I I U M A N i ' A T H O L O G Y - - V O L U M E 7, NUMBER 5
2. 3. 4. 5.
6. 7. 8.
mitted to the Executive Council. Evanston, Illinois, Associatinn of American Medical Colleges. 1965. Citizens Comndssitm on Graduate Medical Education. Chicago, Illinois, American Medical Association, 1966. Carnegie Contmission on lligher Education: lligher Education and the Nation's tteahh. New York, McCraw-llill Book Cotnl'mny. 19711. l'hysicians fl)r the Future. Report of tile Macy Comntission. New York, Josiah Macy Foundation, 1976. Ad Iloc Comnfiuee on Graduate Medical Educalion of the Association of American M&lical Colleges: hnplicalions of academic medical centers taking responsibility for graduate medical education. J. Med. Edttc., 47:778-t, 1972. Corm, R. B.: Should laboratory medicine become a separate medical spcciahy? lltnn. Path., 6:2-1, 1975. Gill, T., Benson, E., Defendi, V., Grishant, J., Marchesi, V. T., Scarpclli, I)., and Van lzmcker, J.: Manpower needs in pathology. Fed. I'roc., Jul}" 1976. Goodale, F., and Gander r G. W.: The future of imthology: a Delphi study by pathology dcpartntent chairntcn. J. Med. Educ. (In press.)
SUDDEN INFANT DEATH SYNDROME CLAIRE I.ANGSTON, M . I ) . *
T h e sudden infant death S y l l d r o n l e has been defined as tile sudden dcath o f all infant or ) o u n g child, unexl)ected by history, in which a t h o r o u g h postmortenl examination fails to demonstrate an adequate cause for death. T h e s y n d r o m e represents tile greatest single cause o f death in infants ill re;Ill)" developed countries between the ages o f one week mad one ) ' e a r ) ' " In a study o f 224 infmlts tinder tile age o f two years who died suddenly and unexl)ectedl )" in King County, only 53 (2.t per cent) were found to have a lethal lesion at autol)sy.' O f tile remainder, the minor morl)hologic abnormalities present could not be considered an adequate cause for death. T h e incidence varies from about 1 to 3 per 1000 live births, t ' ' and tllere is a tendency for the incidence to increase with increasing geographic latitude even within the same countr)'. T o r o n t o , in Canada, has onc o f the highest r e p o r t e d incidences. T h e peak incidence is between two and three nlomhs o f age, with an age spread o f one week to 12 months. Tile s)'ndrome occurs througllout the year, but there a p p e a r s to bc an increased frequency in tile winter months anti tills seems to be true in the southern as well as the northern hcnlisphere.'-' T h e r e is a male i)rcl)ondcrance o f about 3 to 2. T h e frequency o f the s)'ndrome is increased ill infants o f low birth weight. It is *Assistant i'rofessor, l)epartnmnt of l'athology,
and l.ecturer, l ) e p a r t m e n t o f Pediatrics, Universit)' of Manitoba Facuh)" of Medicine. Associate l'athologist, Children's Centre, l l e a h h Sciences Centre, Winnipeg, Manitoba, Canada.
approxinmtel)" I0 times more conunon in infants with a birth weigllt between 3V2 and 4 pounds than ill infants witll a birth weight between 7z/2 and 8V2 pounds. I)espite the fiequent history o f low birth weight, tile subsequent medical Ilistory is generall) u n r e m a r k able. Children from lower socioeconomic g r o u p families and nomvhite families sllow an increased incidence o f the sudden infant deatll syndrome, as do children of ) o u n g mothers and those with a history of illegitimacy. T h e s e infants characteristically die d u r i n g sleep, and almost half of them have had an upl)er r e s p i r a tory i,lfecti(m d u r i n g the two week p e r i o d prior to death, t Although b)" definition there is no adequate cause for death demonstrated at postmortem examination, there are several characteristic morpllologic findings ill tile s u d d e n infant death syndrome. These include petechine, particularly on tile intrathoracic viscera, including tile tll}'nms, epicardiunl, and pleura, as well as lmlmtmary edema and congestion. Also there is fiequently Ilistologic evidence o f recent respiratory infection, ahhough these changes are insullicie,u in tltelnselves to account for de,lth, a A wide variety o f etiologies have bccn proposed to explain this syndrome. T h e y range f l o m simple mechanical suffocation to several imaginative hypotheses, inchlding tile now discredited condition o f staws thymicol)'lul)llaticus, ovcrwhelming bacterial or viral infection, various immunologic deficiencies, anapllylaxis, and a wide variety of Imtative metabolic or nutritiolml disorders. A h h o u g h tile etiology remains unknown, there are several hypotheses that Imve gained a certain a m o u n t of credibility in tile recent past. It had been proposed that these deaths are d u e to an abnormality ill the cardiac conduction system o f these infants; however, tills abnormality has recently bccn recognized to be a normal histologic feature of the infant conducting systeln. 4 An allergic etiology, with cow's milk generall)' being tile lnost widely implicated allergen, has been proposed by a variety o f investigators. This hyl)otllesis suggests that death results from an overwhehning allergic reaction fifllowing tile inhalation o f cow's milk. T h e r e are data that contradict tills h)Imthesis. Studies of mast cells in file airwa)'s of these children do not regularly show increased degranulation, which would SUl)port tile hyl)othesis. In addition, aminlilk mltibodies in these childrell have not l)een significantly d i f ferent frolll those ill controls, s Further investigations of tim ilnmunologic responses in tile s u d d e n infant death syndronle suggest that these infants are not dift'erent from controls in terms o f a variety o f inlmunologic variables, including levels of ilnlnunoglot)ltl~ls
CURRENT TOPICS and specific antibody tilers? T h e r e has been recent preliminary evidence for a deficiency o f secretory component o f IgA in some of these childrcn. This, Ilowever, has not yet bccn confirnted attd its implications are not clear. At present it seems u,tlikely that prinmry hypersensitivity is tile basis for the syndroIne. T h e evidence fiJr it relationshill to feeding patterns remains coxttroversial; it now appears that breast feeding does not convey tile protective ntecltanism previot,sly claimed, and that illfants who exhibit tile syndronte who have been breast fed ntay in fact die at ;m earlier age than bottle fed infants. Overwhehning infection, espccially viral infectio,t, has been considered by many to be etiologic, for in many but not all cases of tile sudden infant death syndrome virus call be recovered from a variety of tissues at postntorteln. Large cpide,niologic surveys, however, have shown all isolation rate for virus not significantly different front that ill controls. Moreover, ill a significam proportion of illfants with the s)ndvonle no vir;ll agcnt is isolatcdf~ T h e occasional presence o f minor inflamnlatory lesions o f the respiratory tract and the concomitant isolation o f respiratory viral pathogens do suggest that infection may be all intportant contributing factor in children already at risk for tile syndrome. A current theory suggests that file primary defect ill the s u d d e n infaqt deatll s y n d r o m e invohes the respiratory control mecllanism ;rod that some dysfunction o f respiratory control may be responsible for tile ntajority of these deaths. Tllere is no substantial evidence for tile presence o f a cln'onic or recurrent disturbance o f ventilation p r o d u c i n g chronic o r recurrent hypoxentia. T h e morplmlogic correlates o f chronic hypoxcmi;t havc bccn recognized by a nuntber o f investigators and a p p e a r to bc ;tn inaportant morphologic feature iq the sudcle,i infant death syodronte. Initial studies showed an increased muscle mass ill tile small iml mona D" arteries o f alllicted infants COnlpared to nonllypoxic controls. A varicty of other morphologic correlates o f chronic hypoxcnlia have now been recognized ill infants with the s)'ndrolne. "l'hese inclttdc an increased retention o f brown fat, an abnolnlal retention of extrantedullary Ilematopoiesis, and a Ileavy right ventricle. 7 Stlcll infalltS also exllibit a variety o f nonspecific d l a n g e s , which, although not l)lim;iry evidence for chronic hypoxemia, are certai,lly consistertt with it. T h e s e children sllow impaired postnatal growtll iIlld have been said to show subtle evidence o f delayed mental and motor developntent. No longer is it possible to postulate a hypotllesis based on allegcd absence of lesions at necropsy, since these children SllOWchanges similar to those seen ill cases of cltronic
Ilypoxenlia due to known C;lUSCS. Tllerefore. tile s u d d e n infant death syndronte cannot bc considered to be an isolated or solitary acute episode resulting ill s u d d e n deatll but nntst be coqsidercd the terminal manifestation of a c h r o n i c disorder. More iml)ortantly, it ntay become possible t l u o u g h a better u n d e r s t a n d i n g o f this underlying dysfu,lction to clcvise a diagnostic test to identify tllese children at risk. It has generally been considered that tile chro,tic IDpoxenlia o f whicll these children show nlOrl~hologic evidence is due to.sb~ne diso l d e r of central respiratory control. T h e evidence for this is largcly anecdotal, but ill nlally series o f infants altlicted by tile syndronle there are a few who have a history o f almeic spells, and occasionally iqfams who have been studied for almea have later been fot,nd suddenly dead. Sleep a l m e a has been postulated as tile mccllmlisnl o f the sudden intant death syndronlc; it is thought to increase in fi-equency with infection and is a more frctluent occurrence ill the p r e t e r m intaut, s In contrast, several recent studies suggest that the dysfiutction ill the s u d d e n infant death s y n d r o m e is ill l~eripheral respiratory control or is related to recurrent airway obstruction and is not a central mechanisnl. T o n k i n has shown that the airwa)" of tile y o u n g infant is particularly vuh~eral)le to occlusion at tile Olollllaryngeal level and postulates tllat this occlusion ntay be caused by ntuscle relaxation dul'ing REM sleep, tile increased m a n d i b u l a r ntobility of thc young child, or a hypotonia which she feels is related to infection.'-' A h h o u g h it remains to be confit'med, changes such as tllese certainly could produce recurrent airway obstruction, wllich alight rcsuh in the morphologic changes described ill tile s)'ndronle. A recent study o f tile carotid body in tile sudden infant deatll syndrome showed interesting and somewhat unexpected findings. If chronic hypoxia ill tile syndronle occurs because o f a defect in central respiratory contl'()l o r r c c t l r r e n t i l h w a y obstruction, tile carotid bodies should show enlargement ill all thcsc children, as is regularly found in tile chronic h)'lmxia o f ahitude and of clnonic airllow obstruction. This, Imwever, was not the case, ;rod ill the majority of altlictctl infants the carotid bodies had a stllmolln;ll vohune, only a small plOl)Ortion having enlarged carotid bodies. ~ Thcsc observations suggest that peripheral mecllanisnts o f respiratory control may be inqmrtant in tile genesis of this syndrome. Tlnls tllele may be a g r o u p r inthnts with disorders of central lespiratory control, a g r o u p witll disorders o f peripheral respiratory contlOl, and a g r o u p with recurrent obstruction of the airways. All these groups could
7, N U M B E R 5
manifest the m o r p h o l o g i c c h a n g e s o f c h r o n i c h y p o x e m i a described, which could r e s u h in s u d d e n infant death.
... there i~ a special providence iu the fall of a sparrow. I f it be uow, it is not to come; if it be not to come, it will be now; if it be uot now, yet it will come: the readiuess is all."
4. Valdes-Dapena, M. A., Greene, M., Basavanand,
-- The Tragedy of Hamlet, Prince of Deumark 6. References
i. Bergman, A. B., Ray, C. G., Pomeroy, M. A., Wahl, P. W., and Beckwith,J. B.: Studies of tile sudden infant death syndrome in King County, Washingto,L III. Epklemiology. l'ediatrics, 49: 860-870, 1972. 2. Tonkin, S.: Sudden infant death syndrome: hypothesis of causation, i'ediatrics, 55:650661, 1975. 3. Ferris, J. A. J., Aherne, W. A., Locke, W. S., McQuillcn, J., and Gardner, P. S.: Sudden and unexpected deaths in infants: histology and virology. Brit. Med. J., 2:439-442, 1973.
N., Catllerman, R., and Truex, R. C.: Tile myocardial conduction system ill sudden death in infancy. New Eng. J. Mcd., 2S9:1179-1180, 1973. Valdes-l)ape,m, M.: l'rogress in sudden iqthnt death research, 1963-1969. In Bergman, A. B., Beckwith, J. B., and Ray, C. G. (Editors): Sudden Infant 1)eath Syndrome. Proceedings of the Second I qternational Conference on Causes of Suddcn Dcath in Infants. Seattle, University of Washiqgto,i Press, 1970, pp. 3-13. Urquhart, G. E. D., and Grist, N. R.: Virologic studies of sudden unexplained infant death in Glasgow, 1967-1970. J. Clin. Path., 25:443-t46, 1972. Naeye, R. U, Whalen, P., Ryser, M., and Fisher, R.: Cardiac and other abnormalities in tile sudden infant death syndrome. Amer. j. Path., 82:1-8, 1976. Steinschncider, A. L.: l'rohmged apnca wad the sudden infant death syndrome: clinical and laboratory observations. Pediatrics, 50:6.t6654, 1972. Naeye, R., Fisher, R., Ryser, M., and Whalen, 1'.: Carotid body in the sudden infant death syndrome. Science, 191:567-569, 1976.