eneurosis

Attention deficit hyperactivity disorder (ADHD), andenuresis 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 incontrolling the urinary bladder, resulting in repeatedepisodes 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 andadolescence. Under rubric F98.0, enuresis of non-organicorigin is defined as a disorder characterized by involuntarypassage of urine during the day and/or night, inappropriatefor 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 fiveyears; the frequency of episodes of micturition must be atleast two per month in children aged less than seven yearsand at least one per month in children of seven years andolder; 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 threemonths in a row.

Depending on age, enuresis is divided into primary andsecondary [1, 2, 4, 18]. Children with primary (persistent)enuresis (80–90% of cases) have never been able to controlmicturition or have been able to control it for no more than3–6 months. Secondary (acquired, regressive) enuresis(10–20% of cases) occurs when a prolonged period of con-trol of micturition, lasting from several months (at least 3–6months) 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. Suvorinova1

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. 50–55, February,2010.

The incidences of comorbid disorders and the status of neuropsychological executive functions were eval-uated in two groups of patients aged 5–14 years: patients with attention deficit hyperactivity disorder(ADHD) in combination with enuresis (53 patients) and ADHD without enuresis (71 patients). Most casesof 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-defiantbehavioral disorder, anxiety disorders, ticks, and encopresis, seen in 77.7% of cases as compared with60.6% in group 2. The presence of enuresis in patients with ADHD was associated with a significantincrease in the incidence of anxiety disorders (54.7% as compared with 39.4%). In addition, at age 5–9years, patients with ADHD with enuresis had a tendency to a higher frequency of oppositional-defiantbehavioral disorder and encopresis; those aged 10–14 years showed an increase in the proportion withobsessive-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 ofPediatrics, Russian State Medical University, Moscow; e-mail: [email protected].

2 Morozov Pediatric City Clinical Hospital, Department ofHealth, 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 daytimewhile the child is awake (in 5% of cases), and mixed-typeenuresis (daytime plus nocturnal), which is seen in about10% of cases.

The main pathogenetic mechanisms of enuresis includedelay in maturation of the central nervous system (CNS),impairments to activation reactions during sleep, inheritedmechanisms, impairments of the rhythm of antidiuretic hor-mone secretion, the actions of psychological factors andstress, and the effects of urological lesions [1, 2, 4]. Theclinical interaction between enuresis and other psychoneu-rological disorders has been studied in relation to delays inthe rates of CNS maturation preventing the timely forma-tion of voluntary control of micturition. The combination ofenuresis and externalized disorders, i.e., ADHD and behav-ioral impairments, is quite widespread [9, 18]. Publisheddata indicate that the incidence of nocturnal enuresis is par-ticularly high among children with ADHD, amounting to21–32%, which is 1.8–6 times higher than among their con-temporaries [9, 13, 15]. Thus, investigation of 140 childrenwith ADHD detected nocturnal enuresis in 25% of cases ascompared with 10.8% in a group of 120 contemporaries [9].A high incidence of nocturnal enuresis was observed in agroup of 204 children (170 boys and 34 girls) with ADHDaged 5–13 years studied by ourselves: 14% among boys and12% 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 thecharacteristics of this cohort of patients. In accordance withthe diagnostic criteria of the DSM-IV [10], 15.0% ofpatients had the combined form of ADHD, while 22.5% hadADHD with predominance of impairment of attention and2.5% had ADHD with predominance of hyperactivity andimpulsivity. 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 andits relative resistance to treatment. However, there havebeen few studies of comorbidity in enuresis and the resultsare 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 ofneuropsychological functions1 in two groups of patients –patients with ADHD combined with enuresis and patientswith ADHD without enuresis.

MATERIALS AND METHODS

Group 1 (53 patients) included children with ADHDand enuresis; group 2 (71 patients) included children withADHD without enuresis. Patients were aged from five to 14years. The distribution of patients in terms of age and sex isshown in Table 1. All patients were observed and investi-gated in out-patient conditions.

The diagnosis of ADHD was established in accordancewith ICD-10 criteria [6] for hyperkinetic disorder (rubricF90), which are similar to the DSM-IV criteria for the com-bined form of ADHD [10]. Diagnoses of enuresis were alsomade in accordance with ICD-10 criteria.

Comorbid disorders were identified using the full ver-sion of the “Diagnostic Questionnaire for the Detection ofAffective Disorders and Schizophrenia Present andLifetime” (D-QEDS-PP) in children and adolescents, whichis a version adapted to the Russian language [5] of the orig-inal methodology of the Kiddie-Schedule for Affective

Zavadenko, Kolobova, and Suvorinova526

TABLE 1. Distribution of Study Patients by Age and Gender

Study groupsNumber of patients

ADHD combined with enuresis ADHD without enuresis

Age 5–9 years 32 45

boys 20 36

girls 12 9

Age 10–14 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 mentalprocesses.

Disorders and Schizophrenia (Present and Lifetime Version)[12]. The D-QEDS-PP is designed for the diagnosis ofongoing and previous behavioral, affective, and psychoticdisorders, 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 withreports from all available sources of information (school,developmental charts, medical histories, etc.).

In neuropsychological investigation of patients, thefocus was placed on measures characterizing so-calledexecutive functions (EF), which are supported by the pre-frontal areas of the frontal lobes of the brain. This wasaddressed using a computerized version of the Wisconsincard sorting test [11]. This was presented to patients agedover 6.5 years. A row of four cards bearing images differingin 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 amonitor screen in front of the patient. A total of 128 newcards were presented during the investigation, each ofwhich had similarity to one of the four imaged in the upperrow. The subject had to sort the new cards, identifying bythemselves the feature by which they corresponded to theimages in the upper row. Each new card was moved to aposition beneath the card sharing this characteristic. Studiesincluded at least six series of tasks, each of which was com-pleted after ten correct responses in a row. The total numberof responses could not exceed 128, so fewer than six serieswas sufficient for a significant number of errors. The natureof the task (i.e., the card selection principle) changed with-out warning the subject after ten correct responses in a rowand the experimenter gave no advice, merely reporting thecorrectness 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 ofnon-perseverative errors (%), and the proportion of respons-es at the conceptual level (%). Many children with ADHDshow reductions in these measures as compared withhealthy contemporaries.

RESULTS

Most (50 of 53) patients with ADHD in group 1 hadprimary nocturnal enuresis; only one (a 12-year-old girl)had secondary nocturnal enuresis and two (a six-year-oldgirl and an 11-year-old boy) had primary daytime enuresis.

Comorbid disorders in children and adolescents withADHD of both groups consisted of oppositional-defiantbehavioral disorder and various forms of anxiety disorders,as well as tics and encopresis (Table 2). Other impairmentswhich published data indicate can accompany ADHD,

including asocial behavioral disorder and mood disorder,were not seen in our patients. However, attention is drawnto the fact that among patients with ADHD and enuresis,comorbid disorders were seen more frequently (77.4% ofcases), while among patients with ADHD without enuresis,they were significantly less frequent (60.6%, p < 0.05). Thiswas 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 ofpatients, showed specific (simple) and social phobias.Furthermore, some children of both groups were diagnosedwith separation-associated anxiety disorder and one boyfrom group 1 had post-traumatic stress disorder.

Although the incidences of oppositional-defiantbehavioral disorder, tics, and encopresis among patientswith ADHD combined with enuresis and ADHD withoutenuresis (Table 2) were similar, they were different in dif-ferent age subgroups; this also applied to the incidence ofanxiety disorders. Figure 1 shows results obtained fromassessment of these states in age subgroups 5–9 years and10–14 years, which may reflect the behavioral characteris-tics of patients with ADHD and enuresis at different ageperiods. Thus, at 5–9 years, patients with ADHD and enure-sis had higher incidences not only of anxiety disorders, butalso oppositional-defiant behavioral disorder than patientswith ADHD without enuresis (34.4% vs. 26.7%), and thisalso applied to encopresis (9.4% vs. 4.4%). At age 10–14years, patients with ADHD and enuresis had markedlyhigher incidences of obsessive-compulsive disorder (42.9%vs. 23.1%) and tics (14.3% vs. 7.0%), while the incidenceof oppositional-defiant behavioral disorder, althoughremaining at a quite high level, was lower (38.1%) than incontemporaries with ADHD without enuresis (53.8%).

According to current concepts, the cause of the mainmanifestations 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 fromthe point of view of inadequately formed EF. Thus, thediagnosis of comorbid diseases in the present study wassupplemented by comparative evaluation of the state of EFin patients of the two groups using the Wilcoxon card sort-ing test, which is an informative method for assessingabstract thought in patients aged more than 6.5 years, whichalso addresses flexibility in solving cognitive tasks, the abil-ity to switch attention, the capacity of working memory, andthe ability to maintain consistent responses. The test resultsfrom 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 ADHDwith 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 withADHD. Overall, test results showed the increases in theproportions of erroneous responses typical for ADHDpatients, with both perseverative and non-perseverativeerrors, along with a simultaneous decrease in the proportionof correct responses; some improvement in these measuresin patients aged 10–14 as compared with those aged 6–9years was also quite consistently seen, though most patientsof both age subgroups produced lower results than expect-ed on the basis of age norms.

DISCUSSION

The studies reported here showed that ADHD patientsaged 5–14 years were characterized by an increased inci-dence of comorbidity for disorders such as oppositional-defiant behavioral disorder, anxiety disorders, tics, andencopresis. Among patients with ADHD without enuresis,the total proportion of cases with comorbidity for thesesame conditions was significantly lower, at 60.6%, com-

pared with 77.7% in group 1. The presence of enuresis inADHD was associated with an increased incidence of anx-iety disorders, particularly because of generalized anxietyand obsessive-compulsive disorders.

The two age subgroups of patients with ADHD com-bined with enuresis showed the following characteristics.At age 5–9 years, there was a tendency to higher incidencesof oppositional-defiant behavioral disorder and encopresis,while at 10–14 years of age there were minor increases inthe incidences of obsessive-compulsive disorder and ticsas compared with patients with ADHD without enuresis(the difference was not statistically significant).

As the absolute majority of cases of enuresis amongthe ADHD study patients had primary nocturnal enuresis(50 of 53), these data can be applied to the combination ofADHD with primary nocturnal enuresis. Delayed matura-tion of the CNS plays a significant role among the mainmechanisms of the pathogenesis of both ADHD and prima-ry enuresis. In particular, in the case of ADHD, this appliesto delayed maturation of the prefrontal cortex of the frontallobes, while disturbances of the rhythm of antidiuretic hor-


TABLE 3. Results from the Wisconsin Card Sorting Test in Patients with ADHD (M ± m)

Parameter, %

Patients aged 6–9 years Patients aged 10–14 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 diurnalvariations in the volume of urine produced. Thus, in normalsubjects, less urine is produced at night than during the day,because nocturnal ADH secretion is greater. In childrenADH secretion levels change with maturation and reachvalues close to those in adults at about 12 years of age.Delays in CNS maturation can produce impairments to thecircadian ADH secretion rhythm, including decreases in itslevel 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 havea 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 peptideanalog of ADH [1, 4]. The antidiuretic effect of this agent isgreater than that of the natural hormone and its actions onvessel walls and the smooth musculature of the internalorgans are minimized, so it does not produce significantside effects. The mechanism of action of desmopressin in

enuresis consists of a decrease in nocturnal urine formationin the renal canaliculi to a volume not exceeding the func-tional capacity of the urinary bladder in children, allowingretention until waking in the morning. The clinical efficacyof 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 in50–80% patients in different studies, though there is thepossible complication of recurrences after withdrawal of themedication, such that treatment should be adequately pro-longed [1, 18]. This agent is recommended as a first-linetherapy in patients with isolated primary nocturnal enuresis.We have published clinical data on the value of its use inpatients with ADHD combined with enuresis [2], thoughthis question requires further study.

Another approach to the drug-based treatment of pri-mary enuresis, which has been used for many years and isregarded by some authors as the method of choice, is basedon the tricyclic antidepressants Melipramine (imipramine)and amitriptyline. The precise mechanism of action of theseagents in enuresis is unclear, though it is believed not to beassociated with the antidepressant actions or with influ-ences on the arousal systems of the brain or sleep.


Fig. 1. Incidences (%) of various comorbid disorders in the two subgroups of ADHD patients – those aged 5–9 years (a) and thoseaged 10–14 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 ofthe urinary bladder by means of its peripheral anticholiner-gic and spasmolytic actions. The treatment of enuresis withMelipramine is preferentially restricted to older childrenand adolescents in whom desmopressin has failed to producethe desired outcome. Positive responses to Melipramine areobtained in about 40% of patients with enuresis [18].However, the use of tricyclic antidepressants, especially forprolonged periods, is associated with a number of risks tohealth because of the side effects of these agents. In partic-ular, the anticholinergic effects of tricyclic antidepressantscan be undesirable, inducing atonia of the urinary bladderand urinary retention. Furthermore, other serious sideeffects 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 shouldbe emphasized that enuresis is not an isolated condition ina quite large proportion of children, such that the approachto its treatment should be addressed in the context of thedetection and correction of all disorders and abnormalitiespresent in the affected child. In this regard, there is particu-lar interest in the comorbidity of enuresis with ADHD, asmutually exacerbating influences from these two conditionscannot be excluded. It should be noted that the cause of thehigh incidence of cases in which ADHD is associated withenuresis is ultimately unclear, though it may be explainedby both the high incidence of each of these conditions in thechild population and the similarities in their pathogeneticmechanisms. The leading role in the pathogenesis of bothADHD and enuresis is currently believed to be a commonneurobiological factor, particularly delayed maturation ofthe CNS and inherited mechanisms. Although the inheri-tance of ADHD and enuresis appear not to be mediated bythe 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. Inthese situations, the physician generally asks a series ofquestions: which of the disorders is the more severe,whether the conditions should be treated sequentially orsimultaneously, whether monotherapy should be used withsequential changes in treatment agents when they are noteffective or whether combined treatment should be provid-ed, etc. Considering the high incidence of the association ofenuresis and ADHD, the development of appropriate treat-ment methods for such patients is of great scientific andpractical relevance.

One of the most promising directions in this area is theuse of the new drug atomoxetine hydrochloride (Strattera).This is the only agent currently available in Russia whichwas specifically developed and approved for the treatmentof ADHD. The high efficacy of atomoxetine in relation to awide spectrum of the abnormalities seen in ADHD has

received repeated support in controlled clinical trials and isbeyond doubt. In many of these studies, children with con-comitant enuresis showed significant regression the signs ofboth ADHD and enuresis [14, 16, 19]. Unfortunately, thereis as yet insufficient evidence of the efficacy of atomoxetinein the treatment of enuresis without ADHD for the recom-mendations for the use of atomoxetine to be widened toinclude enuresis.

At the same time, children and adolescents with simul-taneous ADHD and enuresis should start treatment usingatomoxetine monotherapy, as the stress in selecting treat-ment should be on the timely and adequate correction of thesigns of ADHD, as the long-term consequences of ADHDare more severe than those of enuresis. Furthermore, whentreating these patients with atomoxetine, the physicianexpects 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 treatmentled to decreases in the frequency or the cessation of noctur-nal micturition in patients with enuresis both combined withADHD and without ADHD. In one of these studies, Sumneret al. [17] noted the efficacy of atomoxetine in the treatmentof nocturnal enuresis in children and adolescents aged 6–18years in out-patient conditions. Atomoxetine at a dose of 1.5mg/kg/day was used in 42 children (of which 10 had ADHD)for 12 weeks, while 41 children (17 with ADHD) receivedplacebo; treatment results were evaluated in terms of thenumber of “dry” nights per week. Atomoxetine treatment ofchildren with enuresis significantly increased the number of“dry” nights per week. A total of 15 atomoxetine-treatedchildren showed increases in the number of “dry” nights byfactors of two or more, while there were only six suchpatients in the placebo group. The mean increase in the num-ber of “dry” nights during atomoxetine treatment increasedfrom 1.5 at the beginning of treatment to three at the end.Thus, atomoxetine therapy gave positive treatment effects innocturnal enuresis.

Thus, the combination of ADHD with enuresis in chil-dren and adolescents is a complex problem from both theclinical and the therapeutic points of view. A significant num-ber of the study patients had comorbid pathology extendingbeyond the range of the two disorders under discussion here– including affective disorders, behavioral impairments, andtics. The multiple nature of the clinical signs has the resultthat it is difficult to embrace the process of treating suchpatients within a single algorithm. Atomoxetine monothera-py has distinct advantages in children and adolescents withADHD combined with primary nocturnal enuresis, as it pro-duces significant reductions in the severity of both ADHDand enuresis. Furthermore, the positive effects of atomoxe-tine should also be considered in other conditions comorbidwith ADHD, particularly anxiety disorders and oppositional-defiant behavioral disorder and tics.


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