Key Words: Children-Atopic dermatitis-. Sleep pruritus. ... NREM sleep measures included the amounts of time spent in stages 1,2,3, and 4. The. REM sleep ...
Sleep 12(4):309-314, Raven Press, Ltd., New York © 1989 Association of Professional Sleep Societies
Sleep and Nighttime Pruritus in Children with Atopic Dermatitis Jaime M. Monti, *Raul Vignale, and Daniel Monti Departments of Pharmacology and Therapeutics and *Dermatology, School of Medicine, Clinic Hospital, Montevideo, Uruguay
Summary: The number of scratching episodes and average frequency with which they started during each sleep stage as well as the effects of nighttime pruritus on objective sleep parameters in nine children with atopic dermatitis were assessed in the sleep laboratory. Scratching episodes occurred during rapid eye movement (REM) sleep and non-REM (NREM) sleep. The largest average frequency corresponded to stage 1, followed by stage 2, REM sleep, stage 4, and stage 3. Sleep maintenance was markedly altered. Total sleep time decrease was related mainly to smaller amounts of stage 4 NREM sleep. REM sleep percentage of total sleep time was increased as compared with normal children of the same age. Furthermore, in six of nine patients REM sleep latency was found to be decreased. Key Words: Children-Atopic dermatitisSleep pruritus.
Atopic dermatitis (AD) is a chronic inflammatory disease of the skin characterized by pruritus, dryness, and erythema (1). It begins at an early age, with 85% of patients affected within the first 5 years (2,3). Severe nighttime pruritus is a common feature in patients affected by AD. It was our aim to determine if nocturnal scratching was related to a particular sleep stage. In addition, we evaluated the effect of nighttime pruritus and scratching on objective sleep parameters. METHODS Nine children (four boys and five girls) 3-15 years of age (mean age 8.3 ± 3.9 years) with the diagnosis of AD were selected to participate in this study. They were outpatients at the Department of Dermatology and presented an unremitting history of nighttime pruritus for the last 2 years. All systemic and local medication was discontinued 7 days prior to the beginning of
Accepted for publication March 1989. Address correspondence and reprint requests to Dr. J. M. Monti at Department of Pharmacology and Therapeutics, Hospital de Clinicas, PI Montevideo, Uruguay.
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the study (Table 1). A full explanation of the study was given to parents and children and informed consent was obtained. Subjects spent 2 nights in the laboratory. The first night was used for adaptation. Children reported to the sleep laboratory 1 h before bedtime for electrode application. They remained in bed for 8 hlnight with continuous polysomnographic recordings consisting of frontal, parietal, and occipital electroencephalogram (at 50 !LVIcm for 1-30 Hz), electrooculogram (right and left outer canthi), and bipolar electromyogram (chin muscles). In addition, two electrodes were fixed to the ulnar side of the ventral surface of each forearm to record muscle potentials from scratching movements. The speed of the paper drive was 15 mm/s. Each sleep record was scored in 20-s epochs using the established criteria of Rechtschaffen and Kales (4). The visually scored sleep variables were grouped into three main categories: sleep continuity measures, rapid eye movement (REM) sleep measures, and non-REM (NREM) sleep measures. Measures of sleep continuity included sleep latency (from lights out until the onset of stage 2 NREM sleep for 5 uninterrupted min), total wake time, wake time after sleep onset, number of awakenings, and total time asleep. The NREM sleep measures included the amounts of time spent in stages 1,2,3, and 4. The REM sleep measures comprised REM sleep time and latency (from first spindle to REM sleep onset) and number of REM periods (a lapse of REM sleep of up to 5 min that was followed by more REM sleep was scored as one REM period). We also determined the number and duration of scratching episodes as well as the sleep stage in which they arose. RESULTS Scratching episodes were observed to arise during stages 1,2,3, and 4 NREM sleep and REM sleep (Table 2). The total number of scratching bouts was 152. When the TABLE 1. Population description Patient no.
Atopic dermatitis
Sex
Age (yrs)
Severity
Predominant localization
2
F M
7 15
Mild Moderate
Facial and flexural areas Antecubital and popliteal areas
3
F
7
Mild
4
M
11
Popliteal, gluteal, and perineal areas Facial and flexural areas
5
F
4
Severe
Facial, antecubital, abdominal, and popliteal areas
6
F
6
Moderate
7
M
3
Moderate
8
M
10
Moderate
Facial, antecubital, and popliteal areas Facial, antecubital, and gluteal areas Facial, axillary, gluteal, and popliteal areas
9
F
12
Moderate
1
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Moderate
Antecubital and popliteal areas
Previous treatment Topical corticosteroid Topical corticosteroid and petrolatum Topical corticosteroid Topical corticosteroid and oral ampicillin Oral and topical corticosteroids; bathing with salty water Topical corticosteroid and petrolatum Oral and topical corticosteroids Oral corticosteroid and ampicillin; topical corticosteroid and antihistamine (HI) Topical corticosteroid and chloromycetin
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TABLE 2. Number of scratching episodes and average frequency with which they started during each sleep cycle Patient no. 1 2 3 4 5 6 7 8 9 Total no. Average frequency (min)
Stage 1
Stage 2
4 (0.2) 5 (0.1) 1 (0.02) 7 (0.2) 18 (1.3) 13 (0.5)
1 (0.005) 11 (0.07) 10 (0.03) 4 (0.02) 10 (0.04) 6 (0.03) 1 (0.005) 7 (0.03) 11 (0.05)
48 2.3
Stage 3
Stage 4
Stage REM 2 (0.02) 6 (0.07) 5 (0.03) 1 (0.009) 7 (0.05)
1 (0.02) 6 (0.1) 3 (0.07) 2 (0.03)
3 (0.06) 1 (0.04) 5 0.12
61 0.28
4 (0.03) 2 (0.02)
11 0.20
27 0.22
Total recording time amounted to 480 min. No. of scratching episodes for each patient during sleep stages is given. Nos. in parentheses indicate the average frequency with which they started during each sleep stage (duration in min of sleep stages for each patient is shown in Table 4).
number of scratching episodes was examined by thirds of night, a nonsignificant trend toward a larger number of bouts was observed during the second third. We also quantified the average frequency with which scratching episodes started during NREM sleep and REM sleep. Average frequency was greatest for stage 1, followed by stage 2, REM sleep, stage 4, and stage 3 (Table 2). The total amount of time during which patients scratched ranged from 11.0 to 84.6 min, with a mean value of 30.3 ± 7.4 min. As shown in Table 3, during the recording night NREM sleep latency was within the normal range. On the other hand, total wake time, wake time after sleep onset, and the number of nocturnal awakenings were markedly increased. Total sleep time decrease was related to smaller amounts of NREM sleep (Table 4). When NREM sleep stages were considered, a striking decrease of stage 4 could be observed, while stages 1,2,3, and REM sleep in minutes were within normal levels. Nevertheless, REM percentage of total sleep time showed a marked increase. Mean values corresponding to REM sleep latency amounted to 84.0 min. However, in six of nine children the latency of the first REM period was below normal levels, amounting to 23, 59, 63, 68, 71, and 78 min, respectively. TABLE 3. Sleep continuity measures in children with nighttime pruritus Patient no.
Sleep latency (NREM)
Total wake time (min)
Wake time after sleep onset (min)
1 2 3 4 5 6 7 8 9
24 5 8 13 13 8 28 0 29
53 200 8 50 39 17 72 4 33
35 195 4 42 31 13 55
X
14.2 3.5 0--29
53.9 19.8 4-200
43.2 19.9 4-195
SEM Range
4
10
Total no. of wakes 2 15 4 7 19 11 9 2 2 7.9 2.1 2-19
Total sleep time (min) 427 278 471 429 441 463 406 476 444 426.1 20.0 278-476
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TABLE 4. Sleep stages in children with nighttime pruritus: NREM and REM sleep
Patient no.
NREM sleep time (min)
Stage I (min)
264 194 379 276 329 330 322 317 329
I 2 3 4 5 6 7 8 9
x SEM Range
304.4 17.7 194-379
23 22 24 20 49 35 30 14 26 27.0 3.4
14-49
Stage 2 (min) 203 159 297 228 238 222 190 206 204 216.2 12.7 159-297
Stage 3 (min) 32
Stage 4 (min)
50 27 37 47 39 51 26
6 2 8 I 5 26 63 46 73
35.6 4.4 II-51
25.6 9.4 1-73
11
REM sleep (min)
REM sleep (% of TST)
163 84 92 153 112 133 84 159 115
38.2 30.2 19.5 35.7 25.4 28.7 20.7 33.4 25.9
121.7 10.6 84-163
28.6 2.1 19.5-38.2
REM sleep latency 78 23 152 63 110 68 132 59 71 84.0 13.4 23-152
No. of REM periods 4 5 3 5 5 5 4 5 5 4.6 0.24 3-5
TST, total sleep time.
DISCUSSION Scratching episodes occurred during NREM sleep and REM sleep, with a nonsignificant trend toward a larger number of bouts during the second third of night. As previously shown in a group of middle-aged patients with AD (5), the frequency with which scratching movements started during light NREM sleep (stages 1 and 2) was higher as compared with deep NREM sleep (stages 3 and 4). The frequency corresponding to REM sleep was just about that of stage 2. When individual data were considered, no relationship could be observed between the number of scratching episodes, their appearance during the night, and sex, age, severity of dermatitis, localization, and previous treatments. According to Coble et al. (6), recovery from the "first-night" effect in normal children is almost complete for measures of sleep continuity and NREM sleep during night 2. However, values corresponding to REM sleep latency decrease significantly from night 1 (x = 141.6) to night 2 (x = 126.2 min), with almost no further change on night 3 (x = 122.3 min). On the other hand, REM sleep time in minutes and as percentage of total sleep time shows a progressive and significant increase from night 1 (x = 82.7 min, 18.1%) to night 3 (x = 101.2 min, 21.3%). In our patients, the mean value corresponding to NREM sleep latency on night 2 was slightly smaller as compared with that reported in normal children (6). In contrast, total wake time and number of wakes were markedly increased, while stage 4 NREM sleep was conspicuously decreased. As compared with normal children of the same age, REM sleep latency was markedly decreased in six of nine patients and REM percentage increased irrespective of age or severity of disease. Altered sleep continuity is likely to be a consequence of nighttime pruritus and scratching. However, decreased stage 4 sleep and REM sleep latency and increased REM sleep incidence are probably related to a different mechanism. Increased REM sleep percentage and decreased REM sleep latency have been described also in narcoleptic children (7). Moreover, Lahmeyer et al. (8) and Emslie et aI. (9) showed REM sleep latency to be significantly decreased and number of REM periods increased in depressed children. Whether similar neurochemical changes subserve REM sleep increase in three seemingly unrelated diseases is something worthwhile to be investigated. Sleep, Vol. 12, No.4, 1989
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Abnormalities in the effect and metabolism of acetylcholine and monoamines have been described in AD. Thus, acetylcholine levels are elevated in the skin and plasma of children with AD (10). In regard to the noradrenergic system, there is evidence suggesting an increased binding of norepinephrine as well as an augmented number of (Xl-adrenoceptors in atopic skin (11). Phosphodiesterase activity is also increased in children with AD, which results in reduced cyclic AMP levels after stimulation with catecholamines. As a consequence, cyclic nucleotide control of cell functions becomes inadequate (10). Moreover, levels of histamine are elevated in the skin of AD patients, and increased plasma levels of the neurotransmitter have been also reported in occasional patients (12). Acetylcholine and several monoamines including norepinephrine and histamine have been proposed to modulate sleep and wakefulness (13-15). However, there is no evidence of whether abnormalities in their release or metabolism occur at central sites in patients with AD. Children with AD show also immunologic abnormalities. Accordingly, serum immunoglobulin E (lgE) levels are increased, circulating T-Iymphocytes are decreased, and monocyte function is reduced, which tends to indicate a depressed cell-mediated immunity (10,16). Although the highest levels of serum IgE are shown mainly in patients with extensive skin disease, no correlation seems to exist between duration of scratch and IgE levels (17). Recently, Krueger and Kamovsky (18) proposed a relationship between sleep and the immune response. Relevant to our topic are their studies with muramyl peptides. Thus, the N-acetylmuramyl dipeptide shows immunoreactive and somnogenic properties in laboratory animals (19). Accordingly, during its administration slow wave sleep increases while REM sleep tends to decrease. Human recombinant interferon U2 has been found to increase slow wave sleep in rabbits (20). Interestingly enough, interferon production is decreased in cells from atopic as compared with nonatopic children (21). Although muramyl peptides and interferon have been shown to be present in mammalian tissues, there is no evidence of whether changes in their availability at central sites occur during pathological conditions. However, it is worthwhile to speculate that deficits in the functional activity of these two sleep factors could be partly related to sleep disturbances in children with AD. REFERENCES 1. Hanifin 1M. Atopic dermatitis. In: Rake! RE, ed. Conn's current therapy. Philadelphia: WB Saunders, 1987:688-91.
2. Rajka G. Atopic dermatitis. In: Rock A, ed. Major problems in dermatology. London: WB Saunders, 1975:4-35.
3. Butler 1M, Hanifin 1M. Immunology of atopic dermatitis. In: Mackie RM, ed. Current perspectives in immunodermatology. Edinburgh: Churchill Livingstone, 1984:64-73. 4. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: Brain Information Service/Brain Research Institute of California, 1968. 5. Savin JA, Paterson WD, Oswald 1. Scratching during sleep. Lancet 1973;2:296-7. 6. Coble PA, Kupfer Dl, Taska LS, Kane 1. EEG sleep of normal healthy children. Part I: findings using standard measurement methods. Sleep 1984;7:289-303. 7. Guilleminault C. Narcolepsy and its differential diagnosis. In: Guilleminault C, ed. Sleep and its disorders in children. New York: Raven Press, 1987:181-94. 8. Lahmeyer HW, Poznanski EO, Bellur SN. EEG sleep in depressed adolescents. Am J Psychiatry 1983;140: 1150--3.
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9. Emslie OJ, Roffwarg HP, Rush AJ, Weinberg WA, Parkin-Feigenbaum L. Sleep EEG findings in depressed children and adolescents . .tlm J Psychiatry 1987;144:668-70.
10. Hanifin JM. Atopic dermatitis. J Am Acad DermatoI1982;6:1-13. II. Szentivanyi A, Heim 0, Schultze P, Szentivanyi J. Adrenoceptor binding studies with 3Hdihydroalprenolol and 3H-dihydroergocryptine on membranes of lymphocytes from patients with atopic disease. Acta Derm Venereal 1980;92:19-21. 12. Butler 1M, Chan SC, Stevens S, Hanifin 1M. Increased leukocyte histamine release associated with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol 1983; 71:490-8. 13. Monti 1M. Catecholamines and the sleep-wake cycle. 1. EEG and behavioral arousal. Life Sci 1982; 30: 1145-57. 14. Monti 1M. Catecholamines and the sleep-wake cycle. II. REM sleep. Life Sci 1983;32: 1401-15. 15. Monti 1M, PeJlejero MT, Jantos H, Pazos S. Role of histamine in the control of sleep and waking. In: Wauquier A, Monti JM, Gaillard 1M, Radulovacki M, eds. Sleep-neurotransmitters and neuromodulators. New York: Raven Press, 1985:197-210. 16. Kragballe K, Herlin T. Monocyte cytotoxicity in clinical exacerbation and remission of atopic dermatitis. Acta Derm Venereal 1980;92:103-5. 17. Aoki T, Kushimoto H, Kobayashi E, Ogushi Y. Computer analysis of nocturnal scratch in atopic dermatitis. Acta Derm Venereal 1980;92:33-7. 18. Krueger 1M, Kamovsky ML. Sleep and the immune response. Ann NY Acad Sci 1988;496:510--6. 19. Krueger 1M, Kamovsky ML, Martin SA. Pappenheimer 1R, Walter J, Biemman K. Peptidoglycans as promoters of slow-wave sleep. II. Somnogenic and pyrogenic activities of some naturally occurring muramyl peptides; correlations with mass spectrometric structure determination. J Bioi Chem 1984; 259: 12659-62. 20. Krueger JM, Dinarello CA, Shoham S, Davenne D, Walter J, Kubillus S. Interferon alpha-2 enhances slow-wave sleep in rabbits. Inl J Immunopharmacol 1987;9:23-30. 21. Strannegard IL, Strannegard O. Natural killer cells and interferon production in atopic dermatitis. Acta Derm Venereal 1980;92:48-51.
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