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Autonomic Neuropathy and the Genitourinary System
0022-534 7/78/1193-0299$02.00/0 Vol. 119, t,fo.rch Printed in U.S.A..
UROLOGY Copyright© 1978 by The Williams & Wilkins Co.
THE JOURNAL OF
Review Article AUTONOMIC NEUROPATHY AND THE GENITOURINARY SYSTEJVI WILLIAM E. BRADLEY From the Department of Neurology, University of Minnesota, Minneapolis, Minnesota
ABSTRACT
Autonomic and pudenda! neuropathies are frequent and neglected diseases a:ffecting the genitourinary system. In the initial stages they frequently are asymptomatic. Autonomic neuropathy is seen in association with peripheral neuropathy in a wide range of metabolic diseases, including diabetes mellitus. Diagnosis can only be made directly by elect:rophysiologic methods. Treatment is based upon an adequate laboratory study of genitourinary function. There are 2 major categories of neurologic diseases affecting the genitourinary system: 1) those that result in reflex disturbances, affecting the brain and spinal cord and including stroke, Parkinson's disease, spinal cord injury and multiple sclerosis and 2) those affecting the peripheral innervation of the bladder and sex organs. The second group of neurologic diseases is referred to as peripheral neuropathy and frequently affects autonomic function and the peripheral nerve innervation of the distal portions of the upper and lower extremities. The autonomic component of this group of diseases frequently is asymptomatic at the initial onset. Recently, reflex dysfunctions of the lower urinary tract have been defined by increasing sophisticated use of cystometry.1-6 Reflex disturbances are easily elicitable and management is well defined. On the other hand, autonomic neuropathy is neglected frequently in diagnosis. Peripheral and autonomic neuropathy is caused by neuropathic change in peripheral autonomic and pudendal nerve innervation, has a greater incidence than reflex disturbances and is directly confirmable only by electrophysiological testing of peripheral pathways. 7 Monitoring of nocturnal penile tumescence also has been of significant aid in the assessment of these patients. 8 Recent pathological studies of peripheral neuropathy have provided a rational method for clinical assessment and for prognosis. 9 These initial studies accentuate the future need for examination of smooth and striated muscle biopsies in affected patients. The autonomic innervation of the bladder and sex organs consists of preganglionic, ganglionic and postganglionic components and is essentially a motor pathway. However, sensory innervation of autonomically innervated organs as well as the pudendal innervation of striated muscle sphincters also may be affected by the neuropathy and are included with autonomic neuropathy for completeness of discussion. Furthermore, this .review will necessarily reflect the bias in research efforts towards assessment of urinary dysfunction over sexual dysfunction. ETIOLOGY
The etiologies of autonomic and peripheral neuropathy are multitudinous. They may occur in 1) diabetes mellitus, 10 2) uremia, 11 3) hepatic disease, 12 4) hypothyroidism, 13 5) chronic alcoholism, 14 6) inflammatory neuropathies, 15 including Guilliai.n-Barre disease, 7) collagen vascular diseases, 16 8) association with carcinoma of certain organs, particularly the lung, 17 299
and 9) prolonged recurrent overdistension of the bladder secondary to reflex disturbances. 18 NEUROPATHOLOGY
The neuropathic change in autonomic neuropathy has been reported to affect either the myelin or Schwann layer, the axon o.r the neural filaments comprising the axon or Some neuropathies, especially those associated with diabetes mellitus, may initially affect the myelin layer covering a sensory axon. 1s-21 Thus, sensory impairment to bladder filling is observed frequently on the cystometrograms of diabetic patients. If only the myelin or Schwann layer is affected then repair by remyelination occurs. This repair myelin is associated with a slowing of the speed of action potentials traversing the axon. This slowing of conduction velocity in bladder innervation is detectable by electrophysiological laboratory studies and is of importance in the early detection of diabetic autonomic neuropathy. 22 Other neuropathies, such as those occurring in Guillain-Barre disease, may affect the axon and myelin layer, resulting in interruption of the flow of action potentials in the peripheral innervation of the genitourinary system. This interruption may result in acute urinary retention. After the acute episode reinnervation and restoration of function occur. In summary, peripheral and autonomic neuropathy may be demyelinating or axonal. Recently, autonomic and peripheral neuropathies have been characterized anatomically, physiologically and pathologically. NEUROANATOMY
The peripheral autonomic and pudendal innervation of the bladder and sexual organs has been investigated in the experimental animal. 23 , 24 These investigations have stressed the complexity of innervation and have provided the structural basis for neurophysiologic studies. However, no similar data are available in human studies except for those relating to spinal innervation. 25 These have been obtained by anesthetic blockade of individual spinal roots. Not only are there no available data on the fiber compositim:i of the innervation of the human genitourinary system but there is no single publication available on the morphology of the pelvic ganglia. A similar state exists on the course, fiber distribution and spinal localization of the pudendal nucleus in man. These studies are a necessary and useful preliminary to the
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adoption of biopsy techniques for determination of neuropathy and myopathy in the different end organs. NEUROPHYSIOLOGY
The input-output relationships of the autonomic and pudendal innervation of the pelvic viscera have been determined in the cat. 26 ' 27 These relationships have indicated synaptic organization in the spinal nuclei as well as the fiber spectrum composition of the peripheral innervation. These fiber compositions and conduction velocities have been used to establish electrophysiologic tests for detection of autonomic neuropathy in man. 22 The animal and patient studies have indicated that there are 3 peripheral neural pathways involved in normal voiding, any one or all of which may be affected by neuropathic change. These include 1) the afferent fibers of loop III, 28 resulting in incoordination of bladder evacuation, 2) loop IVB, comprising sensory and motor components of the pudendal innervation of the periurethral striated muscle, and 3) the preganglionic and postganglionic motor innervation of the smooth muscle of the urinary detrusor. Similar studies of the ejaculatory pathways have been performed in man. 29 Clinical neurophysiologic examination in man can be performed to confirm the presence of a peripheral neuropathy affecting the large nerve trunks to the muscles of the distal portions of the upper and lower extremities. This examination, consisting of electromyographic techniques, is conducted in 2 steps. Step 1. Measurement of the transit time of electrically induced action potentials in the peroneal, anterior tibial, median and ulnar nerves: Normal values of these conduction velocities have been established in the adult. In a peripheral neuropathy affecting the large nerve trunks conduction velocities may be slowed or the action potentials may be blocked. The latter results from extensive axonal interruption and is reported as a conduction block. Step 2. Needle electrode examination of the affected musculature in the extremities: When there is axonal interruption as a result of the peripheral neuropathy then denervation of the muscles results. The electrical manifestations of this denervation include the appearance of fibrillation potentials. These are short duration, low amplitude potentials appearing spontaneously in the muscle at rest. Other potentials with different configurations can be observed when reinnervation and repair occur. Clinical neurophysiologic evaluations of the peripheral innervation of the bladder and detrusor muscle have been performed also in man. These consist of insertion of a catheter with bipolar concentric electrodes mounted on the tip and at fixed distances along the shaft. Electrical stimuli are delivered to the detrusor muscle and periurethral striated muscle. These stimuli result in the production of action potentials that traverse the afferent arm of loop III or the afferent arm of loop IVB. Both of these afferent pathways end by synapsing on motoneurons in the pudendal nucleus. Impulses are then generated and result in electromyographic activity in the anal sphincter. These changes in electromyographic activity in the anal sphincter are recordable by an anal plug with surface electrodes. The transit time for the beginning of the anal sphincter contraction has been determined to be 50 to 70 msec. in healthy volunteers. With autonomic or pudenda! neuropathy, such as in diabetes mellitus, there is slowing of the conduction velocity in these pathways. To further supplement confirmation of the presence of autonomic neuropathy affecting the genitourinary system cystometry and sphincter electromyography have been reported to be of considerable value. Monitoring of nocturnal penile tumescence during sleep also has been reported to be of value in evaluation of impotence. 30
CLINICAL SYMPTOMS AND COURSE
Characteristically, peripheral neuropathy is manifested by paresthesiae in the distal portions of the extremities. Occasionally, these sensations have been reported as the only manifestations of the peripheral neuropathy in diabetes mellitus. Profound weakness of the muscles in the distal portions of the extremities also has been reported, particularly in GuillainBarre disease. There also has been reported to be involvement of other autonomic systems, including the vasomotor, alimentary tract and sweating. Clinical examination shows sensory loss in the distal portions of the extremities and the deep tendon reflexes, particularly at the ankles, have been reported as characteristically depressed. DIFFERENTIAL DIAGNOSIS
The differential diagnosis of autonomic neuropathy includes diseases affecting the cauda equina or spinal innervation of the genitourinary tract. The etiology of cauda equina injury includes 1) spinal arachnitis, 2) after traumatic injury, 3) spinal cord tumor and 4) spinal stenosis. The clinical findings unique to cauda equina injury and differentiating it from peripheral neuropathy include loss of perianal sensation, anal sphincter laxity, and hamstring muscle and buttock weakness. DIABETIC NEUROPATHY
The most thoroughly investigated peripheral and autonomic neuropathy has been that occurring in diabetes mellitus. The incidence of this disease has been estimated to affect 10 million Americans. 31 Diabetic peripheral neuropathy has been classified into symmetrical polyneuropathy and asymmetrical multiple mononeuropathy. 32 Genitourinary dysfunction has been reported to occur in association with either form of peripheral neuropathy. When bladder and sex dysfunctions occur in conjunction with symmetrical polyneuropathy they are secondary to autonomic neuropathy. When genitourinary dysfunction occurs in association with multiple mononeuropathy it can be caused by infarction of the roots of the cauda equina. Sensory neuropathy has been reported as the most frequent manifestation of a symmetrical polyneuropathy in diabetes mellitus. 33 The deep tendon reflexes in the lower extremities are absent or impaired, with the ankle reflex most frequently depressed or absent. Hypoesthesia and hypalgesia frequently occur in the hands and feet. In these patients symptoms of autonomic dysfunction in systems other than genitourinary also have been reported. These include 1) Vasomotor dysfunction manifested as postural hypotension and syncope. Recently, evidence of myocardial denervation has been reported in diabetic patients. 34 2) Disturbances of sweating, anhidrosis, have been reported to occur initially in the lower extremities, followed by a more extensive distribution. These have been indicated to be caused by a postganglionic lesion of the sudomotor fibers. 35 3) Abnormalities of esophageal and gastric function have been cited in diabetes mellitus. 36 Dysfunction of these organs, like genitourinary neuropathy, frequently is asymptomatic in the initial stages. Dilatation, reduction or absence of peristalsis and delay in emptying are visualized on radiographic examination. 4) Sexual37, 38 and bladder dysfunctions39' 40 have been reported in diabetes mellitus. The clinical assessment of diabetic cystopathy has included cystometry, denervation sensitivity testing,41 pelvic floor electromyography42 and the application of reflex-evoked potentials. 43 Investigation in the experimental animal has demonstrated correlation between neuropathic change in the myelin layer and diabetic cystopathy. Cystometry has shown detrusor areflexia and positive denervation sensitivity test. Detrusor areflexia was associated with elevation of the threshold of the first sensation of filling. Sphincter studies by needle electrode examination have been reported to show denervation poten-
AUTONOMIC NEUROPATHY AND THE GENITOURINARY SYSTEM
tials. Reflex-evoked responses have been reported in diabetic patients to show increased transit time or latency. They were demonstrated previously in healthy subjects to be from 50 to 80 msec. In a group of normal diabetic patients with normal cyst-0metric examination all patients had increased latencies. In some patients with abnormal cystometrograms no response could be evoked in the anal sphincter by stimulation of the bladder wall. This lack of response was interpreted as caused by conduction block. Patients with juvenile onset diabetes had similar responses to adult onset. No correlation was demonstrated between increased latencies and severity, and/or duration of the diabetes. These have been initial studies of diabetic cystopathy and have indicated the value of electrophysiologic techniques in the evaluation of these patients. Prospective studies are required to determine if detection of autonomic neuropathy prior to symptoms aids in establishing a program for prevention of deterioration. UREMIC NEUROPATHY
The incidence of uremic neuropathy is 65 per cent for patients prior to dialysis for chronic renal failure. Neuropathy is several times more common in male than female subjects. The duration and severity of the uremia are more important than the nature of the renal disease to the development of the neuropathy. Uremic neuropathy is characterized by sensory and motor symptoms and signs affecting the legs more than the arms. Loss of reflexes is the first physical sign of neuropathy consisting of loss of ankle jerks followed by knee jerks. The incidence of autonomic dysfunction in these patients is unknown but can be considered an impediment to the use of renal transplantation. The most reliable indicator of peripheral nerve dysfunction has been the determination of motor nerve conduction velocities. The neuropathologic features include disruption of the myelin layers and axons in the peripheral nerves. HEPATIC NEUROPATHY
In hepatic disease, such as non-alcoholic cirrhosis, examination of peripheral nerve specimens has disclosed a demyelinative type of peripheral neuropathy. These findings are distinctive from the axonal degeneration occurring in alcoholic neuropathy. Autonomic dysfunction in the genitourinary tract has not been reported but can be anticipated by modern testing. THYROID DISEASE
Diffuse peripheral neuropathy can occur in hypothyroidism and is manifested clinically by paresthesia and pain in the extremities. Loss of the ankle jerks and slowing of conduction velocities in the peripheral nerves may be present. Autonomic neuropathy has not been reported in clinical studies but can be anticipated to be detected by electrophysiologic investigations. ALCOHOLIC NEUROPATHY
The incidence of alcoholic neuropathy in chronic alcoholism has been estimated at approximately 10 per cent. There is abuse of alcohol in association with deficiency of dietary intake. The pathologic change in alcoholic neuropathy is a non-inflammatory degeneration of the peripheral nerves. The process is more intensive than in the distal segments. The layer and the axon cylinders are disrupted. INFLAMMATORY NEUROPATHIES
The most commonly recognized form of inflammatory neuropathy is Guillain-Barre disease. The major complaint is weakness. The severity of motor weakness covers a range
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from mild ataxia to paralysis of all motor nerves. Weakness occurs first in the legs and is associated with abolition of tendon reflexes. Urinary retention and loss of bladder sensation can occur early. The electromyogram shows conduction velocity in the peripheral axons. Autonomic neuropathy is common but its precise incidence has not been established. The cystometric examination shows detrusor ar· eflexia and impairment of sensation. COLLAGEN VASCULAR DISEASE
Peripheral neuropathy can occur in polyarteritis nodosa and rheumatoid arthritis. Autonomic neuropathy has not been reported clinically in these patients but can be anticipated. CARCINOMATOUS NEUROPATHY
Peripheral neuropathy occurs in patients with cancer of the lung and breast. The incidence has been estimated at l to 2 per cent. The neuropathy is primarily a sensory neuropathy. The symptoms usually are numbness and paresthesiae of the extremities. The symptoms of neuropathy may precede those of the primary tumor by 6 months. The onset is subacute with progression over a period of months. The site the associated cancer is that of lung, with oat cell the usual histologic type. 44 No reports of autonomic neuropathy have been cited in clinical studies. TREATMENT
Several questions remain to be answered in the management of patients with autonomic and pudenda! neuropathy. In the diabetic patient with impotence who is asymptomatic of urinary tract symptoms what is the treatment of choice when laboratory studies confirm the presence of neuropathy affect· ing the bladder? Only prospective studies can determine if more rigorous diabetic control can prevent progression of the disease. If the patient is symptomatic of urinary tract dysfunction but detrusor dysfunction has not occurred, as shown residual urine volume determination, then bethanechol is an ideal drug for improving smooth muscle function. The response may be increased by the presence of denervation sensitivity. However, diarrhea may impede the use of this drug. When the response of the detrusor muscle is impaired by the presence of extensive myopathy and fibrosis then clean self-intermittent catheterization, 45 with or without the use of bacterial suppressants, may give good therapeutic results The impact of treatment on the long-term prevention of bladder and renal deterioration in these patients is unknown. Neural and muscle biopsy would aid in objective assessment. Sexual dysfunction can be managed either by counseling or the insertion of a penile prosthesis. 46 Fortunately, ejaculation and orgasm frequently are preserved in the presence of pro .. found impotence. CONCLUSIONS
One of the most common and most neglected areas of lower urinary tract dysfunction secondary to neurologic disease is that of autonomic and pudenda! neuropathy. These patients frequently are asymptomatic and diagnosis is confirmed electro physiologic testing of peripheral pathways. Early detection is assumed to prevent long-term deterioration but must await prospective studies. REFERENCES
Bradley, W. E., Timm, G. W. and Scott, F. B.: Cystometry Introduction. Urology, 5: 424, 1975. 2. Bradley, W. E., Timm, G. W. and Scott, F. B.: Cystometry H Central nervous system organization of detrusor reflex. Urology, 5: 578, 1975. 3. Bradley, W. E., Timm, G. W. and Scott, F. B.: Cystometry HI. Cystometers. Urology, 5: 843, 1975. 1.
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4. Bradley, W. E., Timm, G. W. and Scott, F. B.: Cystometry IV. Neuromuscular transmission in urinary bladder. Urology, 6: 520, 1975. 5. Bradley, W. E., Timm, G. W. and Scott, F. B.: Cystometry V. Bladder sensation. Urology, 6: 654, 1975. 6. Bradley, W. E. and Timm, G. W.: Cystometry VI. Interpretation. Urology, 7: 231, 1976. 7. Andersen, J. T., Bradley, W. E. and Timm, G. W.: Electrophysiological techniques for study of urethral and vesical innervation. Scand. J. Urol. Nephrol., 10: 189, 1976. 8. Karacan, I., Williams, R. L., Thornby, J. I. and Salis, P. J.: Sleep-related penile tumescence as a function of age. Amer. J. Psychiat., 132: 932, 1975. 9. Thomas, P. K.: The morphological basis for alterations in nerve conduction in peripheral neuropathy. Proc. Roy. Soc. Med., 64: 295, 1971. 10. Jordan, W.R. and Crabtree, H. H.: Paralysis of the bladder in diabetic patients. Arch. Intern. Med., 55: 17, 1935. 11. Pakkenberg, H., Nielsen, B., Larsen, N. A. and Christoffersen, P.: Uremic polyneuropathy, clinical and pathological aspects. Z. Neurol., 200: 267, 1971. 12. Dayan, A. D. and Williams, R.: Demyelinating peripheral neuropathy and liver disease. Lancet, 2: 133, 1967. 13. Crevasse, L. E. and Logue, R. B.: Peripheral neuropathy in myxedema. Ann. Intern. Med., 50: 1433, 1959. 14. Victor, M. and Adams, R. D.: Effect of alcohol on nervous system. Res. Nerv. Ment. Dis. Proc., 32: 526, 1953. 15. Pleasure, D. E., Lovelace, R. E. and Duvoisin, R. C.: The prognosis of acute polyradiculoneuritis. Neurology, 18: 1143, 1968. 16. Prineas, J.: Polyneuropathies of undetermined cause. Acta Neurol. Scand., 46, suppl. 44, 1970. 17. Mason, R. W.: Bronchial carcinoma presenting as a polyneuritis. Lancet, 1: 203, 1948. 18. Bradley, W., Markland, C. and Chou, S.: Classifying neurologic dysfunction of the urinary bladder. In: The Neurogenic Bladder. Edited by S. Boyarsky. Baltimore: The Williams & Wilkins Co., 1967. 19. Thomas, P. K. and Lascelles, R. G.: The pathology of diabetic neuropathy. Quart. J. Med., 35: 489, 1966. 20. Chopra, J. S., Hurwitz, L. J. and Montgomery, D. A. D.: The pathogenesis of sural nerve changes in diabetes mellitus. Brain, 92: 391, 1969. 21. Chopra, J. S. and Fannin, T.: Pathology of diabetic neuropathy. J. Path., 104: 175, 1971. 22. Andersen, J. T. and Bradley, W. E.: Early detection of diabetic visceral neuropathy. Diabetes, 25: 1100, 1976. 23. Bradley, W. E. and Teague, C. T.: Spinal cord organization of micturition reflex afferents. Exp. Neurol., 22: 504, 1968. 24. Bradley, W. E.: Regulation of the micturition reflex by negative feedback. J. Urol., 101: 400, 1969. 25. Rockswold, G. L., Bradley, W. E. and Chou, S. N.: Effect of sacral nerve blocks on the function of the urinary bladder in
humans. J. Neurosurg., 40: 83, 1974. 26. Bradley, W. E. and Teague, C.: Electrophysiology of pelvic and pudenda! nerves in the cat. Exp. Neurol., 35: 378, 1972. 27. Bradley, W. E.: Urethral electromyelography. J. Urol., 108: 563, 1972. 28. Bradley, W. E., Timm, G. W. and Scott, F. B.: Innervation of the detrusor muscle and urethra. Urol. Clin. N. Amer., 1: 3, 1974. 29. Dick, H. C., Bradley, W. E., Scott, F. B. and Timm, G. W.: Pudendal sexual reflexes. Urology, 3: 376, 1974. 30. Karacan, I.: Clinical value of nocturnal erection in the prognosis and diagnosis of impotence. Med. Asps. Human Sexual., 4: 27, 1970. 31. Wintrobe, M. M.: Harrison's Principles of Internal Medicine, 3rd ed. New York: McGraw-Hill Book Co., 1974. 32. Lamontagne, A. and Buchthal, F.: Electrophysiological studies in diabetic neuropathy. J. Neurol. Neurosurg. Psychiat., 33: 442, 1970. 33. Downie, A. W. and Newell, D. J.: Sensory nerve conduction in patients with diabetes mellitus and controls. Neurology, 11: 876, 1961. 34. Wheeler, T. and Watkins, P. J.: Cardiac denervation in diabetes. Brit. Med. J., 4: 584, 1973. 35. Goodman, J. I.: Diabetic anhidrosis. Amer. J. Med., 41: 831, 1966. 36. Goyal, R. K. and Spiro, H. M.: Gastrointestinal manifestation of diabetes mellitus. Med. Clin. N. Amer., 55: 1031, 1971. 37. Rubin, A. and Babbott, D.: Impotence and diabetes mellitus. J.A.M.A., 168: 498, 1958. 38. Ellenberg, M. and Weber, H.: Retrograde ejaculation in diabetic neuropathy. Ann. Intern. Med., 65: 1237, 1966. 39. Ellenberg, M.: Diabetic neurogenic vesical dysfunction. Arch. Intern. Med., 117: 348, 1966. 40. Balfour, J. and Ankenman, G. J.: Atonic.neurogenic bladder as a manifestation of diabetic neuropathy. J. Urol., 76: 746, 1956. 41. Lapides, J., Friend, C. R., Ajemian, E. P. and Reus, W. S.: Denervation supersensitivity as a test for neurogenic bladder. Surg., Gynec. & Obst., 114: 241, 1962. 42. Fagerberg, S. E., Petersen, I., Steg, G. and Wilhelmsen, L.: Motor disturbances in diabetes mellitus. A clinical study using electromyography and nerve conduction velocity determination. Acta Med. Scand., 174: 711, 1963. 43. Andersen, J. T. and Bradley, W. E.: Abnormalities of bladder innervation in diabetes mellitus. Urology, 7: 442, 1976. 44. Croft, P. B. and Wilkinson, M.: Carcinomatous neuromyopathy, its incidence in patients with carcinoma of the lung and carcinoma of the breast. Lancet, 1: 184, 1963. 45. Lapides, J., Diokno, A. C., Lowe, B. S. and Kalish, M. D.: Followup on unsterile, intermittent self-catheterization. J. Urol., 111: 184, 1974. 46. Scott, F. B., Bradley, W. E. and Timm, G. W.: Management of erectile impotence. Use of an implantable, inflatable prosthesis. Urology, 2: 80, 1973.
UROLOGY Copyright© 1978 by The Williams & Wilkins Co.
THE JOURNAL OF
Review Article AUTONOMIC NEUROPATHY AND THE GENITOURINARY SYSTEJVI WILLIAM E. BRADLEY From the Department of Neurology, University of Minnesota, Minneapolis, Minnesota
ABSTRACT
Autonomic and pudenda! neuropathies are frequent and neglected diseases a:ffecting the genitourinary system. In the initial stages they frequently are asymptomatic. Autonomic neuropathy is seen in association with peripheral neuropathy in a wide range of metabolic diseases, including diabetes mellitus. Diagnosis can only be made directly by elect:rophysiologic methods. Treatment is based upon an adequate laboratory study of genitourinary function. There are 2 major categories of neurologic diseases affecting the genitourinary system: 1) those that result in reflex disturbances, affecting the brain and spinal cord and including stroke, Parkinson's disease, spinal cord injury and multiple sclerosis and 2) those affecting the peripheral innervation of the bladder and sex organs. The second group of neurologic diseases is referred to as peripheral neuropathy and frequently affects autonomic function and the peripheral nerve innervation of the distal portions of the upper and lower extremities. The autonomic component of this group of diseases frequently is asymptomatic at the initial onset. Recently, reflex dysfunctions of the lower urinary tract have been defined by increasing sophisticated use of cystometry.1-6 Reflex disturbances are easily elicitable and management is well defined. On the other hand, autonomic neuropathy is neglected frequently in diagnosis. Peripheral and autonomic neuropathy is caused by neuropathic change in peripheral autonomic and pudendal nerve innervation, has a greater incidence than reflex disturbances and is directly confirmable only by electrophysiological testing of peripheral pathways. 7 Monitoring of nocturnal penile tumescence also has been of significant aid in the assessment of these patients. 8 Recent pathological studies of peripheral neuropathy have provided a rational method for clinical assessment and for prognosis. 9 These initial studies accentuate the future need for examination of smooth and striated muscle biopsies in affected patients. The autonomic innervation of the bladder and sex organs consists of preganglionic, ganglionic and postganglionic components and is essentially a motor pathway. However, sensory innervation of autonomically innervated organs as well as the pudendal innervation of striated muscle sphincters also may be affected by the neuropathy and are included with autonomic neuropathy for completeness of discussion. Furthermore, this .review will necessarily reflect the bias in research efforts towards assessment of urinary dysfunction over sexual dysfunction. ETIOLOGY
The etiologies of autonomic and peripheral neuropathy are multitudinous. They may occur in 1) diabetes mellitus, 10 2) uremia, 11 3) hepatic disease, 12 4) hypothyroidism, 13 5) chronic alcoholism, 14 6) inflammatory neuropathies, 15 including Guilliai.n-Barre disease, 7) collagen vascular diseases, 16 8) association with carcinoma of certain organs, particularly the lung, 17 299
and 9) prolonged recurrent overdistension of the bladder secondary to reflex disturbances. 18 NEUROPATHOLOGY
The neuropathic change in autonomic neuropathy has been reported to affect either the myelin or Schwann layer, the axon o.r the neural filaments comprising the axon or Some neuropathies, especially those associated with diabetes mellitus, may initially affect the myelin layer covering a sensory axon. 1s-21 Thus, sensory impairment to bladder filling is observed frequently on the cystometrograms of diabetic patients. If only the myelin or Schwann layer is affected then repair by remyelination occurs. This repair myelin is associated with a slowing of the speed of action potentials traversing the axon. This slowing of conduction velocity in bladder innervation is detectable by electrophysiological laboratory studies and is of importance in the early detection of diabetic autonomic neuropathy. 22 Other neuropathies, such as those occurring in Guillain-Barre disease, may affect the axon and myelin layer, resulting in interruption of the flow of action potentials in the peripheral innervation of the genitourinary system. This interruption may result in acute urinary retention. After the acute episode reinnervation and restoration of function occur. In summary, peripheral and autonomic neuropathy may be demyelinating or axonal. Recently, autonomic and peripheral neuropathies have been characterized anatomically, physiologically and pathologically. NEUROANATOMY
The peripheral autonomic and pudendal innervation of the bladder and sexual organs has been investigated in the experimental animal. 23 , 24 These investigations have stressed the complexity of innervation and have provided the structural basis for neurophysiologic studies. However, no similar data are available in human studies except for those relating to spinal innervation. 25 These have been obtained by anesthetic blockade of individual spinal roots. Not only are there no available data on the fiber compositim:i of the innervation of the human genitourinary system but there is no single publication available on the morphology of the pelvic ganglia. A similar state exists on the course, fiber distribution and spinal localization of the pudendal nucleus in man. These studies are a necessary and useful preliminary to the
300
BRADLEY
adoption of biopsy techniques for determination of neuropathy and myopathy in the different end organs. NEUROPHYSIOLOGY
The input-output relationships of the autonomic and pudendal innervation of the pelvic viscera have been determined in the cat. 26 ' 27 These relationships have indicated synaptic organization in the spinal nuclei as well as the fiber spectrum composition of the peripheral innervation. These fiber compositions and conduction velocities have been used to establish electrophysiologic tests for detection of autonomic neuropathy in man. 22 The animal and patient studies have indicated that there are 3 peripheral neural pathways involved in normal voiding, any one or all of which may be affected by neuropathic change. These include 1) the afferent fibers of loop III, 28 resulting in incoordination of bladder evacuation, 2) loop IVB, comprising sensory and motor components of the pudendal innervation of the periurethral striated muscle, and 3) the preganglionic and postganglionic motor innervation of the smooth muscle of the urinary detrusor. Similar studies of the ejaculatory pathways have been performed in man. 29 Clinical neurophysiologic examination in man can be performed to confirm the presence of a peripheral neuropathy affecting the large nerve trunks to the muscles of the distal portions of the upper and lower extremities. This examination, consisting of electromyographic techniques, is conducted in 2 steps. Step 1. Measurement of the transit time of electrically induced action potentials in the peroneal, anterior tibial, median and ulnar nerves: Normal values of these conduction velocities have been established in the adult. In a peripheral neuropathy affecting the large nerve trunks conduction velocities may be slowed or the action potentials may be blocked. The latter results from extensive axonal interruption and is reported as a conduction block. Step 2. Needle electrode examination of the affected musculature in the extremities: When there is axonal interruption as a result of the peripheral neuropathy then denervation of the muscles results. The electrical manifestations of this denervation include the appearance of fibrillation potentials. These are short duration, low amplitude potentials appearing spontaneously in the muscle at rest. Other potentials with different configurations can be observed when reinnervation and repair occur. Clinical neurophysiologic evaluations of the peripheral innervation of the bladder and detrusor muscle have been performed also in man. These consist of insertion of a catheter with bipolar concentric electrodes mounted on the tip and at fixed distances along the shaft. Electrical stimuli are delivered to the detrusor muscle and periurethral striated muscle. These stimuli result in the production of action potentials that traverse the afferent arm of loop III or the afferent arm of loop IVB. Both of these afferent pathways end by synapsing on motoneurons in the pudendal nucleus. Impulses are then generated and result in electromyographic activity in the anal sphincter. These changes in electromyographic activity in the anal sphincter are recordable by an anal plug with surface electrodes. The transit time for the beginning of the anal sphincter contraction has been determined to be 50 to 70 msec. in healthy volunteers. With autonomic or pudenda! neuropathy, such as in diabetes mellitus, there is slowing of the conduction velocity in these pathways. To further supplement confirmation of the presence of autonomic neuropathy affecting the genitourinary system cystometry and sphincter electromyography have been reported to be of considerable value. Monitoring of nocturnal penile tumescence during sleep also has been reported to be of value in evaluation of impotence. 30
CLINICAL SYMPTOMS AND COURSE
Characteristically, peripheral neuropathy is manifested by paresthesiae in the distal portions of the extremities. Occasionally, these sensations have been reported as the only manifestations of the peripheral neuropathy in diabetes mellitus. Profound weakness of the muscles in the distal portions of the extremities also has been reported, particularly in GuillainBarre disease. There also has been reported to be involvement of other autonomic systems, including the vasomotor, alimentary tract and sweating. Clinical examination shows sensory loss in the distal portions of the extremities and the deep tendon reflexes, particularly at the ankles, have been reported as characteristically depressed. DIFFERENTIAL DIAGNOSIS
The differential diagnosis of autonomic neuropathy includes diseases affecting the cauda equina or spinal innervation of the genitourinary tract. The etiology of cauda equina injury includes 1) spinal arachnitis, 2) after traumatic injury, 3) spinal cord tumor and 4) spinal stenosis. The clinical findings unique to cauda equina injury and differentiating it from peripheral neuropathy include loss of perianal sensation, anal sphincter laxity, and hamstring muscle and buttock weakness. DIABETIC NEUROPATHY
The most thoroughly investigated peripheral and autonomic neuropathy has been that occurring in diabetes mellitus. The incidence of this disease has been estimated to affect 10 million Americans. 31 Diabetic peripheral neuropathy has been classified into symmetrical polyneuropathy and asymmetrical multiple mononeuropathy. 32 Genitourinary dysfunction has been reported to occur in association with either form of peripheral neuropathy. When bladder and sex dysfunctions occur in conjunction with symmetrical polyneuropathy they are secondary to autonomic neuropathy. When genitourinary dysfunction occurs in association with multiple mononeuropathy it can be caused by infarction of the roots of the cauda equina. Sensory neuropathy has been reported as the most frequent manifestation of a symmetrical polyneuropathy in diabetes mellitus. 33 The deep tendon reflexes in the lower extremities are absent or impaired, with the ankle reflex most frequently depressed or absent. Hypoesthesia and hypalgesia frequently occur in the hands and feet. In these patients symptoms of autonomic dysfunction in systems other than genitourinary also have been reported. These include 1) Vasomotor dysfunction manifested as postural hypotension and syncope. Recently, evidence of myocardial denervation has been reported in diabetic patients. 34 2) Disturbances of sweating, anhidrosis, have been reported to occur initially in the lower extremities, followed by a more extensive distribution. These have been indicated to be caused by a postganglionic lesion of the sudomotor fibers. 35 3) Abnormalities of esophageal and gastric function have been cited in diabetes mellitus. 36 Dysfunction of these organs, like genitourinary neuropathy, frequently is asymptomatic in the initial stages. Dilatation, reduction or absence of peristalsis and delay in emptying are visualized on radiographic examination. 4) Sexual37, 38 and bladder dysfunctions39' 40 have been reported in diabetes mellitus. The clinical assessment of diabetic cystopathy has included cystometry, denervation sensitivity testing,41 pelvic floor electromyography42 and the application of reflex-evoked potentials. 43 Investigation in the experimental animal has demonstrated correlation between neuropathic change in the myelin layer and diabetic cystopathy. Cystometry has shown detrusor areflexia and positive denervation sensitivity test. Detrusor areflexia was associated with elevation of the threshold of the first sensation of filling. Sphincter studies by needle electrode examination have been reported to show denervation poten-
AUTONOMIC NEUROPATHY AND THE GENITOURINARY SYSTEM
tials. Reflex-evoked responses have been reported in diabetic patients to show increased transit time or latency. They were demonstrated previously in healthy subjects to be from 50 to 80 msec. In a group of normal diabetic patients with normal cyst-0metric examination all patients had increased latencies. In some patients with abnormal cystometrograms no response could be evoked in the anal sphincter by stimulation of the bladder wall. This lack of response was interpreted as caused by conduction block. Patients with juvenile onset diabetes had similar responses to adult onset. No correlation was demonstrated between increased latencies and severity, and/or duration of the diabetes. These have been initial studies of diabetic cystopathy and have indicated the value of electrophysiologic techniques in the evaluation of these patients. Prospective studies are required to determine if detection of autonomic neuropathy prior to symptoms aids in establishing a program for prevention of deterioration. UREMIC NEUROPATHY
The incidence of uremic neuropathy is 65 per cent for patients prior to dialysis for chronic renal failure. Neuropathy is several times more common in male than female subjects. The duration and severity of the uremia are more important than the nature of the renal disease to the development of the neuropathy. Uremic neuropathy is characterized by sensory and motor symptoms and signs affecting the legs more than the arms. Loss of reflexes is the first physical sign of neuropathy consisting of loss of ankle jerks followed by knee jerks. The incidence of autonomic dysfunction in these patients is unknown but can be considered an impediment to the use of renal transplantation. The most reliable indicator of peripheral nerve dysfunction has been the determination of motor nerve conduction velocities. The neuropathologic features include disruption of the myelin layers and axons in the peripheral nerves. HEPATIC NEUROPATHY
In hepatic disease, such as non-alcoholic cirrhosis, examination of peripheral nerve specimens has disclosed a demyelinative type of peripheral neuropathy. These findings are distinctive from the axonal degeneration occurring in alcoholic neuropathy. Autonomic dysfunction in the genitourinary tract has not been reported but can be anticipated by modern testing. THYROID DISEASE
Diffuse peripheral neuropathy can occur in hypothyroidism and is manifested clinically by paresthesia and pain in the extremities. Loss of the ankle jerks and slowing of conduction velocities in the peripheral nerves may be present. Autonomic neuropathy has not been reported in clinical studies but can be anticipated to be detected by electrophysiologic investigations. ALCOHOLIC NEUROPATHY
The incidence of alcoholic neuropathy in chronic alcoholism has been estimated at approximately 10 per cent. There is abuse of alcohol in association with deficiency of dietary intake. The pathologic change in alcoholic neuropathy is a non-inflammatory degeneration of the peripheral nerves. The process is more intensive than in the distal segments. The layer and the axon cylinders are disrupted. INFLAMMATORY NEUROPATHIES
The most commonly recognized form of inflammatory neuropathy is Guillain-Barre disease. The major complaint is weakness. The severity of motor weakness covers a range
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from mild ataxia to paralysis of all motor nerves. Weakness occurs first in the legs and is associated with abolition of tendon reflexes. Urinary retention and loss of bladder sensation can occur early. The electromyogram shows conduction velocity in the peripheral axons. Autonomic neuropathy is common but its precise incidence has not been established. The cystometric examination shows detrusor ar· eflexia and impairment of sensation. COLLAGEN VASCULAR DISEASE
Peripheral neuropathy can occur in polyarteritis nodosa and rheumatoid arthritis. Autonomic neuropathy has not been reported clinically in these patients but can be anticipated. CARCINOMATOUS NEUROPATHY
Peripheral neuropathy occurs in patients with cancer of the lung and breast. The incidence has been estimated at l to 2 per cent. The neuropathy is primarily a sensory neuropathy. The symptoms usually are numbness and paresthesiae of the extremities. The symptoms of neuropathy may precede those of the primary tumor by 6 months. The onset is subacute with progression over a period of months. The site the associated cancer is that of lung, with oat cell the usual histologic type. 44 No reports of autonomic neuropathy have been cited in clinical studies. TREATMENT
Several questions remain to be answered in the management of patients with autonomic and pudenda! neuropathy. In the diabetic patient with impotence who is asymptomatic of urinary tract symptoms what is the treatment of choice when laboratory studies confirm the presence of neuropathy affect· ing the bladder? Only prospective studies can determine if more rigorous diabetic control can prevent progression of the disease. If the patient is symptomatic of urinary tract dysfunction but detrusor dysfunction has not occurred, as shown residual urine volume determination, then bethanechol is an ideal drug for improving smooth muscle function. The response may be increased by the presence of denervation sensitivity. However, diarrhea may impede the use of this drug. When the response of the detrusor muscle is impaired by the presence of extensive myopathy and fibrosis then clean self-intermittent catheterization, 45 with or without the use of bacterial suppressants, may give good therapeutic results The impact of treatment on the long-term prevention of bladder and renal deterioration in these patients is unknown. Neural and muscle biopsy would aid in objective assessment. Sexual dysfunction can be managed either by counseling or the insertion of a penile prosthesis. 46 Fortunately, ejaculation and orgasm frequently are preserved in the presence of pro .. found impotence. CONCLUSIONS
One of the most common and most neglected areas of lower urinary tract dysfunction secondary to neurologic disease is that of autonomic and pudenda! neuropathy. These patients frequently are asymptomatic and diagnosis is confirmed electro physiologic testing of peripheral pathways. Early detection is assumed to prevent long-term deterioration but must await prospective studies. REFERENCES
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