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Neurogenic Disorders of Micturition
Common Neurologic Problems
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Neurogenic Disorders of Micturition
Dennis O'Brien, DVM, PhD*
Disorders of micturition are a common sequelae to neurologic disease occurring anywhere from the sacral cord and its nerves to the frontal cortex. In human beings, renal disease is one of the most frequent causes of death in patients with injuries to the spinal cord, accounting for up to 40 per cent of the fatalities . 21 In veterinary medicine, urinary complications of neurologic disease are even more of a problem because an incontinent pet is often unacceptable to the owner and is subsequently euthanatized. Fortunately, research and clinical experience over the last 15 years have contributed a great deal to our understanding of how the lower urinary tract functions, how those functions are disrupted by neurologic disease, and how they can be manipulated pharmacologically to make the animal a more acceptable pet.
NORMAL FUNCTION OF THE LOWER URINARY TRACT Anatomy The lower urinary tract is composed of the bladder and urethra and their associated musculature (Fig. 1). The bladder serves as the reservoir for the storage of urine between voidings. The bladder wall contains a layer of smooth muscle, the detrusor muscle, which contracts during micturition to expel urine from the bladder. 7, 38 In other tissues, smooth muscle cells are joined by tight junctions that allow transmission of excitation between muscle cells without a one-to-one innervation. However, there is currently no evidence that such electrical coupling plays a significant role in the detrusor muscle. 18 The musculature of the urethra serves as a sphincter to prevent leakage of urine during storage. The neck of the bladder and the proximal urethra contain smooth muscle that forms the internal urethral sphincter. 7 • II, 12,33. 38 In the cat, the internal sphincter is composed of circular layers that act 'Diplomate, American College of Veterinary Internal Medicine (Neurology); Assistant Professor of Neurology, Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, Missouri Veterinary Clinics of North America: Small Animal Practice-Vol. 18, No.3, May 1988
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DetftJ$Or internal urethral sphincter external urethral sphincter
/r'~d;~Figure 1. Anatomy of the bladder and urethra. The bladder contains a layer of smooth muscle, the detrusor. The urethral sphincter is composed of a smooth muscle internal sphincter and a striated muscle external sphincter. The muscles of the pelvic diaphragm also provide sphincter-like function .
as a sphincter and longitudinal layers that probably serve to open the urethra during micturition. 12. 24 In the dog, circular and oblique fibers are intermixed, and only sphincter functions have been described. I . 2. II The internal sphincter lies largely within the abdominal cavity, so that any increase in intraabdominal pressure, such as occurs during coughing, is transmitted to the sphincter as well as the bladder, aiding in the maintenance of continence. 2o In the distal portions of the urethra, a layer of striated muscle forms the external urethral sphincter. lB. 37. 38 The muscles of the pelvic diaphragm also provide voluntary sphincter function to the distal urethra. lB. 37 Motor Innervation The efferent (motor) innervation of the lower urinary tract has somatic, sympathetic, and parasympathetic components (Fig. 2A). The somatic innervation via the pudendal nerve arises from sacral cord segments (primarily SI-2 with some contribution of L7 and S346. 53. 64). The pudendal nerve provides voluntary control over the external urethral sphincter and perineal musculature. lB. 36. 37 Sympathetic innervation arises from the lumbar cord (LI-4 in the dog;51. 52 L2-5 in cat46). These nerves synapse in the caudal mesenteric ganglia and then form the hypogastric nerve. The hypogastric nerve provides adrenergic innervation to the bladder, to pelvic (parasympathetic) ganglia, and to the internal urethral sphincter. 14. 15. 18.37 The receptors within the bladder are predominantly beta-adrenergic rec,eptors, which, when stimulated, produce relaxation of the detrusor muscle. 32. 33. 43 The internal urethral sphincter contains primarily alpha-adrenergic receptors, which cause constriction of the sphincter, 1.32.33 although beta-adrenergic relaxation has also been demonstrated. I In addition, sympathetic innervation of the pelvic ganglia appears to inhibit parasympathetic activity during bladder filling . 14. 15 Parasympathetic innervation originates in .the sacral cord (SI-346. 51. 52. 60) and forms the pelvic nerves. These preganglionic neurons synapse in the pelvic plexus and ganglia within the bladder wall. The postganglionic
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8 Figure 2. A, Efferent innervation of the bladder and urethra with somatic (pudendal nerve), sympathetic (hypogastric nerve), and parasympathetic (pelvic nerve) components. The somatics control external sphincter tone. The sympathetics promote bladder filling by inhibiting bladder contraction and increasing internal sphincter tone. Parasympathetics stimulate bladder contraction . Reciprocal urethral and detrusor functions are coordinated by the brain-stem micturition center, which is in turn under voluntary control of higher centers. B, Afferent innervation of the bladder and urethra. Stretch receptors in the bladder transmit information on distention via the pelvic nerve. Pain receptors in the bladder relay information on overdistention via the pelvic and hypogastric nerves. The pudendal nerve carries information on stretch, flow, and pain from the urethra. All relay information to the brain-stem micturition center and to higher centers via the thalamus.
parasympathetic nerves provide cholinergic innervation, primarily to the detrusor, causing contraction during micturition. 14, 15, 18, 37 Sensory Innervation An equally important, although often overlooked, component of the innervation of the lower urinary tract is the afferent (sensorS') innervation (Fig. 2B). Stretch receptors in the bladder wall detect fullness of the bladder and trigger micturition through afferents in the pelvic nerves. In addition, there are nerve endings in the submucosa of the bladder that only respond to extreme distention of the bladder and are probably pain receptors. These nerves project to the lumbar and sacral cord via the hypogastric and pelvic nerves, respectively. Afferents from the urethra detecting flow, distention, and pain also project to the sacral cord via the pudendal nerve. 14, 15, 18. 37
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Central Integration In the neonatal kitten and puppy, micturition is a sacral spinal reflex elicited by the licking of the perineum by the mother. 14. 19 This local reflex control is lost at 7 to 12 weeks in kittens l4 and 3 to 4 weeks in puppies, 19 and sacral micturition reflexes can no longer be elicited. 14 Relaxation of the bladder and some sphincter functions continue to be mediated at the spinal level in adults,14. 18 but the major control of voiding resides in the brain stem at the level of the pons.5 This brain-stem micturition center receives sensory information from the stretch and pain receptions in the bladder and responds to distention by coordinating sphincter relaxation with detrusor contraction to produce micturition. 14. 15. 18 Voluntary control of the brain stem micturition center involves a number of higher brain areas , including the cerebral cortex, basal ganglia, thalamus, and even the cerebellum. Most exert an inhibitory influence over micturition, although facilitative influences have also been described.8. 14. 15. 18. 34 Physiology of Micturition Normal function of the lower urinary tract involves a reciprocal relationship between the detrusor and urethral sphincter. This allows for low-pressure filling of the bladder during the storage phase and permits low-pressure expulsion of the urine during the voiding phase. 14. 15.31. 37. 38 During the storage phase (Fig. 3A), contraction of the urethral sphincters prevents leakage of urine through the urethra and maintains continence. The internal, involuntary sphincter receives tonic alpha-adrenergic stimulation via the hypogastric nerve. 14. 32. 33 The external sphincter maintains constant tone but also contains fast-twitch muscle fibers that respond quickly to temporary increases in pressure. 2. 18 In addition, contraction of the external sphincter tends to suppress the micturition reflex. 38 Beta-adrenergic sympathetics directly inhibit the detrusor muscle, promoting lowpressure filling of the bladder. 14. 18. 43 In addition, other sympathetics inhibit transmission through the parasympathetic ganglia, which decreases cholinergic stimulation of the detrusor. 14. 37 When bladder capacity is approached, stretch receptors in the bladder signal the brain-stem micturition center of the need for micturition (Fig. 3B).14. 15. 18. 37 Voluntary initiation of micturition involves contraction of the abdominal muscles and relaxation of the perineal muscles. 15 This is followed by an increase in parasympathetic input to the bladder and a contraction of the detrusor. The initiation of a detrusor contraction inhibits alphaadrenergic tone to the urethral sphincter. 14.15 In addition, there is probably beta-adrenergic inhibition of the sphincter24 . 32 and, in the cat, active opening of the sphincter by the longitudinal fibers. 12. 2'4 The coordination of detrusor contraction and sphincter relaxation allows for voiding but prevents high pressures from developing within the bladder. The sensation of urine flow through the urethra provides secondary reinforcement of the micturition reflex and facilitates complete emptying of the bladder. 15 EFFECTS OF LESIONS Sphincter or Detrusor Muscles Primary sphincter incompetence is most commonly seen in neutered female dogs but is also seen in neutered males. 4.26.27 Even though neutered
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B
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Figure 3. A, Filling/storage phase. Bladder tone is actively inhibited by beta-adrenergic innervation of the detrusor. Urethral closure is maintained by alpha-adrenergic innervation of the internal sphincter and cholinergic innervation of the external sphincter. B, Voiding phase. Detrusor contraction is initiated by cholinergic parasympathetics. Sphincter relaxation is mediated by decreased alpha-adrenergic and somatic cholinergic influence on the internal and external sphincter, respectively. Active sphincter relaxation and opening may be mediated via adrenergic innervation of the sphincter and cholinergic innervation of longitudinal fibers of the urethra in the cat (not shown).
animals show little change in their basal hormone levels, 56 the removal of the gonads somehow alters internal sphincter function, rendering a certain percentage of neutered animals incontinent. Urethral pressure profiles may show a decrease in sphincter tone. Estrogens have been shown to promote alpha-adrenergic effects at the internal sphincter. 10 Primary sphincter incompetence results in incontinence, which tends to be worse when the animal is recumbent or sleeping and may be exaggerated by excitement or movement. 4. 26 Because only the sphincter is involved: the animals are capable of normal micturition and have little residual urine after urination. Obstruction of the outflow of urine, either through mechanical obstruction or sphincter spasm, can result in overdistention of the bladder. If the distention is not relieved promptly, permanent atony of the detrusor muscle may result. 20.37.49 Because, as stated earlier, there is no good evidence that tight junctions play a significant role in the detrusor muscle, the atony probably results from direct injury to the muscle cells or their innervation, rather than disruption of tight junctions_18. 37. 38 The result is an atonic,
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unresponsive bladder. The animal is incapable of normal micturition and has a large residual volume of urine. Sphincter tone may be normal or increased, and the resistance to expression of the bladder would be proportional. If there is not complete obstruction, the animal may show overflow incontinence once the pressure in the bladder exceeds the urethral resistance. Sacral Cord and Nerves: The Lower Motor Neuron Bladder Lesions of the sacral cord, cauda equina, or pelvic and pudendal nerves abolish both voluntary and reflex micturition, producing what is referred to as the lower motor neuron (LMN) bladder.7 Experimentally, denervation of the bladder does not result in a complete loss of bladder tone, and the complete bladder atony seen in clinical cases is probably secondary to overdistention and infection more than denervation. 2o. 37 Nonetheless, detrusor contraction is abolished and the bladder retains a large residual volume of urine . With complete lesions, the external sphincter is also denervated and develops flaccid paralysis. 37. 38. 49 Because the internal sphincter is innervated by the hypogastric nerve originating in the lumbar cord, innervation to the internal sphincter can remain intact. The sacral lesion abolishes normal sensory input from stretch receptors in the detrusor; thus, the internal sphincter cannot respond to increased bladder pressure with relaxation and remains fixed. 18, 37 As a result, the distended bladder may be easy to express or show resistance. Once the bladder fills, overflow incontinence will result. Some pain receptors in the hypogastric nerve may also be spared so that the animal may have a sensation of discomfort and make unsuccessful attempts to urinate. 18. 20 Generally, other signs of sacral cord or nerve involvement would be expected, such as fecal incontinence, hindlimb ataxia/paresis, loss of anal and bulbocavernous reflexes, and loss of sensation to appropriate dermatomes. Feline dysautonomia is characterized by a degeneration of the peripheral autonomic nervous system; thus, it is associated with loss of bladder function in 17 to 18 per cent of the cases. The cats become incontinent, and the bladder is atonic. There is little involvement of somatic components, although the anal reflex may be lost. Other signs of autonomic disturbance such as dilated pupils, dry mucous membranes, and gastrointestinal disturbances are inevitably present. 23, 57, 61 Suprasacral Spinal Lesions: The Upper Motor Neuron Bladder Lesions above the sacral cord level and below the pons disrupt the normal coordination of micturition by the brain-stem micturition center. 14, 15, 37 Initially, a complete lesion abolishes the micturition'response. Although originally thought to represent a "spinal shock" phenomena, the initial loss appears to be more of a loss of normal coordination (dyssynergia, see below) than a true spinal shock. 25 In cats, a coordinated micturition reflex in response to bladder distention returns over a period of time (4 to 38 days in experimental studies 14 , 15,54). This upper motor neuron (UMN) or "reflex" bladder is a purely sacral reflex without voluntary control. With the development of the UMN bladder, the neonatlil micturition response to perineal stimulation may also return. 14 Secondary reinforcement of mictu-
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rition is lost; thus, these spinal reflex responses are usually weak and incomplete, leaving a large residual volume of urine following voiding. In dogs, the presence of spinal reflex control of micturition following cord transection has been questioned,49 although the author has seen reflexive urination in response to perineal stimulation in a dog with chronic transverse cord injury at the TL region. With the UMN bladder, the urethral sphincters usually become hypertonic, although normal tone or atonia may also be present. 20, 38, 49, 54 When hypertonicity develops, the bladder is very difficult to express. If detrusor contractions return, then a condition of reflex dyssynergia may develop. In reflex dyssynergia, the normal coordination of sphincter relaxation and detrusor contraction is disrupted, so that the detrusor contracts against a constricted sphincter. 37, 48, 67 This can be due to hypertonicity of either the internal sphincter or, more commonly, the external sphincter. Although dyssynergia is a common problem in human beings with spinal injuries,37, 67 its existence in dogs has been questioned. 49 Suprasacral spinal injury would be associated with other signs of UMN involvement such as exaggerated myotatic reflexes and postural reaction deficits, Brain-stem lesions would affect cranial nerves as well as motor and sensory tracts. Higher Lesions: Voluntary Control Lesions above the level of the pons do not generally abolish micturition but do affect voluntary control of it. 8, 18, 38, 55 This may result in either urge incontinence or unconscious urination. With urge incontinence, the animal has a warning that micturition is about to occur but cannot stop it from occurring. Nocturia is common. The volume of urine voided can vary from smaller to larger than normal but -the postvoiding residual is low. 38, 55 In unconscious urination, there is no awareness or control, and micturition occurs whenever threshold is reached. The detrusor may become hyperreflexic, resulting in a low threshold and frequent, lowvolume urinations, The residual urine volume is low. Urination tends to be equally frequent during the night or day. 38, 55 Depending on the location of the lesion, other signs reflecting damage to that area would be expected. Thus, with cerebral, limbic, or hypothalamic lesions, behavioral changes may occur, With thalamic or basal ganglia lesions, there should be sensory or motor deficits, respectively. Cerebellar lesions would produce typical signs of dysmetria and tremors, DIAGNOSTIC APPROACH The diagnostic approach to a patient with a disorder of micturition involves attempting to define the type of disorder, establishing whether the disorder is neurogenic, localizing the lesion if it is neurogenic, establishing the etiology, and, if the underlying cause cannot be eliminated, devising rational symptomatic therapy. The clinical approach to such a . patient is summarized in Table 1. 41, 42, 49, 55, 59 It includes a thorough history with emphasis on the pattern of urination
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Table 1. Clinical Evaluation of the Patient with a Disorder of Micturition HISTORY
Neutering or other urogenital surgeries Housebreaking and patterns prior to onset of signs Onset and progression of signs Voluntary attempts to urinate-success of attempts, straining Frequency, pattern (nocturnal, daytime, both), awareness Volume of urination or leakage Behavioral changes, defecation, gait abnormalities PHYSICAL EXAM
Rectal exam-anal tone, prostate Bladder palpation-size (pre- and post-voiding), tone, resistance to expression Observe urination--control, awareness, stream, ability to interrupt NEUROLOGIC EXAM
Mental status Motor functions Perineal sensation Sacral reflexes INITIAL DATABASE
Measure post-voiding volume of urine Urinalysis and culture Metabolic profile Radiographs-urethrogram, cystogram, IVP, spinal URODYNAMIC STUDIES
Cystometrogram and flowmetry Urethral pressure profile Sphincter and perineal muscles (EMG) Pudendal evoked potential Bulbocavernosus latency
or incontinence, behavioral changes, and other signs of neurologic disease. A thorough physical examination should include palpation of the prostate and assessment of bladder size, tone, and ease of expression. Urination should be observed, if possible, and postvoiding urine volume measured. Normal postvoiding residual should be less than 0.2 to 0.4 ml per kg, or about 10 m!. 42. 49 A thorough neurologic examination should assess mental status, motor function, perineal sensation, anal tone, and sacral reflexes. A chemistry profile will aid in ruling out metabolic diseases, such as diabetes and hypothyroidism, that may secondarily produce neurogenic disorders. A urinalysis and urine culture not only rule out a current infectious etiology but also serve as a baseline for detection of future problems. Radiographic examination of the lower and upper urinary tract rules out structural problems and proVides baseline infQrmation for monitoring the effects of neurogenic disorders. Spinal studies may be necessary to rule out an operable lesion. Electrophysiologic tests are not readily available except at referral institutions. Generally, a reasonable diagnosis can be made and a rational approach to therapy devised based on the initial database. However, in cases in which questions exist, response to therapy is inadequate, or irreversible surgical corrections are considered, slectrodiagnostics may be necessary to precisely define the nature of the dysfunction. The cystometrogram is a measure of pressure within the bladder during
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filling and detrusor contraction. It provides information on the compliance of the bladder, threshold of the detrusor reflex, and strength of contraction. 40. 47 Sensitivity of the bladder to direct-acting cholinergic drugs such as bethanechol can also be measured by cystometrogram. When the bladder is denervated, it becomes supersensitive to cholinergic stimulation and will respond to doses of bethanechol that would not affect a normal bladder. 17. 50 By simultaneously recording EMG from the urethral sphincter, the degree of coordination between detrusor contraction and sphincter relaxation can be assessed and dyssynergia detected. 49 In cases of dyssynergia or mechanical obstruction, the pressure developed by detrusor contraction can be critical information, because major complications such as ureteral reflux and ascending infections occur at higher bladder pressures (greater than 40 cm H 20 in human beings38) and may require aggressive measures to control. The urethral pressure profile provides a measure of resting sphincter tone throughout the urethra. It can detect sphincter incompetence and obstruction. 22. 49. 58 The resting pressure, however, may not correlate with a functional problem. 49 A more accurate assessment of urethral resistance can be made by measuring urine flow during a cystometrogram (uroflowmetry).40 However, the technique is more invasive and may present undue risk to a patient with urinary tract infection or other complications. 49 Electromyography of the perineal musculature can be useful in detecting LMN involvement of other muscles innervated by the sacral cord segments. Care must be taken in interpreting anal sphincter EMG because spontaneous activity can be difficult to interpret. 44. 62 Sensory function of the pudendal nerve and spinal pathways can be assessed by recording somatosensory evoked potentials from the brain or spinal cord following pudendal nerve stimulation. 53 Reflex evoked muscle potential can also be studied in the perineum to assess integrity of the pudendal nerve and sacral cord segments. By stimulating the dorsal nerve of the clitoris or penis and recording from the anal sphincter, the bulbocavernosus reflex can be objectively assessed. Electrophysiologic measures are more sensitive in detecting the presence of weak reflexes and provide information on latency and amplitude of the response. 45 Routine nerve conduction studies can also help rule out diffuse neuropathies. CLASSIFICATION OF DISORDERS AND RATIONAL THERAPY
If the underlying cause of the micturition disorder cannot be treated directly (for example, in irreversible spinal cord injury), then therapy must be directed at relieving at least those signs associated with the greatest morbidity. In order to do so, it is necessary to be able to functionally classify the disorder so that one can arrive at a rational therapy. Numerous classification schemes for neurogenic disorders of micturition have been described. 7. 20. 65 Although some may be more accurate in localizing the lesion and describing the disorder, a relatively simple classification that directs therapy appropriately divides the problem into disorders of the storage phase and those of the voiding phase, then further subdivides these
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Table 2. Classification and Therapy of Disorders of Micturition DISORDER
OBJECTIVE
AGENTS
Storage Phase Sphincter Bladder
Enhance sphincter tone Decrease bladder contraction
Alpha agonists Anticholinergics Muscle relaxants Beta agonists? Calcium channel blockers?
Voiding Phase Internal sphincter External sphincter
Decrease sphincter tone Decrease sphincter tone
Alpha antagonists Central muscle relaxants Direct muscle relaxants
Enhance bladder contraction
Cholinergics? Beta agonists?
Bladder Mixed
Correct most serious problem
? = Drugs that have not been fully evaluated clinically or have questionable efficacy.
into disorders caused by the sphincter and those caused by the bladder (Table 2).65 FAILURE OF STORAGE The storage phase requires accommodation of increasing volumes of urine at low pressure, absence of inappropriate detrusor contractions, and a closed urethral sphincter. Disruption of any of these functions can result in incontinence. 65 Appropriate therapy will depend on whether there is failure of the sphincter or the bladder. Dosages for the more commonly used drugs are summarized in Table 3. It should be noted that most of the drug dosages are empirical. It is wise to start at the lower end of the dose range and titrate the dosage depending on side effects and efficacy. Failure of Storage Due to the Sphincter In cases in which sphincter incompetence exists, therapy will be directed at increasing sphincter tone. This can be accomplished by increasTable 3. Most Commonly Used Drug Dosages CLASS
Cholinergic Anticholinergic Alpha agonist Alpha antagonist Beta agonist Beta antagonist Smooth muscle relaxants Skeletal muscle relaxants
DRUG
Bethanechol Propantheline Phenylpropanolamine Phenoxybenzamine Salbutamol Propranolol Oxybutynin Aminopromazine Flavoxate Dantrolene Diazepam
DOG
CAT
2.5-25 mg, tid 7.5-30 mg, bid-tid 1.5 mg/kg, tid
2.5-5 mg, tid 7.5 mg, tid
0.5 mg/kg, sid-tid 1 mg, tid 10 mg, tid 2-5 mg, bid-tid 2 mg/kg, bid 100-200 mg, tid-gid 1-5 mg/kg, bid 2-10 mg, tid-qid
Same 5 mg, tid 1 mg, bid Same 0.5 mg/kg, bid 1 mg, tid
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ing internal urethral sphincter tone through alpha-adrenergic agonists (that is, drugs that stimulate the alpha-adrenergic receptors of the internal sphincter muscle). 32. 33. 65 Phenylpropanolamine (1.5 mg per kg, three times a day) has been shown to increase urethral pressure in normal and neutered dogs32. 33. 56 and improve continence in cases of sphincter incompetence. 56 Side effects seen include dry mucous membranes and occasional restlessness. 56 Imipramine, which increases alpha-adrenergic tone by blocking reuptake of noradrenaline, has been shown to increase internal sphincter tone experimentally but has not been evaluated clinically for efficacy or side effects. The side effect that was reported in short-term experiments was sedation. 30 Hormone replacement therapy may be useful in sphincter incompetence secondary to neutering,4 although serious side effects such as bone marrow suppression and hepatotoxicity need to be considered. Surgical techniques for correction of incontinence due to sphincter incompetence have been described l3. 27 for cases that fail to respond to medical therapy.
Failure of Storage Due to the Bladder Failure of storage due to the bladder can be caused by a loss of compliance or detrusor hyperreflexia. Both conditions occur most commonly with cystitis, and controlling any underlying infection is imperative. 20. 49 Hyperreflexia also characterizes loss of higher control, such as occurs in senility or cerebellar lesions. 8 • 49. 55 The objective of therapy is to promote bladder relaxation and inhibit detrusor contraction. Anticholinergics block the normal parasympathetic stimulation of the detrusor. 33. 55. 65 Propantheline is the most commonly recommended drug at doses of 7.5 to 30 mg, two to three times a day. Side effects include dry mucous membranes, constipation, and retention of urine. 32. 42. 59 Direct-acting smooth muscle relaxants such as aminopromazine (2 mg per kg, twice a day),9 flavoxate (100 to 200 mg, three to four times a day), or oxybutynin (2 to 5 mg, two to three times a day)49.59 have also been recommended. These drugs tend to have a slow onset of action and several weeks of therapy may be necessary before the success of therapy can be determined. 59 Calcium channel blocking drugs such as verapamil have been used experimentally but await clinical trials. 3 Beta-adrenergic agonists promote bladder relaxation experimentally,43 and salbutamol has been recommended at a dose of 1 mg, three times a day. 42
FAILURE OF VOIDING Failure to void can result from deficient detrusor contraction or outflow obstruction, either physical or functional. Both lead to large residual volumes of urine. Secondary overflow incontinence may occur when bladder pressure exceeds the urethral resistance. Regardless of the cause of failure of voiding, the foremost objective of therapy is to keep the bladder from becoming overdistended, thus preventing irreversible damage to the detrusor. Manual expression of the bladder may be adequate if there is no increase in sphincter tone and the bladder is not already traumatized by
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overdistention. Otherwise, sterile catheterization of the bladder at least three, preferably four times a day is required. Catheterization should be performed following exercising the animal to assess residual volume. If therapy is effective and the postvoiding volume is low, the frequency of catheterization may be decreased. 21. 49 T
Failure of Voiding Due to the Sphincter With UMN lesions, sphincter spasticity may develop. If the detrusor response is intact but not coordinated with sphincter relaxation, then reflex dyssynergia occurs. 48, 67 The objective of therapy in either case is to relieve the functional outflow obstruction by decreasing sphincter tone and thus preventing high bladder pressures from occurring. 65 Appropriate therapy depends on whether the increase in tone is due primarily to the internal or external sphincter. Without urodynamic studies, this can be difficult to determine, but fortunately, combination therapy is not contraindicated. The internal sphincter tone can be effectively decreased by drugs that block alpha-adrenergic receptors. Phenoxybenzamine has been effective experimentally and clinically at doses of 0.5 mg per kg, once to three times a day.3l, 49, 59 The drug has a slow onset of action, so several days may be required to assess efficacy. Side effects reported include weakness (hypotension) and tachycardia. External sphincter tone can be decreased through the use of skeletal muscle relaxants. Diazepam (2 to 10 mg, three to four times a day) acts centrally to produce muscle relaxation. 49, 59 Direct-acting muscle relaxants such as dantrolene (1 to 5 mg per kg, three times a day) have also been used. Side effects include weakness, sedation (diazepam), and hepatotoxicity (dantrolene).29, 49. 59 In human beings, surgical resection of the sphincters or their nerve supply may be used when drug therapy fails. 37, 65 Such extreme measures would require urodynamic confirmation of the dysfunction and have not been adequately evaluated in veterinary medicine. Failure of Voiding Due to the Bladder Failure of voiding due to a failure of the detrusor to contract can result from direct damage to the detrusor muscle from overdistention, from lesions of the pelvic nerve, or from central lesions that abolish the micturition reflex. The objective of therapy is to enhance detrusor contractility. It is important, however, to ensure that there is no obstruction to outflow, because enhanced contractility with increased outflow resistance would aggravate ureteral reflux.38, 65 The cholinergic drug bethanechol (2.5 to 10 mg, three times a day subcutaneously; 2 to 15 mg, three times a day orally) is often recommended for the treatment of bladder atony.9. 41. 49. 59 Although bethanechol can stimulate bladder contraction, especially in the denervated bladder, experimental work suggests that beth an echo I may simultaneously enhance sphincter tone , thus leading to outflow obstruction. This effect is only partially reversed by alpha-adrenergic antagonists. 17, 35 Side effects with bethanechol therapy are common and include salivation, diarrhea, and abdominal pain. 59 Metaclopramide ha~ been shown to enhance bladder contractions experimentally but has not been shown to be of use clinically.39 Beta-adrenergic antagonists have also been recommended, but
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efficacy has not been proven. 32• 42 Naloxone will promote detrusor activity in normal and paraplegic animals, presumably through the blockade of a tonic inhibition of micturition by an endogenous opiate. 6 . 28. 63 Tolerance appears to develop quickly, however, and trials in human beings have yielded mixed results .63 , 66 With supraspinal lesions, micturition can sometimes be stimulated by eliciting neonatal spinal micturition reflexes. 14 This is best accomplished by placing the animal in a bathtub and gently stimulating the perineum with a warm, moist cloth, Such micturition is seldom complete, however, and residual volumes of urine may still be a problem . In cases of bladder atony due to overdistention of the bladder, pharmacologic therapy is of little benefit. Maintaining decompression of the bladder via continuous or intermittent catheterization is the most effective therapy. Function usually returns in 1 to 2 weeks if therapy is successful, but the prognosis in such cases is always guarded. 49
FAILURE OF VOIDING AND STORAGE Often failure of storage and failure of voiding may occur in the same patient. In a suprasacral spinal lesion, for example, the bladder may be hyperreflexive, but the sphincter may be spastic. In such cases, therapy must be directed at the more serious of the problems. Generally, the prevention of infection and reflux by maintaining low residual volumes of urine and low bladder pressure is more important than maintenance of continence. 37. 65 The owners, however, may consider improved continence worth the price of a shorter life expectancy.
COMPLICATIONS OF BLADDER DYSFUNCTION Urinary tract infections are probably the most serious complication of neurogenic disorders of micturition. Large residual volumes of urine and the need for frequent catheterization predispose the animal to cystitis . This requires frequent urinalysis, culture, and treatment with administration of appropriate antibiotics to control the infections . If there is increased outflow resistance or diminished sensory function of the bladder, the normal lowpressure storage and expulsion of urine may be affected. Increased bladder pressure can \ead to hydroureter, hydronephrosis, ascending infection, and renal failure. Periodic intravenous pyelograms may be necesslfry to monitor for such progressive changes. 21. 37. 49 In spite of adequate care and monitoring, the incidence of complications will be high, and a guarded prognosis is warranted in most cases.
REFERENCES 1. Awad SA, Downie JW: The effect of adrenergic drugs and hypogastric nerve stimulation on the canine urethra. Invest Urol 13:298-301, 1976
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2. Awad SA, Downie JW: Relative contributions of smooth and striated muscles to the canine urethral pressure profile. Br J Urol 48:347-354, 1976 3. Awad SA, Downie JW, Kiruluta HG: Pharmacologic treatment of disorders of bladder and urethra: A review. Can J Surg 22:515-518, 1979 4. Barsanti JA, Finco DR: Hormonal responses to urinary incontinence. In Kirk RW (ed): Current Veterinary Therapy VIII. WB Saunders Co, Philadephia, 1983, pp 1086-1087 5. Barrington FJF: The effect of lesions of the hind- and mid-brain on micturition in the cat. J Exp PhysioI15:81-102, 1925 6. Booth AM, Hisamitsu T, Kawatani M, et al: Regulation of urinary bladder capacity by endogenous opioid peptides. J Urol 133:339-342, 1985 7. Bors E, Comarr AE: Neurological Urology. Baltimore, University Park Press, 1971 8. Bradley WE, Timm GW: Physiology of micturition. Vet Clin North Am 4:487-500, 1974 9. Chew DJ, DiBartola SP, Fenner WR: Pharmacologic manipulation of urination. In Kirk RW (ed): Current Veterinary Therapy IX. WB Saunders Co, Philadelphia, 1986, pp 1207-1212 10. Creed KE: Effect of hormones on urethral sensitivity to phenylephrine in normal and incontinent dogs. Res Vet Sci 34:177-181, 1983 11. Cullen WC, Fletcher TF, Bradley WF: Histology of the canine urethra. II. Morphometry of the male pelvic urethra. Anat Rec 199:187-195, 1981 12. Cullen WC, Fletcher TF, Bradley WF: Morphometry of the male feline pelvic urethra. J UroI129:186-189, 1983 13. Dean PW, Novotny MJ, O'Brien DP: Prosthetic sphincter for urinary incontinence: Results in 3 cases. J Am Anim Hosp Assoc 1988 (in press) 14. deGroat WC: Nervous control of the urinary bladder of the cat. Brain Res 87:201-211, 1975 15. deGroat WC, Booth AM: Physiology of the urinary bladder and urethra. Ann Intern Med 92:312-315, 1980 16. Diokno AC, Koppenhoefer R: Bethanechol chloride in neurogenic bladder dysfunction. Urology 8:455-458, 1976 17. EI-Salmy S, Downie JW, Awad SA: Bladder and urethral function and supersensitivity to subcutaneously administered bethanechol. J UroI134:1011-1018, 1985 18. Fletcher TF, Bradley WE: Neuroanatomy of the bladder-urethra. J Urol 119:153-160, 1978 19. Fox MW: Integrative Development of Brain and Behavior in the Dog. Chicago, University of Chicago Press, 1971 20. Gibbon NOK: Nomenclature of neurogenic bladder. Urology 8:423-431, 1976 21. Graham SD: Present urological treatment of spinal cord injury patients. J Urol 126:1-4, 1981 22. Gregory CR: Electromyographic and urethral pressure profilometry: Clinical application in male cats. Vet Clin North Am [Small Anim Pract] 14:567-574, 1984 23. Guilford WG, O'Brien DP, Allert A, et al: Feline dysautonomia: A case report with comment on diagnosis by autonomic nervous system function testing. J Am Vet Med Assoc (in press) 24. Hassouna M, Abdel-Hakim A, Abdel-Rahman M, et al: Response of urethral smooth muscles to pharmacological agents. I. CholinergiC and adrenergic agonists and antagonists. J UroI129:1262-1264, 1983 25. Hassouna M, Galeano C, Abdel-Rahman M, et al: Vesicourethral motility following acute spinal cord transection in the cat. J UroI131:370-373, 1984 26. Holt PE: Urinary incontinence in the bitch due to sphincter ml1chanism incompetence: Prevalence in referred dogs and retrospective analysis of sixty cases. J Small Anim Pract 26:181-190, 1985 27. Holt PE: Urinary incontinence in the bitch due to sphincter mechanism incompetence: Surgical treatment. J Small Anim Pract 26:237-246, 1985 28. Jubelin B, Galeano C, Ladouceur D, et al: Effect of enkephalin on the micturition cycle of the cat. Life Sci 34:2015-2027, 1984 29. Khalaf 1M, Foley G, Elhilali MM: The effect of dantrium on the canine urethral pressure profile. Invest Urol17:188-190, 1979 30. Khanna OP, Elkouss G, Heber D, et al: Imipramine hydrochloride: Pharmacodynamic effects on lower urinary tract offemale dogs. Urology 6:48-51 , 1975
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31. Khanna OP, Gonick P: Effects of phenoxybenzamine hydrochloride on canine lower urinary tract. Urology 6:323-330, 1975 32. Khanna OP, Heber D, Gonick P: Cholinergic and adrenergic neuroreceptors in urinary tract of female dogs. Urology 5:616-623, 1975 33. Khanna OP: Disorders of micturition: Neuropharmacologic basis and results of drug therapy. Urology 8:316-328, 1976 34. Leach GE, Farasaee A, Kark P, et al: Urodynamic manifestations of cerebellar ataxia. J Urol 128:348-350, 1982 35. Light JK, Scott FB: Bethanechol chloride and the traumatic cord bladder. J UroI128:85-87, 1982 36. Lincoln J, Crowe R, Bokor J, et al: Adrenergic and cholinergic innervation of the smooth muscle of the urethra. J UroI135:402-407, 1986 37. McGuire EJ: Clinical Evaluation and Treatment of Neurogenic Vesical Dysfunction. Baltimore, Williams & Wilkins, 1984 38. McGuire EJ: The innervation and function of the lower urinary tract. J Neurosurg 65:278285,1986 39. Mitchell WC, Venable DD: Effects of metaclopramide on detrusor function . J Urol 134:791-794, 1985 40. Moreau PM , Lees GE, Hobson HP: Simultaneous cystometry and uroflowmetry for evaluation of micturition in two dogs. J Am Vet Med Assoc 183:1084-1088, 1983 41. Moreau PM: Neurogenic disorders of micturition in the dog and cat. Compend Con tin Ed Pract Vet 4:12-22, 1982 42. Moreau PM : Neurogenic disorders of micturition: Diagnosis and therapy. In Proceedings of the American College of Veterinary Internal Medicine, 1986, pp 4/85-92 43. Nishizawa 0, Fukada T, Matsuzaki A, et al: Role of the sympathetic nerve in bladder and urethral sphincter function during the micturition cycle in the dog evaluated by pressure flow EMG study. J UroI134:1259-1261, 1985 44. O'Brien DP, Dean PW: Unpublished observations, 1987 45. O'Brien DP, Dean PW: Pudendo-anal (bulbocavernosus) reflex electrophysiology in the dog. Proc Am Coli Vet Intern Med, Abstracts, 1988 46. Oliver JE, Bradley WE, Fletcher TF: Spinal cord representation of the mictUrition reflex. J Comp NeuroI137:329-346, 1969 47. Oliver JE, Young WO: Air cystometry in dogs under xylazine induced restraint. Am J Vet Res 34:1433-1435, 1973 48. Oliver JE : Dysuria caused by reflex dyssynergia. In Kirk RW (ed): Current Veterinary Therapy VIII. Philadelphia, WB Saunders Co, 1983 49. Oliver JE, Horlein BF, Mayhew IG : Veterinary Neurology. Philadelphia, WB Saunders Co, 1987 50. Pavlak is AJ, Siroky MB, Krane RJ : Neurogenic detrusor areflexia: Correlation of perineal electromyography and bethanechol chloride supersensitivity testing. J Urol 129:11821184, 1983 51. Petras JM, Cummings JF: Sympathetic and parasympathetic innervation of the urinary bladder and urethra. Brain Res 153:363-369, 1978 52. Purington PT, Oliver JE : Spinal origin of innervation to the bladder and urethra of the dog. Exp Neurol 65:422-434, 1979 53. Purington PT, Oliver JE, Kornegay IN, et al: Cortical averaged evoked potentials produced by pudendal nerve stimulation in dogs. Am J Vet Res 44:446-448, 1983 54. Rampal G, Mignard P: Behavior of the urethral striated sphincter and of the bladder in the chronic spinal cat. Pflugers Arch 353:33-42, 1975 , 55. Resnick NM, Yalla SV: Management of urinary incontinence in the elderly. N Engl J Med 313:800-805, 1985 56. Richter KP, Ling GV: Clinical response and urethral pressure profile changes after phenylpropanolamine in dogs with primary sphincter incompetence. J Am Vet Med Assoc 187:605--611, 1985 57. Rochlitz I: Feline dysautonomia (the Key-Gaskell or dilated pupil syndrome): A preliminary survey. J Small Anim Pract 25:587-598, 1984 58. Rosin AH, Rosin E, Oliver J: Canine urethral pressure profile. Am J Vet Res 41:11131116, 1980 59. Rosin AH, Ross L: Diagnosis and pharmacological management of disorders of urinary continence in the dog. Compend Contin Ed Pract Vet.3:601-609, 1981
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60. Samson MD, Reddy VK: Localization of the sacral parasympathetic nucleus in the dog. Am J Vet Res 43:1833-1836. 1982 61. Sharp NJH, Nash AS, Griffiths IR: Feline dysautonomia (the Key-Gaskell syndrome): A clinical and pathological study of forty cases. J Small Anim Pract 25:599-615, 1984 62. Swash M, Snooks SJ: Electromyography in pelvic floor disorders. In Henry MM, Swash M (eds): Coloproctology and the Pelvic Floor. Boston, Butterworths, 1985, pp 88-103 63. Thor KB, Roppolo JR, deGroat WC: Naloxone induced micturition in unanesthetized paraplegic cats. J UroI129:202-205, 1983 64. Ueyama T, Mizuno N, Nomura JS, et al: Central distribution of afferent and efferent components of the pudendal nerve in cats. J Comp Neurol 222:38-46, 1984 65. Wein AJ: Classification of neurogenic voiding dysfunction. J UroI125:605-609, 1981 66. Wheeler JS. Robinson q, Culkin OJ, et al: Naloxone efficacy in bladder rehabilitation of spinal cord injury patients. J Urol 137:1202-1205, 1987 67. Yalla SV, Blunt KJ. Fam BA, et al: Detrusor-urethral sphincter dyssynergia. J Urol 118:1026-1029, 1977 Department of Veterinary Medicine and Surgery College of Veterinary Medicine University of Missouri Columbia, Missouri 65211
0195--5616/88 $0.00
+ .20
Neurogenic Disorders of Micturition
Dennis O'Brien, DVM, PhD*
Disorders of micturition are a common sequelae to neurologic disease occurring anywhere from the sacral cord and its nerves to the frontal cortex. In human beings, renal disease is one of the most frequent causes of death in patients with injuries to the spinal cord, accounting for up to 40 per cent of the fatalities . 21 In veterinary medicine, urinary complications of neurologic disease are even more of a problem because an incontinent pet is often unacceptable to the owner and is subsequently euthanatized. Fortunately, research and clinical experience over the last 15 years have contributed a great deal to our understanding of how the lower urinary tract functions, how those functions are disrupted by neurologic disease, and how they can be manipulated pharmacologically to make the animal a more acceptable pet.
NORMAL FUNCTION OF THE LOWER URINARY TRACT Anatomy The lower urinary tract is composed of the bladder and urethra and their associated musculature (Fig. 1). The bladder serves as the reservoir for the storage of urine between voidings. The bladder wall contains a layer of smooth muscle, the detrusor muscle, which contracts during micturition to expel urine from the bladder. 7, 38 In other tissues, smooth muscle cells are joined by tight junctions that allow transmission of excitation between muscle cells without a one-to-one innervation. However, there is currently no evidence that such electrical coupling plays a significant role in the detrusor muscle. 18 The musculature of the urethra serves as a sphincter to prevent leakage of urine during storage. The neck of the bladder and the proximal urethra contain smooth muscle that forms the internal urethral sphincter. 7 • II, 12,33. 38 In the cat, the internal sphincter is composed of circular layers that act 'Diplomate, American College of Veterinary Internal Medicine (Neurology); Assistant Professor of Neurology, Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, Missouri Veterinary Clinics of North America: Small Animal Practice-Vol. 18, No.3, May 1988
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DetftJ$Or internal urethral sphincter external urethral sphincter
/r'~d;~Figure 1. Anatomy of the bladder and urethra. The bladder contains a layer of smooth muscle, the detrusor. The urethral sphincter is composed of a smooth muscle internal sphincter and a striated muscle external sphincter. The muscles of the pelvic diaphragm also provide sphincter-like function .
as a sphincter and longitudinal layers that probably serve to open the urethra during micturition. 12. 24 In the dog, circular and oblique fibers are intermixed, and only sphincter functions have been described. I . 2. II The internal sphincter lies largely within the abdominal cavity, so that any increase in intraabdominal pressure, such as occurs during coughing, is transmitted to the sphincter as well as the bladder, aiding in the maintenance of continence. 2o In the distal portions of the urethra, a layer of striated muscle forms the external urethral sphincter. lB. 37. 38 The muscles of the pelvic diaphragm also provide voluntary sphincter function to the distal urethra. lB. 37 Motor Innervation The efferent (motor) innervation of the lower urinary tract has somatic, sympathetic, and parasympathetic components (Fig. 2A). The somatic innervation via the pudendal nerve arises from sacral cord segments (primarily SI-2 with some contribution of L7 and S346. 53. 64). The pudendal nerve provides voluntary control over the external urethral sphincter and perineal musculature. lB. 36. 37 Sympathetic innervation arises from the lumbar cord (LI-4 in the dog;51. 52 L2-5 in cat46). These nerves synapse in the caudal mesenteric ganglia and then form the hypogastric nerve. The hypogastric nerve provides adrenergic innervation to the bladder, to pelvic (parasympathetic) ganglia, and to the internal urethral sphincter. 14. 15. 18.37 The receptors within the bladder are predominantly beta-adrenergic rec,eptors, which, when stimulated, produce relaxation of the detrusor muscle. 32. 33. 43 The internal urethral sphincter contains primarily alpha-adrenergic receptors, which cause constriction of the sphincter, 1.32.33 although beta-adrenergic relaxation has also been demonstrated. I In addition, sympathetic innervation of the pelvic ganglia appears to inhibit parasympathetic activity during bladder filling . 14. 15 Parasympathetic innervation originates in .the sacral cord (SI-346. 51. 52. 60) and forms the pelvic nerves. These preganglionic neurons synapse in the pelvic plexus and ganglia within the bladder wall. The postganglionic
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b(ainstem
mICturition
center
A
b~nI(f1f71
mlCtuntlon
cent.
8 Figure 2. A, Efferent innervation of the bladder and urethra with somatic (pudendal nerve), sympathetic (hypogastric nerve), and parasympathetic (pelvic nerve) components. The somatics control external sphincter tone. The sympathetics promote bladder filling by inhibiting bladder contraction and increasing internal sphincter tone. Parasympathetics stimulate bladder contraction . Reciprocal urethral and detrusor functions are coordinated by the brain-stem micturition center, which is in turn under voluntary control of higher centers. B, Afferent innervation of the bladder and urethra. Stretch receptors in the bladder transmit information on distention via the pelvic nerve. Pain receptors in the bladder relay information on overdistention via the pelvic and hypogastric nerves. The pudendal nerve carries information on stretch, flow, and pain from the urethra. All relay information to the brain-stem micturition center and to higher centers via the thalamus.
parasympathetic nerves provide cholinergic innervation, primarily to the detrusor, causing contraction during micturition. 14, 15, 18, 37 Sensory Innervation An equally important, although often overlooked, component of the innervation of the lower urinary tract is the afferent (sensorS') innervation (Fig. 2B). Stretch receptors in the bladder wall detect fullness of the bladder and trigger micturition through afferents in the pelvic nerves. In addition, there are nerve endings in the submucosa of the bladder that only respond to extreme distention of the bladder and are probably pain receptors. These nerves project to the lumbar and sacral cord via the hypogastric and pelvic nerves, respectively. Afferents from the urethra detecting flow, distention, and pain also project to the sacral cord via the pudendal nerve. 14, 15, 18. 37
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Central Integration In the neonatal kitten and puppy, micturition is a sacral spinal reflex elicited by the licking of the perineum by the mother. 14. 19 This local reflex control is lost at 7 to 12 weeks in kittens l4 and 3 to 4 weeks in puppies, 19 and sacral micturition reflexes can no longer be elicited. 14 Relaxation of the bladder and some sphincter functions continue to be mediated at the spinal level in adults,14. 18 but the major control of voiding resides in the brain stem at the level of the pons.5 This brain-stem micturition center receives sensory information from the stretch and pain receptions in the bladder and responds to distention by coordinating sphincter relaxation with detrusor contraction to produce micturition. 14. 15. 18 Voluntary control of the brain stem micturition center involves a number of higher brain areas , including the cerebral cortex, basal ganglia, thalamus, and even the cerebellum. Most exert an inhibitory influence over micturition, although facilitative influences have also been described.8. 14. 15. 18. 34 Physiology of Micturition Normal function of the lower urinary tract involves a reciprocal relationship between the detrusor and urethral sphincter. This allows for low-pressure filling of the bladder during the storage phase and permits low-pressure expulsion of the urine during the voiding phase. 14. 15.31. 37. 38 During the storage phase (Fig. 3A), contraction of the urethral sphincters prevents leakage of urine through the urethra and maintains continence. The internal, involuntary sphincter receives tonic alpha-adrenergic stimulation via the hypogastric nerve. 14. 32. 33 The external sphincter maintains constant tone but also contains fast-twitch muscle fibers that respond quickly to temporary increases in pressure. 2. 18 In addition, contraction of the external sphincter tends to suppress the micturition reflex. 38 Beta-adrenergic sympathetics directly inhibit the detrusor muscle, promoting lowpressure filling of the bladder. 14. 18. 43 In addition, other sympathetics inhibit transmission through the parasympathetic ganglia, which decreases cholinergic stimulation of the detrusor. 14. 37 When bladder capacity is approached, stretch receptors in the bladder signal the brain-stem micturition center of the need for micturition (Fig. 3B).14. 15. 18. 37 Voluntary initiation of micturition involves contraction of the abdominal muscles and relaxation of the perineal muscles. 15 This is followed by an increase in parasympathetic input to the bladder and a contraction of the detrusor. The initiation of a detrusor contraction inhibits alphaadrenergic tone to the urethral sphincter. 14.15 In addition, there is probably beta-adrenergic inhibition of the sphincter24 . 32 and, in the cat, active opening of the sphincter by the longitudinal fibers. 12. 2'4 The coordination of detrusor contraction and sphincter relaxation allows for voiding but prevents high pressures from developing within the bladder. The sensation of urine flow through the urethra provides secondary reinforcement of the micturition reflex and facilitates complete emptying of the bladder. 15 EFFECTS OF LESIONS Sphincter or Detrusor Muscles Primary sphincter incompetence is most commonly seen in neutered female dogs but is also seen in neutered males. 4.26.27 Even though neutered
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A
J
B
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)AChf+)
I
Figure 3. A, Filling/storage phase. Bladder tone is actively inhibited by beta-adrenergic innervation of the detrusor. Urethral closure is maintained by alpha-adrenergic innervation of the internal sphincter and cholinergic innervation of the external sphincter. B, Voiding phase. Detrusor contraction is initiated by cholinergic parasympathetics. Sphincter relaxation is mediated by decreased alpha-adrenergic and somatic cholinergic influence on the internal and external sphincter, respectively. Active sphincter relaxation and opening may be mediated via adrenergic innervation of the sphincter and cholinergic innervation of longitudinal fibers of the urethra in the cat (not shown).
animals show little change in their basal hormone levels, 56 the removal of the gonads somehow alters internal sphincter function, rendering a certain percentage of neutered animals incontinent. Urethral pressure profiles may show a decrease in sphincter tone. Estrogens have been shown to promote alpha-adrenergic effects at the internal sphincter. 10 Primary sphincter incompetence results in incontinence, which tends to be worse when the animal is recumbent or sleeping and may be exaggerated by excitement or movement. 4. 26 Because only the sphincter is involved: the animals are capable of normal micturition and have little residual urine after urination. Obstruction of the outflow of urine, either through mechanical obstruction or sphincter spasm, can result in overdistention of the bladder. If the distention is not relieved promptly, permanent atony of the detrusor muscle may result. 20.37.49 Because, as stated earlier, there is no good evidence that tight junctions play a significant role in the detrusor muscle, the atony probably results from direct injury to the muscle cells or their innervation, rather than disruption of tight junctions_18. 37. 38 The result is an atonic,
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unresponsive bladder. The animal is incapable of normal micturition and has a large residual volume of urine. Sphincter tone may be normal or increased, and the resistance to expression of the bladder would be proportional. If there is not complete obstruction, the animal may show overflow incontinence once the pressure in the bladder exceeds the urethral resistance. Sacral Cord and Nerves: The Lower Motor Neuron Bladder Lesions of the sacral cord, cauda equina, or pelvic and pudendal nerves abolish both voluntary and reflex micturition, producing what is referred to as the lower motor neuron (LMN) bladder.7 Experimentally, denervation of the bladder does not result in a complete loss of bladder tone, and the complete bladder atony seen in clinical cases is probably secondary to overdistention and infection more than denervation. 2o. 37 Nonetheless, detrusor contraction is abolished and the bladder retains a large residual volume of urine . With complete lesions, the external sphincter is also denervated and develops flaccid paralysis. 37. 38. 49 Because the internal sphincter is innervated by the hypogastric nerve originating in the lumbar cord, innervation to the internal sphincter can remain intact. The sacral lesion abolishes normal sensory input from stretch receptors in the detrusor; thus, the internal sphincter cannot respond to increased bladder pressure with relaxation and remains fixed. 18, 37 As a result, the distended bladder may be easy to express or show resistance. Once the bladder fills, overflow incontinence will result. Some pain receptors in the hypogastric nerve may also be spared so that the animal may have a sensation of discomfort and make unsuccessful attempts to urinate. 18. 20 Generally, other signs of sacral cord or nerve involvement would be expected, such as fecal incontinence, hindlimb ataxia/paresis, loss of anal and bulbocavernous reflexes, and loss of sensation to appropriate dermatomes. Feline dysautonomia is characterized by a degeneration of the peripheral autonomic nervous system; thus, it is associated with loss of bladder function in 17 to 18 per cent of the cases. The cats become incontinent, and the bladder is atonic. There is little involvement of somatic components, although the anal reflex may be lost. Other signs of autonomic disturbance such as dilated pupils, dry mucous membranes, and gastrointestinal disturbances are inevitably present. 23, 57, 61 Suprasacral Spinal Lesions: The Upper Motor Neuron Bladder Lesions above the sacral cord level and below the pons disrupt the normal coordination of micturition by the brain-stem micturition center. 14, 15, 37 Initially, a complete lesion abolishes the micturition'response. Although originally thought to represent a "spinal shock" phenomena, the initial loss appears to be more of a loss of normal coordination (dyssynergia, see below) than a true spinal shock. 25 In cats, a coordinated micturition reflex in response to bladder distention returns over a period of time (4 to 38 days in experimental studies 14 , 15,54). This upper motor neuron (UMN) or "reflex" bladder is a purely sacral reflex without voluntary control. With the development of the UMN bladder, the neonatlil micturition response to perineal stimulation may also return. 14 Secondary reinforcement of mictu-
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rition is lost; thus, these spinal reflex responses are usually weak and incomplete, leaving a large residual volume of urine following voiding. In dogs, the presence of spinal reflex control of micturition following cord transection has been questioned,49 although the author has seen reflexive urination in response to perineal stimulation in a dog with chronic transverse cord injury at the TL region. With the UMN bladder, the urethral sphincters usually become hypertonic, although normal tone or atonia may also be present. 20, 38, 49, 54 When hypertonicity develops, the bladder is very difficult to express. If detrusor contractions return, then a condition of reflex dyssynergia may develop. In reflex dyssynergia, the normal coordination of sphincter relaxation and detrusor contraction is disrupted, so that the detrusor contracts against a constricted sphincter. 37, 48, 67 This can be due to hypertonicity of either the internal sphincter or, more commonly, the external sphincter. Although dyssynergia is a common problem in human beings with spinal injuries,37, 67 its existence in dogs has been questioned. 49 Suprasacral spinal injury would be associated with other signs of UMN involvement such as exaggerated myotatic reflexes and postural reaction deficits, Brain-stem lesions would affect cranial nerves as well as motor and sensory tracts. Higher Lesions: Voluntary Control Lesions above the level of the pons do not generally abolish micturition but do affect voluntary control of it. 8, 18, 38, 55 This may result in either urge incontinence or unconscious urination. With urge incontinence, the animal has a warning that micturition is about to occur but cannot stop it from occurring. Nocturia is common. The volume of urine voided can vary from smaller to larger than normal but -the postvoiding residual is low. 38, 55 In unconscious urination, there is no awareness or control, and micturition occurs whenever threshold is reached. The detrusor may become hyperreflexic, resulting in a low threshold and frequent, lowvolume urinations, The residual urine volume is low. Urination tends to be equally frequent during the night or day. 38, 55 Depending on the location of the lesion, other signs reflecting damage to that area would be expected. Thus, with cerebral, limbic, or hypothalamic lesions, behavioral changes may occur, With thalamic or basal ganglia lesions, there should be sensory or motor deficits, respectively. Cerebellar lesions would produce typical signs of dysmetria and tremors, DIAGNOSTIC APPROACH The diagnostic approach to a patient with a disorder of micturition involves attempting to define the type of disorder, establishing whether the disorder is neurogenic, localizing the lesion if it is neurogenic, establishing the etiology, and, if the underlying cause cannot be eliminated, devising rational symptomatic therapy. The clinical approach to such a . patient is summarized in Table 1. 41, 42, 49, 55, 59 It includes a thorough history with emphasis on the pattern of urination
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Table 1. Clinical Evaluation of the Patient with a Disorder of Micturition HISTORY
Neutering or other urogenital surgeries Housebreaking and patterns prior to onset of signs Onset and progression of signs Voluntary attempts to urinate-success of attempts, straining Frequency, pattern (nocturnal, daytime, both), awareness Volume of urination or leakage Behavioral changes, defecation, gait abnormalities PHYSICAL EXAM
Rectal exam-anal tone, prostate Bladder palpation-size (pre- and post-voiding), tone, resistance to expression Observe urination--control, awareness, stream, ability to interrupt NEUROLOGIC EXAM
Mental status Motor functions Perineal sensation Sacral reflexes INITIAL DATABASE
Measure post-voiding volume of urine Urinalysis and culture Metabolic profile Radiographs-urethrogram, cystogram, IVP, spinal URODYNAMIC STUDIES
Cystometrogram and flowmetry Urethral pressure profile Sphincter and perineal muscles (EMG) Pudendal evoked potential Bulbocavernosus latency
or incontinence, behavioral changes, and other signs of neurologic disease. A thorough physical examination should include palpation of the prostate and assessment of bladder size, tone, and ease of expression. Urination should be observed, if possible, and postvoiding urine volume measured. Normal postvoiding residual should be less than 0.2 to 0.4 ml per kg, or about 10 m!. 42. 49 A thorough neurologic examination should assess mental status, motor function, perineal sensation, anal tone, and sacral reflexes. A chemistry profile will aid in ruling out metabolic diseases, such as diabetes and hypothyroidism, that may secondarily produce neurogenic disorders. A urinalysis and urine culture not only rule out a current infectious etiology but also serve as a baseline for detection of future problems. Radiographic examination of the lower and upper urinary tract rules out structural problems and proVides baseline infQrmation for monitoring the effects of neurogenic disorders. Spinal studies may be necessary to rule out an operable lesion. Electrophysiologic tests are not readily available except at referral institutions. Generally, a reasonable diagnosis can be made and a rational approach to therapy devised based on the initial database. However, in cases in which questions exist, response to therapy is inadequate, or irreversible surgical corrections are considered, slectrodiagnostics may be necessary to precisely define the nature of the dysfunction. The cystometrogram is a measure of pressure within the bladder during
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filling and detrusor contraction. It provides information on the compliance of the bladder, threshold of the detrusor reflex, and strength of contraction. 40. 47 Sensitivity of the bladder to direct-acting cholinergic drugs such as bethanechol can also be measured by cystometrogram. When the bladder is denervated, it becomes supersensitive to cholinergic stimulation and will respond to doses of bethanechol that would not affect a normal bladder. 17. 50 By simultaneously recording EMG from the urethral sphincter, the degree of coordination between detrusor contraction and sphincter relaxation can be assessed and dyssynergia detected. 49 In cases of dyssynergia or mechanical obstruction, the pressure developed by detrusor contraction can be critical information, because major complications such as ureteral reflux and ascending infections occur at higher bladder pressures (greater than 40 cm H 20 in human beings38) and may require aggressive measures to control. The urethral pressure profile provides a measure of resting sphincter tone throughout the urethra. It can detect sphincter incompetence and obstruction. 22. 49. 58 The resting pressure, however, may not correlate with a functional problem. 49 A more accurate assessment of urethral resistance can be made by measuring urine flow during a cystometrogram (uroflowmetry).40 However, the technique is more invasive and may present undue risk to a patient with urinary tract infection or other complications. 49 Electromyography of the perineal musculature can be useful in detecting LMN involvement of other muscles innervated by the sacral cord segments. Care must be taken in interpreting anal sphincter EMG because spontaneous activity can be difficult to interpret. 44. 62 Sensory function of the pudendal nerve and spinal pathways can be assessed by recording somatosensory evoked potentials from the brain or spinal cord following pudendal nerve stimulation. 53 Reflex evoked muscle potential can also be studied in the perineum to assess integrity of the pudendal nerve and sacral cord segments. By stimulating the dorsal nerve of the clitoris or penis and recording from the anal sphincter, the bulbocavernosus reflex can be objectively assessed. Electrophysiologic measures are more sensitive in detecting the presence of weak reflexes and provide information on latency and amplitude of the response. 45 Routine nerve conduction studies can also help rule out diffuse neuropathies. CLASSIFICATION OF DISORDERS AND RATIONAL THERAPY
If the underlying cause of the micturition disorder cannot be treated directly (for example, in irreversible spinal cord injury), then therapy must be directed at relieving at least those signs associated with the greatest morbidity. In order to do so, it is necessary to be able to functionally classify the disorder so that one can arrive at a rational therapy. Numerous classification schemes for neurogenic disorders of micturition have been described. 7. 20. 65 Although some may be more accurate in localizing the lesion and describing the disorder, a relatively simple classification that directs therapy appropriately divides the problem into disorders of the storage phase and those of the voiding phase, then further subdivides these
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Table 2. Classification and Therapy of Disorders of Micturition DISORDER
OBJECTIVE
AGENTS
Storage Phase Sphincter Bladder
Enhance sphincter tone Decrease bladder contraction
Alpha agonists Anticholinergics Muscle relaxants Beta agonists? Calcium channel blockers?
Voiding Phase Internal sphincter External sphincter
Decrease sphincter tone Decrease sphincter tone
Alpha antagonists Central muscle relaxants Direct muscle relaxants
Enhance bladder contraction
Cholinergics? Beta agonists?
Bladder Mixed
Correct most serious problem
? = Drugs that have not been fully evaluated clinically or have questionable efficacy.
into disorders caused by the sphincter and those caused by the bladder (Table 2).65 FAILURE OF STORAGE The storage phase requires accommodation of increasing volumes of urine at low pressure, absence of inappropriate detrusor contractions, and a closed urethral sphincter. Disruption of any of these functions can result in incontinence. 65 Appropriate therapy will depend on whether there is failure of the sphincter or the bladder. Dosages for the more commonly used drugs are summarized in Table 3. It should be noted that most of the drug dosages are empirical. It is wise to start at the lower end of the dose range and titrate the dosage depending on side effects and efficacy. Failure of Storage Due to the Sphincter In cases in which sphincter incompetence exists, therapy will be directed at increasing sphincter tone. This can be accomplished by increasTable 3. Most Commonly Used Drug Dosages CLASS
Cholinergic Anticholinergic Alpha agonist Alpha antagonist Beta agonist Beta antagonist Smooth muscle relaxants Skeletal muscle relaxants
DRUG
Bethanechol Propantheline Phenylpropanolamine Phenoxybenzamine Salbutamol Propranolol Oxybutynin Aminopromazine Flavoxate Dantrolene Diazepam
DOG
CAT
2.5-25 mg, tid 7.5-30 mg, bid-tid 1.5 mg/kg, tid
2.5-5 mg, tid 7.5 mg, tid
0.5 mg/kg, sid-tid 1 mg, tid 10 mg, tid 2-5 mg, bid-tid 2 mg/kg, bid 100-200 mg, tid-gid 1-5 mg/kg, bid 2-10 mg, tid-qid
Same 5 mg, tid 1 mg, bid Same 0.5 mg/kg, bid 1 mg, tid
NEUROGENIC DISORDERS OF MICTURITION
539
ing internal urethral sphincter tone through alpha-adrenergic agonists (that is, drugs that stimulate the alpha-adrenergic receptors of the internal sphincter muscle). 32. 33. 65 Phenylpropanolamine (1.5 mg per kg, three times a day) has been shown to increase urethral pressure in normal and neutered dogs32. 33. 56 and improve continence in cases of sphincter incompetence. 56 Side effects seen include dry mucous membranes and occasional restlessness. 56 Imipramine, which increases alpha-adrenergic tone by blocking reuptake of noradrenaline, has been shown to increase internal sphincter tone experimentally but has not been evaluated clinically for efficacy or side effects. The side effect that was reported in short-term experiments was sedation. 30 Hormone replacement therapy may be useful in sphincter incompetence secondary to neutering,4 although serious side effects such as bone marrow suppression and hepatotoxicity need to be considered. Surgical techniques for correction of incontinence due to sphincter incompetence have been described l3. 27 for cases that fail to respond to medical therapy.
Failure of Storage Due to the Bladder Failure of storage due to the bladder can be caused by a loss of compliance or detrusor hyperreflexia. Both conditions occur most commonly with cystitis, and controlling any underlying infection is imperative. 20. 49 Hyperreflexia also characterizes loss of higher control, such as occurs in senility or cerebellar lesions. 8 • 49. 55 The objective of therapy is to promote bladder relaxation and inhibit detrusor contraction. Anticholinergics block the normal parasympathetic stimulation of the detrusor. 33. 55. 65 Propantheline is the most commonly recommended drug at doses of 7.5 to 30 mg, two to three times a day. Side effects include dry mucous membranes, constipation, and retention of urine. 32. 42. 59 Direct-acting smooth muscle relaxants such as aminopromazine (2 mg per kg, twice a day),9 flavoxate (100 to 200 mg, three to four times a day), or oxybutynin (2 to 5 mg, two to three times a day)49.59 have also been recommended. These drugs tend to have a slow onset of action and several weeks of therapy may be necessary before the success of therapy can be determined. 59 Calcium channel blocking drugs such as verapamil have been used experimentally but await clinical trials. 3 Beta-adrenergic agonists promote bladder relaxation experimentally,43 and salbutamol has been recommended at a dose of 1 mg, three times a day. 42
FAILURE OF VOIDING Failure to void can result from deficient detrusor contraction or outflow obstruction, either physical or functional. Both lead to large residual volumes of urine. Secondary overflow incontinence may occur when bladder pressure exceeds the urethral resistance. Regardless of the cause of failure of voiding, the foremost objective of therapy is to keep the bladder from becoming overdistended, thus preventing irreversible damage to the detrusor. Manual expression of the bladder may be adequate if there is no increase in sphincter tone and the bladder is not already traumatized by
540
DENNIS O'BRIEN
overdistention. Otherwise, sterile catheterization of the bladder at least three, preferably four times a day is required. Catheterization should be performed following exercising the animal to assess residual volume. If therapy is effective and the postvoiding volume is low, the frequency of catheterization may be decreased. 21. 49 T
Failure of Voiding Due to the Sphincter With UMN lesions, sphincter spasticity may develop. If the detrusor response is intact but not coordinated with sphincter relaxation, then reflex dyssynergia occurs. 48, 67 The objective of therapy in either case is to relieve the functional outflow obstruction by decreasing sphincter tone and thus preventing high bladder pressures from occurring. 65 Appropriate therapy depends on whether the increase in tone is due primarily to the internal or external sphincter. Without urodynamic studies, this can be difficult to determine, but fortunately, combination therapy is not contraindicated. The internal sphincter tone can be effectively decreased by drugs that block alpha-adrenergic receptors. Phenoxybenzamine has been effective experimentally and clinically at doses of 0.5 mg per kg, once to three times a day.3l, 49, 59 The drug has a slow onset of action, so several days may be required to assess efficacy. Side effects reported include weakness (hypotension) and tachycardia. External sphincter tone can be decreased through the use of skeletal muscle relaxants. Diazepam (2 to 10 mg, three to four times a day) acts centrally to produce muscle relaxation. 49, 59 Direct-acting muscle relaxants such as dantrolene (1 to 5 mg per kg, three times a day) have also been used. Side effects include weakness, sedation (diazepam), and hepatotoxicity (dantrolene).29, 49. 59 In human beings, surgical resection of the sphincters or their nerve supply may be used when drug therapy fails. 37, 65 Such extreme measures would require urodynamic confirmation of the dysfunction and have not been adequately evaluated in veterinary medicine. Failure of Voiding Due to the Bladder Failure of voiding due to a failure of the detrusor to contract can result from direct damage to the detrusor muscle from overdistention, from lesions of the pelvic nerve, or from central lesions that abolish the micturition reflex. The objective of therapy is to enhance detrusor contractility. It is important, however, to ensure that there is no obstruction to outflow, because enhanced contractility with increased outflow resistance would aggravate ureteral reflux.38, 65 The cholinergic drug bethanechol (2.5 to 10 mg, three times a day subcutaneously; 2 to 15 mg, three times a day orally) is often recommended for the treatment of bladder atony.9. 41. 49. 59 Although bethanechol can stimulate bladder contraction, especially in the denervated bladder, experimental work suggests that beth an echo I may simultaneously enhance sphincter tone , thus leading to outflow obstruction. This effect is only partially reversed by alpha-adrenergic antagonists. 17, 35 Side effects with bethanechol therapy are common and include salivation, diarrhea, and abdominal pain. 59 Metaclopramide ha~ been shown to enhance bladder contractions experimentally but has not been shown to be of use clinically.39 Beta-adrenergic antagonists have also been recommended, but
NEUROGENIC DISORDERS OF MICTURITION
541
efficacy has not been proven. 32• 42 Naloxone will promote detrusor activity in normal and paraplegic animals, presumably through the blockade of a tonic inhibition of micturition by an endogenous opiate. 6 . 28. 63 Tolerance appears to develop quickly, however, and trials in human beings have yielded mixed results .63 , 66 With supraspinal lesions, micturition can sometimes be stimulated by eliciting neonatal spinal micturition reflexes. 14 This is best accomplished by placing the animal in a bathtub and gently stimulating the perineum with a warm, moist cloth, Such micturition is seldom complete, however, and residual volumes of urine may still be a problem . In cases of bladder atony due to overdistention of the bladder, pharmacologic therapy is of little benefit. Maintaining decompression of the bladder via continuous or intermittent catheterization is the most effective therapy. Function usually returns in 1 to 2 weeks if therapy is successful, but the prognosis in such cases is always guarded. 49
FAILURE OF VOIDING AND STORAGE Often failure of storage and failure of voiding may occur in the same patient. In a suprasacral spinal lesion, for example, the bladder may be hyperreflexive, but the sphincter may be spastic. In such cases, therapy must be directed at the more serious of the problems. Generally, the prevention of infection and reflux by maintaining low residual volumes of urine and low bladder pressure is more important than maintenance of continence. 37. 65 The owners, however, may consider improved continence worth the price of a shorter life expectancy.
COMPLICATIONS OF BLADDER DYSFUNCTION Urinary tract infections are probably the most serious complication of neurogenic disorders of micturition. Large residual volumes of urine and the need for frequent catheterization predispose the animal to cystitis . This requires frequent urinalysis, culture, and treatment with administration of appropriate antibiotics to control the infections . If there is increased outflow resistance or diminished sensory function of the bladder, the normal lowpressure storage and expulsion of urine may be affected. Increased bladder pressure can \ead to hydroureter, hydronephrosis, ascending infection, and renal failure. Periodic intravenous pyelograms may be necesslfry to monitor for such progressive changes. 21. 37. 49 In spite of adequate care and monitoring, the incidence of complications will be high, and a guarded prognosis is warranted in most cases.
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60. Samson MD, Reddy VK: Localization of the sacral parasympathetic nucleus in the dog. Am J Vet Res 43:1833-1836. 1982 61. Sharp NJH, Nash AS, Griffiths IR: Feline dysautonomia (the Key-Gaskell syndrome): A clinical and pathological study of forty cases. J Small Anim Pract 25:599-615, 1984 62. Swash M, Snooks SJ: Electromyography in pelvic floor disorders. In Henry MM, Swash M (eds): Coloproctology and the Pelvic Floor. Boston, Butterworths, 1985, pp 88-103 63. Thor KB, Roppolo JR, deGroat WC: Naloxone induced micturition in unanesthetized paraplegic cats. J UroI129:202-205, 1983 64. Ueyama T, Mizuno N, Nomura JS, et al: Central distribution of afferent and efferent components of the pudendal nerve in cats. J Comp Neurol 222:38-46, 1984 65. Wein AJ: Classification of neurogenic voiding dysfunction. J UroI125:605-609, 1981 66. Wheeler JS. Robinson q, Culkin OJ, et al: Naloxone efficacy in bladder rehabilitation of spinal cord injury patients. J Urol 137:1202-1205, 1987 67. Yalla SV, Blunt KJ. Fam BA, et al: Detrusor-urethral sphincter dyssynergia. J Urol 118:1026-1029, 1977 Department of Veterinary Medicine and Surgery College of Veterinary Medicine University of Missouri Columbia, Missouri 65211