Enuresis: A maturational lag

Abstract

Enuresis is not a disease, but a disorder caused by delays in the maturation of three physiological processes: persistence of spontaneous bladder contractions, bladder volume exceeding the nocturnal functional bladder capacity and persistence of elevated sleep/arousal thresholds. Enuresis has been subtyped into two different groups, depending on whether the predominant feature is frequent small voidings (excessive bladder contractions) or large urinary volume (volume-dependent). The clinical pattern demonstrated by the enuretic child depends on the severity of the maturational lag. In practice, a mix of these types is most common.

Enuresis, although a common childhood concern, elicits great emotional turmoil for both the child and the care-giver alike (1). Many factors have been implicated in its genesis, but three fundamental processes have been identified in the etiology: spontaneous bladder contractions persisting well beyond the usual period for their disappearance; a reduced response to, or secretion of, antidiuretic hormone (ADH); and an inability to arouse to the stimulus of a large or contracting bladder (1). These three mechanisms are maturational events in the developing child and are present with varying degrees of severity in any one individual. Thus, the clinical manifestations may vary from child to child, depending on the constellation of maturational lags that are present. In addition, the focus of our therapeutic approach may vary depending on the interplay of these factors. The normal processes of the maturation of bladder continence, the physiological alterations responsible for enuresis and the various clinical forms of enuresis are reviewed (2).

MATURATION OF BLADDER CONTINENCE

The fetus must expel bladder urine. As bladder urine increases, a critical volume is reached (functional bladder capacity), which initiates a spontaneous reflex contraction that is mediated by the sacrospinal ganglia. As the bladder contraction ensues, the increased bladder pressure overcomes the detrusor muscles at the bladder neck and spontaneous emptying occurs (3). As the infant grows and matures, control centres in the pons and medulla initiate inhibitory signals that slowly dampen this reflex over a period of years (4). Thus, the infant voids larger volumes less often. The amplitudes of these inhibitory signals increase until they eventually completely suppress spontaneous contractions. This may not occur until mid-childhood, ages six to 10 years (2). However, the child achieves daytime (social) continence much earlier when he or she becomes aware of increasing bladder volume and develops the act of volitional voiding, which is initiated through the cerebral cortex. Nighttime continence is achieved in association with the abolition of spontaneous bladder contractions, mediated by the pons and medulla; a nocturnal bladder volume less than the nocturnal functional bladder capacity (NFBC), which is ADH-dependent; and the achievement of prolonged rapid eye movement (REM) sleep and attainment of sleep arousal (5,6).

What are the consequences of delays in maturation of these fundamental mechanisms? If there is a lack of attainment of inhibition by the pons, spontaneous bladder contractions persist that may be manifested by any one or combinations of daytime frequency, urgency, urge incontinence and ‘squatting’. During the night, if the secretion of or response to ADH is suboptimal, then the NFBC is exceeded, a bladder contraction is induced and enuresis may result. This is the circumstance in the child with an infantile pattern of nonrapid eye movement (NREM) sleep and elevated arousal thresholds.

Thus, the etiology of enuresis can be considered to be a triad of a persistence of spontaneous bladder contractions, bladder volume that exceeds the NFBC, secondary to a reduced secretion of or response to ADH, and an elevated sleep arousal threshold. These three processes may mature at differing rates such that one or a combination of these factors may predominate (2). Depending on whether one factor or a combination of factors dominates, various clinical manifestation in the enuretic child will result (Figure 1).

Figure 1).

Interplay of the maturational factors responsible for enuresis. ADH Antidiuretic hormone

Enuresis has been classified into two distinct subtypes: volume-dependent or type 1, and detrusor-dependent or type 2 (7). One can add another parameter, that of a mixed or type 3 (ie, features of both type 1 and 2). Volume-dependent children generally have normal bladder function but demonstrate nocturnal polyuria, which is considered to be a manifestation of diminished ADH response. Detrusor-dependent children have reduced NFBC secondary to the persistence of spontaneous bladder contractions. However, historically, children rarely fall into such distinct pathophysiological entities or clinical patterns and the majority are more likely to demonstrate a combination of these features or a mix of clinical features.

Although traditionally enuresis has been separated into nocturnal, or monosymptomatic (ie, only nighttime enuresis) and diurnal enuresis (day and night wetting), pathophysiologically they are probably the same disorder, with the diurnal group having a more severe maturational lag in the resolution of spontaneous bladder contractions. Similarly, secondary enuresis has been considered to differ etiologically from primary enuresis, yet clinically, these children do not differ significantly from primary enuretics. Their abnormalities lie in a delay in the transition from infantile sleep patterns to the adult state.

EVIDENCE OF MATURATIONAL LAGS

Spontaneous bladder contractions

Enuretic children have been found to have smaller functional bladder capacities (ie, the volume that initiates a bladder contraction or the subjective feeling of a full bladder), than night dry children (5). This is sufficient to cause daytime frequency and urgency, and occasional incontinence. Nocturnal cystometries have also demonstrated small nocturnal volumes initiating spontaneous contractions. Many night dry children with bladder irritation due to infection develop enuresis due to the initiation of spontaneous bladder contractions (8). Some children with no bladder symptoms have spontaneous bladder contractions (8) and most children with ‘unstable bladders’ (ie, those with persistent bladder contractions), slowly resolve by adolescence (9). Thus persistence of spontaneous bladder contractions is an essential element in nocturnal enuresis.

ADH effects

Some enuretic children void more than once per night (1). Earlier studies on adolescent enuretics revealed a failure of a nocturnal augmentation of ADH (11). Subsequent studies have shown only a few individuals who may demonstrate this phenomenon (11). However, many enuretics have large nocturnal urine volumes and excessive sodium excretion, implying a relative insensitivity to normal amounts of ADH (11,12). It has been noted that the onset of type 1 diabetes mellitus may be heralded by enuresis, giving further support to the relationship to nocturnal urinary volume (13). Enuresis can often be induced in night dry children by increased fluid consumption before bedtime (14). It has also been shown that 12% of night dry children have higher urinary volumes at night than during the day (15). Thus, nocturnal polyuria is a common feature in many children, but causes enuresis only in those children with persistent spontaneous contractions and who are unable to arouse to this stimulus.

Sleep arousal

Why are some children so difficult to arouse? Sleep architecture in infants differs from that in adults. Sleep cycles are short in infants, lasting 50 to 60 min, but more than 2 h in the adult (15). The infant spends equal portions in REM and NREM sleep, whereas the adult spends 80% in REM sleep. It is also known that enuresis does not occur in REM sleep. The infant alternates between REM and NREM sleep, and the adult spends the first third of the night in NREM and the last third in REM sleep (Figure 2) (16). As the infant matures, the nonarousal states become longer and the arousal states slowly disappear to meld into the adult pattern. Transition usually is complete between late childhood and early adolescence. Because enuresis rarely occurs in REM sleep (17), the transition from intermittent NREM and REM sleep to prolonged nonarousable NREM sleep may cause enuresis to appear in a previously night dry child; this is known as secondary enuresis. Enuresis is also more likely to occur in the first two thirds of the night (18).

Figure 2).

Comparison of infant, enuretic and adult sleep/arousal patterns (rapid eye movement versus nonrapid eye movement)

Arousability plays a pivotal role in the enuretic child. Wolfish et al (18) compared the arousability of enuretic boys to age matched controls by placing inserts into the ears of each child and sounding tones of 110 dB. In the first third of the night, only 3% of the enuretic boys were arousable. This increased to 12% in the second third and 18% in the final third, compared with controls who awoke 61% of the time. Enuretic episodes were inversely proportionate to the arousability. This study demonstrated the nonarousability of enuretic children and showed that as many as 40% of night dry normal controls were difficult to arouse.

CONCLUSIONS

Three main features are central to the presence of nocturnal enuresis: the initiation of spontaneous bladder contractions when the functional bladder capacity is exceeded, excessive nocturnal bladder volume (urine production) and the failure to arouse to these stimuli. Each one is subject to maturation, but may do so at varying rates. A child may have any one or all of these features and not be enuretic, depending on the severity and mix or maturational lag. Thus, children may demonstrate a variety of clinical manifestations, including daytime frequency and urgency, nocturia (but may be night dry if they are arousable), enuresis of either subtype, or more commonly, a mixture of the two subtypes, diurnal enuresis, or secondary enuresis. The end result is dependent on the mix of the various factors and their severities.