperreflexia is the most common urodynamic finding, followed by hyperreflexia with detrnsor external sphincter dyssynergia (DESD), hypocontractility, and/or areflexia.* Moreover, up to 80% of asymptomatic patients show abnormalities on urodynamic examination; a small number of patients have normal studies.2x3 The relationship between the disability status, disease duration, urinary symptoms, and urodynamic findings in patients with MS has been analyzed.4-13In some studies no correlation was found,4.10 whereas in others a positive single4*5,7-9x12 or multiple11,13relationship between neurologic findings and urologic abnormalities was reported. The aim of this study was to correlate neurologic status, duration of disease, lower urinary tract dysfunction, and onset of urinary dysfunction during the course of disease with urodynamic findings in patients with MS. METHODS Between January 1993 and December 199.5, a total of 116 consecutively admitted patients with MS and micturition disorders underwent neuro-urologic assessment. Seventy-seven were women (mean age 46.7 2 11 years, range 24 to 71) and 39 were men (mean age 47.5 ? 10.2 years, range 26 to 72). Overall, the duration of MS ranged from 10 to 480 months (mean 174 i 100 months); for women the duration ranged from 10 to 480 months (mean 182 I 99) and for men, from 12 to 408 months (mean 158 t 101). Overall, the interval between the onset of the disease and micturition disorders ranged from 0 to 360 months (mean 82.7 t 85.5), and the duration of micturition disorders ranged from 1 to 336 months (mean 86 -+ 74). Neurologic assessment. The diagnosis of MS was confirmed according to Poser’s criteria,14 and the disease course was defined in each patient as either “relapsing-remitting” or “chronic progressive.” The severity of disease was assessedby Kurtzke’s Expanded Disability Status Scale (EDSS) and its Functional Systems,ls and patients’ activities of daily life were assessedby the Barthel Index.i6 Urologic assessment. The urologic assessment consisted of a history, physical examination, and urodynamic investigation. Voiding symptoms were classified as irritative, obstructive, or urinary incontinence. Urgency, frequency (need to void every 2 hours or less), urge incontinence, nocturia (more than once per night), and enuresis were classified as irritative symptoms. Hesitancy, interrupted or weak urine stream, and sensation of incomplete bladder emptying were classified as obstructive. The number of symptoms (irritative and/or obstructive plus incontinence) was computed and was used in assessing the severity of voiding disorders (for example, a patient with frequency, nocturia, enuresis, and hesitancy was considered as having three irritative symptoms and one obstructive symptom, and a symptoms score of 4). Urodynamic assessment. At the time of urodynamic investigation, patients were free from urinary tract infection and were

Patient characteristics.

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not receiving any drug that would influence detrusor and sphincter behavior. Urodynamic assessment was carried out according to the International Continence Society recommendation.17 Urodynamic examination consisted of water cystometry at 37°C at a filling rate of 50mLlmin, with a 6F double-lumen catheter for infusion and recording of intravesical pressure and a 10F intrarectal balloon catheter for recording of abdominal pressure, with patients in the supine position. Pelvic floor activity was recorded by means of unipolar needle electromyography and electrodes were positioned in the bulbocavernous muscle in men and directly in the urethral striated sphincter in women. Pressure/flow study was conducted with patients sitting on a flow-chair, and residual urine volume was measured by catheterization after cystometry. Detrusor hyperreflexia, detrusor areflexia, and DESD were defined according to International Continence Society standards.17Detrusor hypocontractility was recognized on standard cystometry by the presence of residual urine of >7OmL, ilow rate of 60 (men) and 40cm water (women) and maximum flow rate of < 12ml/sec with standard pressure/flow study in the absence of DESD. Finally, detrusor leak point pressure was defined as the bladder pressure at the moment of urinary leak during cystometry.19 Data analysis. Statistical analysis was performed using the x2 test, and the differences between means were calculated with the student t test. The results were considered statistically significant if p = .05. RESULTS Neurologic status. Mean patient disability, expressed as EDSS, was 6.0 2 2.2 points. Mean EDSS progression rate was .43 points per year. Mean Kurtzke Functional Systems scores were: pyramidal 3.6, cerebellar 2.1, brain stem 1.6, sensory 1.4, sphincter 2.4, visual 0.7, and mental 1.3. Mean Barthel Index was 50.4 i 28.2. Thirty patients (26%) showed a relapsingremitting disease course, whereas the remaining 86 (74%) showed a chronic progressive course. The Babinski sign was elicited in 96 patients (83%), and 90 (78%) showed a hyperreflexia; perineal sensibility was abolished in 3 patients (3%) and reduced in 5 (4%), whereas lower-limb sensibility was abolished in 1 (1%) and reduced in 10 (9%). Micturition complaints. At the time of urologic assessment, 110 patients (95%) voided spontaneously, although some of them needed abdominal straining, suprapubic percussion, or the CredC maneuver to empty their bladder. The remaining 6 patients (5%)-2 men and 4 women-had indwelling catheters because of severe urinary incontinence or retention. Twenty patients (17%) reported voiding disturbances as the presenting symptom of the disease. These disturbances were isolated in 8 (7%) and associated with other neurologic disturbances in 12 (10%). In the patients without indwelling catheter, urinary incontinence was reported by 88 patients (79.%), 25 of whom were men (64%) and 63 women (82%). Irritative symptoms were reported by 108 patients (98%), 35 of whom were men (95%) and 73 women (100%). Obstructive symptoms were Arch

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reported by 60 patients (54%), 22 of whom were men (59%) and 38 women (52%). Irritative symptoms alone were reported by 49 patients (45%), and both irritative and obstructive symptoms were reported by 59 patients (55%). The most common combination of symptoms reported was that of urge incontinence and interrupted urinary stream (25%), followed by urge incontinence, hesitancy, and interrupted urinary stream (11%). One man developed obstructive symptoms. Urodynamicfinding. Urodynamic abnormalities were observed in 104 of 116 patients (90%). Detrusor hyperreflexia was present in 94 patients (81%). Detrusor areflexia was observed in four patients (3%)-2 men and 2 women. Bladder capacity was reduced in 36 patients (31%) and increased in 13 (11%). Bladder compliance was reduced in 12 patients (lo.%). Hypocontractile detrusor was observed in 16 patients (14%); of these, 11 showed detrusor hyperreflexia and 5 detrusor normoreflexia. DESD was diagnosed in 49 patients (42.%). Fifteen patients (14%)-10 with DESD, and 5 without DESD-showed poor relaxation of the bladder neck during voiding (detrusor internal sphincter dyssynergia). Finally, no urodynamic abnormality was identified in 12 symptomatic patients (lo%)4 men and 8 women. Relation between micturition complaints and urodynamic findings. Patients reporting micturition disorders at the onset of MS had symptoms for a significantly longer time. They also had a more severe urologic picture (table l), characterized by a significantly higher number of symptoms, sensation at lower bladder filling volume, and higher amplitudes of uninhibited detrusor contractions. No significant differences were found with regard to other clinical features. Patients with detrusor hyperreflexia were divided into two groups: group 1 consisted of the patients who reported bladder sensation at an uninhibited detrusor contraction threshold (reduced bladder sensation), and group 2 consisted of the patients who did not. The duration of voiding disorders was 120 months in group 1 and 69.5 months in group 2 (p = .03); the detrusor uninhibited contractions threshold was 142.2mL vs 217SmL (p = .008); bladder capacity was 219.2mL vs 294.7mL (p = .037). Significant relationships were observed between detrusor hyperreflexia and dyssynergia and urinary incontinence; in particular, urinary incontinence was related to a lower duration and a lower threshold of uninhibited detrusor contractions (p = ,002 and p = .047, respectively) (table 2). Irritative symptoms were related to both hyperreflexia and dyssynergia,

Table

1: Onset

Symptoms With Urinary Dysfunction (20 patients)

Without Urinary Dysfunction (96 patients)

p

Voiding symptom score (points) Bladder sensation threshold (mL) Amplitude of uninhibited contrac-

4.6 107.2

3.7 165.2

.Ol .005

tions (cm H,O) Symptoms duration (months) Disease duration (months)

77.6 136.3 136.35

60.8 70.6 184.29

.0039 ,001

EDSS (points) Pyramidal system Cerebellar system Brainstem Sensitive Sphincter Mental

system system system system

(points) (points) (points) (points) (points)

(points)

5.89 3.5 1.85 1.64 1.21 2.85 .81

6.38

.052 .33 ,831

3.57 2.14

.36

1.6 1.31 2.18 1.5

.89 .77 0.2 0.1

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Table 2: Incontinence

Irritative Voiding

symptoms symptoms

Uninhibited Uninhibited

No: 24 Patients

Yes: 88 Patients

2.25 3.14

3.46 4.16

283sec 185.7mL

156.42 253.3

.002 ,047

391.59 5.59

291.9 6.48

.Ol .0048

1.71 1.62

2.28 2.44

score

contractions contractions

duration threshold

Bladder capacity EDSS score Cerebellar Sphincter

system system

Detrusor Sphincter

score score

hyperreflexia dyssynergia

14 pts, 60% 5 pts, 20%

81 pts, 92% 44 pts, 50%

D .0008 ,001

,036 .007 .OOOl .Ol

being more frequent in patients with hyperreflexia (3.27 vs 2.9, p = .Ol) and with dyssynergia (3.4 vs 2.9,~ = .04). Urologic and neurologic relationship. A significant relationship was found between urinary incontinence and irritative symptoms (the urgency, frequency, urge incontinence triad) and both severity of EDSS and cerebellar system score (table 2). Irritative symptoms were significantly related to the presence of the Babinski sign (3.2 irritative points in patients with Babinski vs 2.5 in patients without; p = .029). In this series we did not find any other relationship between obstructive symptoms and DESD. It was impossible to find any relationship between symptoms and bladder areflexia because the small number of patients with areflexia did not allow any statistical analysis. A relationship was observed between detrusor hyperreflexia and DESD and the involvement of the pyramidal tract: the pyramidal system score and the presence of the Babinski sign and lower-limb tendon hyperreflexia (table 3). The same relationship was found with the severity of EDSS and the Barthel Index, which depend largely on the degree of pyramidal dysfunction. Finally, the significant negative relationship between detrusor hypocontractility and EDSS (p = .Ol), pyramidal (p = .Ol), and Barthel Index (p = .006) is worthy of note (table 3). DISCUSSION In our series we observed some relationships that have not been reported. The most interesting clinical finding was that patients who had voiding disorders as the presenting symptom Table 3: Urodynamic

Patterns

and Neurologic No

Detrusor

hyperreflexia

22 patients 4.87

EDSS score Pyramidal system Sphincter system

score score

Barthel index Sphincter dyssynergia Detrusor

Barthel Babinski Detrusor

67.85

dyssynergia

EDSS score Sphincter system Sensorial system

score score

index sign hypocontractility

EDSS score Pyramidal system Barthel index

2.63

score

Status Yes

94 patients 6.48 3.68 2.52

0

45.7 52%

67 patients

49 patients

5.8 2

0.97

6.7 2.6 1.63

54.4 62%

40 90%

100 patients 6.52

16 patients 5.39

3.7 44.8

2.9 67.5

P

,003 .017 .0006 .0048 ,003

.02 .03 .Ol .04 .015

.Ol .Ol .006

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of the diseasealso had a higher number of urinary disorders and more severe abnormal urodynamic findings, such as the amplitude of detrusor contractions and a significantly lower bladder sensation threshold. A significant difference in neurologic status, however, was not present and diseaseduration was lower (although not significantly) in these patients. Complaints about micturition duration were more numerous in patients with bladder disorders at the onset of MS. Since symptoms are a product of dysfunction, in our opinion the duration of complaints is an index of bladder dysfunction duration; thus, we found that bladder dysfunction duration was higher in patients with micturition complaints at the onset of the disease. The relationship between disease duration, micturition complaints, and severity of bladder dysfunction is not clear. Koldewijn and colleagues13 found no significant relationship between disease duration and micturition complaints, but a positive one with the severity of detrusor dysfunction. Awad and coworkers,” however, showed that the duration of MS was higher in patients with urinary symptoms. We found no relation between the duration of the disease and any other clinical feature. However, the finding that the severity of vesicosphincteric dysfunction is higher in patients complaining of micturition disorders at the onset of MS suggests that urinary tract dysfunction duration (demonstrated by the length of micturition complaints) is one of the factors that influence bladder dysfunction severity. There are probably two orders of explanation for this relationship: (1) a longer duration of micturition centers and pathway involvement means formation of new demyelinating lesions and enlargement of the older ones; and (2) bladder modifications (for example, bladder neck and wall sclerosisas a consequence of urinary infections, uretral stenosis, etc.) can occur over time and worsen the urodynamic picture. Bladder dysfunction is considered one of the main causes of morbidity and hospitalization in patients with MS. It has been shown that in patients with MS or spinal cord injury, the more severe the micturition disorders, the higher the risk of developing upper urinary tract disease.20~21Furthermore, this risk could be prevented or reduced by an appropriate treatment (for example, anticholinergic drugs plus clean intermittent catheterization). Therefore, patients presenting with micturition disorders at the beginning of the disease should be followed rigorously regardless of disease duration and overt neurologic disorders and undergo appropriate therapy of micturition disorders as soon as possible. We observed a significant relationship between the cerebellar system score and both irritative symptoms and urinary incontinence (p = .036), but we failed to observe such a significant relationship between the cerebellar system score and detrusor hyperreflexia. An explanation for this may be that voiding problems are more important in patients with severe cerebellar ataxia because of postural derangement before or during micturition and because of limb ataxia, which makes selfcatheterization more difficult. We also found a significant relationship between both irritative symptoms and incontinence and detrusor hyperreflexia as well as DESD, which other authors failed to show.22 Furthermore, there was a significant relationship between urinary incontinence and the parameters accounting for the severity of detrusor hyperreflexia, such as uninhibited detrusor contraction threshold, duration, and reduction of bladder cystometric capacity (table 2). Although this may mean that evaluation of symptoms can be used as an index of urodynamic abnormalities, we were not able to show any significant relationship between voiding disorders and detrnsor areflexia because of the small number of patients with detrusor areflexia. Arch

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With regard to pathophysiologic mechanisms, both detrusor hyperreflexia and DESD were significantly related to pyramidal system score and to the signs of the involvement of pyramidal tract (the Babinski sign and lower-limb tendon hyperreflexia) and consequently to the EDSS score and Barthel Index. These findings confirm the relationship already reported between bladder dysfunction and pyramidal system involvement.11,13 The usual explanation for this correlation is the demyelination deep in the lateral columns of the spinal cord where the reticulospinal and corticospinal tracts lie, which could block the conduction of inhibitory efferents to the sacral micturition center. The uninhibited sacral micturition center may account for detrusor hyperreflexia and DESD.11,13 Nevertheless, other explanations are possible. In our series, patients who reported coincident bladder sensation and uninhibited detrusor contraction threshold (reduced sensation) on urodynamics showed a longer duration of voiding disorders and a more severe detrusor hyperreflexia. Detrusor hyperreflexia with reduced bladder sensation is probably an etiologically distinct subclass of detrusor hyperactivity. This particular urodynamic picture (named uninhibited overactive bladder) could be linked to a more serious neuro-urologic involvement in patients with MS or to a different pathogenesis of the disorder: for example, it has been shown that in elderly people it may be a consequence of the lesion of cortical structure, in particular of “cortical neuropathy,” especially in the frontal lobe.23 In elderly people this type of abnormality seems to be associated with regional underperfusion of the frontal lobes, where the voluntary control of voiding originates.23-25 It has been suggested that lesions of these centers may lead to detrusor hyperreflexia with reduced bladder sensation. The results also show a significant inverse relationship between detrusor hypocontractility and neurologic status (EDSS and pyramidal system score as well as Barthel Index), while Koldewijn13 observed a significant positive relationship between hypocontractility and EDSS. The incidence of patients with detrusor normoreflexia (which show better neurologic status [table 31) is higher in the hypocontractility group. The usual explanation for detrusor hypocontractility is a drop in the “positive neural drive” from rostra1 structures in patients suffering spinal cord lesions. l2 In our series, the finding of a group of patients with normoreflexic and hypocontractile bladder and with less important pyramidal system involvement suggests another possible pathogenesis of the disorder, such as peripheral neuropathy.26 Although some authorsz7 have shown an increase in a Schwann cell marker in the bladder tissue of patients with MS, indicating neuronal demyelination at that level, this hypothesis needs to be confirmed by further neurophysiologic studies. Finally, no urodynamic abnormality was identified in 12 symptomatic patients because (1) four patients had a “relapsingremitting” disease and urodynamic assessment was performed during a remission phase; (2) five patients showed subliminal uninhibited detrusor contractions that did not fulfill ICS standards for detrusor hyperreflexia; (3) in the remaining three patients, standard urodynamic investigation may have been inadequate and ambulatory urodynamics should have been applied; and (4) urinary disturbances may not depend on real urologic dysfunction, but on other neurologic impairments (eg, aphasia, limbs ataxia, or cognitive impairment). CONCLUSIONS The significant relationship between the nature and severity of micturition disorders, urodynamic abnormalities, and the severity of neurologic disorders indicates that clinical evaluation on the basis of both micturition disorders and neurologic Arch

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status plays a role in the initial assessment of patients with MS. In particular, patients who report voiding disorder as the presenting symptom of MS should be submitted to a strict follow-up. Furthermore, our data suggest that although the most common cause of altered bladder control in MS is spinal pathology, other pathogeneses may occur, such as the involvement of cortical centers and/or peripheral neuronal lesions. Acknowledgment: The authors thank Professor John Ditunno (Michie Professor and Chairman of the Department of Rehabilitation Medicine, Thomas Jefferson University, Philadelphia, PA) for his kind suggestions and editing. References 1. Weinshenker BG. Natural history of multiple sclerosis. Ann Neurol 1994;36 Suppl:S6-11. 2. Hinson JL, Boone TB. Urodynamics and multiple sclerosis. Urol Clin North Am 1996;23:475-81. 3. Bemelmans BLH, Hommes OR, Van Kerrebroek PE, Lemmens WAJG, Doesburg WH, Debmyne FMJ. Evidence for early lower urinary tract dysfunction in clinically silent multiple sclerosis. J Urol 1991;145:1219-24. 4. Miller H, Simpson CA, Yeates WK. Bladder dysfunction in multiple sclerosis. BMJ 1965;1:1265-9. 5. Ritter G, Grabner F. Die zystometriche untersuchung des multiplesclerose-kranken. Dtsch Med Wochenschr 1968;93:1942. 6. Bradley WE, Logothesis JL, Tinun GW. Cystometric and sphincter abnormalities in multiple sclerosis. Neurology 1973;23:1131-9. 7. Andersen JT, Bradley WE. Abnormalities of detrusor and sphincter function in multiple sclerosis. Br J Urol 1976;48:193-8. 8. Bradley WE. Urinary bladder dysfunction in multiple sclerosis. Neurology 1978;28(8 Suppl1):52-8. 9. Philp T, Read DJ, Higson RH. The urodynamic characteristics of multiple sclerosis. Br J Urol 1981;53:672-5. 10. Goldstein I, Siroky MB, Sax DS, Krane RJ. Neurourologic abnormalities in multiple sclerosis. J Urol 1982;128:541-5. 11. Awad SA, Gajewski JB, Sogbein SK, Murray TJ, Field CA. Relationship between neurological and urological status in patients with multiple sclerosis. J Urol 1984;132:499-502. 12. Betts CD, D’Mellow MT, Fowler CJ. Urinary symptoms and the neurological features of bladder dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry 1993;56:245-50. 13. Koldewijn EL, Hommes OR, Lemmens WAJG, Debmyne FM, Van Kerrebroek PEV. Relationship between lower urinary tract abnormalities and disease-related parameters in multiple sclerosis. J Urol 1995;154:169-73. 14. Poser CM. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31, 15. Kurtzke SF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: 1444-52. 16. Mahoney F, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J Rehabil 1965;2:61-5. 17. Abrams P, Blaivas JG, Stanton SL, Anderson JT. The standardisation of terminology of lower urinary tract function. The Intemational Continence Society Committee on Standardisation of Terminology. Stand J Urol Nephrol 1988;114 Suppl:5-19. 18. Toppercer A, Tetreault JP. Compliance of the bladder: an attempt to establish normal values. Urology 1979;14:204-9. 19. McGuire EJ, Cespedes RD, O’Connell HE. Leak-point pressures. _ Urol Clin North Arn 23:253-62. 20. Giannantoni A. Scivoletto G. Di Stasi SM. Silecchia A. FinazziAgrb E, Micali F, et al. Clean intermittent catheterization and prevention of renal disease in spinal cord injury patients. Spinal Cord 1998;36:29-32. 21. Giannantoni A, Scivoletto G, Di Stasi SM, Grass0 MG, Vespasiani G, Castellano V Urological dysfunctions and upper urinary tract involvement in multiple sclerosis patients. Neurourol Urodyn 1998;17:89-98. 22. Gonor SE, Carroll DJ, Metcalfe JB. Vesical dysfunction in multiple sclerosis. Urology 1985;2.5:429-31.

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23. Grif&hs DJ, McCracken PN, Harrison GM, Gormley EA, Moore K, Hooper R, et al. Cerebral aetiology of urinary urge incontinence in elderly people. Age Ageing 1994;23:246-50. 24. Fall M, Ohlsson BL, Carlsson CA. The neurogenic overactive bladder: classification based on urodynamics. Br J Urol 1989;64: 368-73. 25. Morrison JFB. Bladder control: role of higher levels of the central nervous system. In: Torrens M, Morrison JFB, editors. The

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physiology of the lower urinary tract. London: Springer-Verlag; 1987. 26. Mayo ME, Chetner MP. Lower urinary tract dysfunction in multiple sclerosis. Urology 1992;39:67-70. 27. Gu J, Polak JM, Deane A, Cocchia A, Michetti F. Increase of S- 100 immunoreactivity in the urinary bladder from patients with multiple sclerosis, an indication of peripheral neuronal lesion. Am J Clin Pathol 1984;82:649-54.

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