Selikowitz, M., Zilibowitz, M. (1980) ‘Heterozygous expression of X-linked mental retardation and X chromosome marker fra(X) (q27).’ New England Journal of Medicine,

23. Sherman, S. L. , Morton, N. E., Jacobs, P. A., Turner, G. (1984) ‘The marker (X) syndrome: a cytogenetic and genetic analysis.’ Annals of Human Genetics, 48, 21-37.

24. Brondum-Nielsen, K., Tommerup, N., Poulsen, H., Jacobson, P., Beck, B., Mikkelsen, K. (1983) ‘Carrier detection and X inactivation studies in the fragile (X) syndrome: cytogenetic studies in 63 obligate and potential carriers of fragile (X).’ Human Genetics, 64, 240-245.

25. Fryns, J. P. (1984) ‘The fragile X syndrome: a study of 83 families.’ Clinical Genetics, 26, 497-528.

26. Fryns, J. P., Van den Berghe, H. (1982) ‘Transmission of fragile (X) (q27) from normal males.’ Human Genetics, 61, 262-263.

27. Froster-Iskenius, U., Bodeker, K., Oepen, T., Matthes, R., Piper, U., Schwinger, E. (1986) ‘Folic acid treatment in males and females with fragile-X syndrome. American Journal of Medical Genetics, 23, 273-289.

28. Young, R . S. , Jaramillo, C., McCombs, J. L., Morre, C. M., Jorgenson, R. J . (1986) ‘Fragile-X mental retardation syndrome transmitted through intellectually normat males: implications for genetic counseling. Southern Medical Journal, 79, 405-409.

29. Sherman, S. L., Jacobs, P. A., Morton, N. E., Froster-lskenius, U., Howard-Peebles, P. N., Nielsen, K. B., Partington, M. W., Sutherland, G. R., Turner, G., Watson, M. (1985) ‘Further segregation analysis of the fragile X syndrome with special reference to

303, 662-664.

Nasa I Okstruction in Childhood: the Obstructive Sleep Apnoea Syndrome

THERE is no doubt that upper respiratory tract infections are common among young children, with risks of sequelae such as conductive deafness. Another problem can be difficulty in breathing through the nose. The nasal passages may be narrow to start with, and congestion of the mucous membrane and the accumulation of secretions make their contribution. Often there is a history of

transmitting males.’ Human Genetics, 69,

30. Davies, K. E. (1986) ‘DNA studies of X-linked mental retardation associated with a fragile site of Xq27.’ American Journal of Medical Genetics, 23, 633-642.

31. Lejeune, J. (1981) ‘MCtabolisme des monocarbones et syndrome de 1’X fragile.’ Bulletin de I’Academie Nationale de Mkdecine,

32. Lejeune, J . (1982) ‘Is the fragile-X syndrome amenable to treatment?’ Lancet, 1, 273-274.

33. Harpey, J. P. (1982) ‘Treatment of fragile-)<.’ Pediafrics, 69, 670.

34. Brown, W. T., Jenkins, E. C., Friedman, E., Brooks, J., Cohen, I. L., Duncan, C., Hill, A. L., Malik, M. N., Morris, V., Wolf, E., Wisniewski, K., French, J. H. (1984) ‘Folic acid therapy in the fragile X.’ American Journal of Medical Genetics, 17, 289-297.

35. Carpenter, N. J., Barber, D. H., Jones, M., Lindley, W., Carr, C. (1983) ‘Controlled six- month study of oral folk acid therapy in boys with fragile X-linked mental retardation. American Journal of Human Genetics, 35, Abstract, 243, 82a.

36. Gustavson, K. H., Dahlbom, K., Flood, A., Holmgren, G., Blomquist, H. K., Sanner, G. (1985) ‘Effect of fol,k acid treatment in the fragile-)< syndrome. Clinical Genetics, 27, 463-467.

37. Hagerman, R. J., Jackson, A. W., Levitas, A., Braden, M., McBogg, P., Kemper, M., McGavran, L., Berry, R., Matus, I., Hagerman, P. J. (1986) ‘Oral folk acid versus placebo in the treatment of males with the fragile X syndrome.’ American Journal of Medical Genetics, 23, 241-262.

289-299.

165, 1197-1206.

‘c) W N

N VI N

0- m

W 00

2

breathing through the mouth and of snoring at night. The child constantly holds the mouth open and has obvious difficulties if asked to take a deep breath with the mouth closed. Breathing through the mouth will result in a number of disabilities, for example the development of incorrect pronounciation with hypo- nasal speech.

Complications which have not received the attention they deserve are the sleep- associated problems that inadequate ventilation can cause. Many of the conditions associated with hypo- ventilation are rare, such as the failure of autonomic ventilation (Ondine’s curse), neuromuscular dysfunction (e.g. myo- pathies and severe hypotonic cerebral palsy), the obestiy hyperventilation syndrome, and acute emergencies (for example epiglottitis); but this annotation is directed to the possibility of structural 261

2 .- 0 c)

c)

c 4

abnormalities of the upper respiratory tract causing chronic disabilities.

Such abnormalities leading to nasal obstruction and sleep apnoea include enlarged tonsils and adenoids, claimed to be the most common cause', choanal atresia or stenosis, nasal septa1 deviation, nasal haematoma or tumours, and facial deformities such as those associated with Down syndrome' or the Hurler, Pierre- Robin and Crouzon syndromes. If the structural abnormality is marked it may well affect the child's sleep. Normally sleep is divided into stages, starting with the slow wave or quiet stage and alternating through the night with the rapid-eye-movement (REM) stage at intervals of 60 to 90 minutes. During REM sleep there is an irregular breathing pattern, with frequent periods of apnoea lasting less than 10 seconds. Hypotonia is characteristic of these periods and arousals are depressed.

The obstructive sleep apnoeic syndrome has been defined as the occurrence of at least 30 apnoeic episodes, each lasting more than 10 seconds, in a seven-hour sleep period. Associated symptoms and signs are excessive daytime sleepiness; loud snoring, with or without respiratory pauses; insomnia; recent onset of nocturnal enuresis; abnormal or increased activity in sleep; the need to sleep sitting up or abnormal positions during sleep (such as on elbows and knees); frequent arousals; mouth-breathing; behavioural and mood changes and declining school performance, with suspicion of mental retardation. More rarely there can be disorientation on waking, with hypnogogic hallucinations, morning headache, irritability, systemic and pulmonary hypertension, cor pulmonale, pectus excavatum, polycythaemia and evidence of right ventricular hypertrophy on ECG and x-ray3.

The family history can be of interest. Parents and siblings of children with obstructive sleep apnoea sometimes give a history of symptoms of this condition, suggesting an inherited predisposition to airway obstruction or to an abnormality of respiratory control, or both4. There are individual susceptibilities to the development of cor pulmonale, perhaps

262 because of abnormal reactivity of

pulmonary vasculature to hypoxia5, and it is well to note that infective and metabolic stresses, manifest as minor illnesses in infancy, can have respiratory consequences that are potentially dangerous, or even lethal6.

Cinefluorescopy during sleep in children with obstructive sleep apnoea shows that the soft palate falls backward against the posterior pharynx, the tongue moves posteriorly (glossoptosis) and the lateral walls of the hypopharynx approximate medially during inspiration whenever the collapsing force of negative inspiratory pressure exceeds the dilating force of pharyngeal airway-maintaining muscular contraction'. It has also been shown that when contrast medium was installed into the nasopharynx of children with airway obstruction due to large tonsils and adenoids, the contrast was aspirated more frequently into the lungs, suggesting that the aspirated secretions of these children may be the cause of repeated infections of the lungs'.

Sleep appears to predispose to airway obstruction by depressing airway- maintaining musculature, for example the genioglossus muscles which pull the tongue forward out of the oropharynx. The recumbent posture may play a part, as somnolence then tends to be worse, possibly because of hypercarbiag.

Not all children with large tonsils and adenoids exhibit such sleep disturbances, so there must be a number of other factors operating in affected children. It seems probable that the central nervous system control of respiration and muscle tone plays a part in this problem.

In central apnoea breathing ceases because the respiratory centre fails to initiate respiration, recorded by an absence of chest movement or by a change in endoesophageal pressure and lack of nasal and oral inflow. It has been suggested that in the syndrome of congenital central alveolar hypo- ventilation (Ondine's curse) there may be a defect involving the integration of chemoreceptor information, more than a direct defect of central chemoreceptors". Obstructive apnoea, on the other hand, is the unsuccessful maintenance of an airflow in spite of the respiratory effort, as seen by increased chest-wall and

abdominal movements and increased negative endoesophageal pressure'. Enlarged tonsils and adenoids are not the only cases of obstruction; there are other mechanisms, such as pharyngeal collapse during sleep".

Alveolar hypoventilation, whatever the primary cause, results in respiratory acidosis during sleep, with compensatory alkalosis starting during the day and persisting. This can further depress respiration in a vicious circle, with increasingly severe respiratory acidosis. If drugs are given for sedation they may add to the respiratory depression, and if oxygen is used for any reason it can also suppress residual hypoxic drive and increase hypoventilation. The acidosis, hypercapnia and hypoxia can lead to pulmonary hypertension and cor pulmonale (enlargement of the right side of the heart, with elevated right-sided pressure and pulmonary hypertension).

The suggested mental retardation may be merely the consequence of excessive sleepiness and its effects, especially in school. This is supported by the apparent improvement in intelligence following the relief of airway obstruction'*.

Morning headache can be explained by the fact that upper-airway apnoeas are associated with tremendous swings in intrathoracic pressure. These fluctuations lead to marked changes in blood-flow and modification of thoracic and abdominal pressure. Then a progressive increase in intracranial pressure secondary to such changes during sleep leads to the headache^'^. If obesity follows a long period of upper-airway obstruction from enlarged tonsils and adenoids, the additional stress may cause clinical problems and produce what has been termed the 'chubby puffer syndrome'. Perhaps lack of exercise is one reason for increased weight. Although somnolence can be marked, even resulting in the child falling asleep in the upright position, the obesity is never as gross as in the Pickwickian syndrome14.

Excessive daytime sleepiness may be confused with narcolepsy, but in the former case the patient does not wake refreshed after sleep; and what appears to be hyperactivity may be merely the child's efforts to avoid going to sleep, and often

n W N these children do fight sleep.

c1 Diagnosis is often delayed because the significance of the symptoms is missed: as has been said, 'We see only what we look G The possibility of such symptoms and signs, and even of poor growth and 2, development, being related to upper- -3 e this is particularly relevant among the less affluent members of society'. A number 2 of studies have suggested this possibility 3

N

m m for; we recognise only what we know'". 0'

airway obstruction is not considered, and s! of delayed diagnosis. For example 3 KRAVATH et al. '* reported three children with sleep apnoea, alveolar hypo-

s ventilation, apparent mental retardation and poor growth, all associated with enlarged tonsils and adenoids. A 3 particular reason for delayed diagnosis is

-3 that the major manifestations occur 6 during sleep, so may not be witnessed.

BROUILLETTE et a1.16 studied 22 infants and children, 15 boys and seven girls, whose histories suggested complete or partial airway obstruction during sleep. There were long delays in referral, with an average of 23 months; and 16 had serious sequelae, including cor pulmonale, failure to thrive, permanent neurological damage, behaviour disturbances, hyper- somnolence and developmental delay. Clinical and x-ray evaluations confirmed narrowing of the upper airways in 21, enlargement of the tonsils and adenoids in 14, micrognathia in three, facial abnormalities in three, and one with cleft palate and tonsillar hypertrophy. Prolonged partial airway obstruction during sleep resulted in significant hypercarbia in 11 and hypoxia in five. Those authors also emphasis the importance of examination during sleep, and affected children easily fall asleep in the examination room. This will lead to earlier diagnosis, as there may be no difficulty in breathing while they are awake during the day.

Diagnosis must depend on the history and examination showing signs of allergy, infections, rhinorrhoea, polyps; or anatomical problems such as deviation of the septum, the size of the tonsils and adenoids; speech problems; signs of cor pulmonale, for example rhales in the chest; a prominent PZ heart-sound and gallop rhythm; enlargement of the liver

.% .u 'D - .d

E

Y

263

v)

0

0

.- * .- 4

and spleen; oedema of the limbs and raised blood-pressure. Apart from observation during sleep, x-ray of the neck and examination with radio-opaque materials can be helpful. Additional information can be obtained from respiratory and cardiac monitoring, videotapes, arterial blood-gas deter- minations, especially before and after insertion of a nasopharyngeal tube, and cardiac catheterisation’. The use of a nasopharyngeal tube is well tolerated in diagnosis and treatment.

Nasal, laryngotracheal and other abnormalities must be excluded before obstructive episodes are attributed to enlarged tonsils and adenoids. Also, there is no doubt that retrognathia and excessive obesity can be associated with upper-airway obstruction in producing cardiopulmonary complications. Laryn- goscopy, bronchoscopy, and oesophageal contrast studies may be needed if there is any suspicion of anomalies.

Permanent relief can be obtained by removal of the tonsils and adenoids; and the sleep apnoea syndrome should be included in the possible indications for this operation”. However, it must be emphasised that large tonsils and adenoids alone do not warrant surgery; significant symptoms must be witnessed and relevant tests must be positive. Subsequent rapid growth of the child can be impressive, and operation can cure the cardiac cornpli~ations’~~ ’*. If it is not possible to the remove the airway obstruction, respiratory stimulants such as caffeine, theophylline and pemoline can be considered3.

To illustrate the effects of treatment, 20 of the 22 patients of BROUILLETTE and colleagues improved after surgery which relieved airway obstruction. They had less laboured breathing, quieter and more restful sleep, decreased nocturnal arousal and improved development. Of those tested, growth curves became normal in six, and there was ECG improvement of cor pulmonale in 12 and improvement of blood-gas abnormalities or airway obstruction on polygraphic monitoring in 1416. 17 of the 32 children investigated by FRANK et all9 were operated on. All had been given polysomnograms (EEG,

264 electro-oculogram, chin electromyogram,

ECG, thermistors to detect airflow, chest- abdomen bellows pressure transducer to detect thoraco-abdominal movements, and when possible measurements of blood oxygen saturation). When the poly- somnograms were repeated after operation in seven of the children there was a significant improvement in the number of obstructive apnoeas and in other apnoea indices. 14 of the 17 had had tonsillectomy and adenoidectomy, two a tracheostomy and one an incision of a nasal septa1 haematoma.

MANGAT and colleagues” carried out all-night polygraphic monitoring of sleep and respiration on four infants with apnoeic episodes and disturbed sleep patterns. These studies, after the tonsils and adenoids had been removed, confirmed the improved sleep patterns and relief of the obstructive episodes. None of these patients had any cardiac complication, which may have been because of their early diagnosis, so stressing the importance of this in terms of prevention.

HODGES and WAILOO~’ reported two children with dramatic improvement in weight-gain and general wellbeing after adenotonsillectomy, having previously suffered from failure to thrive, enlarged tonsils and associated obstructive apnoea. For another child it was only the monitoring of oxygen, which showed serious intermittent hypoxia during the night, which persuaded the surgeon to remove the tonsils and adenoids, with subsequent improvement”.

Further research is needed to define the boundary between normal and abnormal breathing and to understand more about the effects of intermittent hypoventilation on daytime functioning’. Also, more studies are needed to confirm that obstructive sleep apnoea is a common indication for tonsillectomy and adenoidectomy or other types of surgery”, although reversing alveolar hypoventilation does seem to result in dramatic improvement of sleep apnoea, daytime sleepiness, snoring, disturbed sleep and other symptoms. Techniques such as continuous monitoring of skin- surface oxygen and carbon dioxide tensions may be helpful in evaluating children with obstructive sleep apnoea

and in deciding whether surgery is neededz3. The symptoms may well be due to a combination of central nervous system dysfunction and nasal obstruction, from whatever cause, but the evidence so far suggests that removal of enlarged tonsils and adenoids is one of the most effective ways of influencing the situation.

NEIL GORDON Booth Hall Children’s Hospital, Blackley, Manchester M9 2AA.

References 1. Mandel, E. M., Reynolds, C. F. (1981) ‘Sleep

disorders associated with upper airway obstruction in children.’ Pediatric Clinics of North America, 28, 897-903.

2. Southall, D. P., Stebbens, V. A,, Mirza, R., Lang, M. H., Croft, C. B., Shinebourne, E. A. (1987) ‘Upper airway obstruction with hypoxaemia and sleep disruption in Down syndrome. ’ Developmental Medicine and Child Neurology, 29, 734-742.

3. Mark, J. D., Brooks, J . G. (1984) ‘Sleep associated airway problems in children.’ Pediatric Clinics of North America, 31,

4. Eliaschar, I., Lavie, P., Halperin, E., Gordon, C., Alroy, G. (1980) ‘Sleep apneic episodes as indications for adenotonsillectomy.’ Archives of Otolaryngology, 106, 492-496.

5 . Macartney, F. J., Panday, J., Scott, 0. (1969) ‘Cor pulmonale as, a result of chronic nasopharyngeal obstruction due to hypertrophied tonsils and adenoids.’ Archives of Disease in Childhood, 44, 585-592.

6. Abreu e Silva, F. A,, MacFadyen, U. M., Williams, A., Simpson, H. (1986) ‘Sleep anpoea during upper respiratory infection and metabolic alkalosis nn infancy.’ Archives of Disease in Childhood, 61, 1056-1062.

7. Cozzi, F., Pierro, A. (1985),‘Glossoptosis-apnea syndrome in infancy. Pediatrics, 75,

907-918.

836-843. 8. Konno, A,, Hoshimo, T., Togawa, K. (1980)

‘Influence of upper airway obstruction by enlarged tonsils and adenoids upon recurrent infection of the lower airway in childhood.’ Laryngoscope, 90, 1709- 17 16.

9. Ainger, L. E. (1968) ‘L.arge tonsils and adenoids

in small children with cor pulmonale.’ British Heart Journal, 30, 356-362.

10. Guilleminault, C., McQuitty, J., Ariagno, R. L., Challamel, M. J., Korobkin, R., McCleod, R. E. (1982) ‘Congenital central alveolar hypoventilation syndrome in six infants.’ Pediatrics, 70, 684-694.

11. Mills, R. P. (1987) ‘Tonsillar enlargement and failure to thrive.’ British Medical Journal, 295, 855.

12. Kravath, R. E., Pollak, C. P., Borowiecki, B. (1977) ‘Hypoventilation during sleep in children who have lymphoid airway obstruction treated by nasopharangeal tube and T. and A.’ Pediatrics, 59, 865-871.

13. Guilleminault, C., Eldridge, F. L., Simmons, F. B., Dement, W. C. (1976) ‘Sleep apnea in eight children.’ Pediatrics, 58, 23-30.

14. Stool, S. E., Eavey, R. D., Stein, N. L., Sharrar, W. G. (1977) ‘The ‘chubby puffer’ syndrome.’ Clinical Pediatrics, 16, 43-50.

15. Sosman, M. C., Dodd, G. D., Jones, W. D., Pillmore, G. U. (1957) ‘The familial occurrence of pulmonary alveolar microlithiasis.’ American Journal of Roentgenology, 71, 947-1012.

16. Brouillette, R. T., Fernbach, S. K., Hunt, C. E. (1982) ‘Obstructive sleep apnea in infants and children.’ Journal of Pediatrics, 100, 31-40.

17. Levy, A. M., Tabakin, B. S., Hanson, J. S., Markewicz, R. M. (1967) ‘Hypertrophied adenoids causing pulmonary hypertension and severe congestive heart failure.’ New England Journal of Medicine, 211, 506-5 11.

18. Talbot, A. R., Robertson, W. (1973) ‘Cardiaf failure with tonsil and adenoid hypertrophy. Archives of Otolaryngology, 98, 277-281.

19. Frank, Y., Kravath, R. E., Pollak, C. P., Weitzman, E. G. (1983) ‘Obstructive sleep apnea and its therapy: clinical and polysomnographic manifestations.’ Pediatrics,

20. Mangat, D., Orr, W. C., Smith, R. 0. (1977) ‘Sleep apnea, hypersomnolence and upper airway obstruction secondary to adenotonsillar enlargement.’ Archives of Otolaryngology, 103, 383-386.

21. Hodges, S., Wailoo, M. P. (1987) ‘Tonsillar enlargement and failure to thrive. British Medical Journal, 295, 541-542.

22. Shaw, N. J., Bowler, I., Dear, P. R. F. (1987! ‘Tonsillar enlargement and failure to thrive. British Medical Journal, 295, 1065.

23. Rowe, L. D., Hansen, T. N., Nielson, D., Tooley, W. H. (1980) ‘Continuous measurements of skin surface oxygen and carbon dioxide tensions in obstructive sleep apnea. ’ Laryngoscope, 90, 1797-1 803.

11, 737-742.

0- rn

03 00

0‘

h B

265