Enuresis The disorder of enuresis has been recognized for centuries.

However, substantial progress in the understanding of the disorder did not begin to occur until there were effective treatments. The first effective treatment was the application of the bell-and-pad method of conditioning, which was subsequently followed by pharmacological treatment in the form of imipramine (Tofranil) and more recently desmopressin acetate (DDAVP). Each of these advances has led to etiological research that might explain the efficacy of the particular intervention. The amount of interest in the disorder, as assessed by the number of published articles, has been relatively constant over the last several years. At the beginning of this decade a literature search using the key terms enuresis and children (0 to 18 years), with a time frame of the prior 10 years, yielded a total of 822 citations. A recent search performed with the same parameters produced 570 citations. This chapter reviews the accumulated clinical knowledge concerning enuresis, as well as the emerging research that may lead to a greater understanding of the disorder. Definition Enuresis is defined as the involuntary or intentional voiding of urine. The severity is determined by the frequency of urination; quantity is not a diagnostic consideration per se. Quantity can become a factor in treatment decisions if a child emits only small quantities of urine; in actual practice, quantity usually does not figure heavily into the treatment plan. Frequency, however, can be important in planning a hierarchy of treatment approaches. The major diagnostic qualifier relates to age of onset. Finally, the definition precludes a physical cause for the disorder. The length of time before continence is considered established varies in the literature between 6 months and 1 year. The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) does not address that specific chronological issue but rather refers to “a „primary‟ type in which the individual has never established urinary continence, and a „secondary‟ type in which the disturbance develops after a period of established urinary continence.” In practical terms, children who have never maintained continence for more than 1 year are referred to as having primary enuresis, whereas children who have achieved continence for 1 year or longer and then resume wetting are referred to as having secondary enuresis. The disorder is also further defined according to the timing of the episodes throughout the day. Episodes occurring only at night are referred to as nocturnal; daytime wetting is labeled diurnal. Most children display only nocturnal enuresis, but some manifest diurnal or nocturnal and diurnal patterns. History A scholarly review of the history of enuresis found references dating back about 3,550 years to the Papyrus Ebers. The term derives from the Greek word enourein, which means “to void urine.” In retrospect, many of the treatment approaches that were used in the past now appear almost sadistic in nature. Although some of these interventions may have been misguided but well-intentioned therapies (as in the use of leeching for other disorders), they may also reflect the commonly held view that the disorder is somehow under the (direct or indirect) control of the child and that punishment would lead to its cessation. A confluence of somewhat disparate observations contributed to the evolution of the current understanding of enuresis. Although each of these is discussed in more detail in the following sections, a brief reference to them here will provide an overview of the various lines of research and their relative contributions to the present understanding of the disorder. The long-standing observation that enuresis tends to run in families evolved into the observation that a positive

family history was a positive prognostic indicator for response to pharmacological interventions and, ultimately, to sophisticated research with large pedigrees pointing toward specific genetic loci and modes of transmission. The observation that imipramine was an effective treatment for enuresis ushered in the modern era of research because the efficacy of imipramine suggested biological contributions to the etiology of the disorder. Imipramine has now been largely supplanted by DDAVP as a pharmacological treatment modality, and related research into its mechanism of action has contributed interesting insights into the pathophysiology of the disorder. Juxtaposed with the research into pharmacological treatment and organic contributions to the disorder has been the impressive literature, which now dates back several decades, indicating that behavioral treatment in the form of the bell-and-pad method of conditioning is as equally effective as the two leading pharmacological interventions for the disorder. The observation that the wetting episodes usually occur at night also led to decades of research investigating the relation between sleep architecture and the occurrence of enuretic events. Although none of these lines of research has provided a parsimonious explanation, each has provided important contributions to the evolving understanding of the disorder. The accumulating literature with regard to enuresis increasingly suggests that a single unified theory of enuresis that applies to all children will not be identified. Comparative Nosology The variety of differing nosological and diagnostic schemas seen with many disorders does not exist for enuresis. The behavior is concrete and definite: The child wets or does not. That criterion makes it possible to integrate research data from different countries, cultures, and treatment centers with a greater P.3625 reliability than is possible for many other disorders. The efficacy of a given treatment is reported in terms of its effect on the frequency of enuretic events. The primary differences with regard to diagnosis concern the frequency required to make a diagnosis of enuresis as a pathological state and the period of continence necessary to separate primary from secondary enuresis, with a duration of 6 months occasionally being used instead of 1 year. Only slight differences exist between the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and the DSM-IV-TR. The ICD-10 states that enuresis “would not ordinarily be diagnosed in a child under the age of 5 years or with a mental age under 4 years.” This is slightly different from the DSM-IV-TR cutoff of 5 years for chronological and mental age. However, the tables that accompany the ICD-10 indicate the same 5-year cutoff for chronological and mental age as is found in the DSM-IV-TR. The ICD-10 also notes a change in required frequency of enuresis after 7 years of age (at least twice a month before and once a month after). Recent research has suggested there may be a meaningful clinical distinction between monosymptomatic and polysymptomatic enuresis. The latter term refers to those children who not only have nocturnal enuresis, but also have multiple episodes of wetting, daytime wetting, soiling, and signs of bladder hyperactivity. Epidemiology The first comprehensive data concerning the incidence of enuresis came from the Isle of Wight Study. They found that 15.2 percent of boys (7 years of age) were enuretic less than once a week, whereas 6.7 percent were wetting at least once a week or more. In 7-year-old girls, the frequency was 12.2 percent for those wetting less than once a week and 3.3 percent with a frequency of once a week or more. By 9 and 10 years of age, 6.1 percent of the boys were wetting less often

than once a week, and 2.9 percent were wetting once a week or more. The corresponding figures for 9- and 10-year-old girls were 3.5 percent wetting less than once a week and 2.9 percent wetting once a week or more. The frequency for boys decreased considerably by 14 years of age, at which time 1.9 percent were wetting less than once a week, and 1.1 percent were wetting at a frequency of once a week or more. The rates also decreased for girls by 14 years of age, with 1.2 percent wetting less than once a week and only .5 percent wetting once a week or more. A New Zealand study involving 8-year-old children found the prevalence of nocturnal enuresis to be 7.4 percent, with 3.3 percent labeled primary and 4.1 percent labeled secondary. A similar large Scandinavian study involving 7-year-old children reported a prevalence of 9.8 percent, with the highest prevalence (6.4 percent) involving children with nocturnal enuresis, 1.8 percent with diurnal enuresis, and 1.6 percent with mixed nocturnal and diurnal enuresis. A report from Australia described an incidence of 5.1 percent for children in the range from 5 to 12 years of age. A review of the published epidemiological literature concerning enuresis indicates remarkably consistent findings from different countries and cultures, even though the research methods are somewhat variable. A standard consensus format that defines uniform reporting parameters would greatly enhance the epidemiological literature base. The point prevalence figures cited in the DSM-IV-TR are 7 percent of boys and 3 percent of girls at 5 years of age, dropping to 3 percent of boys and 2 percent of girls by 10 years of age. Only 1 percent of boys still wet at age 18 years of age, and still fewer girls wet at this age. The DSM-IVTR also cites a spontaneous remission rate of between 5 and 10 percent per year after 5 years of age. Secondary enuresis may occur at any time, but most commonly it begins between 5 and 8 years of age. Etiology Inclusion in the DSM-IV-TR definition of enuresis of children who wet intentionally with those whose enuresis is involuntary can be problematic. The vast majority of enuretic children do not wet intentionally or even on a subconsciously motivated basis. Increasingly, the research is pointing toward causal factors that may involve irregularities in physiological processes. Clearly, children who wet intentionally are in a different phenomenological grouping than those who do so on an involuntary basis, even if they do meet the other diagnostic requirements. The most likely explanations for voluntary intentional wetting are an oppositional defiant disorder or a psychotic disorder. There are also a small number of children who originally have enuretic events involuntarily and subsequently manifest the behavior on a voluntary learned basis as well. There is a correlation between enuresis and psychological disturbance that increases with age. This association is even more significant for enuresis, which persists into adolescence. Children living in socially disadvantaged situations and experiencing psychosocial stress have a greater frequency of enuresis than those who are not. The type and range of behavioral disturbance seen in children with enuresis are broad, and no marker can reliably differentiate between behaviorally disturbed and nondisturbed enuretic children. Thus, the associated behavioral disturbances are nonspecific and may represent a coincidental or secondary relationship rather than a causal correlation. Further supporting a secondary correlation are the repeated findings that children with enuresis have significantly more developmental delays and minor neurological dysfunction than nonenuretic children, compared to controls and other children attending a psychiatric clinic. Reports of delayed bone development in children with enuresis have also been linked to a possible general delay of maturation as a common underlying factor. However, new studies refute this finding, and no clear conclusion can be drawn at this time. The most recent research into a general developmental delay contributing to enuresis has used evoked potentials

and electromyographic recording of startle eye-blink performance. Separate investigations using these methods have pointed to delayed maturation of brainstem functions. Another approach to this etiological question is represented by a large, longitudinal, populationbased study in the United Kingdom, which compared the intelligence (as assessed by the Wechsler Intelligence Scale for Children–Third Edition [WISC-III]) of controls with children who still exhibited bedwetting in the age range of 7 years and 6 months to 9 years and 3 months. The authors reported that the bedwetting was associated with lower intelligence quotient (IQ) even after children with an IQ of less than 70 were excluded. However, this finding was primarily related to lower scores on the Performance section of the WISC-III. This observation led the authors to conclude that enuresis may be related to deficits in the maturation of the central nervous system. One comprehensive effort reviewed the psychodynamic literature concerning enuresis and encopresis to define the concepts conveyed in that literature and then to determine empirically how often those concepts were verified and supported by the analysis of clinical material. The literature review yielded 24 generalizations that were consistently applied to enuretic and encopretic children. In subsequent statistical analysis of the clinical material, only 2 of the 24 generalizations reached statistical significance. Another recent study in this regard used a standardized behavioral rating scale, the Eyberg Child Behavior Inventory (ECBI), which was applied to children with primary nocturnal enuresis (PNE) (N = 92), a nonclinical control sample (N = 92), and a clinical sample (N = 92). The results indicated that the children with PNE had higher scores than the nonclinical control sample but significantly lower scores than the clinical sample. However, the mean score for the children with PNE was actually lower than the clinical cutoff score that had been determined for the ECBI. Related to the issue of the association between behavioral disturbance and PNE are studies that address the frequency of diagnostic comorbidity. The most commonly reported comorbid diagnosis is attention-deficit/hyperactivity disorder (ADHD). In general, studies have reported that the co-occurrence of ADHD and PNE is P.3626 approximately 30 percent greater than the frequency that would be expected from chance alone. A large contemporary study found that 32 percent of children diagnosed with ADHD also met diagnostic criteria for enuresis, whereas only 14 percent of a control group met the criteria. This finding was statistically significant at the p <.001 level. The rates of primary and secondary enuresis were not significantly different in the two groups. This study then investigated the degree of psychopathology and impairment in the ADHD children (with and without comorbid enuresis) and found no significant differences. Similar findings were reported for the rates of psychopathology when the control children with enuresis were compared to those without the condition. Thus, the diagnosis of enuresis did not appear to increase the risk of psychopathology for the controls or the degree of impairment in the children who also had a diagnosis of ADHD. However, there was a higher incidence of learning disabilities and impaired academic performance in the control children with enuresis when compared to the control children without enuresis. This difference in the incidence of learning disabilities was not found when the ADHD children with enuresis were compared to those without the comorbid disorder, so the cooccurrence of enuresis did not appear to increase the risk of learning disabilities in children with ADHD.

Another investigation used a family pedigree methodology to study the transmission of enuresis in the relatives of index family members who were diagnosed with PNE and in control probands who were diagnosed with ADHD as compared to those without this diagnosis. The results indicated that the two disorders were transmitted independent of one another. Enuresis has been noted to occur statistically more frequently in the premorbid histories of children who develop early adolescent bipolar I disorder as compared to controls. An increased incidence of enuresis and other childhood psychiatric disorders has also been found in the history of adults with bipolar disorder and is associated with earlier onset of the disorder. The association between behavioral disturbance and enuresis is stronger with secondary enuresis. This has been demonstrated by controlled studies and anecdotal reports of an association between the onset of enuresis and the loss of a parent through divorce or death. However, it should be noted that a large study from the Netherlands reported similar rates of psychopathology in children with primary enuresis as compared to those with secondary enuresis. The prevalence of psychodynamic factors in children with secondary enuresis would intuitively make sense because they have, by definition, demonstrated the physiological competence to maintain continence for a prolonged period of time before losing that ability. The most specific study of this association indicated that exposure to four or more stressful life events in a year and delayed acquisition of nocturnal continence were risk factors for the development of secondary enuresis. An association between the occurrence of traumatic events and the development of secondary enuresis has also been demonstrated. There has been one innovative attempt to explore the possible relation between physiological and psychological factors. Specifically, it was postulated that children with enuresis who did not present with a concomitant behavioral disturbance would be those with dysfunctional or abnormal bladders, whereas those with a behavioral disturbance would be more apt to have normal bladders. The study found the converse to be true: The group with behavioral disturbance had more dysfunctional bladders with lower volumes. The behaviorally disturbed group also had a greater number of developmental delays. A subsequent investigation reported no difference in bladder size among controls, children with PNE, and those who had been diagnosed with PNE but who were now continent. It also was demonstrated by two independent investigations that fluid loading can precipitate enuresis in children who have no prior history of enuretic events. The most recent investigations into this issue have used ultrasound techniques, which investigate both the volume capacity of the bladder and the thickness of the bladder wall in both controls and children with enuresis. This research suggested three subtypes: Large-capacity bladder with thick wall; normal-capacity bladder with normal wall thickness; and low-capacity bladder with thick wall. The children with enuresis were then assessed with regard to their response to a treatment with DDAVP. The results indicated that the children with the two abnormal bladder subtypes were less responsive to treatment than those with the normal bladder physiological characteristics. The observation that enuresis tends to occur in family members has been made for some time. A large Scandinavian study involving more than 3,000 children found that a child's risk for developing enuresis was 5.2 times greater if the mother also had the disorder and 7.1 times greater if the father had the disorder, lending further support to a genetic influence. The DSMIV-TR notes that the concordance rate for enuresis is greater in monozygotic twins than in dizygotic twins, and 75 percent of children with enuresis have a similarly affected first-degree biological relative. Within the last few years, there have been tremendous advances in the study of the genetic transmission of enuresis, which suggests that genetic contributions are likely to be

significant in families with multigenerational histories of enuresis. A Scandinavian group identified 11 families that manifested PNE over three generations in a pattern that was suggestive of an autosomal-dominant inheritance, with penetrance greater than 90 percent. Genetic linkage studies with these families indicated markers on chromosome 13q. Similarly designed studies have also implicated chromosomes 4p, 8, 12q, and 22, suggesting genetic heterogeneity. A large multigenerational study that specifically investigated chromosome 22 found that only 39.3 percent of families had linkage to genetic markers on this chromosome. The genetic modes of transmission that have been discussed include sporadic, autosomal recessive, and autosomal dominant. Linkage studies have also suggested the possibility of mutation in the aquaporin-2 (AQP2) water channel locus in families with a dominant mode of transmission of primary enuresis, in that AQP2 appears to be essential for concentrating urine. Although genetic linkage studies continue to provide important information with regard to the etiology of enuresis, it increasingly appears that the genetic contributions are heterogeneous in nature and vary substantially among pedigrees that contain multiple generations of individuals with enuresis. One particularly important etiological hypothesis was that urinary tract obstruction frequently caused enuresis. The significance of that belief revolves around the related implications for surgery to correct the obstruction. Extensive review of the relevant literature found no basis for concluding that bladder neck repair or urethral dilation was a reasonable or effective treatment for enuresis. That generalization does not apply to patients with specific anatomical or pathophysiological findings. Research into the association between sleep physiology and enuretic events has evolved steadily since the 1970s. The research can be seen as evolving through the following four stages. During the first phase of the research, it was postulated that enuretic events were dream equivalents that occurred in deep sleep. The second major theory grew out of the observation that enuretic events originated in delta sleep and followed arousal signals. Thus, enuresis was seen as a disorder of arousal, which led to the hypothesis that enuretic children who were not psychologically disturbed did not produce arousal signals, whereas behaviorally disordered children did but failed to respond to them. The third phase of sleep research is represented by the two largest controlled studies, both of which found that, when the time of night is also considered, enuretic events occur in all sleep stages in proportion to the amount of time spent sleeping in each stage. A fourth phase of investigation has attempted to couple cystometry with sleep studies in an attempt to identify subtypes. A long-debated issue has been whether children with nocturnal enuresis are more difficult to awaken from sleep than other children. Earlier literature had suggested that anecdotal reports from the parents of children with enuresis that they were difficult to arouse stemmed from their lack of experience in attempting to arouse their other children, who did not have enuresis, from a deep sleep. However, recent studies have suggested that children with enuresis may, in fact, be more difficult to arouse than control children. P.3627

The efficacy of DDAVP as a treatment for enuresis has led to the theory that some children lack the ability to concentrate urine produced during the night and thus cannot reduce urine volume, and manifest enuretic episodes as a result. That hypothesis has led to studies investigating the circadian variation of plasma atrial natriuretic peptide (ANP). Children with enuresis have not consistently been found to differ from controls with regard to ANP. In one study, 14 of 55

children with enuresis had lower ANP concentrations than controls, and 9 of the 14 children had an excellent response to treatment with DDAVP. An investigation into the concentration of vasopressin in plasma and urine in 18 children with PNE and 20 matched controls found the concentration of vasopressin in plasma at 8:00 AM was significantly lower in the enuretic group. Total 24-hour urinary vasopressin excretion was also lower in the enuretic group but not significantly so. Another hypothesis that has been investigated is that endogenous arginine vasopressin (AVP) levels would be different in children with enuresis who respond to DDAVP as opposed to those who do not. This would suggest the existence of a specific subgroup of children with enuresis based on their endogenous AVP levels and their positive response to DDAVP. A study involving a small number of subjects supported this hypothesis by indicating that AVP levels in the morning differentiated between controls and children with enuresis, as well as between DDAVP responders and nonresponders. However, a large study that also controlled for water intake over 72 hours and that sampled AVP more frequently found that only 14 of the 55 children with enuresis had a significant decrease in AVP when compared to controls. Of these, 9 had a significant positive response to DDAVP. Further complicating this line of research is the finding that AVP is not secreted in a continuous manner over 24 hours, but rather is secreted in a pulsatile pattern, suggesting that definitive studies of this variable require frequent sampling. Investigations that have adopted this methodology have yielded conflicting results, in that one reported no differences between DDAVP responders and nonresponders, whereas another study with a small number of subjects that used hourly measurements found that in the 11:00 PM to 4:00 AM time period, children with enuresis (N = 9) had significantly lower AVP levels than did controls (N = 8). There have also been related studies into the role of urine osmolality. One hypothesis is that a decreased ability to concentrate urine could contribute to an increase in the volume of urine. In general, these studies indicated that children with enuresis do have lower urinary specific gravities (as compared to controls) but not to a level that reaches statistical significance. It has also been reported that the levels of AVP can be increased in controls and children with enuresis by fluid restriction and, furthermore, that plasma osmolality can effect AVP secretion. In this regard, a comparison of controls, DDAVP nonresponders, and DDAVP responders indicated that fluid deprivation produced an increase in AVP levels in all groups, but the response was less robust in the DDAVP responders than in the other groups. Another variation on this line of research is that refractory enuresis persisting into adolescence and adulthood may be secondary to a relative insensitivity to AVP, which can be positively affected by DDAVP. These observations contribute to the hypothesis that the primary pathophysiology of enuresis may occur at the receptor level, and this may also explain why some children do not respond to DDAVP. Further complicating the research into the mechanism of action of DDAVP are two independent investigations that suggested that there is a central nervous system mechanism that may account for its efficacy in some children with enuresis. Thus, as the foregoing review suggests, what initially appeared to be an intuitive explanation for the mechanism of action of DDAVP has not been supported by a number of studies, and a precise mechanism that applies to all children who respond to DDAVP has not been identified. There have also been investigations that have implicated tubular mechanisms with regard to the urinary excretion of potassium and sodium by children with enuresis. Although this research has primarily focused on the possible mechanism of action of DDAVP, it has also led to a reanalysis

of imipramine's mechanism of action. Imipramine can produce a decrease in the excretion of sodium and potassium, which then produces a reduction in osmolal clearance and a decrease in urinary output. It has also been reported that imipramine can affect the secretion of nocturnal urinary antidiuretic hormone (ADH) and that this may account for its efficacy. Diagnosis and Clinical Features The DSM-IV-TR criteria for enuresis are listed in Table 46-1. These criteria are virtually unchanged from the prior fourth edition of the DSM (DSM-IV) criteria. The concreteness and simplicity of enuresis make the diagnosis relatively easy. The DSM-IV-TR continues the same age criteria that were used in the DSM-IV by specifying that the diagnosis is not made in a child whose chronological or mental age is younger than 5 years of age. The stated rationale is that, by this age, continence can be expected to have occurred. As noted by the reference to a mental age of 5 years of age, children with developmental disabilities may have a greater chronological age. The wetting must occur at least twice per week for at least 3 consecutive months, or, if less frequent, it must produce significant distress or functional impairment. Physical causes, such as a bladder infection, must be excluded. Qualifiers to the diagnosis indicate whether it is primary or secondary enuresis. As previously noted, primary enuresis refers to those children who have never maintained continence for any length of time, whereas secondary enuresis refers to those who had achieved continence for at least 6 to 12 months and then resumed wetting. The other qualifiers refer to the timing of the enuretic event during the day. Although most children exhibit only nocturnal enuresis, some have daytime (diurnal) patterns or a combined nocturnal and diurnal pattern. The inclusion of children who wet intentionally with those who wet involuntarily under the same diagnostic heading can be problematic because that distinction has significant clinical implications. Children who are wetting intentionally almost certainly are doing so P.3628 as a manifestation of a psychological disturbance. Although there is an association between behavioral disturbance and involuntary enuresis, the nature of the correlation is relatively nonspecific. Thus, although the coexistence of other behavioral problems is not a diagnostic issue per se, it is of clinical importance. The ICD-10 criteria for nonorganic enuresis are presented in Table 46-2. Table 46-2. ICD-10 Diagnostic Criteria for Nonorganic Enuresis A. The child's chronological and mental age is at least 5 years. B. Involuntary or intentional voiding of urine into bed or clothes occurs at least twice a month in children younger than 7 years of age and at least once a month in children 7 years of age or older. C. The enuresis is not a consequence of epileptic attacks or of neurological incontinence and is not a direct consequence of structural abnormalities of the urinary tract or any other nonpsychiatric medical condition. D. There is no evidence of any other psychiatric disorder that meets the criteria for other ICD-10 categories. E. Duration of the disorder is at least 3 months. Reprinted with permission from World Health Organization: The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization; 1993.

John was a 10-year-old boy who had consistently wet the bed throughout his life. He averaged three to four nocturnal episodes per week, and his longest period of continence was a few weeks. Thus, John warranted a diagnosis of primary enuresis. John's father had been enuretic until 12 years of age, as were his father and a paternal uncle. Accordingly, the family had always assumed that this was a genetic hereditary disorder that John could not control. In keeping with this perception, John's parents had never adopted a punitive approach to the bedwetting. The wetting was handled in a matter-of-fact manner, with John washing his sheets every morning and showering before going to school. The family sought consultation at this time because John was increasingly being asked to sleep overnight at the homes of friends and also wanted to attend an overnight Boy Scout camp. These concerns led the family to meet with their pediatrician, who suggested a trial of the bell-and-pad method of conditioning. This approach was not effective, in part because the family lived in cramped quarters and the alarm that was meant to awaken John also woke his two brothers who shared the bedroom with him. At this point, the family's pediatrician suggested that they meet with a child psychiatrist with whom she worked. The child psychiatrist described the clinical literature on DDAVP. However, when John's father indicated that his health insurance did not cover prescriptions and that the family was having difficulty covering their household expenses on his income, which was only moderately above minimum wage, the psychiatrist felt compelled to discuss the relative costs of DDAVP and imipramine, which was less expensive than DDAVP. However, the psychiatrist also indicated that John would require a baseline electrocardiogram (ECG) (which his insurance could cover). Ultimately, the family decided that John would need medication only for brief, discrete periods (overnights at friends and 1 to 2 weeks of summer camp) because they had worked out an acceptable plan for responding to the wetting on a day-to-day basis. Furthermore, they reasoned that, within approximately 2 years, John would experience a spontaneous remission of his enuresis, given that this was the family pattern. Thus, they decided that, because DDAVP has a rapid onset of action, they would pay out of pocket for the relatively small amounts of DDAVP that would be needed for these discrete periods over the next 2 years. The pediatrician advised the family of the Federal Drug Administration (FDA) alert regarding the risk of hyponatremia and seizures. They decided to use the oral form of DDAVP because the FDA identified the nasal spray as being more likely to produce hyponatremia and indicated that this form of DDAVP was no longer indicated for childhood enuresis. They were also advised to (1) limit John's fluid intake on the nights when DDAVP was administered, (2) discontinue its use if John developed the flu or another illness that could affect his fluid balance, and (3) discontinue the medication and notify their physician if symptoms of nausea, vomiting, or headache developed. Pathology and Laboratory Examination Because urinary tract infections can produce enuresis, a urinalysis should be part of every evaluation. Using radiographic procedures with contrast media to detect an anatomical or physiological cause for the enuresis is more problematic because the procedures are invasive and painful and the diagnostic yield is low. A large study carried out in a pediatric primary care setting found a 3.7 percent incidence of obstructive lesions in children with enuresis. Others have reported similar findings. The literature cited earlier in the section on etiology concerning the use of noninvasive ultrasound techniques to establish bladder capacity and wall thickness have not been replicated to a degree that would warrant their use on a routine basis. However, they may be of use for children who are refractory to standard treatment.

Differential Diagnosis As suggested previously, the primary differential diagnosis is a urinary tract infection. This is especially true for girls, who are more prone than boys to develop urinary tract infections. A urinary tract infection should be the first consideration for a girl who has been continent for a considerable period of time and has recently begun wetting. Although the diagnostic yield is smaller with boys, a urinalysis should still be carried out. Enuresis can result from anatomical malformations or obstructive lesions, but the percentages are relatively low. If the history and interviews with the child suggest that the enuresis is intentional, then it is almost certainly related to an underlying psychological disturbance. The relation between psychological disturbance and involuntary enuresis is less clear. The coexistence of another behavioral disturbance should be noted and attended to clinically. The most common comorbid psychiatric disorder is ADHD. It has also been documented that enuresis has a negative effect on self-image and that enuretic children have more negative feelings about their disorder as compared to children who have other chronic illnesses. There have also been case reports linking the onset of enuresis in children to the administration of both the selective serotonin reuptake inhibitor (SSRI) antidepressants and the atypical antipsychotic agent risperidone (Risperdal). Thus, the possibility of enuresis as a side effect to these medications should be considered if a chronological correlation exists. Secondary enuresis has also been identified as an important symptom of the abrupt onset of Type 1 Diabetes in children and is related to the polydipsia and polyuria that accompany that disorder. Course and Prognosis The natural history of enuresis is significant because it is a self-limited disorder that can spontaneously remit. The fact that the diagnosis is not made until 5 years of age takes into account children who have delays in toilet training that are not outside the accepted range (between 2 and 5 years of age). The prevalence of enuresis is relatively P.3629 high, between 5 and 7 years of age, and then drops off substantially. The vast majority of enuretic children experience a spontaneous resolution of the problem at some time, and only a few remain enuretic into adulthood. By 14 years of age, only 1.1 percent of boys wet once a week or more. The DSM-IV-TR cites a remission rate of 5 to 10 percent per year after 5 years of age. The peak age for secondary enuresis is between 5 and 8 years of age. Treatment The methods for the treatment of enuresis that have been empirically proven to be effective are primarily behavioral and pharmacological. Psychotherapy may be useful for ameliorating some of the associated behavioral problems that can be seen with enuresis, especially secondary enuresis. A particularly common clinical scenario for secondary enuresis is the development of wetting after the loss of a parent through death or divorce. In these patients, psychotherapy is the primary treatment modality. A review of the efficacy of psychotherapy for primary enuresis found a 20 percent success rate, which is probably not significantly greater than would be expected by the rate of spontaneous remissions and random chance. Behavior Therapy A comprehensive review of several studies determined the success rate for behavioral interventions as 75 percent. Recent studies have yielded comparable response rates. The primary behavioral intervention is the bell-and-pad method of conditioning. A pad is placed on the bed,

with a wire running to a bell. When the child wets, the moisture completes a circuit in the pad, ringing the bell and waking the child. With repeated use, the child learns to awaken before wetting occurs. Several studies have indicated that concomitant behavioral disturbance reduces the likelihood of success of behavioral interventions. Recent behavioral studies have focused on embellishment of the standard method and comparisons with different methods. For example, no difference was found between an audio alarm and a vibratory alarm. A study that compared the basic bell-and-pad method with methods in which the bell and pad were coupled with more response contingencies for wetting versus not wetting found no statistical difference other than a slightly lower relapse rate with the adjunctive use of reward contingencies. One innovative strategy involved replacing the bell and pad with an alarm clock timed to go off after 2 to 3 hours of sleep, when maximum bladder capacity would be expected. The authors reported responses that were equal to results with the standard bell-andpad method. The relationship between bladder capacity and response to behavioral treatment has also been investigated. One study found that bladder capacity did not affect outcome with the bell-and-pad method of conditioning, whereas another found that children with smaller bladder capacities tended to do slightly better when retention-control training was linked to the bell-and-pad method. A meticulous investigation into which treatment variables might relate to the efficacy of the bell-and-pad method found that the inability to be awoken by the alarm correlated significantly with failure, as did low functional bladder capacity. There is some evidence to support the use of biofeedback for children who have small bladder capacities and unstable detrusors and who have been refractory to prior treatment. The newest advance in this behavioral methodology has been the use of an external ultrasonic monitor that is attached to a waistband. The monitor then signals the alarm when the bladder reaches maximal capacity. Clinical research with this device has yielded success rates similar to those with the basic bell and pad and has also reported increases in bladder capacity. The bell-and-pad approach has also been coupled with the use of DDAVP for children who have been refractory to prior treatment owing to family dysfunction or a concomitant behavioral disorder, or both. Although the bell and pad is the most intensively studied method of behavioral intervention, it is not the only type of behavioral treatment. A recent comprehensive review of this subject also noted other behavioral methods, such as evening fluid restriction, nighttime toileting, rewards, overlearning, and retention-control training. Pharmacotherapy The initial description of imipramine's efficacy for enuresis was followed by more than 40 double-blind studies that confirmed its therapeutic value. This marked the advent of the pharmacological era of the treatment of enuresis, with imipramine being the dominant pharmacological entity used for more than two decades. Although imipramine has now been largely replaced by DDAVP, there are still reasons to include a discussion of its use in a comprehensive review of enuresis. Imipramine is still a consideration for children who are refractory to other forms of treatment. There is also a significant cost differential between imipramine and DDAVP, so that imipramine may well be the first pharmacological choice for those families who do not have any form of insurance and who have limited financial resources. Later studies with imipramine focused on the relation between response and concentration of imipramine in the blood. Although one study found no connection between positive response and imipramine concentration alone or in combination with its metabolite desipramine (Norpramin), three studies found a significant correlation between positive response and total concentration of

imipramine and desipramine. More specifically, optimal response was found at combined concentrations (imipramine plus desipramine) of greater than 60 ng/mL in one study and of greater than 80 ng/mL in another. The most recent study also found that efficacy was related to increasing dose but noted tremendous variation in serum concentrations among individual children receiving the same dose. The adverse effect of dry mouth also correlated with concentration in blood, providing clinicians with a crude index of blood concentration in children who are extremely reluctant to have their blood drawn. Clinically, when one encounters a history of a lack of response to imipramine, one must ascertain the specific dose used because nonresponse is frequently related to dose: Primary care physicians often prescribe only 25 to 50 mg per day. However, low-dose responders do exist, and it is reasonable to start treatment at a daily dose of 25 mg, titrating up by 25 mg every 4 to 7 days. This enables identification of the low-dose responders because the response to imipramine usually occurs within 1 to 2 days. The majority of children exhibit a positive response in the range from 75 to 125 mg. The standard maximal limit for dose is 5 mg/kg body weight, and ECG monitoring is recommended at doses greater than 3.5 mg/kg. A pretreatment baseline ECG is also recommended. Blood concentration values may also be clinically useful if higher doses fail to elicit a response. There is also a possible risk of overdose by the child with enuresis. Children can engage in magical thinking, and there have been reports of children who believed that, if taking a few pills would stop the wetting for a night, then consuming the whole bottle would make it disappear forever. Thus, parents should be advised to control the medication carefully and to store it in a secure place. Severe overdoses may require treatment with physostigmine (Antilirium), whereas more moderate overdoses may be treated by the symptomatic management of arrhythmias and seizures. Because the vast majority of children at some point experience spontaneous remission of the enuresis, it does not make sense to prescribe medication for years without checking for a spontaneous remission. One solution to that problem is to taper the imipramine dose at 3-month intervals. Should enuresis reappear as imipramine dose is tapered, it can simply be returned to the optimal level for another 3-month period. Clinically, one often finds that more children remain dry after 3 to 6 months of treatment than can be expected from spontaneous remission alone. In general, treatment with imipramine should be viewed as necessary until spontaneous remission occurs. Three clinical subtypes of enuretic response to imipramine exist: True nonresponders, true responders who maintain a response over time, and transient responders who respond for a few weeks and then resume wetting. Increasing the dose for transient responders usually recaptures the response but only for another few weeks, and ultimately one reaches a point at which the dose cannot be increased further. However, the initial transient response can be replicated after a medication-free interval; thus, one can use the medication for especially important, time-limited social events, such as summer camp. As indicated previously, DDAVP has now surpassed imipramine as the first-line pharmacological approach for enuresis. A thorough review done as early as 1993 revealed 18 randomized, controlled trials, including a total of 689 subjects. Many subjects had been refractory to previous treatment for enuresis. DDAVP reduced enuretic frequency by 10 to 91 percent in these studies. Positive prognostic factors were age (older than 9 years of age) and P.3630

lower pretreatment frequency of enuretic events. In most studies, wetting resumed after the medication was discontinued. Follow-up studies indicated that 5.7 percent of children remained dry after cessation of medication, but many of those cases could have been due to spontaneous remission. The most common reported adverse effects were mild abdominal pain, epistaxis, headache, and nasal stuffiness. Several subsequent studies attempted to find factors that might predict or relate to an increased likelihood of a positive response to DDAVP. No one factor appears to predict a positive response, but larger functional bladder capacity and a positive family history of enuresis appear to be positively correlated with treatment success. Factors that are not reliably related to treatment outcome are urine osmolality, plasma osmolality, ADH secretion, urine production, and nocturnal AVP concentration. However, individual studies can be found that link these factors with a positive outcome. A large contemporary, multicenter follow-up treatment study of DDAVP from Sweden (N = 399) used a 4-week baseline observation phase, a 6-week dose titration period (range from 20 to 40 µg), and a 1-year follow-up period. The study design also included an assessment for the rate of spontaneous remission by means of a 1-week medication-free period every 3 months. Sixtyone percent (N = 245) of the children met the requirement of at least a 50 percent reduction in frequency during the dose titration period that was required to enter the 1-year follow-up phase of the study. The average frequency of enuretic events in the baseline observation period was 5.3 events per week, and this declined to .8 nights by the end of the year-long follow-up period. As with other studies, older age was a positive prognostic sign. Of interest was the observation that 77 children experienced a complete remission of their enuresis within the first 6 months of the active treatment phase. There has been one report of an attempt to increase the rate of spontaneous remission by aggressively titrating the dose until cessation of wetting is obtained and then maintaining this dose for 4 to 6 weeks before beginning to decrease the dose by 10 µg per month until it is discontinued. The authors reported that, by using this strategy, complete remission was achieved for 71 percent of the children. The median length of follow-up was 18 months, and the mean dose of DDAVP was 20 µg. Studies have also specifically investigated the efficacy of DDAVP for children who were refractory to conditioning treatment and imipramine. One of these involving 52 children (dose range from 20 to 40 µg intranasally) found complete cessation of wetting in 53 percent, a partial response in 19 percent, and minimal or no response in 28 percent. A long-term, follow-up study (mean length of follow-up of 13 months) of children treated with DDAVP found no hematological or hormonal adverse effects. Treatment with DDAVP has been compared to the bell-and-pad method of conditioning. The difference in response rate was not statistically significant; 86 percent improved with the bell and pad, and 70 percent improved with DDAVP. Another investigation comparing the combined use of the bell-and-pad method and DDAVP with placebo indicated that the combination achieved significantly more dry nights. Similar results were found in a study comparing alarm monotherapy to alarm treatment coupled with DDAVP. The combination proved superior, especially for children with severe, almost nightly, wetting. The development of oral tablets has greatly simplified the administration of DDAVP. The nasal spray was difficult for some children to use, and this could (in some cases) contribute to variable administration. A controlled multicenter study found no difference in response between oral DDAVP and the traditional nasal spray. A dose of 400 µg produced more dry nights than did a 200-µg dose.

A significant dose–effect correlation was found in a placebo-controlled study that used 200-, 400-, and 600-µg oral doses. In a separate follow-up study (7 years), the rate of spontaneous remission at 2 years and 7 years was reported as greater than would be expected solely on the basis of spontaneous remission. As with other treatment modalities, consistent findings in the clinical literature concerning positive responses to DDAVP are older age, larger bladder capacity, and lower pretreatment frequency of enuresis. The newest innovation in the use of DDAVP has been the development of a sublingual desmopressin oral lyophilisate (MELT). A recent randomized, controlled study that compared this formulation to the oral tablets found it to be equally effective. The children also expressed a greater preference for the MELT. This increase in preference was especially pronounced in the younger age group (5 to 11 years of age). There has been an increasing number of case reports of hyponatremic seizures with prolonged use. A review of 14 articles that reported data on serum sodium concentration in DDAVP-treated patients and 11 articles that reported individuals who developed altered consciousness or a seizure while taking DDAVP for enuresis concluded that hyponatremia is a potential adverse effect of DDAVP treatment. The authors also noted that excess fluid intake was a contributing factor in 6 of the 11 case reports. They concluded that patients receiving DDAVP for nocturnal enuresis should be advised not to consume more than 8 oz of fluid on nights when DDAVP is administered. The data on hyponatremia also suggest that periodic monitoring of serum sodium concentration would be prudent. The number of reported cases of hyponatremia and seizures, including two deaths, prompted the FDA to issue an alert concerning DDAVP in December 2007. The alert identified 61 postmarketing incidents of hyponatremia-related seizures that were related to the use of DDAVP. Sodium levels obtained at the time of the seizure ranged from 104 to 130 mEq/L. A particular concern was that two of the individuals who experienced seizures with hyponatremia died. The intranasal formulation of DDAVP was implicated in 36 of the cases, and 25 of these were individuals younger than the age of 17 years, most of whom were receiving DDAVP for treatment of nocturnal enuresis. The FDA alert concluded that the intranasal formulation of DDAVP was no longer indicated for the treatment of PNE. The alert also suggested that treatment with the tablet form should be halted during illnesses that could produce disturbances in fluid dynamics and/or produce electrolyte imbalance. The alert also recommended that fluids should be restricted from 1 hour before to 8 hours after the administration of the tablets. The latter recommendation is consistent with earlier published reports that linked the amount of fluid intake to the risk of acute hyponatremia. Although imipramine and DDAVP have been the dominant pharmacological treatment modalities over the last several years, there continue to be reports of success with anticholinergic agents. The majority of these reports relate to oxybutynin, both as a first-line intervention and for individuals who are refractory to other interventions. General Treatment Considerations The results of the studies reviewed, in conjunction with the natural history of enuresis, can help the clinician to develop a decision tree tailored to a given child. The first decision, naturally, is whether to treat at all. That decision is affected by the frequency of the wetting, the age of the child, and the amount of psychological distress that the wetting causes the child. Enuresis has a negative effect on the self-esteem of these children, and self-esteem improves after successful treatment. One may choose not to treat a child who is wetting infrequently and who is at an age at which a spontaneous remission may be expected.

If one does elect to treat, it makes sense first to try the bell-and-pad method of conditioning because its efficacy has been repeatedly demonstrated and behavioral intervention is considered less invasive than pharmacological approaches. A large follow-up study that compared observation only with imipramine, DDAVP, and the bell and pad indicated that, although all of the active treatments were significantly superior to observation alone, the positive response was much more likely to be sustained after treatment cessation with the bell and pad than with either pharmacological treatment. Despite these apparent advantages, one large population-based investigation revealed that only a relatively small number of enuretic children (38 percent) saw a physician, and, of that number, only 3 percent were treated with the bell-and-pad method of conditioning, whereas more than one third received pharmacological treatment. A more geographically restricted survey of primary care physicians yielded significantly different responses, in that 80 percent of physicians indicated that they recommended the bell-and-pad method of conditioning. When the bell-and-pad method of treatment is unsuccessful or not feasible, it makes sense to proceed to pharmacological treatment, assuming that the enuresis is severe enough to warrant pharmacological intervention. For decades, imipramine was the first choice for pharmacological treatment. Although precise figures are not available for its relative use in the treatment of PNE, DDAVP appears P.3631 to have surpassed imipramine as the most popular pharmacological treatment. Only recently, with the effect of managed care, have articles appeared that address the financial cost of the various treatments for enuresis. The bell-and-pad method of conditioning appears to be the most cost-effective treatment. It is as effective as the pharmacological approaches, is more likely to lead to sustained improvement after the cessation of active treatment, and requires only the initial expense of the apparatus and replacement pads. Recent suggested retail prices for the basic apparatus ranged from $6.00 to $196.00, depending on the brand chosen. Other expenses to be considered are the time of the professional who counsels the parents on its use and the parental time involved. Imipramine is available generically, so its actual cost is quite modest. Related costs are the physician's time and the cost of a baseline ECG, periodic monitoring of ECG, and periodic blood concentration determinations. The nasal preparation of DDAVP has been available in a generic form for some time. However, as noted earlier, the recent alert by the FDA indicates that the nasal preparation of DDAVP is no longer indicated for primary nocturnal enuresis. The oral preparation is now available generically but is still more expensive than imipramine. The newer sublingual formulation is in Phase III clinical trials and has not yet been approved by the FDA. However, it is available in Canada and the United Kingdom.

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