Primary nocturnal enuresis: current concepts - march 1, 1999 .

Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. AAFP Home Page > News & Publications > Journals > American Family Physician® > Vol. 59/No. 5 (March 1, 1999) MEDLINE:
Primary Nocturnal
• Enuresis (4)
Enuresis: Current
Dartmouth-Hitchcock Medical CenterLebanon, New Hampshire Primary nocturnal enuresis sometimes presents significantpsychosocial problems for children and their parents. Causativefactors may include maturational delay, genetic influence, difficultiesin waking and decreased nighttime secretion of antidiuretic hormone.
Anatomic abnormalities are usually not found, and psychologic causes are unlikely. Evaluation of enuresis usually requires no morethan a complete history, a focused physical examination, and urinespecific gravity and dipstick tests. Nonpharmacologic treatmentsinclude motivational therapy, behavioral conditioning andbladder-training exercises. Pharmacologic therapy includesimipramine, anticholinergic medication and desmopressin. These drugs have been used with varying degrees of success.
Currently, an estimated 5 million to 7 million children in the United Stateshave primary nocturnal enuresis (nighttime bed-wetting). Although increasingattention has been focused on nocturnal enuresis and increasing numbers offamilies have sought assistance from their physicians, questions remainregarding the etiology and management of this condition.
This article reviews the current information on primary nocturnal enuresis, describes various condition. In addition, the author seeks to correct several misconceptions about primary nocturnal enuresis, including the following: that a child's bed-wetting is caused by drinking bed-wetting may occur as a result of a deep sleep pattern; and that the child is too lazy toget out of bed to void. This article focuses on primary nocturnal enuresis and does not address other disorders of elimination,such as urinary tract infection and dysfunctional voiding in patients whoexperience both daytime and nighttime incontinence.
Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. The American Psychiatric Association has defined bed-wetters as children olderthan age five who are incontinent of urine at night.1 The prevalence of nocturnal enuresis has been difficult to estimate because of variations in its definition andin social standards.2,3 It is now generally accepted that 15 to 20 percent ofchildren will have some degree of nighttime wetting at five years of age, with aspontaneous resolution rate of approximately 15 percent per year. Therefore, at15 years of age only 1 to 2 percent of teenagers will still wet the bed.
Some studies report that boys wet the bed more frequently than do girls, but thisfinding has been disputed by other reports.4 One study notes that 80 percent of children with enuresis wet the bed only at night, and approximately 20 percentalso have some daytime wetting.1 The latter group falls into a different categoryand warrants a different evaluation. Etiology
The etiology of primary nocturnal enuresis has been widely debated but is notyet completely understood. The physician should keep in mind that primarynocturnal enuresis is a diagnosis of exclusion, and that all other causes ofbed-wetting must be ruled out. Causes of secondary enuresis include neurogenicbladder and associated spinal cord abnormalities, urinary tract infections, andthe presence of posterior urethral valves in boys or an ectopic ureter in girls.
Posterior urethral valves cause significant voiding symptoms, such as strainingto void and diminished urinary stream. An ectopic ureter causes constantwetting. Despite numerous studies on primary nocturnal enuresis, its etiology remainselusive. Several recent reports have clarified the pathophysiology of enuresis.
The condition appears to be multifactorial, thus further complicating thetherapeutic approach. In addition, the well-recognized spontaneous resolutionrate clouds the search for causative mechanisms. Finally, the various treatmentapproaches and modalities are influenced by the patient's family environmentand by the background and prejudices of the patient, the parents and thephysician. Possible etiologies of primary nocturnal enuresis appear in Table 1. TABLE 1
Possible Etiologies of Primary Nocturnal
Family history, geneidentification, linkage analysis Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. Children withprimary nocturnal enuresis have normal physical examinations secretion in children with primary nocturnal enuresiscauses urine overproduction Maturational Delay
The most commonly accepted cause of nocturnal enuresis, but also the most
difficult to prove, is delayed functional maturation of the central nervous
system, which reduces the child's ability to inhibit bladder emptying at night.
The child's bladder will fill, but the sensory output resulting from the stretching
of the bladder is not perceived or is not sent to the brain and, thus, central
cortical control over the urinary sphincter contraction does not occur. Failure of
the arousal mechanism may also contribute to the inability to inhibit micturition.
Genetic Factors
A family history of nocturnal enuresis is found in most children with the
condition. One study has shown that in families where both parents had
enuresis, 77 percent of children will also have enuresis. In families where only
one parent had enuresis, 44 percent of children will be affected; only 15 percent
of children will have enuresis if neither parent had enuresis.7
Heredity as a causative factor of primary nocturnal enuresis has been confirmedby the identification of a gene marker associated with the disorder. In onestudy,8 Danish researchers evaluated 11 families with primary nocturnalenuresis. The trait showed nearly complete penetrance in these families. Thisstudy seems to suggest the existence of a major dominant gene for primarynocturnal enuresis. This gene appears to be located on chromosome 13.
However, no specific gene locus has yet been identified. The identification ofthis gene marker certainly lifts the burden of guilt from children who haveenuresis and helps to dispel the theory that enuresis is behavioral in origin.
Sleep Disorders
The sleep patterns of patients with enuresis have been studied extensively but
are difficult to interpret because of varying findings. Investigators studying
sleep electroencephalographies have reported a higher incidence of increased
slow brain-wave activity in patients with nocturnal enuresis; however, this has
been considered a nonspecific finding.9 Further studies have not supported this
finding and demonstrate no consistent correlation between abnormal sleep
patterns and bed-wetting.10,11 It appears that patients with enuresis may have
normal sleep patterns, but a recent study11 documented that patients with
Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. nocturnal enuresis have difficulties in waking. Parents report that children whowet the bed usually do so earlier in the night, and some older studies12,13 suggest that wetting episodes occur during slow-wave deep sleep. However, more recentstudies14 have shown that bed-wetting may occur at different stages of sleep.
Nocturnal enuresis has also been associated with upper airway obstruction inchildren, and surgical relief of the obstruction by tonsillectomy, adenoidectomyor both was reported to diminish nocturnal enuresis in up to 76 percent ofpatients.15 Behavior and Psychologic Factors
Psychologic factors are an unlikely cause of primary enuresis in children.
Researchers from New Zealand used a population-based model to follow
children up to 15 years of age. Using specific psychiatric criteria, they found
that children with primary enuresis have essentially the same behavior pattern as
children without primary enuresis.16 On the other hand, results from a Danish
study17 showed that patients with primary nocturnal enuresis seem to have a
poorer sense of belonging to society and clearly have lowered self-esteem. This
study suggests that enuresis itself may lead to psychologic problems in
Anatomic Factors
In cases of isolated primary enuresis, anatomic abnormalities are not usually
found. Findings from two studies18,19 suggest that functional bladder capacity
may be reduced in patients with nocturnal enuresis, but these findings have been
disputed by other researchers who found a low incidence of abnormalities in
bladder function and size when nocturnal enuresis was isolated.20 While some
parents report a small bladder capacity in children with enuresis, this condition
usually is accompanied by daytime symptoms. A history of, or symptoms
consistent with, a urinary tract infection indicate a need for further evaluation by
ultrasonography and voiding cystourethrography. In the absence of symptoms of
urinary tract infection, radiologic evaluation is not recommended for children
with primary nocturnal enuresis.
Secretion of Antidiuretic Hormone
Diurnal and nocturnal variations in the secretion of antidiuretic hormone over a
24-hour period have been reported in humans.21 Studies5,6 have demonstrated
that children with enuresis did not show a normal rise in the nocturnal secretion
of antidiuretic hormone.
Normal increases in the secretion of antidiuretic hormone are a typical response to extended periods of sleep. During this period, the bladder does not empty. In children who sleep between eight and 12 hours per night, the with straightforward increase in the secretion of antidiuretic hormone reduces the amount of urine produced by the kidneys, thus decreasing the amount of urine stored by the bladder. There is limitedevidence that some children with enuresis excrete significantly higher volumesof more diluted urine during sleep than do children without enuresis.22Abnormal secretion of antidiuretic hormone at night may be a significant factorin the etiology of nocturnal enuresis in some children, although studies of genemarkers do not correlate with abnormalities of antidiuretic hormone function.8 Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. Evaluation of Primary Nocturnal Enuresis
The most important factors to consider in the evaluation of patients withenuresis include the following: the patient's age, the severity and perceivedseverity of the problem within the patient's family, the spontaneous resolutionrate and the patient's response to therapy. When assessing the severity andperceived severity of the problem, the physician must consider, for example,that older children tend to suffer much more than younger children from thestigma of bed-wetting. These children may warrant medical intervention thatoffers a quick, safe response that will allow the child to participate in peeractivities. Other important factors include realistic goal setting, as well as properfollow-up. Our experience in treating patients with primary nocturnal enuresis has shownthat a consistent method of treatment and a goal-oriented approach withconsistent follow-up provide the best results. After proper evaluation of thechild and confirmation of the diagnosis of primary nocturnal enuresis, theexpectations of the parents and the child may be assessed, and recommendationsmay be made. Although the vast majority of patients who are treated for nocturnal enuresis arehealthy, the evaluation should be geared toward ruling out anatomicabnormalities of the urinary tract, such as posterior urethral valves, bladderabnormalities, an ectopic ureter or an epispadiac urethra (urethral opening on thedorsum of the penis). A careful medical history and physical examination, including urinalysis, willusually provide sufficient information for the physician to arrive at a diagnosis.
The history should include an assessment of the child's history of voidingpatterns and any previous work-up and therapy. The physical examinationshould include abdominal, genital and neurologic assessments to look forevidence of a distended bladder, spinal lesions and epispadias. Urinalysis shouldinclude urine specific gravity and dipstick tests, which might suggest thepresence of diabetes insipidus. Abnormalities in renal concentrating abilityshould be noted. A urine culture should be obtained only if the patient hassymptoms consistent with urinary tract infection or if urinalysis results arepositive for the presence of red and white blood cells. Urodynamic andradiologic evaluation are not necessary in children with straightforward primarynocturnal enuresis. Psychosocial and family histories are important, as the attitudes of the child andhis or her parents are significant in selecting proper therapy for primarynocturnal enuresis. Treatment
The first step toward proper treatment is to have the child's parents complete aquestionnaire that reviews the child's history of enuresis. The physician shouldalso consider the following points: children younger than six years of age aregenerally not evaluated if they have enuresis and no other ongoing urologicproblems; treatment modalities will not be successful if the parents and the childdo not have a cooperative attitude, and treatment will be unsuccessful if thefamily's social structure and home environment do not provide consistentsupport and care for the child. Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. Consistent follow-up is essential in gauging the results of therapeuticintervention. Objective documentation using a diary can help the physician, thepatient and the family monitor progress. Improvement is usually defined as a 50percent reduction in the number of nights that bed-wetting occurs. Cure orresolution of primary nocturnal enuresis is defined as only one or two wet nightsover a three-month period, and documentation that the child has wakenedspontaneously and gone to the bathroom to void. Treatment of nocturnal enuresis can be divided into two broad categories:nonpharmacologic and pharmacologic. Nonpharmacologic treatment of enuresisincludes motivational therapy, behavior modification (conditioning therapy),bladder-training exercises, psychotherapy, diet therapy and hypnotherapy.
Because of increased awareness that primary nocturnal enuresis can be asignificant psychosocial stressor, pharmacologic treatment of primary nocturnalenuresis has evolved significantly over the past 15 years, and safer, moreeffective medications are now available. Nonpharmacologic Methods
Motivational Therapy. Motivational therapy for the treatment of nocturnal
enuresis involves reassuring the parents and the child, removing the guilt
associated with bed-wetting and providing emotional support to the child. The
child should be instructed about taking responsibility for his or her bed-wetting.
In other words, children with nocturnal enuresis should be helped to understand
the condition and to realize that while they did not cause the problem, they do
have a role in the treatment plan.
Positive reinforcement for desired behavior should be instituted. One way tocarry out a program of motivational therapy is to set up a diary and chart, with areward system for each night the child stays dry. The cure, or resolution rate for children receiving motivational therapy has beenestimated to be only 25 percent (a figure close to the 15 percent rate ofspontaneous resolution), yet up to 70 percent of children with primary nocturalenuresis show marked improvement.23 Long-term follow-up is necessary,however, and a relapse rate of approximately 5 percent has been reported.24 Motivational therapy appears to be a reasonable first-line approach to treatingchildren with primary nocturnal enuresis, especially younger children. However,if therapy is not successful within three to six months, a different treatmentoption (e.g., behavior modification or pharmacologic therapy) should be offered.
Hypnotherapy, diet therapy and psychotherapy are treatment modalities thathave not been widely used in children with primary nocturnal enuresis.
Hypnotherapy has had good success rates in limited trials, but there has been nolong-term follow-up. Diet therapy also may be an option for some patients.
Children with a higher caffeine intake may be more prone to enuretic episodes.
Foods suspected to be contributing agents for enuresis include dairy products,chocolate, and citrus fruits and juices.25 Behavioral Conditioning. Behavioral conditioning in the treatment of primarynocturnal enuresis is based on the use of a signal alarm device. When the childvoids in bed, a moisture-sensing device that has been placed near the genitals isactivated and triggers an alarm. This evokes a conditioned response of wakingand inhibiting urination. Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. Various alarm devices are currently available. The alarm is either a sound or avibratory device. We prefer the vibratory alarm because we have found it to bemore effective than the sound devices in waking children. We do notrecommend using the alarm with children younger than seven years of age. Alarm therapy requires a cooperative and motivated child and family. Parentalinvolvement is very important when using alarm devices. Involvement includesrecording the child's responses to the device and monitoring his or her progress.
Again, use of a diary and a reward system may help reinforce the desiredbehavior. Parents should be told that this form of therapy will require along-term commitment as results may not be evident for several months. Long-term success using signal alarm devices has been reported inapproximately 70 percent of children with primary nocturnal enuresis.26 Werecommend that children use the alarm devices until they experience threeweeks of complete dryness. Relapse rates are higher when the alarm system isdiscontinued after shorter dry periods. Overall, relapse occurs in 20 to 30percent of patients. Relapse is certainly not incompatible with restarting alarmtreatment, and results are generally good with consistent use. Although alarm devices are generally safe, older buzzer systems have beenknown to cause buzzer ulcers. The alarm may fail if the moisture sensor is notpositioned correctly. Smaller units are now available (Table 2). TABLE 2
Some Alarm Devices for the Treatment of Primary
Nocturnal Enuresis
*--Manufacturers' prices, rounded to the nearest dollar. Shipping and handlingcharges are not included.
Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. Another method of behavioral conditioning involves waking the child two tothree hours after he or she has gone to sleep, eliciting a conditioned response ofwaking when the bladder is full. The success rate of this technique is unknown.
Most parents who use this technique report having difficulties in gaining theirchild's cooperation with this program. Bladder-Training Exercises. It is possible that functional bladder capacity maybe reduced in children with enuresis, causing premature bladder emptyingduring the night.27 As mentioned previously, urodynamic studies have notdemonstrated a reduced functional bladder capacity in children with enuresis.20 However, in some children with a small bladder capacity, the use ofbladder-retention training during the day may help increase bladder capacity atnight. This training is accomplished by having the child hold his or her urine forincreasing periods of time. In one study27 of children undergoing six months ofbladder-retention training, 66 percent of children reported some improvement,and 19 percent experienced complete resolution of symptoms. Bladder capacityincreased significantly in patients who responded to this therapy. However, thisis the only study to document such improvements, and results from this studymust be validated by more data. Pharmacologic Therapy
Pharmacologic therapy for the treatment of primary nocturnal enuresis is usually
reserved for use in children older than seven years of age. Two approaches to
drug therapy can be used. One approach is to increase bladder capacity. The
other is to reduce the amount of urine produced by the kidneys. Again, a careful
examination and medical history, including a history of previous treatment,
should be performed before drug therapy is initiated.
Several medications are available for the treatment of primary nocturnal enuresis(Table 3); however, none of these medications cures enuresis. Instead, theyprovide a stopgap measure until the children are able to wake on their ownduring the night to void. Parents should not expect immediate results and shouldbe made aware of the potential side effects of the medications. Because both theparent(s) and the physician are generally reluctant to use medication as afirst-line treatment, drug therapy is often reserved for use in children who haveshown no success with other treatment modalities. In some cases, however,family circumstances and/or the need for quick symptomatic relief may makedrug therapy a valuable first-line option. TABLE 3
Pharmacologic Therapy for the Treatment of Primary
Nocturnal Enuresis
30 tablets, 25 mg, $14.00; generic: 30tablets, 25 mg, $1.75 to $2.00 90 tablets, 5 mg, $44.00; generic: $27.00 to$33.25; 480 mL, generic: $40.00 to $53.00 Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. 90 tablets, 0.125 mg, $34.25; generic: 90tablets, $11.75 to $14.00 60 capsules, $43.75; generic: 60 capsules,$14.25 to $15.00† tablets, $96.75; 0.2 mg, 60 tablets, $156.25 *--Estimated cost to the pharmacist based on average wholesale prices,rounded to the nearest quarter dollar, in Red book. Montvale, N.J.: MedicalEconomics Data, 1997. Cost to the patient will be higher, depending onprescription filling fee. †--Check product for generic equivalency.
Tricyclic Antidepressants. Tricyclic antidepressants, including imipramine(Tofranil), have been used extensively during the past 25 years in the treatmentof primary nocturnal enuresis. Imipramine's exact mechanism of action has notbeen well established, but it may have an impact on enuresis on several levels.
Studies linking enuresis to rapid-eye-movement sleep suggest that tricyclicantidepressants alter the sleep and arousal mechanism.28 However, more recentstudies29 have failed to demonstrate a relationship between sleep stage andenuresis. Imipramine may also have a weak peripheral anticholinergic effect, as well as apossible effect on the sympathetic nerves in the bladder. Furthermore,imipramine has been hypothesized to alter secretion of antidiuretic hormone.30 The initial dosage of imipramine is 25 mg taken one hour before bedtime.
Response should be monitored and, if response is not satisfactory after one ortwo weeks, the dosage can be increased to 50 mg one hour before bedtime inchildren seven to 12 years of age, and up to 75 mg before bedtime in olderchildren. Initial success rates of between 10 and 15 percent have been reported,and a large study30 combining data from eight controlled double-blind trialsreported a long-term cure rate of 25 percent. The optimal duration of therapy hasnot been determined, but the empiric approach is to treat children for three to sixmonths and then wean them from the medication by reducing the dosage inincrements of 25 mg over three to four weeks. Clinical response withimipramine has been shown to correlate with plasma levels.31 Although imipramine has been prescribed extensively with significant results, its use continues to decrease because of the potential for major side effects, including anxiety, insomnia, dry mouth, nausea, personality associated with severe accidental overdose in Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. Anticholinergic Therapy. Anticholinergic medications, such as hyoscyamine(Levsin) and oxybutynin (Ditropan), have a direct effect on smooth musclerelaxation and therefore reduce or decrease the bladder's ability to contract.
Extensive use of anticholinergic agents for the treatment of uninhibited bladdercontraction has been reported, but experience with anticholinergics for thetreatment of enuresis is limited. Hyoscyamine, which has been used to treat irritable bowel syndrome andprimary nocturnal enuresis, is available in timed-release capsules and is reportedto be effective for at least eight to 10 hours. To our knowledge, no studiesreporting the success rate of hyoscyamine for the treatment of enuresis havebeen published. Anecdotal reports and our own experience, however, indicate afavorable response; this preparation may be effective in children with nocturnalenuresis.32 Evidence from a prospective, double-blind study33 of 30 children with enuresis showed no difference in the response of children who were given 10 mg ofoxybutynin at bedtime compared with children who were given placebo.
Oxybutynin is administered in dosages of 5 mg at bedtime in children older thanfive years of age. The dosage may be increased to 10 mg in older children. Thedosage of hyoscyamine is based on weight; however, the extended-release formis given as 0.375 mg at bedtime. The most commonly reported side effects ofanticholinergics in children are dry mouth, facial flushing, drowsiness,constipation, dizziness and occasional tremulousness. In the summer,hyperpyrexia can also be a concern. Desmopressin Acetate. Desmopressin acetate (DDAVP), a synthetic analog ofarginine vasopressin (antidiuretic hormone), has a highly specific antidiureticeffect, a relatively long half-life and an extended duration of action.
Desmopressin is administered through nasal insufflation. It is rapidly absorbedby the nasal mucosa and achieves maximum plasma concentration in about 45minutes. The biologic half-life of desmopressin acetate is four to six hours.34 The use of desmopressin is based on the finding that a subgroup of patients withenuresis had lacked the normal diurnal rhythm of antidiuretic hormoneproduction. In patients without enuresis, production of antidiuretic hormoneincreases during the night and reduces the amount of urine produced, allowingthe child to sleep for extended periods. In one study,35 15 patients with enuresis produced a decreased amount of antidiuretic hormone, compared with 11children without enuresis.
Patients included in several double-blind, randomized trials36-39 evaluating the effectiveness of desmopressin therapy (10 to 40 µg administered intranasally atbedtime) for the treatment of enuresis showed significant improvement inenuresis, with a long-term response rate of 10 to 70 percent.
The initial recommended dosage of desmopressin nasal spray is 20 µg (onespray into each nostril) at bedtime. Response should be evaluated after twoweeks of therapy and, if no response is noted, the dosage can be increased to 40µg at bedtime. Some patients older than 12 years of age can be treated with upto 60 µg intranasally. Interestingly, some patients will respond to as little as 10µg per day. Patients should receive desmopressin for at least three to six monthsand should be monitored carefully for response. The dosage can be taperedslowly after three to six months. Because abrupt discontinuation of therapy can Primary Nocturnal Enuresis: Current Concepts - March 1, 1999 - Americ. result in a high incidence of relapse, the dosage should be reduced slowly byincrements of 10 µg per month. Long-term therapy with desmopressin appearsto be safe. Desmopressin may be used on an as-needed basis in patients who haveresponded to it in the past and need temporary relief of enuresis, such as whenvisiting a summer camp or going on sleepovers. Because of desmopressin's rapid onset of action and good safety profile during the past 10 years, childrencan benefit from intermittent therapy to help them overcome difficultpsychosocial situations. Parents who are reluctant to have their children takemedication for extended periods of time may also feel more comfortable withthis approach.
When compared with placebo, the side effects of desmopressin have beennegligible in all studies reviewed. Occasional epistaxis and abdominal pain havebeen reported. Two reports32,40 of symptomatic hyponatremia in children usingdesmopressin have been published. These reports prompted recommendationsthat serum electrolyte levels be checked after two weeks of therapy, but thispractice has not been carried out universally.
Combination Therapy
Combination drug therapy may be tried in older patients with refractory primarynocturnal enuresis when neither the alarm nor pharmacologic therapy has beeneffective. A recent study41 evaluated the use of combination therapy to treatprimary nocturnal enuresis. Twenty-three patients (17 boys and six girls fromnine to 16 years of age) in whom prior medical therapy had failed were treatedwith desmopressin acetate and hyoscyamine therapy for an average of eightmonths. Patients were monitored monthly, and the dosage of medication wasadjusted as needed. Medications were tapered and discontinued when patientsdid not experience nighttime bed-wetting for at least 80 percent of the time.
Twelve patients (52 percent) were considered dry and off all medications. Eightpatients showed improvement and three patients showed little or no response.
Drug therapy can be combined with the use of alarms to optimizeeffectiveness.42 Marc Cendron, M.D., is a member of the speaker's bureau forRhône-Poulenc Rorer Pharmaceuticals, Inc.
The Author
MARC CENDRON, M.D.,is an associate professor of surgery and pediatrics in the Section of Urology,Department of Surgery, at Dartmouth Medical School, Lebanon, N.H., and apediatric urologist at the Children's Hospital at Dartmouth Medical School. Hereceived a medical degree from Tufts University School of Medicine, Boston, and completed a residency at the Hospital of the University of Pennsylvania,Philadelphia. He also completed a fellowship at the Brady Urological Institute atthe Johns Hopkins Hospital, Baltimore. Dr. Cendron has a special interest invoiding dysfunction, bladder physiology and reconstructive surgery of theurinary tract, as well as the prenatal diagnosis of anomalies. Address correspondence to Marc Cendron, M.D., Section of Urology,Dartmouth-Hitchcock Medical Center, One Medical Center Dr.,Lebanon, NH 03756-0001; e-mail: [email protected]
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36. Rittig S, Knudsen UB, Sorensen S, et al. Long-term double-blind crossover study of desmopressin intranasal spray in the management of nocturnal enuresis. In:Meadows SR, ed. Desmopressin in nocturnal enuresis: proceedings of aninternational symposium. Sutton Coldfield, England: Horus Medical Publications,1988:43-55. 37. Miller K, Klauber GT. Desmopressin acetate in children with severe primary nocturnal enuresis. Clin Ther 1990;12:357-66. 38. Terho P. Desmopressin in nocturnal enuresis. J Urol 1991;145(4):818-20.
39. Mark SD, Frank JD, Mark SD. Nocturnal enuresis. Br J Urol 1995;75:427-34.
40. Simmonds EJ, Mahony MJ, Little JM. Convulsion and coma after intranasal desmopressin in cystic fibrosis. BMJ 1988;297:1614. 41. Cendron M, Klauber J. Combination therapy in the treatment of persistent nocturnal 42. Wille S. Comparison of desmopressin and enuresis alarm for nocturnal enuresis. In: Meadows SR, ed. Desmopressin in nocturnal enuresis: proceedings of aninternational symposium. Sutton Coldfield, England: Horus Medical Publications,1989. Copyright 1999 by the American Academy of Family Physicians.
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