Monosymptomatic Nocturnal Enuresis

REVIEW ARTICLE

Monosymptomatic nocturnal enuresis

Rejane de P. Meneses*

Abstract Objectives: monosymptomatic nocturnal enuresis (MNE) plays a very important role in the practice of pediatrics due to its high prevalence, its psychosocial impact, and its controversial etiology and treatment. Our objective was to show that MNE can be a well-defined clinical entity (monosymptomatic), but it can also be a symptom of urinary disorder, thus requiring a completely different therapeutic approach. Methods: the literature presents numerous publications related to the matter of MNE, thus we tried to select, for this review, the classical and the most recent publications from internationally recognized authors; in addition, we also have a 13-year work experience at the Unit for Urinary Disorders of the Pediatric Nephrology Center of the state of Paraná (Unidade de Distúrbios Miccionais - Centro de Nefrologia Pediatrica do Paraná). Results: the lack of a well-defined, international consensus on the concept, terminology, and classification of MNE is an obstacle for the assessment of the numerous studies found in the literature. The individualization of the MNE clinical entity is the fundamental starting point for providing appropriate guidance for patients. Enuresis can be found in most societies and, thus, it gives way to several interpretations and forms of treatment. There is a consensus, however, on the damage to the self-esteem of enuretic children, and consequently, on the advantage of proper treatment. Conclusions: in most cases, MNE is kept as a family secret while children remain without proper guidance and treatment and suffering with the lack of understanding and damage to their self-esteem. Doctors should survey patients extensively for MNE during pediatric appointments. It is possible to discard other diagnoses with a detailed survey of habits, quality of the urination, and history of urinary infection and a meticulous physical examination. MNE should be faced as a medical problem worthy of the attention of professionals and patients’ families.

J Pediatr (Rio J) 2001; 77 (3): 161-8: enuresis, child, desmopressin, enuresis alarm.

The history of nocturnal enuresis Ebers papyrus, the first document to address enuresis, enuresis by observing children’s difficulty in waking up found in Luxor 3,500 years ago, revealed that mothers and from sleep. In the Byzantine civilization, enuresis was children used to take medicines made from water plants, associated with bladder neck relaxation, and in that case, suggesting that enuresis had a familial nature. Thirty-five tonic beverages such as hot wine or oil were recommended; centuries afterwards, Guyon brought up the family incidence during the Middle Ages, Saint Catherine of Alexandria of enuresis. At the time of Greek Romans, Aristotle, a (whose memorial day is November 25) became known for follower of Plato, was the first to reflect upon the causes of curing enuretic people. During the Renaissance, Paulus Begellardus drew up the first treaty on pediatric medicine which, in its 20th chapter, affirmed that “parents get particularly irritated when their children wet the bed * Chief of the Pediatric Nephrology Center, Hospital Infantil Pequeno regularly, sometimes way into the pubertal stage...”. In Príncipe, Curitiba - Brazil. 1544, Thomas Phaer, the father of Pediatrics in England,

161 162 Jornal de Pediatria - Vol. 77, Nº3, 2001 Monosymptomatic nocturnal enuresis - Meneses RP recommended several therapies that consisted of powdered Scolding and punitive attitudes that attacked children’s rooster windpipe, bladder from animals, intestine and brain self-esteem were recommended for “simulators”, and from mice, in the chapter “Bedwetting” of his work Boke of urethral occlusive devices such as the one invented by Chyldren. Such therapies based on animal organs persisted Wilks, which consisted of a velvet-covered iron tube shaped for several centuries. like a boy’s penis, or that created by Labat, which had the th advantage of leaving circulation free within the cavernous In modern times - starting in the 17 century - the first 1 anatomical studies were performed. The book Practica bodies, were used. Medicinae refers to enuresis as “a cold and damp mood In the 20th century, three events remarkably changed the alteration”, recommending the use of astringents in the history of enuresis: alarm therapy, imipramine and suprapubic region. In the book Partes Duae De Morbis desmopressin. Puerorum, the author almost admits that enuresis is caused by demons and witchcraft. Thomas Dickson, in the 18th century, was the first to Development of vesicourethral sphincter control report the efficiency of suckers in the sacral regions of Soon after birth, urination occurs spontaneously as a enuretic children, considering that most nerves leading to medullary reflex. From the first year of life onwards, two the bladder pass through the sacral foramen. important events take place: increase in bladder capacity The knowledge about physiology started to develop in and neural maturation of frontal and parietal lobes. the 19th century, and clinical observations became similar The cortical command produces the sensation of bladder in the whole literature. Guersent (1815) described the filling; however, neurological maturity to initiate or inhibit hereditary factor, higher incidence among boys and in urination is not present yet. The complete maturity with economically-underprivileged social classes, and the effect voluntary control of external vesicourethral sphincter and of enuresis on children’s mind, by referring to enuresis as ability of cerebral cortex to initiate or inhibit detrusor “an aspect of sadness and shame that also affected their contraction occurs only later. This allows children to control intelligence”. The bladder was considered to be the urinatio and defecation, adjusting them according to socially determinant factor for enuresis due to the weakness, defined patterns. irritability, and lack of sensitivity attributed to it. This At the age of five, 85% of children have total conception originated two forms of treatment: one for vesicourethral control, while the remaining 15% become stimulating and another for slowing down bladder activity. continent at an annual rate of 15%. At the pubertal stage, 2 The stimulation of bladder activity was carried out by the to 5% continue to be enuretic, and in adulthood, this rate is intravesical instillation of several substances or through approximately 1.5 to 3%.2 cold showers in the pubic and perineal region, sea bathing, or use of aromatics. In the late 19th century, galvanic or faradic current Definitions discharges used to be gently applied on the entire genital The word enuresis originated from Greek and means region of enuretic children. Technical reports on this “wetting oneself”. Therefore, it defines socially unacceptable technique became available all over the world, and urinating behavior. th Hernamann-Johnson, in the early 20 century, said that Nocturnal enuresis means urinating during sleep. This “the simplest method consists in introducing a metallic plug episode occurs at least once a month.3 into the bladder and discharge the electric current up to the children’s limit of tolerance”. Trousseau and his followers Since it is a unique symptom after the habitual age at preached the use of soothing therapy, especially one that which children learn to control urination, enuresis is was based on the belladonna, a plant that became very considered monosymptomatic, and presupposes normal popular during a long time. Other hypotheses such as small- functioning of the nervous and urinary systems or absence sized bladder, defective bladder neck, defective trigone and of other well-defined organic conditions as causative agent. If nocturnal enuresis is associated with other symptoms, it urethral meatus with reduced sensitivity led to new treatment 4 options such as bladder distension with fluids, insufflated is considered polysymptomatic. vaginal rings in order to constrict the bladder neck, A recent international agreement suggests classifying cauterization with silver nitrate to sensitize the urethra, and monosymptomatic nocturnal enuresis (MNE) as primary, bedwetting aids that kept a 45 angle between trunk and hips. secondary, familial or polyuric. Primary enuresis refers to inability to maintain urinary control from infancy; secondary Guersent was the first to describe relative nocturnal enuresis is a relapse after control (at least 6 months) has polyuria; only hundreds of years after that, Poulton and been achieved; familial enuresis is when at least one parent Hinden brought this hypothesis to light again, which did not has a previous history of enuresis; and polyuric enuresis is arouse any interest until 1980, when researchers found out when the nocturnal urine volume exceeds functional that enuretic children produced less antidiuretic hormone capacity.3 (ADH) during the night. Monosymptomatic nocturnal enuresis - Meneses RP Jornal de Pediatria - Vol. 77, Nº3 , 2001 163

Epidemiology 2) Delay of the circadian rhythm of antidiuretic The accuracy of data on the prevalence of MNE is hormone (ADH) currently hampered by the lack of standardized criteria for The amount of ADH in the bloodstream, secreted by the the selection of patients, in addition to the influence of posterior pituitary gland, is reduced soon after birth and, geographic, social and cultural factors.5 after one year, ADH levels equal those presented by adults.17 The literature presents an MNE prevalence rate of 3 to ADH levels usually increase during the night, resulting in 22% at the age of seven, and 0.4 to 8.4% at the age of ten.6 reduced urine volume. A disorder in the circadian rhythm of Usually, this rate remains around 10% at the age of seven.7 ADH causes increased urine production, exceeding bladder 18-21 MNE is more frequent in boys up to the age of ten years who capacity and explaining enuresis, although it does not belong to lower social classes; the incidence of MNE is explain why children do not wake up from sleep when the incontestably influenced by genetic factors. After the age of bladder is full. ten, the frequency is the same for both boys and girls.8,9 The mechanisms of circadian rhythm regulation of hydroelectrolytic balance have not been clearly understood yet. Nyctohemeral variations in central volemia and intrathoracic volume receptors influence the production of Pathogenic factors ADH and urine. This circadian rhythm is not present at birth, and undergoes a maturation process during the first MNE is characterized by three evident situations: childhood. A defect or delay in the maturation of the nocturnal urinary urgency, absence of enuresis alarm, and regulating system may give rise to relative nocturnal polyuria. significant higher incidence among children whose parents The identification of genetic markers can optimize the use used to be enuretic or have nocturia. of desmopressin9,22. The response to desmopressin does Based on this evidence, the participation of several not prove this theory, as diuresis is reduced even in children factors has been investigated, including bladder capacity, with normal ADH levels.15 There is a correlation of nocturnal uninhibited detrusor contractions exclusively during sleep, polyuria with low ADH levels and low urine osmolality or volume of nocturnal diuresis, ability to wake from sleep, significant difference in ADH levels after six months of and the presence of enuresis at different sleep stages. desmopressin therapy.17 These investigations prompted classifications that may Some parameters such as urine osmolality, bladder consistently guide the adoption of appropriate therapies. capacity, diurnal and nocturnal diuresis volume, involvement One of these classifications groups MNE into types I and IIa of urinary prostaglandins in water excretion control, if it is secondary to a waking disorder, and type IIb if it is antagonizing the osmotic effect of ADH in the renal medulla, 8 secondary to a nocturnal bladder dysfunction. A recent and levels of aquaporins (proteins that participate in water classification based on possible etiological factors, transportation), have been analyzed in order to predict the considering an abnormality in the circadian rhythm of response or nonresponse to desmopressin therapy.23-25 vasopressin, groups nocturnal enuresis into polyuric, familial, primary and secondary.3 3) Sleep and wakefulness There has been an attempt to define the correlation of enuresis with different sleep stages; however, results have 1) Genetic factors been inconclusive. Parents usually report that their enuretic MNE is a development disorder whose hereditary children have deep sleep, showing a tendency towards component has a heterogeneous character, described since wakening difficulty or inability to recognize the sensation 1890, which involves parents, brothers and sisters and other of bladder filling during sleep.2,20,26,27 The reason for this close relatives, and increases the probability of enuresis by wakening dysfunction may be related to immature thalamic 2 to 6 times. Children whose mother and father have function.28 previous history of enuresis present 77% of chances to Even though there is some difference in terms of suffer from this disorder, and if only one parent used to be wakening patterns in enuretic children, their sleep has enuretic, the chances amount to 44%; however, if there is no presented better quality than that of nonenuretic children; previous parental history of enuresis, the chances drop to Furthermore, enuretic children seldom have sleep disorders 15%. such as nightmares, insomnia, agitation, sleepwalking or Children who were brought up in a kibbutz, away from bruxism.29,30 their parents, have the same hereditary influence. The probability of identical twins having enuresis is 68%, while in nonidentical twins the probability is 36%.9,12-15 4) Bladder capacity and uninhibited detrusor Molecular biology seems to have a better explanation to contractions the genetic transmission of enuresis. Genes found on Small bladder capacity has been described as an MNE chromosomes 12q, 13q and 8q seem to be involved.9,12,13,16 etiologic agent. The limited number of urodynamic studies 164 Jornal de Pediatria - Vol. 77, Nº3, 2001 Monosymptomatic nocturnal enuresis - Meneses RP in enuretic children and the nonstandardized selection of Several diurnal urinating behavior alterations have been patients cast doubt on the interpretation of results2,3,15. No interpreted by family members as distraction or voluntary significant difference has been effectively determined so acts that could be controlled by children, and many times far.30 are not spontaneously reported. The presence of these signs If there is more than one enuretic event on the same night deserves investigation and differentiated treatment. and higher frequency of diurnal urination, or in cases that are refractory to all forms of treatment, it is necessary to rule 2) Physical examination out possible bladder instability through the urodynamic Some alterations that require differentiated diagnosis in study. These children benefit from an anticholinergic relation to other urological events are4: urine spots and treatment.2,3 The definition of MNE presupposes normal fecal residues on underwear; vulvovaginitis, meatitis, vesicourethral sphincter function.30 Uninhibited detrusor perivulvar dermatitis, synechia of the lips, epispadias or contractions that are only present during sleep have been hypospadias; reflex alterations in lower limbs or other described and may express residual immaturity.30 neurological signs; nevus or abnormal pigmentation of the fossula. 5) Psychological implications and nervous system The idea that enuresis is a symptom of emotional stress 3) Additional exams has been replaced with the evidence that most enuretic Qualitative urinalysis and urine culture are necessary in children manifest secondary psychological disorders that order to rule out the presence of leukocyturia, bacteriuria, affect their self-esteem; these children profit from early hematuria, proteinuria, glycosuria, oliguria and bacteriuria. guidance and treatment.31-34 Urinary tract echography is useful in cases in which Organizations such as ERIC (Enuresis Resource and anamnesis is not elucidative. The echography provides Information Center), in England,35 or Brazilian groups of interesting information on the structure of the bladder wall, researchers have conjointly worked with professionals and renal parenchyma, and urinary pathways or even on bladder in society in order to advertise, clarify and research about capacity and the presence of occasional posturination the topic, in addition to encouraging early treatment or residues. This examination may suggest the presence of reducing functional or structural disorders of the urinary tract and, in these cases, if MNE is ruled out, voiding cystourethrography 6) Other factors and/or urodynamic investigation are recommended. Intestinal constipation acts as a mechanical factor, preventing the bladder to expand to its full capacity. Other factors may correlate with enuresis, such as allergy to cow’s milk, effects of caffeine or cocoa derivatives, airway Treatment obstruction (sleep apnea) or even nocturnal fluid overload 1) Treatment onset (induced enuresis).15,23,30 Considering that MNE is a benign condition, its spontaneous resolution rate is approximately 15% per year, the placebo effect is high, and that there is a possibility of relapse after successful treatment, treatment regimens that are free from side effects are preferred. However, the Differential diagnosis effects on enuretic children’s self-esteem is a good indicative 1) Anamnesis sign that the matter deserves serious consideration. During anamnesis, family history, psychosocial The ideal age for treatment onset depends on each background, and the primary and secondary characteristics patient’s individual condition, their maturation, and the of enuresis are investigated. level of family tolerance. General guidance may start before the age of 5, and drug or nondrug treatment may be The following findings during anamnesis almost implemented after the sixth year of life. invariably rule out the diagnosis of MNE10,11: abnormal urination frequency during the day; more than one urination during the night; abnormally high volume of urine; previous 2) Interfering factors history of urinary tract infection; presence of neurological The identification of some factors may help to select the or urological disorders, polyuria, constipation or encopresis; types of treatment, which include sound or vibratory alarm, “frequent chafing”, clothes with smell of urine; diurnal psychological support, or prediction of desmopressin urinating behavior alterations such as involuntary voiding, response. The following factors may interfere with urinary urgency or effort to hold back the urine; weak, therapeutic results: children’s and family’s actual motivation; interrupted or forced flow of urine; suprapubic pain. the difficulty children have in waking up or ability to wake Monosymptomatic nocturnal enuresis - Meneses RP Jornal de Pediatria - Vol. 77, Nº3 , 2001 165 to an alarm or call; presence of encopresis or intestinal This method depends a lot on motivation, that is, patients constipation; presence of night terror, dyslexia, school- who will not mind waking up. Alarm therapy can only be related disorders, rejection, aggressiveness or passiveness, used on children who are able to understand and control the low self-esteem and family hardships; reduced bladder device. capacity or greater volume of nocturnal diuresis compared Before choosing between the sound or vibratory model, to diurnal diuresis; impact of enuresis on family environment; it is important to know which modality is fit for the child. socioeconomic status of the patient. The vibratory model offers the advantage of not waking up other family members. In Brazil, we do not have any 3) Interpretation of therapeutic results enuresis alarms available on the market. In practice, a handcrafted device is used, yielding good results. There has been an attempt to standardize the interpretation of therapeutic results, thus allowing Some causes of treatment failure include unmotivation, comparative studies. A cure or total response to treatment early discontinuation, difficulty in waking up, night terror is equivalent to a reduction of enuretic episodes in at least (children wake up and cannot sleep any longer), behavioral 90% of nights. Improvement or partial response corresponds disorders, inadequate home environment, mother’s anxiety, to a reduction of more than 50%. In some cases, enuresis more than one nocturnal episode, low socioeconomic 15,42 turns into nocturia.3,38 status. The reasons for discontinuation are family history, mother’s intolerance, children’s low self-esteem, and behavioral disorder.43 4) General Guidelines When results are satisfactory, some authors suggest Some preliminary guidelines and nonspecific actions increasing fluid intake before discontinuing alarm therapy. should also be considered for children younger than 5 years If cure or total recovery fails, a combination of alarm old10,39-41: discontinuation of diapers; maintenance of therapy and desmopressin should be used. This combination urinating schedules; bladder voiding before going to bed; allows faster results, providing the family with the perception of bladder filling; awareness of the ability to opportunity to get acquainted with the alarm device, thus control the sphincter either to initiate or stop urination. warranting more definitive results.10,44 The combination of Among the major measures, we have: show children that alarm therapy and desmopressin is recommended for at MNE is very frequent and several schoolmates suffer from least 6 months; after that, only alarm therapy should be used the same problem; try to remove guilt and motivate children; until totally satisfactory results are obtained. This regimen avoid excessive fluid intake at night, eradicate any punitive is recommended especially for older children who were attitudes, and provide positive support instead. refractory to different forms of treatment. A 6-month combination therapy may result in 57% of cure, 21% of partial response, in addition to being safe and free from side 5) Alarm therapy effects.45 The first described device dates back to 1904, when a Imipramine may be used, depending on the patient’s German physician designed a hospital mattress with a social status. mechanism that indicated when nurses had to change the clothes of hospitalized children; some of the children did not wet the bed anymore after spending some time in that 6) Drug treatment hospital.1,42 a) Desmopressin acetate (DDAVP) The therapy yielded good results, approximately 70 to 90% on the medium and long run, with a reduction in the Desmopressin is structurally analogous to the antidiuretic incidence of relapses between 0 and 30%; was also safe and hormone, which reduces the nocturnal production of urine. simple to apply, and did not present side effects. In spite of The 1-deamino-8-D-arginine-vasopressin molecule was this, alarm therapy has been scarcely used in Brazil. The synthesized in 1966. The deamination of N-terminal half- major reasons for this include lack of immediate results, cysteine in position 1 causes an increase in antidiuretic cultural aspects, unavailability, form of commercialization, activity and duration of action (10-12 hours) due to a higher and lack of expertise. action on V2 receptors of collecting duct cells. The The principle of alarm therapy is based upon the electrical replacement of L-arginine at position 8 with D-arginine is conduction of urine. Every time involuntary urination occurs, responsible for the reduction in the vasopressin activity, a sound or vibratory mechanism is triggered, waking children causing the action on V1 receptors of smooth muscle fibers up and having them cease urination. Children may not wake to be almost nonexistent. up immediately or just wake up during or after urination, The efficiency and safe use of desmopressin in MNE has gradually learning to anticipate or perceive urinary urge. been described for over 10 years.46,47 Several literature Expected results are only achieved after at least 4 months of reports show approximately 70% of total and/or partial continued use. response.2,20,39,48-50 166 Jornal de Pediatria - Vol. 77, Nº3, 2001 Monosymptomatic nocturnal enuresis - Meneses RP

The optimization of desmopressin use is based on ranges between 0.5 and 2.0 mg/kg/day, not exceeding 50 parameters such as normal bladder capacity, patient’s age, mg/day up to the age of 12 years and 75 mg/day after this increased volume of nocturnal diuresis, and urinary age. Imipramine is administered in a single dose, osmolarity. The selection of cases, whose pathogenic approximately 2 hours before bedtime, and yields the desired mechanism involved is relative insufficiency of nocturnal results, that is, a reduction of over 50% in enuresis frequency. ADH secretion, may provide higher efficiency. After 2 weeks, the dosage may be readjusted or maintained Desmopressin is available in nasal and oral solutions. for 3 to 6 months, and then gradually reduced until 10 Nasal desmopressin is the most widely used. Oral discontinuation is possible. desmopressin is recommended for children with rhinitis or respiratory tract infections. Dosage equivalence for the c) Anticholinergics nasal solution is 20 mg, and 200 mg, for the oral solution. The dosage may be reduced in 50% or doubled after 2 It is important to emphasize that there is no recommended weeks, depending on the initial response, and maintained use of anticholigernics for MNE. If bladder instability is for 3-4 months, with later gradual reduction.39,40,48,49,51,52 confirmed through urodynamic investigation, we classify enuresis as a symptom of urination disorder, and a specific In the event of relapses, the regimen may be repeated or treatment protocol, including the use of anticholinergics, is combination therapy (desmopressin + alarm) may be used. recommended. The maintenance of desmopressin for longer periods has proved to be safe and more efficient.53 Another option for patients who present good response is to restrict the use of desmopressin to social events, at which enuresis must be 7) Use of alternative medicine avoided. After nasal administration, desmopressin reaches The practices of herbal medicine by means of infusions; its maximum concentration in 40-70 minutes, with a aromatherapy through essential oils such as cypress, known bioavailability of 10% compared to 1% in the oral solution. for its antispasmodic and rebalancing properties; The antidiuretic effect starts 15 to 30 minutes after oligotherapy through the combinations of manganese-zinc, administration, reaching maximum effect between 2-3 and zinc-copper or fluorine, known for their tonic effect on the 10-12 hours. Oral desmopressin has lower bioavailability, sphincter; and naturopathy-iridology, which contemplates and maximum concentration is obtained within one hour. enuresis within a global context involving the digestive Desmopressin must be administered 1 hour before tract and energy consumption, have attempted to show bedtime, and it is necessary that fluid intake be limited to 30 efficacy; however, studies with more appropriate 54 ml/kg, 2 hours before up to 12 hours after administration methodologies are still necessary.56 so that the risk for hyponatremia and even seizures secondary to water intoxication can be avoided. Homeopathy associates a symptomatic, active medication (kreosotum or causticum) with early-night Excellent tolerance and harmlessness have been widely enuresis, and plantago major or chloralum with late-night observed. Some possible side effects are mild headache enuresis. The background treatment takes the morphology (2%), nasal congestion, rhinitis and epistaxis (1%), and and temperament of patients into consideration: calcarea abdominal pain (1%). Desmopressin must not be prescribed carbonica for obesity-prone and slow children; calcarea to children with polydipsia, high blood pressure, or heart phosphoricum for irritable and underweight children; or disease.15 sepia for children who are very sensitive to cold; gelsemium sempervirens when children suffer from sleeplessness; and b) Imipramine chamomilla sempervirens when sleep is agitated. This tricyclic antidepressant has been banned from Crenotherapy also offers some treatment options. Results medical prescriptions due to potentially lethal intoxication obtained through the Lons-le-Saunier Center in France, risk, which are unjustifiable if we consider the benign 15,39 with 5,000 children treated between 1988 and 1992, were nature of enuresis. Imipramine has gained widespread 23% of cure, 68% of improvement, and 9% with no results. use since 1960, although its action mechanism is not clear, and is probably related to anticholinergic and Hypnosis has also been used, and several retrospective sympathomimetic effects. The antidepressant effect does studies were performed, with variable results (44-93%). not seem to be involved, since other antidepressants show Although results have been satisfactory, hypnosis has been no effect on enuresis.10,55 seldom recommended. Despite the toxicity potential of imipramine, it is still a Chiropractics, which consists of manipulation of the therapeutic option in Brazil, especially for preadolescents, spinal framework, yields results similar to those of placebo. since alarm therapy and desmopressin depend on more Acupuncture, traditionally used by the Chinese to treat favorable social conditions. enuresis, has also yielded good results. Foot acupuncture The therapeutic result is nearly similar to that of has also been referred, with 82% of cure, and 16% of desmopressin, also in terms of relapse episodes. The dosage improvement one year after treatment completion.56 Monosymptomatic nocturnal enuresis - Meneses RP Jornal de Pediatria - Vol. 77, Nº3 , 2001 167

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Rittig S, Schaumburg H, Schmidt F, Hunsballe JM, Hansen AF, to successful therapy are family support, children’s Kirk J, et al. Long-term home studies of water balance in patients motivation, everyone’s patience, and especially an accurate with nocturnal enuresis. Scand J Urol Nephrol 1997;31(183):25-7. and differentiated diagnosis, which personalizes MNE 22. Hogg RJ. Genetic factors as predictors for desmopressin treatment treatment. success. Scand J Urol Nephrol 1997;31(183):37-9. 23. Eller DA, Homsy YL, Austin PF, Tanguay S, Cantor A. Spot urine osmolality, age and bladder capacity as predictors of response to desmopressin in nocturnal enuresis. Scand J Urol Nephrol 1997;31(183):41-5. 24. Berlier P. Traitements médicamenteux. In: Cochat P. Énurésie et troubles mictionnels de l’enfant. Paris: Elsevier; 1997. p. 107-15. References 25. Medel R, Dieguez S, Brindo M, Ayuso S, Canepa C, Ruarte A, Podesta ML. Monosymptomatic primary enuresis: differences 1. Guignard JP. 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