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Essential Nocturnal Enuresis Treated with d-Amphetamine Sulphate
THE JOUR:N"AL OF UROLOGY
Vol. 71, No. 2, February 1954 Printed in U.S.A.
ESSENTIAL NOCTURNAL ENURESIS TREATED WITH cl-AMPHETAMINE SULPHATE SAMUEL I. ROLAND From the Sub-Department of Urology, University of California School of Jvfedicine, San Francisco, Calif.
That the treatment of essential nocturnal enuresis in children is not always successful is best shown by the multiplicity of drugs and devices in current use. Essential nocturnal enuresis is defined as urinary incontinence occurring during sleep in the absence of organic defects after the age of three. 1 The association of enuresis with abnormally deep sleep has received little attention in the medical literature, although it is a frequent observation that most adults with enuresis give a history of heavy and sound sleep. 2 • 3 • 4 In our consecutive series of 51 children in whom there was no organic disease of the urinary tract or nervous system, a history of unusually deep sleep, with difficulty in awakening and the ability to sleep through marked noise and stimulation was found in 38 (74.5 per cent). All 51 children had urinary incontinence during the period of sleep, but only 4 were awakened by the stimulus of a wet bed. RATIONAL]] FOR TRBJATMENT
The hypothalamus, primarily its lateral and possibly it,; po,;terior areas, is known to be associated with the mechanisms of mic:turition and sleep-,vaking. Kleitman 5 states that sleep is brought about by a break between the cortex and brain stem, probably in the hypothalamus. vV. Russell Brain 6 considers normal sleep the result of interplay between the cortex and the hypothalamic sleep-waking center. Ranson, Kabat, and Magoun7 found that stimulation of the hypothalamic region induces contraction of the bladder and others8 have shown that bilateral cortical lesions produce signs of release of the bladder reflexes and an increase in the response to detrusor stretch. This is in keeping with Denny-Brown and Robertson's statement 9 that cortical control of the bladder consists of inhibition of spinal reflexes. The action of the hypothalamic: centers for mic:turition is dependent on the intact motor cortex fibers descending through the internal capsule. 10 It is well Accepted for publication February 27, 1953. 1 Seiger, H. W.: Treatment of essential nocturnal enuresis. J. Pediat., 40: 738-749, 1952. Strom-Olsen, R.: Enuresis in adults and abnormality of sleep. Lancet, 2: 133-135, 1950. 3 Heller, W.: Enuresis nocturna und Lehrlingsinternat. Deut. Gesundheit., 6: 1518, 1951. 4 Enuresis. Disabilities Series, Lancet, 1: 537-539, 1949. 5 Kleitman, N.: Sleep. Physiol. Rev., 9: 624-665, 1929. 'Brain, W. Russell: Sleep; normal and pathological. Brit. Med. J., 2: 51-53, 1939. 7 Ranson, S. W., Kabat, H. and JYiagoun, H. W.: Autonomic responses to electrical stimulation of hypothalamus, preoptic region, and septum. Arch. N eurol. & Psychiat., 33: 467-477. 1935. 8 Miller, H. R.: Central Autonomic Regulations in Health and Disease with Special Reference to the Hypothalamus (p. 243). New York· Grune & Stratton, pp. 289, 1942. 9 Denny-Brown, D. and Robertson, E.G.: On the physiology of micturition. Brain, 56: 149-190, 1933. 10 Beattie, ,T. and Kerr, A. S.: The effect of diencephalic stimulation on urinarv bladder tonus. Brain, 59: 302-314, 1936. · 2
216
ESSENTIAL ENURESIS
217
known that subcortical lesions in the frontal region may cause both incontinence and excessive sleep, as distinct from coma.11 After the operation of prefrontal leucotomy, the combination of drowsiness, deep sleep, and urinary incontinence during the first week or two is common. 2 While our knowledge of the mechanism of micturition is incomplete, there seems to be an anatomic-functional relationship between deep sleep and urinary incontinence. Consequently, a clinical study was undertaken to see if enuresis could be blocked by the sleep-opposing action of amphetamine. MATERIALS AND METHODS
A consecutive series of 51 patients were screened by physical examination, urinalysis, sacral x-rays if indicated, and by cystoscopic studies in children suspected of having organic urological difficulty. In none of these patients was any organic illness or deformity found; they all fitted in the category commonly called psychogenic or essential nocturnal enuresis. The ages ranged from 4 to 12 years. There -were 30 female and 21 male patients. Thirty-eight children (74.5 per cent) had a history of unusually deep or prolonged sleep. All were given 5 mg. of cl-amphetamine sulphate in an elixir, at bedtime, for one week. They were requested to void before going to bed, and were instructed to turn off an alarm clock that had been set to ring 4 hours later. The child was told to arise, turn off the alarm, void, and return to bed. At no time was the parent to assist the child in turning off the alarm or to guide the child to the toilet. If the treatment was unsuccessful after 1 week at the 5 mg. dose, it was raised to 10 mg. and the same awakening routine was used. If two dry nights occurred in the first week, the smaller dosage was continued for 3 weeks and then stopped. Even if enuresis ceased, the routine was continued for 21 days. If enuresis persisted after the 10 mg. dosage for 2 weeks, the treatment was discontinued. A dosage of 15 mg. was tried, but in our experience it was of no value if the 10 mg. quantity had been proved unsuccessful. No toxic or untoward reactions ,vere reported, nor was sleeplessness, unusual restlessness or alertness noted during the period of therapy. RESULTS
Forty-seven out of 51 cases, or 92 per cent of the cases treated, were relieved of enuresis within three weeks and remained dry at night with only rare incontinence for at least six months thereafter, the period for which all cases were followed. Thirty-nine of the patients were dry within a week after beginning the 5 mg. dosage and seven of these responded immediately after the initial dosage; but most cases required from three to five nights of treatment before enuresis was interrupted. In the remaining 8 cases in which improvement was observed, it was necessary to give 10 mg. after treatment for 7 days with the smaller dosage had failed. In the remaining 4 cases no results were obtained even after one month's re-trial following a month without therapy. One case was retreated in 30 days and did well after 4 doses of 10 mg. of cl-amphetamine 11 Michaels, J. and Rudoy, JVI.: Use of ephedrine sulfate in control of enuresis in schizophrenic regression . .J. Nerv. & Ment. Dis., 111: 147-153, 1950.
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SAMUEL I. ROLAND
sulphate on 4 successive nights and has remained continent for the past 14 months. The patients who were counted as successfully treated had an occasional incontinent night, but none had more than 8 incontinent nights in 6 months, with more than half of them completely relieved of their nocturnal enuresis with no subsequent incontinent nights. DISCUSSION
The results from the method described have been compared with those of other methods of therapy of essential nocturnal enuresis reported in the past 30 years. Statistically, our method appears to have given better results than any previously described. It has been compared with the use of ephedrine, 11 • 12 D-desoxyephedrine,13 atropine, 14 chorionic gonadotropin,1 5 thyroid extract, 16 testosterone,17 other endocrine therapy,18 an epiphyseal preparation, 19 pervitin, 3 and various mechanical devices. 20 , 21 The treatment with amphetamine sulphate has a rational physiologic basis, is inexpensive, lacks toxicity or hazard, and can be recommended for the treatment of this common and difficult problem. SUMMARY AND CONCLUSIONS
Of 51 children with essential nocturnal enuresis, 38 (74.5 per cent) gave a history of excessively heavy and prolonged sleep. Ninety-two per cent of all patients responded effectively to cl-amphetamine sulphate given as described. In some, increased dosage gave a prompt response when a lesser amount was unsuccessful. No untoward reaction to cl-amphetamine sulphate was observed. It appeared that the tolerance to this drug was greater than normal in these patients. Brookfield, R. W.: Ephedrine in the treatment of enuresis. Lancet, 2: 623-625, 1937. Kittredge, W. E. and Brown, H. G.: Ephedrine sulfate in the treatment of nocturnal enuresis. New Orleans M. & S. J., 96: 562-567, 1944. 14 Watson, W. P.: Atropine in enuresis. Arch. Pediat., 6: 709-716, 1889. 15 Cioffari, M. S. and Clark, H. G.: Treatment of enuresis in children by means of chorionic gonadotropin. Arch. Pediat., 64: 61-64, Feb. 1947. 16 Bustamante Espinoza, W.: Algunos casos de enuresis tratados con extracto tiroideo. Rev. chilena de pediat., 14: 124-131, Feb. 1943. 17 Schultz, F. W.: Testosterone propionate (androgen) therapy of enuresis. Pediat. Americas, 2: 309-313, 1944. 18 Schultz, F. W. and Anderson, C. E.: Endocrine treatment of enuresis. J. Clin. Endocrinol., 3: 405-407, 1943. .. 19 Popovici-Lupa, M. and Popescu-Tanaseanu, A.: U:ber die Beeinflussung der kindlichen Enuresis nocturna
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Vol. 71, No. 2, February 1954 Printed in U.S.A.
ESSENTIAL NOCTURNAL ENURESIS TREATED WITH cl-AMPHETAMINE SULPHATE SAMUEL I. ROLAND From the Sub-Department of Urology, University of California School of Jvfedicine, San Francisco, Calif.
That the treatment of essential nocturnal enuresis in children is not always successful is best shown by the multiplicity of drugs and devices in current use. Essential nocturnal enuresis is defined as urinary incontinence occurring during sleep in the absence of organic defects after the age of three. 1 The association of enuresis with abnormally deep sleep has received little attention in the medical literature, although it is a frequent observation that most adults with enuresis give a history of heavy and sound sleep. 2 • 3 • 4 In our consecutive series of 51 children in whom there was no organic disease of the urinary tract or nervous system, a history of unusually deep sleep, with difficulty in awakening and the ability to sleep through marked noise and stimulation was found in 38 (74.5 per cent). All 51 children had urinary incontinence during the period of sleep, but only 4 were awakened by the stimulus of a wet bed. RATIONAL]] FOR TRBJATMENT
The hypothalamus, primarily its lateral and possibly it,; po,;terior areas, is known to be associated with the mechanisms of mic:turition and sleep-,vaking. Kleitman 5 states that sleep is brought about by a break between the cortex and brain stem, probably in the hypothalamus. vV. Russell Brain 6 considers normal sleep the result of interplay between the cortex and the hypothalamic sleep-waking center. Ranson, Kabat, and Magoun7 found that stimulation of the hypothalamic region induces contraction of the bladder and others8 have shown that bilateral cortical lesions produce signs of release of the bladder reflexes and an increase in the response to detrusor stretch. This is in keeping with Denny-Brown and Robertson's statement 9 that cortical control of the bladder consists of inhibition of spinal reflexes. The action of the hypothalamic: centers for mic:turition is dependent on the intact motor cortex fibers descending through the internal capsule. 10 It is well Accepted for publication February 27, 1953. 1 Seiger, H. W.: Treatment of essential nocturnal enuresis. J. Pediat., 40: 738-749, 1952. Strom-Olsen, R.: Enuresis in adults and abnormality of sleep. Lancet, 2: 133-135, 1950. 3 Heller, W.: Enuresis nocturna und Lehrlingsinternat. Deut. Gesundheit., 6: 1518, 1951. 4 Enuresis. Disabilities Series, Lancet, 1: 537-539, 1949. 5 Kleitman, N.: Sleep. Physiol. Rev., 9: 624-665, 1929. 'Brain, W. Russell: Sleep; normal and pathological. Brit. Med. J., 2: 51-53, 1939. 7 Ranson, S. W., Kabat, H. and JYiagoun, H. W.: Autonomic responses to electrical stimulation of hypothalamus, preoptic region, and septum. Arch. N eurol. & Psychiat., 33: 467-477. 1935. 8 Miller, H. R.: Central Autonomic Regulations in Health and Disease with Special Reference to the Hypothalamus (p. 243). New York· Grune & Stratton, pp. 289, 1942. 9 Denny-Brown, D. and Robertson, E.G.: On the physiology of micturition. Brain, 56: 149-190, 1933. 10 Beattie, ,T. and Kerr, A. S.: The effect of diencephalic stimulation on urinarv bladder tonus. Brain, 59: 302-314, 1936. · 2
216
ESSENTIAL ENURESIS
217
known that subcortical lesions in the frontal region may cause both incontinence and excessive sleep, as distinct from coma.11 After the operation of prefrontal leucotomy, the combination of drowsiness, deep sleep, and urinary incontinence during the first week or two is common. 2 While our knowledge of the mechanism of micturition is incomplete, there seems to be an anatomic-functional relationship between deep sleep and urinary incontinence. Consequently, a clinical study was undertaken to see if enuresis could be blocked by the sleep-opposing action of amphetamine. MATERIALS AND METHODS
A consecutive series of 51 patients were screened by physical examination, urinalysis, sacral x-rays if indicated, and by cystoscopic studies in children suspected of having organic urological difficulty. In none of these patients was any organic illness or deformity found; they all fitted in the category commonly called psychogenic or essential nocturnal enuresis. The ages ranged from 4 to 12 years. There -were 30 female and 21 male patients. Thirty-eight children (74.5 per cent) had a history of unusually deep or prolonged sleep. All were given 5 mg. of cl-amphetamine sulphate in an elixir, at bedtime, for one week. They were requested to void before going to bed, and were instructed to turn off an alarm clock that had been set to ring 4 hours later. The child was told to arise, turn off the alarm, void, and return to bed. At no time was the parent to assist the child in turning off the alarm or to guide the child to the toilet. If the treatment was unsuccessful after 1 week at the 5 mg. dose, it was raised to 10 mg. and the same awakening routine was used. If two dry nights occurred in the first week, the smaller dosage was continued for 3 weeks and then stopped. Even if enuresis ceased, the routine was continued for 21 days. If enuresis persisted after the 10 mg. dosage for 2 weeks, the treatment was discontinued. A dosage of 15 mg. was tried, but in our experience it was of no value if the 10 mg. quantity had been proved unsuccessful. No toxic or untoward reactions ,vere reported, nor was sleeplessness, unusual restlessness or alertness noted during the period of therapy. RESULTS
Forty-seven out of 51 cases, or 92 per cent of the cases treated, were relieved of enuresis within three weeks and remained dry at night with only rare incontinence for at least six months thereafter, the period for which all cases were followed. Thirty-nine of the patients were dry within a week after beginning the 5 mg. dosage and seven of these responded immediately after the initial dosage; but most cases required from three to five nights of treatment before enuresis was interrupted. In the remaining 8 cases in which improvement was observed, it was necessary to give 10 mg. after treatment for 7 days with the smaller dosage had failed. In the remaining 4 cases no results were obtained even after one month's re-trial following a month without therapy. One case was retreated in 30 days and did well after 4 doses of 10 mg. of cl-amphetamine 11 Michaels, J. and Rudoy, JVI.: Use of ephedrine sulfate in control of enuresis in schizophrenic regression . .J. Nerv. & Ment. Dis., 111: 147-153, 1950.
218
SAMUEL I. ROLAND
sulphate on 4 successive nights and has remained continent for the past 14 months. The patients who were counted as successfully treated had an occasional incontinent night, but none had more than 8 incontinent nights in 6 months, with more than half of them completely relieved of their nocturnal enuresis with no subsequent incontinent nights. DISCUSSION
The results from the method described have been compared with those of other methods of therapy of essential nocturnal enuresis reported in the past 30 years. Statistically, our method appears to have given better results than any previously described. It has been compared with the use of ephedrine, 11 • 12 D-desoxyephedrine,13 atropine, 14 chorionic gonadotropin,1 5 thyroid extract, 16 testosterone,17 other endocrine therapy,18 an epiphyseal preparation, 19 pervitin, 3 and various mechanical devices. 20 , 21 The treatment with amphetamine sulphate has a rational physiologic basis, is inexpensive, lacks toxicity or hazard, and can be recommended for the treatment of this common and difficult problem. SUMMARY AND CONCLUSIONS
Of 51 children with essential nocturnal enuresis, 38 (74.5 per cent) gave a history of excessively heavy and prolonged sleep. Ninety-two per cent of all patients responded effectively to cl-amphetamine sulphate given as described. In some, increased dosage gave a prompt response when a lesser amount was unsuccessful. No untoward reaction to cl-amphetamine sulphate was observed. It appeared that the tolerance to this drug was greater than normal in these patients. Brookfield, R. W.: Ephedrine in the treatment of enuresis. Lancet, 2: 623-625, 1937. Kittredge, W. E. and Brown, H. G.: Ephedrine sulfate in the treatment of nocturnal enuresis. New Orleans M. & S. J., 96: 562-567, 1944. 14 Watson, W. P.: Atropine in enuresis. Arch. Pediat., 6: 709-716, 1889. 15 Cioffari, M. S. and Clark, H. G.: Treatment of enuresis in children by means of chorionic gonadotropin. Arch. Pediat., 64: 61-64, Feb. 1947. 16 Bustamante Espinoza, W.: Algunos casos de enuresis tratados con extracto tiroideo. Rev. chilena de pediat., 14: 124-131, Feb. 1943. 17 Schultz, F. W.: Testosterone propionate (androgen) therapy of enuresis. Pediat. Americas, 2: 309-313, 1944. 18 Schultz, F. W. and Anderson, C. E.: Endocrine treatment of enuresis. J. Clin. Endocrinol., 3: 405-407, 1943. .. 19 Popovici-Lupa, M. and Popescu-Tanaseanu, A.: U:ber die Beeinflussung der kindlichen Enuresis nocturna
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