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Wetting The Bed: Integrative Approaches to Nocturnal Enuresis
PEDIATRICS
WETTING THE BED: INTEGRATIVE APPROACHES TO NOCTURNAL ENURESIS Timothy P. Culbert, MD, and Gerard A. Banez, PhD
ating back as far as 1550 BC, a broad spectrum of alternative therapies have been used in the treatment of bedwetting (nocturnal enuresis or NE), including what some might consider unorthodox approaches such as herbal remedies, mechanical devices, culturally defined rituals, urological procedures, dietary interventions, and behavioral modification techniques. Some of these were cruel or even harmful and few apparently helped, with little in the way of rigorous scientific evidence to guide the clinical practitioner.1 Consider the unfavorable risk-benefit ratio and obvious discomfort of interventions for NE, such as penal clamps, urethral cauterization, ingestion of a brew of “hares testicle with brain and wine,” or insertion of a sheep’s fat suppository, among the many interesting options utilized at some point in history for treating NE.2 Thankfully, a number of modern day treatment approaches for NE—physical and psychological, conventional and complementary—all show promise from an effectiveness standpoint, each offering unique possibilities for benefit. From an etiological perspective, NE remains a mystery, with genetic, urological, psychological, neurodevelopmental, and hormonal factors all playing a potential role in the development and maintenance of the disorder. As such, the multifactorial nature of NE lends itself to consideration of holistic or integrative treatment approaches that draw from a variety of healing traditions. These may be combined, prioritized, and individualized to each patient.
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EPIDEMIOLOGY Epidemiologically, generally accepted figures suggest that 6% to 10% of schoolaged children aged five to 16 years suffer from NE,3 and approximately 15% of children achieve spontaneous remission of NE annually.4 In healthy adults, there is
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an estimated prevalence of NE of 0.5%.5 Studies from various countries indicate an international prevalence rate for children aged six to 11 years3,6,7 from 1.4% to 28%. For example, a study of Korean children with NE aged seven to 12 years suggested an overall prevalence of 9.2%.8 In a sample from a rural community in southwestern Nigeria, among 644 children aged six to 12 years, the prevalence of NE was reported to be 17.6%. In that sample, the majority of respondents stated they used herbs or traditional medicine to treat enuresis.9 In a Turkish study, 12.4% of school children aged six to 16 years reported experiencing NE.10 A Chinese study of children identified a prevalence of 4.3% among children aged six to 16 years, with significantly more boys than girls experiencing NE.11 In this study, children with NE were also found to be at increased risk of behavioral, emotional, and academic problems. DEFINITIONS This article adopts the definitions utilized by the International Continence Society, an international group of scholars with an ongoing interest in NE.12 Bedwetting is given the diagnostic term nocturnal enuresis (NE), and in this article, refers to children who do not have daytime symptoms to suggest disorders of the lower urinary tract such as overactive bladder or any other complicating/contributing organic factors. Wetting both day and night is termed urinary incontinence and will not be reviewed here. Primary nocturnal enuresis (PNE) is defined as the involuntary discharge of urine at night in children aged five years or older who do not have congenital or acquired defects of the central nervous system or urinary tract and have not experienced a dry period of more than six months. Secondary nocturnal enuresis (SNE) is defined as above for PNE except for the fact
that these individuals have experienced a period of dryness of more than six months, followed by relapse. The Diagnostic and Statistical Manual for Mental Disorders, 4th edition, defines primary and secondary NE similarly.13
ETIOLOGIC MECHANISMS The etiology of PNE remains unclear and is often described as multifactorial or biobehavioral, potentially involving neurological, urological, sleep, genetic, and psychological influences. Neurological Factors One potential underlying cause is thought to involve delayed maturation of bladder mechanisms and possibly delay in the development of portions of the central nervous system required for maintenance of continence. Studies have suggested that children with NE may show signs of delayed maturation of the nervous system.14 Research evaluating autonomic nervous system parameters in enuretic children provides conflicting viewpoints, with one suggesting “parasympathetic nervous system hyperactivity” when compared with normal controls.15 In contrast, another study, which measured heart rate variability, suggested that children with NE demonstrate “sympathetic nervous system hyperactivity.”16 Bladder and Kidneys The balance between bladder capacity and the amount of urine produced at night is also an important variable in whether a child will wet or not. Studies have suggested that an impaired circadian rhythm of urine excretion influenced by inadequate antidiuretic hormone production in the evening results in large volumes of dilute urine production while asleep. The high volume of urine produced exceeds the child’s functional bladder capacity.17
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Although children with NE have normal bladder function and structural bladder capacity, nocturnal functional bladder capacity is smaller in individuals with NE. Functional bladder capacity increases as age progresses.3,18 Sleep Sleep structure in children with NE has not been reported to be substantially different as compared with normal controls. Also of note, NE occurs in all sleep stages. Anecdotally, many parents report their children with refractory NE to be deep sleepers who are difficult to arouse at night under any circumstances. Thus, the question of variability in each individual’s arousal response to the sensation of a full bladder has also been raised as a possible etiologic factor. Studies to date, however, have not demonstrated that children with NE are more difficult to arouse.18 Genetics Genetic studies indicate a heritable component to NE in that many parents of children with NE also experienced enuresis as children. In fact, when both parents have a history of childhood NE, almost three fourths of their offspring have enuresis. Studies have suggested possible genetic markers for PNE located on chromosomes 12, 13, and 22.19,20 Psychological and Behavioral Factors Psychological difficulties are likely a result rather than a cause of NE. As a group, children with uncomplicated NE usually experience no more significant psychological problems than other children, albeit parents of children with frequent NE describe more behavioral difficulties.21 Higher rates of NE are associated with certain populations, such as children with attention-deficit/hyperactivity disorder and those with internalizing disorders.22 Morbidity from NE is more commonly psychosocial than physical and can include low self-esteem, embarrassment, teasing, interference with peer activities such as sleepovers or summer camp participation, and parental frustration/anger that can lead to abusive behaviors (verbal, emotional, or physical).23,24 For SNE, emotional factors such as stress, abuse, and divorce may often play an important mediating role.18,25,26
Medical Factors Assessment of NE must include evaluation for nocturnal seizures; spinal cord lesions; sleep disordered breathing (obstructive sleep apnea); conditions that create polyuria (diabetes insipidus, diabetes mellitus); urologic abnormalities, including bladder instability and distal obstruction of the urinary tract; urinary tract infection; and extrinsic factors creating pressure on the bladder such as constipation or tumor.3,18
CONVENTIONAL TREATMENT Conventional Treatment Conventional approaches to NE have primarily included pharmacological and psychological interventions with variable effectiveness, potential side effects, and in some cases, significant relapse rates upon discontinuation of treatment. Recently, the Cochrane Database of Systematic Reviews27–30 has provided excellent coverage of this area. Medications Tricyclic antidepressants such as imipramine and desipramine can be effective in reducing the total number of wet nights while children are taking them, but most children relapse when the medication is discontinued.28 In addition, potential side effects, serious adverse effects with overdose, and the potential need to monitor blood levels and electrocardiograms limit their usefulness. Anticholinergic medications such as oxybutynin are generally not effective when compared with placebo in the treatment of NE.31 Widely used as a first-line agent, desmopressin does decrease wet nights and results in increased initial treatment success when compared with placebo. However, relapse rates after treatment discontinuation are high.27 Alarms Alarm interventions are an effective treatment for nocturnal bedwetting in children. Alarms appear more effective than desmopressin or tricyclics by the end of treatment and in long-term follow-up. When compared with no treatment, about two thirds of children became dry during alarm use. Nearly half who persisted with alarm use remained dry after treatment finished, compared with almost none after no treatment.6 The use of a simple over-
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learning procedure in which fluids are deliberately increased toward the end of treatment has been shown to decrease relapse.32 Other Psychological/Behavioral Treatments Simple behavioral strategies such as encouraging children to get up to urinate during the night, discouraging evening fluids, and emptying the bladder at bedtime are often recommended to children with NE. Though these strategies make common sense and can be helpful to children who have infrequent nighttime wetting, they are usually insufficient for treatment of repeated nocturnal voiding. Behavioral approaches that target waking schedules33,34 or a cognitive-behavioral approach that addresses maladaptive thoughts felt to contribute to wetting35 have shown promise, as discussed by Mellon and McGrath.36 However, empirical support for these approaches is limited by the lack of existing experimental rigor and depth of research. A number of studies have evaluated multicomponent treatments that consist of the urine alarm in combination with other behavioral strategies. For example, the dry-bed training approach developed by Azrin et al37 (1974) consists of a waking schedule, positive practice, cleanliness training, and the urine alarm. Dry-bed training has been found to have an average success rate of 75.3% in less than four weeks but is highly demanding on the child and family.38 Those interested in urine alarm treatment may be better served trying the basic urine alarm treatment prior to attempting a multicomponent approach. Though the resolution of wetting may require a longer period of time, eventual success rates are essentially comparable.
RATIONALE FOR AN INTEGRATIVE APPROACH The multifactorial nature of NE, the issue of treatment refractoriness with conventional approaches, and considerations of risk/benefit in treatment all support an integrative approach for NE treatment. The following benefits can be realized: ●
mind-body (brain-bladder) connections are reinforced
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● ● ● ● ● ● ●
patients are helped by increasing understanding and demystifying the disorder positive expectations for dryness are created each child’s active participation in treatment approaches is promoted the body’s natural healing abilities are facilitated family members are educated to optimize support roles the least invasive, most natural options are utilized whenever possible factors such as time, cost, complexity, and patient preference are considered
SPECIFIC INTEGRATIVE THERAPIES Hypnosis The hypnotic state can be described as an altered state of awareness within which a person’s experience heightened suggestibility. Children as a group demonstrate high hypnotic susceptibility and make excellent candidates for learning self-hypnosis/mental imagery techniques for a variety of childhood disorders, including NE.39,40 Four published reports as well as the authors’ clinical experience suggest that hypnosis, also termed relaxation/mental imagery, can be clinically effective in the treatment of NE, with minimal relapse. In a classic paper, Baumann and Hinman (1974)41 described the successful treatment of 73 boys with bowel and bladder incontinence problems, with a protocol combining short-term anticholinergic medication, treatment of associated constipation as necessary, and what they termed “positive suggestive therapy, most often with hypnosis.” In that series, the majority of the boys with NE (54 of 62) showed improvement in their bedwetting. One of the earliest reports of successful NE treatment came from Dr Karen Olness, a recognized pioneer in hypnotherapy with children.42 Olness describes in detail a case series of 40 children aged 4.5 to 16 years; 20 children had primary NE and 20 had secondary NE. Treatment was individualized in terms of number of sessions and length of time between visits. Patients were taught a brief induction technique, provided with therapeutic suggestions regarding waking up in a dry bed, and instructed to practice this exercise each night prior to bedtime. Most often, patients had a follow-up visit every one to two weeks until they achieved dryness to a
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level of no more than one wet night per month. Length of necessary treatment to achieve dryness varied from one to 28 months. Thirty-one of 40 patients were considered “cured.” Edwards and van Der Spuy43 (1985) treated NE in 48 children aged eight to 13 years, both primary and secondary. Children were treated with six weekly standardized training sessions in one of three conditions: hypnosis plus suggestion, hypnosis alone, or suggestion alone. They found that the children who engaged in hypnosis with specific therapeutic suggestion about having dry nights, as well as the children who engaged in hypnosis without therapeutic suggestion, achieved higher dryness rates than a wait-list control group. Banerjee et al44 (1993) compared imipramine to hypnosis in 50 enuretic children aged five to 16 years. The protocol called for each child in the hypnosis group to first attend three sessions to learn about the anatomy and physiology of the bladder. They were then trained in a hypnosis intervention coupled with therapeutic suggestions about using the toilet appropriately at night. Subjects were encouraged to practice self-hypnosis before going to sleep each night. Children in the imipramine (IMI) condition received 25 mg of IMI each night for the first week of treatment, followed by an additional 25 mg increment of IMI added each week as needed to achieve dryness. In both conditions, parents kept a diary of dry nights. “A positive response” was defined as a reduction of frequency in wet nights versus maintaining a baseline pattern, which was labeled as “no response.” In the first three months, rates of positive response did not differ between the two groups. At six months after cessation of treatments, however, substantially more subjects in the IMI condition had experienced relapse compared with those in the hypnosis condition. In clinical practice, the authors found that a simple drawing reviewing normal anatomy, brain-bladder communication, and discussions of controlling the bladder “gate” while asleep can set the stage for successful, individualized imagery leading to dryness. Acupuncture Acupuncture is a form of treatment utilized in traditional Asian medical systems,
which involves the insertion of needles at designated points in the body that are arranged along energy pathways or meridians that influence organ systems and structures. Acupuncture is thought to restore health by removing energy imbalances and blockages. Modern studies indicate that the mechanisms of therapeutic benefit for acupuncture may include modulation of endogenous opioids and/or autonomic nervous system effects. The mechanism for acupuncture’s effectiveness in improving NE is unknown, but one study suggests that for at least one subset of children with NE who demonstrate a form of bladder instability, acupuncture decreases uninhibited contractions of the detrusor muscle.45 Glazener et al46 reviewed acupuncture studies as part of a systematic review published in 2005. In one randomized controlled trial of 111 subjects, acupuncture appeared to be superior to a sham procedure.47 In another randomized controlled trial comparing acupuncture to a drug combination (meclofenoxate, oryzano, thiamine), acupuncture appeared to have a lower failure rate than the drug combination.48 Bower et al49 (2005) published a systematic review of acupuncture for NE in children. They evaluated 206 abstracts found in Western medical and Traditional Chinese Medicine journals as well as English language alternative medicine journals. Eleven studies were identified as eligible for data abstraction. Although the authors noted that there was tentative evidence for the efficacy of acupuncture in the treatment of childhood NE, they also stated that due to the low methodological quality of the studies, evidence to identify which acupuncture-related procedure is most effective is lacking. In a study of children with NE aged four to 13, Yuksek et al50 (2003) compared an acupressure point stimulation protocol in 12 patients to a control group receiving 0.4mg/kg of oxybutynin. Parents kept careful records of dry nights by completing questionnaires at 15 days, one month, three months, and six months after the start of treatment. At the six-month mark, complete and partial dry night responses were seen in 83.3% and 16.7%, respectively, of patients treated with acupressure as compared with 58.3% and 33.3%, re-
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spectively, of those treated with oxybutynin. Honjo et al51 (2002) evaluated a potential mechanism of action for acupuncture treatment of NE. In this trial, 15 subjects with NE were treated with acupuncture once a week for four weeks while bladder capacity and number of wet nights for each subject were monitored. Patients who improved by decreasing wet nights by at least 50% were considered responders. Response rates were 40% immediately following treatment and 47% two months after treatment. In six of the responders, nocturnal bladder capacity just after treatment was noted to have increased significantly, from 201 to 334 mL. Electroacupuncture (EAP) represents another variation that may be useful, particularly in children with NE who fail other interventions. Bjorkstrom et al52 reported on 25 children with NE aged seven to 16 who had been refractory to previous treatment. Median number of dry nights was 2.3 per week. Each patient received 20 sessions of EAP over eight weeks. Bedwetting, voided volume, sleep, and nocturia were evaluated at three weeks, three months, and six months by using parent dairies. At the three follow-up points, it was found that the number of dry nights improved to 3.0, 4.3, and 5.0 per week, respectively. There were more dry nights in 65% of the children (P ⬍ .001) who received EAP. Yuping et al53 (2006) reported on a series of 56 children with NE, aged four to 14 years, treated with acupuncture. He noted that from the Traditional Chinese Medicine perspective, NE is due to an imbalance between the heart channel and bladder channel with shenmen (HT 7) and weizhong (BL-40) identified as the main treatment points. Treatment of these points was described as involving completion of seven, 28-minute sessions with one needle manipulation. Acupuncture treatment resulted in a “cure” (complete dryness) in 34 of 56 cases. Chiropractic Chiropractic is a widely recognized alternative therapy in which disease is considered the result of abnormal function of the nervous system, especially the spinal cord and nerves. Chiropractic adjustment, which involves manipulation of the spinal column, is used to correct structural devi-
ations and promote normal bodily functions. In considering NE from the chiropractic perspective, joint restrictions in the lumbosacral or sacroiliac joints can irritate the sacral plexus of nerves that supply the bladder and sphincter muscles. A chiropractic adjustment to restore normal motion to these areas can be effective at restoring bladder control— both the child’s ability to detect a full bladder and/or the sphincter’s ability to remain closed until the time of conscious voiding. This type of joint restriction is especially common after a fall onto the buttocks, such as during an athletic activity (soccer, roller skating, sliding). In a 1991 case series, 171 children with NE, aged four to 15 years, were treated with chiropractic adjustments as the number of their wet nights per week was monitored by their parents.54 The median number of wet nights per week changed from 7.0 at study onset, to 5.6 (P ⬍ .01) after two weeks of simply monitoring (but no active treatment), and then to 4.0 (P ⬍ .0001) by the end of treatment. Treatment consisted of specific chiropractic adjustment of the areas of aberrant spinal movement as detected at each visit. Only 15.5% of the subjects were completely dry at the end of treatment. Overall, study authors described 75% as treatment failures and 25% as treatment successes. Two children reported adverse effects from chiropractic treatment during the study (headaches, stiff neck, acute lumbar spine pain). In a controlled trial of chiropractic treatment of 46 children, Reed et al55 (1994) compared “high-velocity, short lever adjustments of the spine” over a 10week treatment period with a “sham adjustment” for children in a control group. The posttreatment mean wet night frequency of 7.6 per two weeks for the treatment group was significantly less than the baseline frequency for that same group of 9.1 wet nights per two weeks (P ⬍ .05). For the control group, there was essentially no change from baseline in number of wet nights; 25% of the treatment group experienced at least a 50% reduction in frequency of wet nights from baseline to posttreatment.
sacral region to 27 patients with enuresis aged six to 14 years, over 10 daily sessions.56 A group of eight patients served as controls and were administered a placebo ultrasound treatment at the same site. In the active treatment group, 22 of 27 patients (81.5%) positively responded, beginning with the first week of treatment, with the effects then sustained at 12month follow-up. Mean number of wet nights in the active treatment group went from 4.9 wet nights per week to 1.5 per week at the 12-month point as compared with the placebo treatment group, which went from five wet nights per week at baseline to 4.3 per week at 12-month follow-up.
Energy/Ultrasound Ultrasound combined with irradiation and heating was applied over the lumbo-
Homeopathy Homeopathic remedies are popular and generally considered to be safe, although
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Diet Certain medical conditions may be precipitated by and/or exacerbated by food allergy, insensitivity, or intolerance. The use of restricted diets has been suggested to be helpful in NE, supported by the notion that enuresis for some may be linked to dietary responses that provoke bladder instability. The evidence supporting this idea is limited. Egger et al57 (1992) examined the use of an oligoantigenic diet in a double-blind crossover design. Twenty-one children with migraine and/or hyperkinetic behavior who also suffered from NE were treated with an oligoantigenic diet. Twelve of the 21 resolved their NE while on the diet. Of the original group, 9 of 21 children, aged 3.5 to 14 years, with migraine or hyperkinetic syndrome, who also had enuresis, and who had been identified as “responders” in the initial phase of the trial, were then moved into the next phase of the study. This subsample of children whose enuresis appeared to improve on an oligoantigenic diet were then tested in a double-blind randomized fashion by reintroducing provoking foods that were felt to affect their bedwetting. Six of nine children did relapse with NE when given test foods compared with zero of nine relapses observed when given nonreactive foods. Provoking foods included chocolate, orange, and milk. Concern about study is that small numbers make it difficult to make reliable comparisons.
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no published studies were identified on the topic of NE. Homeopathy is a therapeutic system that includes the utilization of specially prepared dilute remedies, whose effects when administered to healthy subjects correspond to the manifestations of the disorder in the sick patient. For NE, commonly used preparations have included homeopathic dilutions and combinations of belladonna, causticum, equistem, ferrum phos, lycopodium, pulsatilla, and sepia.58 Herbs One of the earliest treatments for NE consisted of “cypress, juniper berries, and beer” as described in the Papyrus Ebers from 1550 BC. In 1870, Trousseau recommended belladonna, and if that failed, recommended strychnine and stinging nettle.1 Although no published studies in mainstream medical journals could be identified, modern day herbalists suggest St John’s wort (Hypericum perforatum), infusions of horsetail, or corn silk (Zea mays) given through the day to encourage normal nervous control of the bladder. Other herbs suggested for bedwetting include agrimony (Agrimonia eupatoria), American cranesbill (Geranium maculatum), ladies mantle (Alchemilla vulgaris) and parsley (Penloselinum sativum Hoffin). An Ayurvedic perspective on NE suggests that an herbal remedy for children called shilajit may be useful and that sesame seeds can be given to balance vata.59
SUMMARY AND CONCLUSIONS It is rather fascinating that at this point in the evolution of many healing traditions (including Western/allopathic medicine), a common problem such as NE remains a mystery in terms of its precise etiology and preferred treatment. However, that is exactly why NE lends itself to consideration of an integrative approach, considering a variety of safe, reasonable, and cost-effective options. There has been some suggestion that despite the culture of evidencebased medicine practice that is frequently discussed, many physicians resort to pharmacologic treatment of NE with medications like desmopressin, even though empiric support for this treatment (which can be expensive and which has a poor long-
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term cure rate) as a first-line agent is lacking. As Christopherson pointed out “The family of a child with enuresis is entitled to a balanced and informed presentation of the treatment options that are available, their cost in terms of time and expense, the possible negative outcomes, and the probability that each procedure will be successful. Only in this fashion can a family make an informed decision”.60 Many, if not most, pediatricians are not trained in detail about the nondrug and complementary options available for NE, and even if educated about them, may argue that they are too time-consuming to discuss and/or provide in typical office practice (as these take longer than simply writing a prescription). Additionally, patient preference is not always discussed or prioritized in clinical settings, which may influence treatment adherence negatively. Approaches such as alarms, hypnosis, and acupuncture have much to offer, and in terms of overall support appear to be objectively better as first-line treatments for NE than pharmacologic approaches, particularly when considering long-term cure rates after discontinuation of treatment. The benefits of dietary, homeopathic, herbal, and chiropractic therapies for NE are less clear, with a paucity of quality studies to guide the practitioner. These options may, however, be appropriately considered with certain families, but always as balanced with considerations of safety, patient preference, time, and cost. There may well be additional integrative therapies for NE on the horizon, which are yet to be discussed, discovered, or tested, and that will eventually prove to be the first-line answer to this age-old problem.
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of rationale. Neurourol Urodyn. 2005;24: 267-272. Yuksek M, Erdem A, Atalay C, Demirel A. Acupressure vs oxybutinin in the treatment of enuresis. J Int Med Res. 2003;31:552-556. Honjo H, Kawauchi A, Ukimura O, et al. Treatment of monosymptomatic nocturnal enuresis by acupuncture: a preliminary study. Int J Urol. 2002;9:672-676. Bjorkstrom G, Hellstrom A, Andersson S. Electro acupuncture treatment of children with monosymptomatic nocturnal enuresis. Scand J Urol Nephrol. 2000;34:21-26. Yuping W, Runfang L, Hua K. Acupuncture treatment of children nocturnal enuresis-a report of 56 cases. J Trad Chin Med. 2006;26:106-107. Leboeuf C, Brown P, Herman A, Leembruggen K, Walton D, Crisp TC. Chiropractic care of children with nocturnal enuresis: a prospective outcome study. J Manipulative Physiol Ther. 1991;14:110-115. Reed W, Beavers S, Reddy S, Kern G. Chiropractic management of primary nocturnal enuresis. J Manipulative Physiol Ther. 1994;17:596-600. Kosar A, Akkus S, Savas A, Oztürk A, Serel TA, Keçelioglu M. Effect of ultrasound in the treatment of primary nocturnal enuresis. Scand J Urol Nephrol. 2000;34:361-365. Egger J, Carter C, Soothill JF, Wilson J. Effect of diet treatment on enuresis in children with migraine or hyperkinetic behavior. Clin Pediatrics. 1992;31:302-307. Ullman D. Homeopathic Medicine for Children and Infants. New York, NY: Tracher/ Putnam; 1992:49 –51. McIntyre A. Herbal Treatment of Children: Western and Ayurvedic Perspectives. Edinburgh, Scotland: Elsevier; 2005:265– 266. Christopherson E. Is evidence-based treatment sufficient to manage nighttime wetting problems (enuresis)? Arch Pediatr Adolesc Med. 2005;159:1182-1183.
Timothy Culbert, MD, is the medical director of the Integrative Medicine Program, Children’s Hospitals and Clinics, Minneapolis, Minnesota. Gerard A. Banez, PhD, works in the Division of Pediatrics at The Cleveland Clinic, Cleveland, Ohio.
Pediatrics
WETTING THE BED: INTEGRATIVE APPROACHES TO NOCTURNAL ENURESIS Timothy P. Culbert, MD, and Gerard A. Banez, PhD
ating back as far as 1550 BC, a broad spectrum of alternative therapies have been used in the treatment of bedwetting (nocturnal enuresis or NE), including what some might consider unorthodox approaches such as herbal remedies, mechanical devices, culturally defined rituals, urological procedures, dietary interventions, and behavioral modification techniques. Some of these were cruel or even harmful and few apparently helped, with little in the way of rigorous scientific evidence to guide the clinical practitioner.1 Consider the unfavorable risk-benefit ratio and obvious discomfort of interventions for NE, such as penal clamps, urethral cauterization, ingestion of a brew of “hares testicle with brain and wine,” or insertion of a sheep’s fat suppository, among the many interesting options utilized at some point in history for treating NE.2 Thankfully, a number of modern day treatment approaches for NE—physical and psychological, conventional and complementary—all show promise from an effectiveness standpoint, each offering unique possibilities for benefit. From an etiological perspective, NE remains a mystery, with genetic, urological, psychological, neurodevelopmental, and hormonal factors all playing a potential role in the development and maintenance of the disorder. As such, the multifactorial nature of NE lends itself to consideration of holistic or integrative treatment approaches that draw from a variety of healing traditions. These may be combined, prioritized, and individualized to each patient.
D
EPIDEMIOLOGY Epidemiologically, generally accepted figures suggest that 6% to 10% of schoolaged children aged five to 16 years suffer from NE,3 and approximately 15% of children achieve spontaneous remission of NE annually.4 In healthy adults, there is
Pediatrics
an estimated prevalence of NE of 0.5%.5 Studies from various countries indicate an international prevalence rate for children aged six to 11 years3,6,7 from 1.4% to 28%. For example, a study of Korean children with NE aged seven to 12 years suggested an overall prevalence of 9.2%.8 In a sample from a rural community in southwestern Nigeria, among 644 children aged six to 12 years, the prevalence of NE was reported to be 17.6%. In that sample, the majority of respondents stated they used herbs or traditional medicine to treat enuresis.9 In a Turkish study, 12.4% of school children aged six to 16 years reported experiencing NE.10 A Chinese study of children identified a prevalence of 4.3% among children aged six to 16 years, with significantly more boys than girls experiencing NE.11 In this study, children with NE were also found to be at increased risk of behavioral, emotional, and academic problems. DEFINITIONS This article adopts the definitions utilized by the International Continence Society, an international group of scholars with an ongoing interest in NE.12 Bedwetting is given the diagnostic term nocturnal enuresis (NE), and in this article, refers to children who do not have daytime symptoms to suggest disorders of the lower urinary tract such as overactive bladder or any other complicating/contributing organic factors. Wetting both day and night is termed urinary incontinence and will not be reviewed here. Primary nocturnal enuresis (PNE) is defined as the involuntary discharge of urine at night in children aged five years or older who do not have congenital or acquired defects of the central nervous system or urinary tract and have not experienced a dry period of more than six months. Secondary nocturnal enuresis (SNE) is defined as above for PNE except for the fact
that these individuals have experienced a period of dryness of more than six months, followed by relapse. The Diagnostic and Statistical Manual for Mental Disorders, 4th edition, defines primary and secondary NE similarly.13
ETIOLOGIC MECHANISMS The etiology of PNE remains unclear and is often described as multifactorial or biobehavioral, potentially involving neurological, urological, sleep, genetic, and psychological influences. Neurological Factors One potential underlying cause is thought to involve delayed maturation of bladder mechanisms and possibly delay in the development of portions of the central nervous system required for maintenance of continence. Studies have suggested that children with NE may show signs of delayed maturation of the nervous system.14 Research evaluating autonomic nervous system parameters in enuretic children provides conflicting viewpoints, with one suggesting “parasympathetic nervous system hyperactivity” when compared with normal controls.15 In contrast, another study, which measured heart rate variability, suggested that children with NE demonstrate “sympathetic nervous system hyperactivity.”16 Bladder and Kidneys The balance between bladder capacity and the amount of urine produced at night is also an important variable in whether a child will wet or not. Studies have suggested that an impaired circadian rhythm of urine excretion influenced by inadequate antidiuretic hormone production in the evening results in large volumes of dilute urine production while asleep. The high volume of urine produced exceeds the child’s functional bladder capacity.17
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Although children with NE have normal bladder function and structural bladder capacity, nocturnal functional bladder capacity is smaller in individuals with NE. Functional bladder capacity increases as age progresses.3,18 Sleep Sleep structure in children with NE has not been reported to be substantially different as compared with normal controls. Also of note, NE occurs in all sleep stages. Anecdotally, many parents report their children with refractory NE to be deep sleepers who are difficult to arouse at night under any circumstances. Thus, the question of variability in each individual’s arousal response to the sensation of a full bladder has also been raised as a possible etiologic factor. Studies to date, however, have not demonstrated that children with NE are more difficult to arouse.18 Genetics Genetic studies indicate a heritable component to NE in that many parents of children with NE also experienced enuresis as children. In fact, when both parents have a history of childhood NE, almost three fourths of their offspring have enuresis. Studies have suggested possible genetic markers for PNE located on chromosomes 12, 13, and 22.19,20 Psychological and Behavioral Factors Psychological difficulties are likely a result rather than a cause of NE. As a group, children with uncomplicated NE usually experience no more significant psychological problems than other children, albeit parents of children with frequent NE describe more behavioral difficulties.21 Higher rates of NE are associated with certain populations, such as children with attention-deficit/hyperactivity disorder and those with internalizing disorders.22 Morbidity from NE is more commonly psychosocial than physical and can include low self-esteem, embarrassment, teasing, interference with peer activities such as sleepovers or summer camp participation, and parental frustration/anger that can lead to abusive behaviors (verbal, emotional, or physical).23,24 For SNE, emotional factors such as stress, abuse, and divorce may often play an important mediating role.18,25,26
Medical Factors Assessment of NE must include evaluation for nocturnal seizures; spinal cord lesions; sleep disordered breathing (obstructive sleep apnea); conditions that create polyuria (diabetes insipidus, diabetes mellitus); urologic abnormalities, including bladder instability and distal obstruction of the urinary tract; urinary tract infection; and extrinsic factors creating pressure on the bladder such as constipation or tumor.3,18
CONVENTIONAL TREATMENT Conventional Treatment Conventional approaches to NE have primarily included pharmacological and psychological interventions with variable effectiveness, potential side effects, and in some cases, significant relapse rates upon discontinuation of treatment. Recently, the Cochrane Database of Systematic Reviews27–30 has provided excellent coverage of this area. Medications Tricyclic antidepressants such as imipramine and desipramine can be effective in reducing the total number of wet nights while children are taking them, but most children relapse when the medication is discontinued.28 In addition, potential side effects, serious adverse effects with overdose, and the potential need to monitor blood levels and electrocardiograms limit their usefulness. Anticholinergic medications such as oxybutynin are generally not effective when compared with placebo in the treatment of NE.31 Widely used as a first-line agent, desmopressin does decrease wet nights and results in increased initial treatment success when compared with placebo. However, relapse rates after treatment discontinuation are high.27 Alarms Alarm interventions are an effective treatment for nocturnal bedwetting in children. Alarms appear more effective than desmopressin or tricyclics by the end of treatment and in long-term follow-up. When compared with no treatment, about two thirds of children became dry during alarm use. Nearly half who persisted with alarm use remained dry after treatment finished, compared with almost none after no treatment.6 The use of a simple over-
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learning procedure in which fluids are deliberately increased toward the end of treatment has been shown to decrease relapse.32 Other Psychological/Behavioral Treatments Simple behavioral strategies such as encouraging children to get up to urinate during the night, discouraging evening fluids, and emptying the bladder at bedtime are often recommended to children with NE. Though these strategies make common sense and can be helpful to children who have infrequent nighttime wetting, they are usually insufficient for treatment of repeated nocturnal voiding. Behavioral approaches that target waking schedules33,34 or a cognitive-behavioral approach that addresses maladaptive thoughts felt to contribute to wetting35 have shown promise, as discussed by Mellon and McGrath.36 However, empirical support for these approaches is limited by the lack of existing experimental rigor and depth of research. A number of studies have evaluated multicomponent treatments that consist of the urine alarm in combination with other behavioral strategies. For example, the dry-bed training approach developed by Azrin et al37 (1974) consists of a waking schedule, positive practice, cleanliness training, and the urine alarm. Dry-bed training has been found to have an average success rate of 75.3% in less than four weeks but is highly demanding on the child and family.38 Those interested in urine alarm treatment may be better served trying the basic urine alarm treatment prior to attempting a multicomponent approach. Though the resolution of wetting may require a longer period of time, eventual success rates are essentially comparable.
RATIONALE FOR AN INTEGRATIVE APPROACH The multifactorial nature of NE, the issue of treatment refractoriness with conventional approaches, and considerations of risk/benefit in treatment all support an integrative approach for NE treatment. The following benefits can be realized: ●
mind-body (brain-bladder) connections are reinforced
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● ● ● ● ● ● ●
patients are helped by increasing understanding and demystifying the disorder positive expectations for dryness are created each child’s active participation in treatment approaches is promoted the body’s natural healing abilities are facilitated family members are educated to optimize support roles the least invasive, most natural options are utilized whenever possible factors such as time, cost, complexity, and patient preference are considered
SPECIFIC INTEGRATIVE THERAPIES Hypnosis The hypnotic state can be described as an altered state of awareness within which a person’s experience heightened suggestibility. Children as a group demonstrate high hypnotic susceptibility and make excellent candidates for learning self-hypnosis/mental imagery techniques for a variety of childhood disorders, including NE.39,40 Four published reports as well as the authors’ clinical experience suggest that hypnosis, also termed relaxation/mental imagery, can be clinically effective in the treatment of NE, with minimal relapse. In a classic paper, Baumann and Hinman (1974)41 described the successful treatment of 73 boys with bowel and bladder incontinence problems, with a protocol combining short-term anticholinergic medication, treatment of associated constipation as necessary, and what they termed “positive suggestive therapy, most often with hypnosis.” In that series, the majority of the boys with NE (54 of 62) showed improvement in their bedwetting. One of the earliest reports of successful NE treatment came from Dr Karen Olness, a recognized pioneer in hypnotherapy with children.42 Olness describes in detail a case series of 40 children aged 4.5 to 16 years; 20 children had primary NE and 20 had secondary NE. Treatment was individualized in terms of number of sessions and length of time between visits. Patients were taught a brief induction technique, provided with therapeutic suggestions regarding waking up in a dry bed, and instructed to practice this exercise each night prior to bedtime. Most often, patients had a follow-up visit every one to two weeks until they achieved dryness to a
Pediatrics
level of no more than one wet night per month. Length of necessary treatment to achieve dryness varied from one to 28 months. Thirty-one of 40 patients were considered “cured.” Edwards and van Der Spuy43 (1985) treated NE in 48 children aged eight to 13 years, both primary and secondary. Children were treated with six weekly standardized training sessions in one of three conditions: hypnosis plus suggestion, hypnosis alone, or suggestion alone. They found that the children who engaged in hypnosis with specific therapeutic suggestion about having dry nights, as well as the children who engaged in hypnosis without therapeutic suggestion, achieved higher dryness rates than a wait-list control group. Banerjee et al44 (1993) compared imipramine to hypnosis in 50 enuretic children aged five to 16 years. The protocol called for each child in the hypnosis group to first attend three sessions to learn about the anatomy and physiology of the bladder. They were then trained in a hypnosis intervention coupled with therapeutic suggestions about using the toilet appropriately at night. Subjects were encouraged to practice self-hypnosis before going to sleep each night. Children in the imipramine (IMI) condition received 25 mg of IMI each night for the first week of treatment, followed by an additional 25 mg increment of IMI added each week as needed to achieve dryness. In both conditions, parents kept a diary of dry nights. “A positive response” was defined as a reduction of frequency in wet nights versus maintaining a baseline pattern, which was labeled as “no response.” In the first three months, rates of positive response did not differ between the two groups. At six months after cessation of treatments, however, substantially more subjects in the IMI condition had experienced relapse compared with those in the hypnosis condition. In clinical practice, the authors found that a simple drawing reviewing normal anatomy, brain-bladder communication, and discussions of controlling the bladder “gate” while asleep can set the stage for successful, individualized imagery leading to dryness. Acupuncture Acupuncture is a form of treatment utilized in traditional Asian medical systems,
which involves the insertion of needles at designated points in the body that are arranged along energy pathways or meridians that influence organ systems and structures. Acupuncture is thought to restore health by removing energy imbalances and blockages. Modern studies indicate that the mechanisms of therapeutic benefit for acupuncture may include modulation of endogenous opioids and/or autonomic nervous system effects. The mechanism for acupuncture’s effectiveness in improving NE is unknown, but one study suggests that for at least one subset of children with NE who demonstrate a form of bladder instability, acupuncture decreases uninhibited contractions of the detrusor muscle.45 Glazener et al46 reviewed acupuncture studies as part of a systematic review published in 2005. In one randomized controlled trial of 111 subjects, acupuncture appeared to be superior to a sham procedure.47 In another randomized controlled trial comparing acupuncture to a drug combination (meclofenoxate, oryzano, thiamine), acupuncture appeared to have a lower failure rate than the drug combination.48 Bower et al49 (2005) published a systematic review of acupuncture for NE in children. They evaluated 206 abstracts found in Western medical and Traditional Chinese Medicine journals as well as English language alternative medicine journals. Eleven studies were identified as eligible for data abstraction. Although the authors noted that there was tentative evidence for the efficacy of acupuncture in the treatment of childhood NE, they also stated that due to the low methodological quality of the studies, evidence to identify which acupuncture-related procedure is most effective is lacking. In a study of children with NE aged four to 13, Yuksek et al50 (2003) compared an acupressure point stimulation protocol in 12 patients to a control group receiving 0.4mg/kg of oxybutynin. Parents kept careful records of dry nights by completing questionnaires at 15 days, one month, three months, and six months after the start of treatment. At the six-month mark, complete and partial dry night responses were seen in 83.3% and 16.7%, respectively, of patients treated with acupressure as compared with 58.3% and 33.3%, re-
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spectively, of those treated with oxybutynin. Honjo et al51 (2002) evaluated a potential mechanism of action for acupuncture treatment of NE. In this trial, 15 subjects with NE were treated with acupuncture once a week for four weeks while bladder capacity and number of wet nights for each subject were monitored. Patients who improved by decreasing wet nights by at least 50% were considered responders. Response rates were 40% immediately following treatment and 47% two months after treatment. In six of the responders, nocturnal bladder capacity just after treatment was noted to have increased significantly, from 201 to 334 mL. Electroacupuncture (EAP) represents another variation that may be useful, particularly in children with NE who fail other interventions. Bjorkstrom et al52 reported on 25 children with NE aged seven to 16 who had been refractory to previous treatment. Median number of dry nights was 2.3 per week. Each patient received 20 sessions of EAP over eight weeks. Bedwetting, voided volume, sleep, and nocturia were evaluated at three weeks, three months, and six months by using parent dairies. At the three follow-up points, it was found that the number of dry nights improved to 3.0, 4.3, and 5.0 per week, respectively. There were more dry nights in 65% of the children (P ⬍ .001) who received EAP. Yuping et al53 (2006) reported on a series of 56 children with NE, aged four to 14 years, treated with acupuncture. He noted that from the Traditional Chinese Medicine perspective, NE is due to an imbalance between the heart channel and bladder channel with shenmen (HT 7) and weizhong (BL-40) identified as the main treatment points. Treatment of these points was described as involving completion of seven, 28-minute sessions with one needle manipulation. Acupuncture treatment resulted in a “cure” (complete dryness) in 34 of 56 cases. Chiropractic Chiropractic is a widely recognized alternative therapy in which disease is considered the result of abnormal function of the nervous system, especially the spinal cord and nerves. Chiropractic adjustment, which involves manipulation of the spinal column, is used to correct structural devi-
ations and promote normal bodily functions. In considering NE from the chiropractic perspective, joint restrictions in the lumbosacral or sacroiliac joints can irritate the sacral plexus of nerves that supply the bladder and sphincter muscles. A chiropractic adjustment to restore normal motion to these areas can be effective at restoring bladder control— both the child’s ability to detect a full bladder and/or the sphincter’s ability to remain closed until the time of conscious voiding. This type of joint restriction is especially common after a fall onto the buttocks, such as during an athletic activity (soccer, roller skating, sliding). In a 1991 case series, 171 children with NE, aged four to 15 years, were treated with chiropractic adjustments as the number of their wet nights per week was monitored by their parents.54 The median number of wet nights per week changed from 7.0 at study onset, to 5.6 (P ⬍ .01) after two weeks of simply monitoring (but no active treatment), and then to 4.0 (P ⬍ .0001) by the end of treatment. Treatment consisted of specific chiropractic adjustment of the areas of aberrant spinal movement as detected at each visit. Only 15.5% of the subjects were completely dry at the end of treatment. Overall, study authors described 75% as treatment failures and 25% as treatment successes. Two children reported adverse effects from chiropractic treatment during the study (headaches, stiff neck, acute lumbar spine pain). In a controlled trial of chiropractic treatment of 46 children, Reed et al55 (1994) compared “high-velocity, short lever adjustments of the spine” over a 10week treatment period with a “sham adjustment” for children in a control group. The posttreatment mean wet night frequency of 7.6 per two weeks for the treatment group was significantly less than the baseline frequency for that same group of 9.1 wet nights per two weeks (P ⬍ .05). For the control group, there was essentially no change from baseline in number of wet nights; 25% of the treatment group experienced at least a 50% reduction in frequency of wet nights from baseline to posttreatment.
sacral region to 27 patients with enuresis aged six to 14 years, over 10 daily sessions.56 A group of eight patients served as controls and were administered a placebo ultrasound treatment at the same site. In the active treatment group, 22 of 27 patients (81.5%) positively responded, beginning with the first week of treatment, with the effects then sustained at 12month follow-up. Mean number of wet nights in the active treatment group went from 4.9 wet nights per week to 1.5 per week at the 12-month point as compared with the placebo treatment group, which went from five wet nights per week at baseline to 4.3 per week at 12-month follow-up.
Energy/Ultrasound Ultrasound combined with irradiation and heating was applied over the lumbo-
Homeopathy Homeopathic remedies are popular and generally considered to be safe, although
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Diet Certain medical conditions may be precipitated by and/or exacerbated by food allergy, insensitivity, or intolerance. The use of restricted diets has been suggested to be helpful in NE, supported by the notion that enuresis for some may be linked to dietary responses that provoke bladder instability. The evidence supporting this idea is limited. Egger et al57 (1992) examined the use of an oligoantigenic diet in a double-blind crossover design. Twenty-one children with migraine and/or hyperkinetic behavior who also suffered from NE were treated with an oligoantigenic diet. Twelve of the 21 resolved their NE while on the diet. Of the original group, 9 of 21 children, aged 3.5 to 14 years, with migraine or hyperkinetic syndrome, who also had enuresis, and who had been identified as “responders” in the initial phase of the trial, were then moved into the next phase of the study. This subsample of children whose enuresis appeared to improve on an oligoantigenic diet were then tested in a double-blind randomized fashion by reintroducing provoking foods that were felt to affect their bedwetting. Six of nine children did relapse with NE when given test foods compared with zero of nine relapses observed when given nonreactive foods. Provoking foods included chocolate, orange, and milk. Concern about study is that small numbers make it difficult to make reliable comparisons.
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no published studies were identified on the topic of NE. Homeopathy is a therapeutic system that includes the utilization of specially prepared dilute remedies, whose effects when administered to healthy subjects correspond to the manifestations of the disorder in the sick patient. For NE, commonly used preparations have included homeopathic dilutions and combinations of belladonna, causticum, equistem, ferrum phos, lycopodium, pulsatilla, and sepia.58 Herbs One of the earliest treatments for NE consisted of “cypress, juniper berries, and beer” as described in the Papyrus Ebers from 1550 BC. In 1870, Trousseau recommended belladonna, and if that failed, recommended strychnine and stinging nettle.1 Although no published studies in mainstream medical journals could be identified, modern day herbalists suggest St John’s wort (Hypericum perforatum), infusions of horsetail, or corn silk (Zea mays) given through the day to encourage normal nervous control of the bladder. Other herbs suggested for bedwetting include agrimony (Agrimonia eupatoria), American cranesbill (Geranium maculatum), ladies mantle (Alchemilla vulgaris) and parsley (Penloselinum sativum Hoffin). An Ayurvedic perspective on NE suggests that an herbal remedy for children called shilajit may be useful and that sesame seeds can be given to balance vata.59
SUMMARY AND CONCLUSIONS It is rather fascinating that at this point in the evolution of many healing traditions (including Western/allopathic medicine), a common problem such as NE remains a mystery in terms of its precise etiology and preferred treatment. However, that is exactly why NE lends itself to consideration of an integrative approach, considering a variety of safe, reasonable, and cost-effective options. There has been some suggestion that despite the culture of evidencebased medicine practice that is frequently discussed, many physicians resort to pharmacologic treatment of NE with medications like desmopressin, even though empiric support for this treatment (which can be expensive and which has a poor long-
Pediatrics
term cure rate) as a first-line agent is lacking. As Christopherson pointed out “The family of a child with enuresis is entitled to a balanced and informed presentation of the treatment options that are available, their cost in terms of time and expense, the possible negative outcomes, and the probability that each procedure will be successful. Only in this fashion can a family make an informed decision”.60 Many, if not most, pediatricians are not trained in detail about the nondrug and complementary options available for NE, and even if educated about them, may argue that they are too time-consuming to discuss and/or provide in typical office practice (as these take longer than simply writing a prescription). Additionally, patient preference is not always discussed or prioritized in clinical settings, which may influence treatment adherence negatively. Approaches such as alarms, hypnosis, and acupuncture have much to offer, and in terms of overall support appear to be objectively better as first-line treatments for NE than pharmacologic approaches, particularly when considering long-term cure rates after discontinuation of treatment. The benefits of dietary, homeopathic, herbal, and chiropractic therapies for NE are less clear, with a paucity of quality studies to guide the practitioner. These options may, however, be appropriately considered with certain families, but always as balanced with considerations of safety, patient preference, time, and cost. There may well be additional integrative therapies for NE on the horizon, which are yet to be discussed, discovered, or tested, and that will eventually prove to be the first-line answer to this age-old problem.
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5. Hirasing R, van Leerdam F, Bolk-Bennink L, Janknegt R. Enuresis in adults. Scand J Urol Nephrol. 1997;31:533-536. 6. Glazener C, Evans J, Peto R. Alarms for nocturnal enuresis in children. (Cochrane Rev). Cochrane Database Syst Rev. 2005;18: CD002911. 7. Schmidt E. Nocturnal enuresis: an update on treatment. Pediatr Clin NA. 1982;29:21. 8. Lee S, Sohn D, Lee J, Park N, Chung M. An epidemiological study of enuresis in Korean children. BJU Int. 2000;85:869-873. 9. Osungbade K, Oshiname F. Prevalence and perception of nocturnal enuresis in children of a rural community in southwestern Nigeria. Trop Doct. 2003;33:234-236. 10. Gur E, Turhan P, Can G, et al. Enuresis: prevalence, risk factors and urinary pathology among children in Istanbul, Turkey. Pediatrics Int. 2004;46:58-63. 11. Liu X, Sun Z, Uchiyama M, Li Y, Okawa M. Attaining nocturnal urinary control: nocturnal enuresis and behavioral problems in Chinese children aged 6 through 16 years. J Am Acad Child Adolescent Psychiatry. 2000;39:1557-1564. 12. Norgarrd J, van Gool J, Hjalmas K, Djurhuus J, Hellstrom A. Standardization and definitions in lower urinary tract dysfunction in children. BJU Int. 1998;81: (suppl) 13. Diagnosis and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychological Association; 2000:108110. 14. Jarvelin M, Moilanen I, Kangas P, et al. Aetiological and precipitating factors for childhood enuresis. Acta Paediatr Scand. 1991;80:361-369. 15. Yakinci C, Mungen B, Durmaz Y, et al. Autonomic nervous system function in children with nocturnal enuresis. Brain Dev. 1997;19:485-487. 16. Dundaroz M, Denli M, Uzun M, et al. Analysis of heart rate variability in children with primary nocturnal enuresis. Int Urol Nephrol. 2001;32:393-397. 17. Norgaard J, Djurhus J, Watanabe H, Stenberg A, Lettgen B. Experience and current research into the pathophysiology of nocturnal enuresis. Br J Urol. 1997;79:823-835. 18. Sheldon S. Sleep-related enuresis. In: Sheldon S, Ferber R, Kryger M, eds. Principles and Practice of Pediatric Sleep Medicine. Philadelphia, PA: Elsevier Saunders 2005:317326. 19. Eiberg H. Total genome scan analysis in a single extended family for primary nocturnal enuresis. Evidence for a new locus for PNE on chromosome 22q. 11. Eur J Urol. 1998;33:34. 20. Arnell H, Hjälmås K, Jägervall M, et al. The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major
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Timothy Culbert, MD, is the medical director of the Integrative Medicine Program, Children’s Hospitals and Clinics, Minneapolis, Minnesota. Gerard A. Banez, PhD, works in the Division of Pediatrics at The Cleveland Clinic, Cleveland, Ohio.
Pediatrics