Attention deficit hyperactivity disorder (ADHD), and
enuresis are among the most common psychoneurotic dis-
orders in children and adolescents. Enuresis is a patholog- ical state associated with the lack of a developed skill in controlling the urinary bladder, resulting in repeated episodes of involuntary micturition during sleep or waking. The International Classification of Disease 10th Edition (ICD-10) [6] assigns this condition to the category of emo- tional and behavioral disorders with onset in childhood and adolescence. Under rubric F98.0, enuresis of non-organic origin is defined as a disorder characterized by involuntary passage of urine during the day and/or night, inappropriate for age and mental development. The following diagnostic criteria for enuresis are defined in the ICD-10: the chrono- logical and mental ages of the child must be at least five years; the frequency of episodes of micturition must be at least two per month in children aged less than seven years and at least one per month in children of seven years and older; enuresis must not be a direct consequence of anatom- ical anomalies of the urinary tract, epileptic seizures, neu- rological disorders, or any other non-psychiatric disease; involuntary micturition must be seen for at least three months in a row. Depending on age, enuresis is divided into primary and secondary [1, 2, 4, 18]. Children with primary (persistent) enuresis (8090% of cases) have never been able to control micturition or have been able to control it for no more than 36 months. Secondary (acquired, regressive) enuresis (1020% of cases) occurs when a prolonged period of con- trol of micturition, lasting from several months (at least 36 months) to several years, is followed by recurrence of uri- nary incontinence. The timing of episodes of micturition Neuroscience and Behavioral Physiology, Vol. 41, No. 5, June, 2011 Attention Deficit Hyperactivity Disorder and Enuresis in Children and Adolescents N. N. Zavadenko, 1 N. M. Kolobova, 2 and N. Yu. Suvorinova 1 0097-0549/11/4105-0525
2011 Springer Science+Business Media, Inc.
525 Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 110, No. 2, pp. 5055, February, 2010. The incidences of comorbid disorders and the status of neuropsychological executive functions were eval- uated in two groups of patients aged 514 years: patients with attention deficit hyperactivity disorder (ADHD) in combination with enuresis (53 patients) and ADHD without enuresis (71 patients). Most cases of enuresis among patients of group 1 (50 of 53) had primary nocturnal enuresis. This group showed a sig- nificant increase in the total number of cases of comorbidity with such disorders as oppositional-defiant behavioral disorder, anxiety disorders, ticks, and encopresis, seen in 77.7% of cases as compared with 60.6% in group 2. The presence of enuresis in patients with ADHD was associated with a significant increase in the incidence of anxiety disorders (54.7% as compared with 39.4%). In addition, at age 59 years, patients with ADHD with enuresis had a tendency to a higher frequency of oppositional-defiant behavioral disorder and encopresis; those aged 1014 years showed an increase in the proportion with obsessive-compulsive disorder and tics as compared with patients with ADHD without enuresis. Assessment of measures of executive functions using the Wisconsin card sorting test revealed no differ- ences between patients of the two groups. KEY WORDS: attention deficit hyperactivity disorder (ADHD), enuresis, comorbidity, executive functions, treatment. 1 Department of Neurology and Neurosurgery, Faculty of Pediatrics, Russian State Medical University, Moscow; e-mail: zavadenko@mail.ru. 2 Morozov Pediatric City Clinical Hospital, Department of Health, Moscow. discriminate nocturnal enuresis, i.e., urine is passed invol- untarily only at night (85% of cases), and daytime enuresis, in which involuntary micturition occurs during the daytime while the child is awake (in 5% of cases), and mixed-type enuresis (daytime plus nocturnal), which is seen in about 10% of cases. The main pathogenetic mechanisms of enuresis include delay in maturation of the central nervous system (CNS), impairments to activation reactions during sleep, inherited mechanisms, impairments of the rhythm of antidiuretic hor- mone secretion, the actions of psychological factors and stress, and the effects of urological lesions [1, 2, 4]. The clinical interaction between enuresis and other psychoneu- rological disorders has been studied in relation to delays in the rates of CNS maturation preventing the timely forma- tion of voluntary control of micturition. The combination of enuresis and externalized disorders, i.e., ADHD and behav- ioral impairments, is quite widespread [9, 18]. Published data indicate that the incidence of nocturnal enuresis is par- ticularly high among children with ADHD, amounting to 2132%, which is 1.86 times higher than among their con- temporaries [9, 13, 15]. Thus, investigation of 140 children with ADHD detected nocturnal enuresis in 25% of cases as compared with 10.8% in a group of 120 contemporaries [9]. A high incidence of nocturnal enuresis was observed in a group of 204 children (170 boys and 34 girls) with ADHD aged 513 years studied by ourselves: 14% among boys and 12% among girls [3]. Most patients with ADHD were diag- nosed with primary nocturnal enuresis. The highest comor- bidity of nocturnal enuresis with ADHD, 40%, was report- ed by Bayens et al. [7], and may be associated with the characteristics of this cohort of patients. In accordance with the diagnostic criteria of the DSM-IV [10], 15.0% of patients had the combined form of ADHD, while 22.5% had ADHD with predominance of impairment of attention and 2.5% had ADHD with predominance of hyperactivity and impulsivity. Dynamic observations of patients with ADHD for two years showed that enuresis persisted in 72.5% [8], which may indicate the stability of enuresis in ADHD and its relative resistance to treatment. However, there have been few studies of comorbidity in enuresis and the results are contradictory. This particularly applies to the combina- tion of enuresis with internalized disorders. The aim of the present work was to identify the inci- dences of comorbid disorders and the status of a number of neuropsychological functions 1 in two groups of patients patients with ADHD combined with enuresis and patients with ADHD without enuresis. MATERIALS AND METHODS Group 1 (53 patients) included children with ADHD and enuresis; group 2 (71 patients) included children with ADHD without enuresis. Patients were aged from five to 14 years. The distribution of patients in terms of age and sex is shown in Table 1. All patients were observed and investi- gated in out-patient conditions. The diagnosis of ADHD was established in accordance with ICD-10 criteria [6] for hyperkinetic disorder (rubric F90), which are similar to the DSM-IV criteria for the com- bined form of ADHD [10]. Diagnoses of enuresis were also made in accordance with ICD-10 criteria. Comorbid disorders were identified using the full ver- sion of the Diagnostic Questionnaire for the Detection of Affective Disorders and Schizophrenia Present and Lifetime (D-QEDS-PP) in children and adolescents, which is a version adapted to the Russian language [5] of the orig- inal methodology of the Kiddie-Schedule for Affective Zavadenko, Kolobova, and Suvorinova 526 TABLE 1. Distribution of Study Patients by Age and Gender Study groups Number of patients ADHD combined with enuresis ADHD without enuresis Age 59 years 32 45 boys 20 36 girls 12 9 Age 1014 years 21 26 boys 19 21 girls 2 5 All patients 53 71 1 In the Russian literature, executive functions are often designat- ed regulatory or programming functions or the control of mental processes. Disorders and Schizophrenia (Present and Lifetime Version) [12]. The D-QEDS-PP is designed for the diagnosis of ongoing and previous behavioral, affective, and psychotic disorders, as well as enuresis, encopresis, nervous anorexia, bulimia, disorders manifest as tics, alcohol and drug abuse, post-traumatic stress disorder, and adaptation disorders. Investigations included conversations with one or both par- ents and the children themselves, supplemented with reports from all available sources of information (school, developmental charts, medical histories, etc.). In neuropsychological investigation of patients, the focus was placed on measures characterizing so-called executive functions (EF), which are supported by the pre- frontal areas of the frontal lobes of the brain. This was addressed using a computerized version of the Wisconsin card sorting test [11]. This was presented to patients aged over 6.5 years. A row of four cards bearing images differing in terms of three features, i.e., figure shape (triangles, stars, crosses, circles), color (red, yellow, green, blue), and num- ber (from one to four), was presented in the upper part of a monitor screen in front of the patient. A total of 128 new cards were presented during the investigation, each of which had similarity to one of the four imaged in the upper row. The subject had to sort the new cards, identifying by themselves the feature by which they corresponded to the images in the upper row. Each new card was moved to a position beneath the card sharing this characteristic. Studies included at least six series of tasks, each of which was com- pleted after ten correct responses in a row. The total number of responses could not exceed 128, so fewer than six series was sufficient for a significant number of errors. The nature of the task (i.e., the card selection principle) changed with- out warning the subject after ten correct responses in a row and the experimenter gave no advice, merely reporting the correctness or incorrectness of responses. The main mea- sures of the performance of the Wisconsin test are the num- ber of series performed, the total number of errors, the pro- portion of perseverative errors (%), the proportion of non-perseverative errors (%), and the proportion of respons- es at the conceptual level (%). Many children with ADHD show reductions in these measures as compared with healthy contemporaries. RESULTS Most (50 of 53) patients with ADHD in group 1 had primary nocturnal enuresis; only one (a 12-year-old girl) had secondary nocturnal enuresis and two (a six-year-old girl and an 11-year-old boy) had primary daytime enuresis. Comorbid disorders in children and adolescents with ADHD of both groups consisted of oppositional-defiant behavioral disorder and various forms of anxiety disorders, as well as tics and encopresis (Table 2). Other impairments which published data indicate can accompany ADHD, including asocial behavioral disorder and mood disorder, were not seen in our patients. However, attention is drawn to the fact that among patients with ADHD and enuresis, comorbid disorders were seen more frequently (77.4% of cases), while among patients with ADHD without enuresis, they were significantly less frequent (60.6%, p < 0.05). This was mainly because group 1 showed a much higher inci- dence of anxiety disorders than group 2 (54.7% vs. 39.4%, p < 0.05), among which generalized anxiety disorder (20.8% vs. 12.7%) and obsessive-compulsive disorder (30.2% vs. 22.5%) were particularly frequent. Rarer cases, with essentially similar frequencies in both groups of patients, showed specific (simple) and social phobias. Furthermore, some children of both groups were diagnosed with separation-associated anxiety disorder and one boy from group 1 had post-traumatic stress disorder. Although the incidences of oppositional-defiant behavioral disorder, tics, and encopresis among patients with ADHD combined with enuresis and ADHD without enuresis (Table 2) were similar, they were different in dif- ferent age subgroups; this also applied to the incidence of anxiety disorders. Figure 1 shows results obtained from assessment of these states in age subgroups 59 years and 1014 years, which may reflect the behavioral characteris- tics of patients with ADHD and enuresis at different age periods. Thus, at 59 years, patients with ADHD and enure- sis had higher incidences not only of anxiety disorders, but also oppositional-defiant behavioral disorder than patients with ADHD without enuresis (34.4% vs. 26.7%), and this also applied to encopresis (9.4% vs. 4.4%). At age 1014 years, patients with ADHD and enuresis had markedly higher incidences of obsessive-compulsive disorder (42.9% vs. 23.1%) and tics (14.3% vs. 7.0%), while the incidence of oppositional-defiant behavioral disorder, although remaining at a quite high level, was lower (38.1%) than in contemporaries with ADHD without enuresis (53.8%). According to current concepts, the cause of the main manifestations of ADHD consists of functional distur- bances to the frontal lobes of the brain, particularly the pre- frontal region, and the signs of ADHD are analyzed from the point of view of inadequately formed EF. Thus, the diagnosis of comorbid diseases in the present study was supplemented by comparative evaluation of the state of EF in patients of the two groups using the Wilcoxon card sort- ing test, which is an informative method for assessing abstract thought in patients aged more than 6.5 years, which also addresses flexibility in solving cognitive tasks, the abil- ity to switch attention, the capacity of working memory, and the ability to maintain consistent responses. The test results from the two groups of patients are presented in Table 3. It follows from these results that in both age sub- groups, the Wilcoxon test results in patients with ADHD with enuresis and ADHD without enuresis were similar, with no statistically significant differences between them. Thus, the presence of enuresis was not accompanied by Attention Deficit Hyperactivity Disorder and Enuresis in Children and Adolescents 527 additional deterioration in the status of EF in patients with ADHD. Overall, test results showed the increases in the proportions of erroneous responses typical for ADHD patients, with both perseverative and non-perseverative errors, along with a simultaneous decrease in the proportion of correct responses; some improvement in these measures in patients aged 1014 as compared with those aged 69 years was also quite consistently seen, though most patients of both age subgroups produced lower results than expect- ed on the basis of age norms. DISCUSSION The studies reported here showed that ADHD patients aged 514 years were characterized by an increased inci- dence of comorbidity for disorders such as oppositional- defiant behavioral disorder, anxiety disorders, tics, and encopresis. Among patients with ADHD without enuresis, the total proportion of cases with comorbidity for these same conditions was significantly lower, at 60.6%, com- pared with 77.7% in group 1. The presence of enuresis in ADHD was associated with an increased incidence of anx- iety disorders, particularly because of generalized anxiety and obsessive-compulsive disorders. The two age subgroups of patients with ADHD com- bined with enuresis showed the following characteristics. At age 59 years, there was a tendency to higher incidences of oppositional-defiant behavioral disorder and encopresis, while at 1014 years of age there were minor increases in the incidences of obsessive-compulsive disorder and tics as compared with patients with ADHD without enuresis (the difference was not statistically significant). As the absolute majority of cases of enuresis among the ADHD study patients had primary nocturnal enuresis (50 of 53), these data can be applied to the combination of ADHD with primary nocturnal enuresis. Delayed matura- tion of the CNS plays a significant role among the main mechanisms of the pathogenesis of both ADHD and prima- ry enuresis. In particular, in the case of ADHD, this applies to delayed maturation of the prefrontal cortex of the frontal lobes, while disturbances of the rhythm of antidiuretic hor- Zavadenko, Kolobova, and Suvorinova 528 TABLE 3. Results from the Wisconsin Card Sorting Test in Patients with ADHD (M m) Parameter, % Patients aged 69 years Patients aged 1014 years ADHD combined with enuresis (n = 16) ADHD without enuresis (n = 19) ADHD combined with enuresis (n = 19) ADHD without enuresis (n = 15) Erroneous responses 31.7 3.5 33.0 3.0 21.2 2.4 22.5 3.0 Perseverant errors 15.1 1.9 17.4 2.1 10.3 0.8 9.3 1.4 Non-perseverative errors 16.4 2.1 15.6 1.3 11.0 1.7 12.9 2.0 Responses at the conceptual level 59.8 5.2 58.7 4.0 73.6 3.5 71.3 4.6 TABLE 2. Incidence of Comorbid Disorders in the Two Groups of Patients Comorbid disorders ADHD combined with enuresis, % ADHD without enuresis, % p Any comorbid disorder (one or more) 77.4 60.6 <0.05 Oppositional-defiant behavioral disorder 35.8 36.6 Anxiety disorders 54.7 39.4 <0.05 generalized anxiety disorder 20.8 12.7 simple phobias 5.7 11.3 social phobias 5.7 4.2 obsessive-compulsive disorder 30.2 22.5 Tics 9.4 7.0 Encopresis 5.7 4.2 Note. Total values for comorbid disorders were greater than 100% because some patients had two or more concomitant disorders. mone (ADH) secretion are among the important patho- genetic mechanisms of enuresis. The circadian ADH secretion rhythm produces diurnal variations in the volume of urine produced. Thus, in normal subjects, less urine is produced at night than during the day, because nocturnal ADH secretion is greater. In children ADH secretion levels change with maturation and reach values close to those in adults at about 12 years of age. Delays in CNS maturation can produce impairments to the circadian ADH secretion rhythm, including decreases in its level during the night, which is clinically apparent in chil- dren with nocturnal enuresis [1, 4]. Impairments to the reg- ulation of ADH in primary nocturnal enuresis may be genet- ically determined. As many patients with primary nocturnal enuresis have a deficiency of ADH secretion in the nocturnal hours, desmopressin (Minirin) has received wide use in the treat- ment of nocturnal enuresis, this being a synthetic peptide analog of ADH [1, 4]. The antidiuretic effect of this agent is greater than that of the natural hormone and its actions on vessel walls and the smooth musculature of the internal organs are minimized, so it does not produce significant side effects. The mechanism of action of desmopressin in enuresis consists of a decrease in nocturnal urine formation in the renal canaliculi to a volume not exceeding the func- tional capacity of the urinary bladder in children, allowing retention until waking in the morning. The clinical efficacy of desmopressin in the treatment of enuresis has been sup- ported in a series of double-blind, placebo-controlled trials; positive responses to treatment have been obtained in 5080% patients in different studies, though there is the possible complication of recurrences after withdrawal of the medication, such that treatment should be adequately pro- longed [1, 18]. This agent is recommended as a first-line therapy in patients with isolated primary nocturnal enuresis. We have published clinical data on the value of its use in patients with ADHD combined with enuresis [2], though this question requires further study. Another approach to the drug-based treatment of pri- mary enuresis, which has been used for many years and is regarded by some authors as the method of choice, is based on the tricyclic antidepressants Melipramine (imipramine) and amitriptyline. The precise mechanism of action of these agents in enuresis is unclear, though it is believed not to be associated with the antidepressant actions or with influ- ences on the arousal systems of the brain or sleep. Attention Deficit Hyperactivity Disorder and Enuresis in Children and Adolescents 529 Fig. 1. Incidences (%) of various comorbid disorders in the two subgroups of ADHD patients those aged 59 years (a) and those aged 1014 years (b); 1) ADHD with enuresis; 2) without enuresis. ARVI = acute respiratory viral infections; AD = anxiety dis- orders; GAD = generalized anxiety disorder; OCD = obsessive-compulsive disorder. Melipramine has been shown to decrease the excitability of the urinary bladder by means of its peripheral anticholiner- gic and spasmolytic actions. The treatment of enuresis with Melipramine is preferentially restricted to older children and adolescents in whom desmopressin has failed to produce the desired outcome. Positive responses to Melipramine are obtained in about 40% of patients with enuresis [18]. However, the use of tricyclic antidepressants, especially for prolonged periods, is associated with a number of risks to health because of the side effects of these agents. In partic- ular, the anticholinergic effects of tricyclic antidepressants can be undesirable, inducing atonia of the urinary bladder and urinary retention. Furthermore, other serious side effects of thee agents are known, including cardiotoxicity, suppression of hematopoiesis, and exacerbation of bron- chial asthma. Returning to the results of the present study, it should be emphasized that enuresis is not an isolated condition in a quite large proportion of children, such that the approach to its treatment should be addressed in the context of the detection and correction of all disorders and abnormalities present in the affected child. In this regard, there is particu- lar interest in the comorbidity of enuresis with ADHD, as mutually exacerbating influences from these two conditions cannot be excluded. It should be noted that the cause of the high incidence of cases in which ADHD is associated with enuresis is ultimately unclear, though it may be explained by both the high incidence of each of these conditions in the child population and the similarities in their pathogenetic mechanisms. The leading role in the pathogenesis of both ADHD and enuresis is currently believed to be a common neurobiological factor, particularly delayed maturation of the CNS and inherited mechanisms. Although the inheri- tance of ADHD and enuresis appear not to be mediated by the same genes, the molecular genetic basis of the comor- bidity of ADHD and enuresis requires specific studies [18]. Cases of comorbidity of several conditions often gen- erate problems in determining therapeutic strategies. In these situations, the physician generally asks a series of questions: which of the disorders is the more severe, whether the conditions should be treated sequentially or simultaneously, whether monotherapy should be used with sequential changes in treatment agents when they are not effective or whether combined treatment should be provid- ed, etc. Considering the high incidence of the association of enuresis and ADHD, the development of appropriate treat- ment methods for such patients is of great scientific and practical relevance. One of the most promising directions in this area is the use of the new drug atomoxetine hydrochloride (Strattera). This is the only agent currently available in Russia which was specifically developed and approved for the treatment of ADHD. The high efficacy of atomoxetine in relation to a wide spectrum of the abnormalities seen in ADHD has received repeated support in controlled clinical trials and is beyond doubt. In many of these studies, children with con- comitant enuresis showed significant regression the signs of both ADHD and enuresis [14, 16, 19]. Unfortunately, there is as yet insufficient evidence of the efficacy of atomoxetine in the treatment of enuresis without ADHD for the recom- mendations for the use of atomoxetine to be widened to include enuresis. At the same time, children and adolescents with simul- taneous ADHD and enuresis should start treatment using atomoxetine monotherapy, as the stress in selecting treat- ment should be on the timely and adequate correction of the signs of ADHD, as the long-term consequences of ADHD are more severe than those of enuresis. Furthermore, when treating these patients with atomoxetine, the physician expects regression of the signs of both ADHD and enuresis. The grounds for this are provided by results of recent stud- ies [16, 17], in which double-blind, randomized, placebo- controlled trials demonstrated that atomoxetine treatment led to decreases in the frequency or the cessation of noctur- nal micturition in patients with enuresis both combined with ADHD and without ADHD. In one of these studies, Sumner et al. [17] noted the efficacy of atomoxetine in the treatment of nocturnal enuresis in children and adolescents aged 618 years in out-patient conditions. Atomoxetine at a dose of 1.5 mg/kg/day was used in 42 children (of which 10 had ADHD) for 12 weeks, while 41 children (17 with ADHD) received placebo; treatment results were evaluated in terms of the number of dry nights per week. Atomoxetine treatment of children with enuresis significantly increased the number of dry nights per week. A total of 15 atomoxetine-treated children showed increases in the number of dry nights by factors of two or more, while there were only six such patients in the placebo group. The mean increase in the num- ber of dry nights during atomoxetine treatment increased from 1.5 at the beginning of treatment to three at the end. Thus, atomoxetine therapy gave positive treatment effects in nocturnal enuresis. Thus, the combination of ADHD with enuresis in chil- dren and adolescents is a complex problem from both the clinical and the therapeutic points of view. A significant num- ber of the study patients had comorbid pathology extending beyond the range of the two disorders under discussion here including affective disorders, behavioral impairments, and tics. The multiple nature of the clinical signs has the result that it is difficult to embrace the process of treating such patients within a single algorithm. 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